Green Chemistry MicrowaveAssisted Organometallic
Reaction
Green Chemistry
To promote innovative chemical
technologies that reduce or eliminate the
use or generation of hazardous substances
in the design manufacture and use of
chemical products
What does the Chemical Industry do for us
Green chemistry
is aboutbull Waste Minimisation at Sourcebull Use of Catalysts in place of Reagentsbull Using Non-Toxic Reagentsbull Use of Renewable Resourcesbull Improved Atom Efficiencybull Use of Solvent Free or Recyclable Environmentally
Benign Solvent systems
Green Chemistry = Responsibility
Why is there no lsquoGreen Geologyrsquo or lsquoGreen Astronomyrsquo
Because chemistry is the science that introduces new substances into the world and we have a responsibility for their impact in the worldrdquo
- Ronald Breslow
Green Chemistry is also calledhellip A new approach to designing chemicals and chemical
transformations that are beneficial for human health and the environment
An innovative way to design molecules and chemical transformations for sustainability
Meeting the needs of the current generation without compromising the ability of future generations to meet their own needs
Benign by design
Pollution prevention at the molecular level
What is Green Chemistry
bull Green chemistry is the study of how to design chemical products and processes in ways that are sustainable and not harmful for humans and the environment
bull Three components catalysis solvents non-toxic
bull 12 principles of green chemistry
Green Chemistry Is About
Cost
Waste
Materials
Hazard
Risk
Energy
bull Chemistry is a very prominent part of our daily lives
bull Chemical developments also bring new environmental problems and harmful unexpected side effects which result in the need for lsquogreenerrsquo chemical products
bull A famous example is the pesticide DDT
Why do we need Green Chemistry
1 PreventionIt is better to prevent waste than to treat or clean up waste after it has been created
2 Atom EconomySynthetic methods should be designed to maximise the incorporation of all materialsused in the process into the final product
3 Less Hazardous Chemical SynthesisWherever practicable synthetic methods should be designed to use and generatesubstances that possess little or no toxicity to people or the environment
4 Designing Safer ChemicalsChemical products should be designed to effect their desired function while minimisingtheir toxicity
5 Safer Solvents and AuxiliariesThe use of auxiliary substances (eg solvents or separation agents) should be madeunnecessary whenever possible and innocuous when used
6 Design for Energy EfficiencyEnergy requirements of chemical processes should be recognised for their environmentaland economic impacts and should be minimised If possible synthetic methods should beconducted at ambient temperature and pressure
The 12 Principles of Green Chemistry (1-6)
The 12 Principles of Green Chemistry (7-12)
7 Use of Renewable FeedstocksA raw material or feedstock should be renewable rather than depleting whenever technically and economically practicable
8 Reduce DerivativesUnnecessary derivatization (use of blocking groups protectionde-protection and temporary modification of physicalchemical processes) should be minimised or avoided if possible because such steps require additional reagents and can generate waste
9 CatalysisCatalytic reagents (as selective as possible) are superior to stoichiometric reagents
10 Design for DegradationChemical products should be designed so that at the end of their function they break down into innocuous degradation products and do not persist in the environment
11 Real-time Analysis for Pollution PreventionAnalytical methodologies need to be further developed to allow for real-time in-process monitoring and control prior to the formation of hazardous substances
12 Inherently Safer Chemistry for Accident PreventionSubstances and the form of a substance used in a chemical process should be chosen to minimise the potential for chemical accidents including releases explosions and fires
What is ldquoGreenrdquoSustainable Kinder and gentler to people and the planet
Green Chemistry
The cost of usinghazardous materials
Conventional Heating vs Alternative Energy Source
Conventional Heating Bunsen burnerOil bathHeating mantleAlternative Energy SourcesMicrowaveUltrasoundSunlight UV Electonchemistry
Clean Chemical Synthesis UsingAlternative Reaction Methods
Alternative Energy SourcesMicrowaveUltrasoundSunlight UV
AlternativeReactionMediaSolvent-free Supercritical FluidsIonic LiquidsWaterPolyethylene glycol (PEG)Solvent free
Microwaves in Synthesis
bull While fire is now rarely used in synthetic chemistry it was not until Robert Bunsen invented the burner in 1855 that the energy from this heat source could be applied
bull There is some controversy about the origins of the microwave power cavity called the magnetron ndash the high-power generator of microwave power
The British were particularly forward-looking in deploying radar for air defense with a system called Chain Home which began operation in 1937
Originally operating at 22 MHz frequencies increased to 55 MHz 1921 was published by AW Hull the earliest description of the magnetron a
diode with a cylindrical anode1940 It was developed practically by Randall and Booth at the University of
Birmingham in England they verified their first microwave transmissions 500 W at 3 GHz
A prototype was brought to the United States in September of that year to define an agreement whereby United States industrial capability would undertake the development of microwave radar
1940 the Radiation Laboratory was established at the Massachusetts Institute of Technology to exploit microwave radar More than 40 types of tube would be produced particularly in the S-band (ie 300 MHz) The growth of microwave radar is linked with Raytheon Company and PL Spencer who found the key to mass production
History or how it all beganhellip
bull 1946 Dr Percy Spencer-the magnetron inventor he has found a variety of technical applications in the chemical and related industries since the 1950s in particular in the food-processing drying and polymer
bull surprisingly microwave heating has only been implemented in organic synthesis since the mid-1980s
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
History or how it all beganhellip
bull 1969 ldquo Carrying out chemical reactions using microwave energy rdquo JW Vanderhoff ndash Dow Chemical Company US 3432413
bull 1986 ldquoThe Use of Microwave Ovens for Rapid Organic Synthesisrdquo Gedye R N et alTetrahedron Lett 1986 27 279
bull 1986 ldquoApplication of Commercial Microwave Ovens to Organic Synthesisrdquo Giguere R J and Majetich G Tetrahedron Lett 1986 27 4945
Energy Use in ConventionalChemical Processes
Heating Stirring Piping
Transporting Cooling
Problem of Conventional Heating
You heat what you donrsquot want to heat
Solvents for reactions apparatus
heated up and cool it down
Double energy penalty without any
apparent ldquobenefitrdquo
Energy Consumptions
Three ways to get the reaction done but different energy bills to pay
Microwaves
bull MW reactors operate at 245 GHzbull Electric field oscillates at 49 x 109 timessec ndash
10oCsec heating rate
Electromagnetic Spectrum
Neas E Collins M Introduction to Microwave Sample Preparation Theory and Practice 1988 p 8
Schematic of a Microwave
E= electric fieldH= magnetic field= wavelength (122 cm for 2450 MHz)c= speed of light (300000 kms)
Microwaves Application in Heating Food
1946 Original patent (P L Spencer)1947 First commercial oven1955 Home models1967 Desktop model1975 US sales exceed gas ranges1976 60 of US households havemicrowave ovens
Spectrum Electromagnetic
bull Electric field component
bull Responsible for dielectric heating
bull Dipolar polarization
bull Conduction
bull Magnetic field component
Microwaves ndash Dipolar Rotationbull Polar molecules have intermolecular forces which give any motion of the
molecule some inertia
bull Under a very high frequency electric field the polar molecule will attempt to follow the field but intermolecular inertia stops any significant motion before the field has reversed and no net motion results
bull If the frequency of field oscillation is very low then the molecules will be polarized uniformly and no random motion results
bull In the intermediate case the frequency of the field will be such that the molecules will be almost but not quite able to keep in phase with the field polarity
bull In this case the random motion resulting as molecules jostle to attempt in vain to follow the field provides strong agitation and intense heating of the sample
bull At 245 GHz the field oscillates 49 x 109 timess which can lead to heating
rates of 10 degC per second when powerful waves are used
MW Heating Mechanism
Alternating electric field Withhigh frequency
NoconstraintContinuous electric field
Two mechanisms Dipolar rotation polarizationIonic Conduction mechanism
Microwave Dielectric HeatingMechanisms
Dipolar PolarizationMechanism
Conduction Mechanism
Dipolar molecules try toalign to an oscillating fieldby rotation
Ions in solution will moveby the applied electricfield
Mingos D M P et al Chem Soc Rev 1991 20 1 and 1998 27 213
Microwave vs Oil-bath Heating
J-S Schanche Mol Diversity 2003 7 293wwwpersonalchemistry-com wwwbiotagecom
Conventional Heating byConduction
ConductiveheatHeating byconvectioncurrentsSlow andenergyinefficientprocess
temperature on the outside surface isin excess of the boiling point of liquid
Direct Heating by MicrowaveIrradiation
bullSolventreagent absorbs MW energybull Vessel wall transparent to MWbullDirect in-core heatingbullInstant on-off
Inverted temperature gradients
Molecular Speeds
Molecular Speeds
Microwave Ovens
Cooking Chemistry Cooking Food
Household MW ovens
The Use of Microwave Ovens for Rapid Organic Synthesis R Gedye et al Tetrahedron Lett 1986 27 279
Publications on MW-AssistedOrganic Synthesis
7 Synthetic Journals JOrgChemOrgLettTetrahedron LettTetrahedron SynthCommun Synlett SynthesisAll Journals (Full Text) Dedicated instruments only (Anton Paar Biotage CEM Milestone Prolabo)
Industrial Chemical Applications of Microwave Heating
Food Processing+ Defrosting+ Drying roasting baking+ Pasteurization
Drying Industry+ Wood fibers textiles+ Pharmaceuticals+ Brick concrete walls
Polymer Chemistry+ Rubber curing vulcanization+ Polymerization
CeramicsMaterials+ Alumina sintering+ Welding smelting gluing
Plasma+ SemiconductorsWaste Remediation+ Sewage treatment
Analytical Chemistry+ Digestion+ Extraction+ Ashing
Biochemistry Pathology+ Protein hydrolysis+ PCR proteomics+ Tissue fixation+ Histoprocessing
Medical+ Diathermy tumor detection+ Blood warming+ Sterilization (Anthrax)+ Drying of catheters
Books on Microwave-Assisted Synthesis
1048707 Fundamentals of Microwave Application1048707 Alternative Laboratory MicrowaveInstruments1048707 Chemistry Applications1048707 Biochemistry Applications1048707 Laboratory Microwave Safety
Hayes B LCEM PublishingMatthews NC2002
(ACS Professional Reference Book) H M Kingston S J Haswell (eds)
Microwaves in Organic and Medicinal ChemistryKappe C O and Stadler AWiley-VCH Weinheim 2005 ISBN 3-527-31210-2410 pages ca 1000 references
Books on Microwave-Assisted Synthesis
Lidstoumlm PTierney J P(Eds)BlackwellScientific2005
Loupy Andre (Ed)Wiley-VCH Weinheim 2003 ISBN 3-527-30514-9523 pages 2000 refs
Book (2 volumes) Wiley-VCHA Loupy editSecond Edition(2006) 22 Chapters
Astra Zeneca ResearchFoundation Kavitha PrintersBangalore India 2002azrefiastrazenecacom
Practical Microwave Synthesis for Organic Chemists - Strategies Instruments and Protocols
Edition - 2009 X 310 Pages Hardcover Monograph
Books on Microwave-Assisted Synthesis
Microwave Ovens
Monomodal instrument
Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005
Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia
Multimodal instrument
+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile
Monomodal Vs Multimodal
Monomodal Vs Multimodal
Thermal Effects
bullMore efficient energetic coupling of solvent with microwaves
promotes higher rate of temperature increase
bull Inverted heat transfer volumetric
bull ldquoHot spotsrdquo in monomode microwaves
bull Selective on properties of material (solvents catalysts
reagents intermediates products susceptors)
Recent Applications of Microwave-Assisted Synthesis-MAOS
Hydrolysis of benzamide
thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)
The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions
R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958
Solvent-free Reactions or Solid-Solid Reactions
ldquoNo reaction proceeds without solventrdquo
Aristotle
Solventless syntheses
Green chemistry enabled advancement
Solvent-free Organic Synthesis
Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed
i n t o a p o w e r f u l m e t h o d o l o g y a s i t
reduces the amount of toxic waste produced and therefore becomes less harmful to the
e n v i r o n m e n t
Solvent-free Organic Synthesis
bull Clean and efficient synthesis
bull Economic and environmental impact
bull Fast reaction kinetics
Best solvent is no solvent
Adolf von Baeyer
Synthesis of Indigo
Towardsbenign
synthesiswith
remarkableVersatility
G W V Cave C LRaston J L ScottChemCommun
2001 2159
Solid-State General Oxidation with with Urea H2O2 Complex
R S Varma and K P Naiker Org Letters 1999 1 189
Solvent-free Oxidative Preparation of Heterocycles
Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157
Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones
Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199
Solvent-free Reduction
F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245
Carbon-Carbon Bond Formation
Toda Tanada Iwata J Org Chem 1989 54 3007
Solventless Photo Coupling and Photo Rearangements
Y Ito S Endo J Am Chem Soc 1997 119 5974
Shin Keating Maribay J Am Chem Soc 1996 118 7626
Solvent - Free Condensation
Z Gross et al Org Letters 1999 1 599
Solid-State Preparationof Dumb-bell-shaped C120
Wang Komatsu Murata Shiro Nature 1997 387 583
Advantages of Solid Mineral Supports(Alumina Silica and Clay)
Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area
The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity
Solids are generally easier and safer to handle than liquids or gaseous reagents
Inexpensive recyclable and environmentally benign nature
Solid-supported Solventless Reactions
bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation
R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43
Supported ReactionsUsing Microwaves
E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945
Microwave-Assisted Deacetylationon Alumina
Varma et al J Chem Soc Perkin Trans 1 999 (1993)
Deprotection of Benzyl Esters viaMicrowave Thermolysis
A practical alternative to traditional catalytic hydrogenation
Varma et al Tetrahedron Lett 34 4603 (1993)
Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of
Carbonyl Compounds Using Microwaves
Varma Meshram Tetrahedron Lett 38 5427 (1997)
Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm
PersulfatendashClay using Microwave and Ultrasonic Irradiation
Varma Meshram Tetrahedron Lett 38 7973 (1997)
Solid Supported Solvent-freeOxidation under MW
Varma et al Tetrahedron Lett 1997 38 2043 and 7823
Solvent-free Reduction Using MW
Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction
Varma et al Tetrahedron Lett 1997 38 4337
Hydrodechlorination under continuous MW
Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)
Synthesis of Heterocyclic Compounds
Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)
Synthesis of Heterocyclic Compounds
Organometallic Reactions
Rearrangements
Rearrangements
INDOLIZINES
Heterocyclic systems 10- electronics
Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine
Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds
N
1
2
34567
8R2
R3
R1
Why interest for indolizinic products
Strong fluorescent properties luminiscent products luminiscent products
Potentially fluorescents marker Potentially laserldquoscintillatersrdquo
bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999
Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )
Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2
ldquoCalcium-entryrdquo blockers
Indolizines by irradiation with microwaves in MCR
RBr
O+
N
R1 R2+N
R2
R1
COR
AcOAl2O3 Mw
R=Ph p-Tolil Stiril
R1= H COOMeR2= COOEt COOMe
Asymmetric indolizines by irradiation with microwaves in MCR
R1
O
Cl+ R2
N NEtOOC
OOMe
Br BrN N
EtOOC
COR1
R2COR1
R2
OOMe
2 [Pd(PPh3)2Cl24 CuI
20 echiv Et3N THF tc 2h
R1=Ph 4-OMe-C6H4R2= Ph
U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003
A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new indolizines
[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical
II
IHH
COORCOOR
N C C
O
R2NCC
O
R1
(B)
(A)
R1
O
C C N R2
O
CCN
H H
ROOC COOR
R1
O
C C N R2
O
CCN
COOR COOR
ROOC COOR
2
2 ROOC C C COOR
R1
O
C CH N R2
O
CCHN
H H
N NCH CHC C
O O
R1 R2
- 2 HX TEAanhydrous solvents
X-
X-
N NCH2 CH2C C
O O
R1 R2
C C COORH
R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5
Y=H NO2 OCH3 CH3 Cl BrX=Br Cl
bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998
bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001
bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004
bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new substituted pyridinium-indolizines
Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate
COO NO2CHC
N NH3C
OR
I IN NH3C
OR
IN NH3C
OR
I
H
KFNMP
-HI
NMP
95oC 30 min
N NH3CO
RN NH3C
O
R
O OO
NO2
O
NO2
-2[H]-2[H]
II
I II
N NH3CO
R
O O
NO2
IN NH3C
O
R
O O
NO2
I
(9a-d)(10a-d)
(15a-d)
(A) (B)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
12
34
56
78 9
10
11
12 3
4
56
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Green Chemistry
To promote innovative chemical
technologies that reduce or eliminate the
use or generation of hazardous substances
in the design manufacture and use of
chemical products
What does the Chemical Industry do for us
Green chemistry
is aboutbull Waste Minimisation at Sourcebull Use of Catalysts in place of Reagentsbull Using Non-Toxic Reagentsbull Use of Renewable Resourcesbull Improved Atom Efficiencybull Use of Solvent Free or Recyclable Environmentally
Benign Solvent systems
Green Chemistry = Responsibility
Why is there no lsquoGreen Geologyrsquo or lsquoGreen Astronomyrsquo
Because chemistry is the science that introduces new substances into the world and we have a responsibility for their impact in the worldrdquo
- Ronald Breslow
Green Chemistry is also calledhellip A new approach to designing chemicals and chemical
transformations that are beneficial for human health and the environment
An innovative way to design molecules and chemical transformations for sustainability
Meeting the needs of the current generation without compromising the ability of future generations to meet their own needs
Benign by design
Pollution prevention at the molecular level
What is Green Chemistry
bull Green chemistry is the study of how to design chemical products and processes in ways that are sustainable and not harmful for humans and the environment
bull Three components catalysis solvents non-toxic
bull 12 principles of green chemistry
Green Chemistry Is About
Cost
Waste
Materials
Hazard
Risk
Energy
bull Chemistry is a very prominent part of our daily lives
bull Chemical developments also bring new environmental problems and harmful unexpected side effects which result in the need for lsquogreenerrsquo chemical products
bull A famous example is the pesticide DDT
Why do we need Green Chemistry
1 PreventionIt is better to prevent waste than to treat or clean up waste after it has been created
2 Atom EconomySynthetic methods should be designed to maximise the incorporation of all materialsused in the process into the final product
3 Less Hazardous Chemical SynthesisWherever practicable synthetic methods should be designed to use and generatesubstances that possess little or no toxicity to people or the environment
4 Designing Safer ChemicalsChemical products should be designed to effect their desired function while minimisingtheir toxicity
5 Safer Solvents and AuxiliariesThe use of auxiliary substances (eg solvents or separation agents) should be madeunnecessary whenever possible and innocuous when used
6 Design for Energy EfficiencyEnergy requirements of chemical processes should be recognised for their environmentaland economic impacts and should be minimised If possible synthetic methods should beconducted at ambient temperature and pressure
The 12 Principles of Green Chemistry (1-6)
The 12 Principles of Green Chemistry (7-12)
7 Use of Renewable FeedstocksA raw material or feedstock should be renewable rather than depleting whenever technically and economically practicable
8 Reduce DerivativesUnnecessary derivatization (use of blocking groups protectionde-protection and temporary modification of physicalchemical processes) should be minimised or avoided if possible because such steps require additional reagents and can generate waste
9 CatalysisCatalytic reagents (as selective as possible) are superior to stoichiometric reagents
10 Design for DegradationChemical products should be designed so that at the end of their function they break down into innocuous degradation products and do not persist in the environment
11 Real-time Analysis for Pollution PreventionAnalytical methodologies need to be further developed to allow for real-time in-process monitoring and control prior to the formation of hazardous substances
12 Inherently Safer Chemistry for Accident PreventionSubstances and the form of a substance used in a chemical process should be chosen to minimise the potential for chemical accidents including releases explosions and fires
What is ldquoGreenrdquoSustainable Kinder and gentler to people and the planet
Green Chemistry
The cost of usinghazardous materials
Conventional Heating vs Alternative Energy Source
Conventional Heating Bunsen burnerOil bathHeating mantleAlternative Energy SourcesMicrowaveUltrasoundSunlight UV Electonchemistry
Clean Chemical Synthesis UsingAlternative Reaction Methods
Alternative Energy SourcesMicrowaveUltrasoundSunlight UV
AlternativeReactionMediaSolvent-free Supercritical FluidsIonic LiquidsWaterPolyethylene glycol (PEG)Solvent free
Microwaves in Synthesis
bull While fire is now rarely used in synthetic chemistry it was not until Robert Bunsen invented the burner in 1855 that the energy from this heat source could be applied
bull There is some controversy about the origins of the microwave power cavity called the magnetron ndash the high-power generator of microwave power
The British were particularly forward-looking in deploying radar for air defense with a system called Chain Home which began operation in 1937
Originally operating at 22 MHz frequencies increased to 55 MHz 1921 was published by AW Hull the earliest description of the magnetron a
diode with a cylindrical anode1940 It was developed practically by Randall and Booth at the University of
Birmingham in England they verified their first microwave transmissions 500 W at 3 GHz
A prototype was brought to the United States in September of that year to define an agreement whereby United States industrial capability would undertake the development of microwave radar
1940 the Radiation Laboratory was established at the Massachusetts Institute of Technology to exploit microwave radar More than 40 types of tube would be produced particularly in the S-band (ie 300 MHz) The growth of microwave radar is linked with Raytheon Company and PL Spencer who found the key to mass production
History or how it all beganhellip
bull 1946 Dr Percy Spencer-the magnetron inventor he has found a variety of technical applications in the chemical and related industries since the 1950s in particular in the food-processing drying and polymer
bull surprisingly microwave heating has only been implemented in organic synthesis since the mid-1980s
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
History or how it all beganhellip
bull 1969 ldquo Carrying out chemical reactions using microwave energy rdquo JW Vanderhoff ndash Dow Chemical Company US 3432413
bull 1986 ldquoThe Use of Microwave Ovens for Rapid Organic Synthesisrdquo Gedye R N et alTetrahedron Lett 1986 27 279
bull 1986 ldquoApplication of Commercial Microwave Ovens to Organic Synthesisrdquo Giguere R J and Majetich G Tetrahedron Lett 1986 27 4945
Energy Use in ConventionalChemical Processes
Heating Stirring Piping
Transporting Cooling
Problem of Conventional Heating
You heat what you donrsquot want to heat
Solvents for reactions apparatus
heated up and cool it down
Double energy penalty without any
apparent ldquobenefitrdquo
Energy Consumptions
Three ways to get the reaction done but different energy bills to pay
Microwaves
bull MW reactors operate at 245 GHzbull Electric field oscillates at 49 x 109 timessec ndash
10oCsec heating rate
Electromagnetic Spectrum
Neas E Collins M Introduction to Microwave Sample Preparation Theory and Practice 1988 p 8
Schematic of a Microwave
E= electric fieldH= magnetic field= wavelength (122 cm for 2450 MHz)c= speed of light (300000 kms)
Microwaves Application in Heating Food
1946 Original patent (P L Spencer)1947 First commercial oven1955 Home models1967 Desktop model1975 US sales exceed gas ranges1976 60 of US households havemicrowave ovens
Spectrum Electromagnetic
bull Electric field component
bull Responsible for dielectric heating
bull Dipolar polarization
bull Conduction
bull Magnetic field component
Microwaves ndash Dipolar Rotationbull Polar molecules have intermolecular forces which give any motion of the
molecule some inertia
bull Under a very high frequency electric field the polar molecule will attempt to follow the field but intermolecular inertia stops any significant motion before the field has reversed and no net motion results
bull If the frequency of field oscillation is very low then the molecules will be polarized uniformly and no random motion results
bull In the intermediate case the frequency of the field will be such that the molecules will be almost but not quite able to keep in phase with the field polarity
bull In this case the random motion resulting as molecules jostle to attempt in vain to follow the field provides strong agitation and intense heating of the sample
bull At 245 GHz the field oscillates 49 x 109 timess which can lead to heating
rates of 10 degC per second when powerful waves are used
MW Heating Mechanism
Alternating electric field Withhigh frequency
NoconstraintContinuous electric field
Two mechanisms Dipolar rotation polarizationIonic Conduction mechanism
Microwave Dielectric HeatingMechanisms
Dipolar PolarizationMechanism
Conduction Mechanism
Dipolar molecules try toalign to an oscillating fieldby rotation
Ions in solution will moveby the applied electricfield
Mingos D M P et al Chem Soc Rev 1991 20 1 and 1998 27 213
Microwave vs Oil-bath Heating
J-S Schanche Mol Diversity 2003 7 293wwwpersonalchemistry-com wwwbiotagecom
Conventional Heating byConduction
ConductiveheatHeating byconvectioncurrentsSlow andenergyinefficientprocess
temperature on the outside surface isin excess of the boiling point of liquid
Direct Heating by MicrowaveIrradiation
bullSolventreagent absorbs MW energybull Vessel wall transparent to MWbullDirect in-core heatingbullInstant on-off
Inverted temperature gradients
Molecular Speeds
Molecular Speeds
Microwave Ovens
Cooking Chemistry Cooking Food
Household MW ovens
The Use of Microwave Ovens for Rapid Organic Synthesis R Gedye et al Tetrahedron Lett 1986 27 279
Publications on MW-AssistedOrganic Synthesis
7 Synthetic Journals JOrgChemOrgLettTetrahedron LettTetrahedron SynthCommun Synlett SynthesisAll Journals (Full Text) Dedicated instruments only (Anton Paar Biotage CEM Milestone Prolabo)
Industrial Chemical Applications of Microwave Heating
Food Processing+ Defrosting+ Drying roasting baking+ Pasteurization
Drying Industry+ Wood fibers textiles+ Pharmaceuticals+ Brick concrete walls
Polymer Chemistry+ Rubber curing vulcanization+ Polymerization
CeramicsMaterials+ Alumina sintering+ Welding smelting gluing
Plasma+ SemiconductorsWaste Remediation+ Sewage treatment
Analytical Chemistry+ Digestion+ Extraction+ Ashing
Biochemistry Pathology+ Protein hydrolysis+ PCR proteomics+ Tissue fixation+ Histoprocessing
Medical+ Diathermy tumor detection+ Blood warming+ Sterilization (Anthrax)+ Drying of catheters
Books on Microwave-Assisted Synthesis
1048707 Fundamentals of Microwave Application1048707 Alternative Laboratory MicrowaveInstruments1048707 Chemistry Applications1048707 Biochemistry Applications1048707 Laboratory Microwave Safety
Hayes B LCEM PublishingMatthews NC2002
(ACS Professional Reference Book) H M Kingston S J Haswell (eds)
Microwaves in Organic and Medicinal ChemistryKappe C O and Stadler AWiley-VCH Weinheim 2005 ISBN 3-527-31210-2410 pages ca 1000 references
Books on Microwave-Assisted Synthesis
Lidstoumlm PTierney J P(Eds)BlackwellScientific2005
Loupy Andre (Ed)Wiley-VCH Weinheim 2003 ISBN 3-527-30514-9523 pages 2000 refs
Book (2 volumes) Wiley-VCHA Loupy editSecond Edition(2006) 22 Chapters
Astra Zeneca ResearchFoundation Kavitha PrintersBangalore India 2002azrefiastrazenecacom
Practical Microwave Synthesis for Organic Chemists - Strategies Instruments and Protocols
Edition - 2009 X 310 Pages Hardcover Monograph
Books on Microwave-Assisted Synthesis
Microwave Ovens
Monomodal instrument
Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005
Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia
Multimodal instrument
+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile
Monomodal Vs Multimodal
Monomodal Vs Multimodal
Thermal Effects
bullMore efficient energetic coupling of solvent with microwaves
promotes higher rate of temperature increase
bull Inverted heat transfer volumetric
bull ldquoHot spotsrdquo in monomode microwaves
bull Selective on properties of material (solvents catalysts
reagents intermediates products susceptors)
Recent Applications of Microwave-Assisted Synthesis-MAOS
Hydrolysis of benzamide
thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)
The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions
R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958
Solvent-free Reactions or Solid-Solid Reactions
ldquoNo reaction proceeds without solventrdquo
Aristotle
Solventless syntheses
Green chemistry enabled advancement
Solvent-free Organic Synthesis
Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed
i n t o a p o w e r f u l m e t h o d o l o g y a s i t
reduces the amount of toxic waste produced and therefore becomes less harmful to the
e n v i r o n m e n t
Solvent-free Organic Synthesis
bull Clean and efficient synthesis
bull Economic and environmental impact
bull Fast reaction kinetics
Best solvent is no solvent
Adolf von Baeyer
Synthesis of Indigo
Towardsbenign
synthesiswith
remarkableVersatility
G W V Cave C LRaston J L ScottChemCommun
2001 2159
Solid-State General Oxidation with with Urea H2O2 Complex
R S Varma and K P Naiker Org Letters 1999 1 189
Solvent-free Oxidative Preparation of Heterocycles
Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157
Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones
Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199
Solvent-free Reduction
F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245
Carbon-Carbon Bond Formation
Toda Tanada Iwata J Org Chem 1989 54 3007
Solventless Photo Coupling and Photo Rearangements
Y Ito S Endo J Am Chem Soc 1997 119 5974
Shin Keating Maribay J Am Chem Soc 1996 118 7626
Solvent - Free Condensation
Z Gross et al Org Letters 1999 1 599
Solid-State Preparationof Dumb-bell-shaped C120
Wang Komatsu Murata Shiro Nature 1997 387 583
Advantages of Solid Mineral Supports(Alumina Silica and Clay)
Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area
The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity
Solids are generally easier and safer to handle than liquids or gaseous reagents
Inexpensive recyclable and environmentally benign nature
Solid-supported Solventless Reactions
bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation
R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43
Supported ReactionsUsing Microwaves
E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945
Microwave-Assisted Deacetylationon Alumina
Varma et al J Chem Soc Perkin Trans 1 999 (1993)
Deprotection of Benzyl Esters viaMicrowave Thermolysis
A practical alternative to traditional catalytic hydrogenation
Varma et al Tetrahedron Lett 34 4603 (1993)
Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of
Carbonyl Compounds Using Microwaves
Varma Meshram Tetrahedron Lett 38 5427 (1997)
Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm
PersulfatendashClay using Microwave and Ultrasonic Irradiation
Varma Meshram Tetrahedron Lett 38 7973 (1997)
Solid Supported Solvent-freeOxidation under MW
Varma et al Tetrahedron Lett 1997 38 2043 and 7823
Solvent-free Reduction Using MW
Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction
Varma et al Tetrahedron Lett 1997 38 4337
Hydrodechlorination under continuous MW
Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)
Synthesis of Heterocyclic Compounds
Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)
Synthesis of Heterocyclic Compounds
Organometallic Reactions
Rearrangements
Rearrangements
INDOLIZINES
Heterocyclic systems 10- electronics
Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine
Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds
N
1
2
34567
8R2
R3
R1
Why interest for indolizinic products
Strong fluorescent properties luminiscent products luminiscent products
Potentially fluorescents marker Potentially laserldquoscintillatersrdquo
bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999
Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )
Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2
ldquoCalcium-entryrdquo blockers
Indolizines by irradiation with microwaves in MCR
RBr
O+
N
R1 R2+N
R2
R1
COR
AcOAl2O3 Mw
R=Ph p-Tolil Stiril
R1= H COOMeR2= COOEt COOMe
Asymmetric indolizines by irradiation with microwaves in MCR
R1
O
Cl+ R2
N NEtOOC
OOMe
Br BrN N
EtOOC
COR1
R2COR1
R2
OOMe
2 [Pd(PPh3)2Cl24 CuI
20 echiv Et3N THF tc 2h
R1=Ph 4-OMe-C6H4R2= Ph
U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003
A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new indolizines
[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical
II
IHH
COORCOOR
N C C
O
R2NCC
O
R1
(B)
(A)
R1
O
C C N R2
O
CCN
H H
ROOC COOR
R1
O
C C N R2
O
CCN
COOR COOR
ROOC COOR
2
2 ROOC C C COOR
R1
O
C CH N R2
O
CCHN
H H
N NCH CHC C
O O
R1 R2
- 2 HX TEAanhydrous solvents
X-
X-
N NCH2 CH2C C
O O
R1 R2
C C COORH
R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5
Y=H NO2 OCH3 CH3 Cl BrX=Br Cl
bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998
bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001
bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004
bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new substituted pyridinium-indolizines
Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate
COO NO2CHC
N NH3C
OR
I IN NH3C
OR
IN NH3C
OR
I
H
KFNMP
-HI
NMP
95oC 30 min
N NH3CO
RN NH3C
O
R
O OO
NO2
O
NO2
-2[H]-2[H]
II
I II
N NH3CO
R
O O
NO2
IN NH3C
O
R
O O
NO2
I
(9a-d)(10a-d)
(15a-d)
(A) (B)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
12
34
56
78 9
10
11
12 3
4
56
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
What does the Chemical Industry do for us
Green chemistry
is aboutbull Waste Minimisation at Sourcebull Use of Catalysts in place of Reagentsbull Using Non-Toxic Reagentsbull Use of Renewable Resourcesbull Improved Atom Efficiencybull Use of Solvent Free or Recyclable Environmentally
Benign Solvent systems
Green Chemistry = Responsibility
Why is there no lsquoGreen Geologyrsquo or lsquoGreen Astronomyrsquo
Because chemistry is the science that introduces new substances into the world and we have a responsibility for their impact in the worldrdquo
- Ronald Breslow
Green Chemistry is also calledhellip A new approach to designing chemicals and chemical
transformations that are beneficial for human health and the environment
An innovative way to design molecules and chemical transformations for sustainability
Meeting the needs of the current generation without compromising the ability of future generations to meet their own needs
Benign by design
Pollution prevention at the molecular level
What is Green Chemistry
bull Green chemistry is the study of how to design chemical products and processes in ways that are sustainable and not harmful for humans and the environment
bull Three components catalysis solvents non-toxic
bull 12 principles of green chemistry
Green Chemistry Is About
Cost
Waste
Materials
Hazard
Risk
Energy
bull Chemistry is a very prominent part of our daily lives
bull Chemical developments also bring new environmental problems and harmful unexpected side effects which result in the need for lsquogreenerrsquo chemical products
bull A famous example is the pesticide DDT
Why do we need Green Chemistry
1 PreventionIt is better to prevent waste than to treat or clean up waste after it has been created
2 Atom EconomySynthetic methods should be designed to maximise the incorporation of all materialsused in the process into the final product
3 Less Hazardous Chemical SynthesisWherever practicable synthetic methods should be designed to use and generatesubstances that possess little or no toxicity to people or the environment
4 Designing Safer ChemicalsChemical products should be designed to effect their desired function while minimisingtheir toxicity
5 Safer Solvents and AuxiliariesThe use of auxiliary substances (eg solvents or separation agents) should be madeunnecessary whenever possible and innocuous when used
6 Design for Energy EfficiencyEnergy requirements of chemical processes should be recognised for their environmentaland economic impacts and should be minimised If possible synthetic methods should beconducted at ambient temperature and pressure
The 12 Principles of Green Chemistry (1-6)
The 12 Principles of Green Chemistry (7-12)
7 Use of Renewable FeedstocksA raw material or feedstock should be renewable rather than depleting whenever technically and economically practicable
8 Reduce DerivativesUnnecessary derivatization (use of blocking groups protectionde-protection and temporary modification of physicalchemical processes) should be minimised or avoided if possible because such steps require additional reagents and can generate waste
9 CatalysisCatalytic reagents (as selective as possible) are superior to stoichiometric reagents
10 Design for DegradationChemical products should be designed so that at the end of their function they break down into innocuous degradation products and do not persist in the environment
11 Real-time Analysis for Pollution PreventionAnalytical methodologies need to be further developed to allow for real-time in-process monitoring and control prior to the formation of hazardous substances
12 Inherently Safer Chemistry for Accident PreventionSubstances and the form of a substance used in a chemical process should be chosen to minimise the potential for chemical accidents including releases explosions and fires
What is ldquoGreenrdquoSustainable Kinder and gentler to people and the planet
Green Chemistry
The cost of usinghazardous materials
Conventional Heating vs Alternative Energy Source
Conventional Heating Bunsen burnerOil bathHeating mantleAlternative Energy SourcesMicrowaveUltrasoundSunlight UV Electonchemistry
Clean Chemical Synthesis UsingAlternative Reaction Methods
Alternative Energy SourcesMicrowaveUltrasoundSunlight UV
AlternativeReactionMediaSolvent-free Supercritical FluidsIonic LiquidsWaterPolyethylene glycol (PEG)Solvent free
Microwaves in Synthesis
bull While fire is now rarely used in synthetic chemistry it was not until Robert Bunsen invented the burner in 1855 that the energy from this heat source could be applied
bull There is some controversy about the origins of the microwave power cavity called the magnetron ndash the high-power generator of microwave power
The British were particularly forward-looking in deploying radar for air defense with a system called Chain Home which began operation in 1937
Originally operating at 22 MHz frequencies increased to 55 MHz 1921 was published by AW Hull the earliest description of the magnetron a
diode with a cylindrical anode1940 It was developed practically by Randall and Booth at the University of
Birmingham in England they verified their first microwave transmissions 500 W at 3 GHz
A prototype was brought to the United States in September of that year to define an agreement whereby United States industrial capability would undertake the development of microwave radar
1940 the Radiation Laboratory was established at the Massachusetts Institute of Technology to exploit microwave radar More than 40 types of tube would be produced particularly in the S-band (ie 300 MHz) The growth of microwave radar is linked with Raytheon Company and PL Spencer who found the key to mass production
History or how it all beganhellip
bull 1946 Dr Percy Spencer-the magnetron inventor he has found a variety of technical applications in the chemical and related industries since the 1950s in particular in the food-processing drying and polymer
bull surprisingly microwave heating has only been implemented in organic synthesis since the mid-1980s
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
History or how it all beganhellip
bull 1969 ldquo Carrying out chemical reactions using microwave energy rdquo JW Vanderhoff ndash Dow Chemical Company US 3432413
bull 1986 ldquoThe Use of Microwave Ovens for Rapid Organic Synthesisrdquo Gedye R N et alTetrahedron Lett 1986 27 279
bull 1986 ldquoApplication of Commercial Microwave Ovens to Organic Synthesisrdquo Giguere R J and Majetich G Tetrahedron Lett 1986 27 4945
Energy Use in ConventionalChemical Processes
Heating Stirring Piping
Transporting Cooling
Problem of Conventional Heating
You heat what you donrsquot want to heat
Solvents for reactions apparatus
heated up and cool it down
Double energy penalty without any
apparent ldquobenefitrdquo
Energy Consumptions
Three ways to get the reaction done but different energy bills to pay
Microwaves
bull MW reactors operate at 245 GHzbull Electric field oscillates at 49 x 109 timessec ndash
10oCsec heating rate
Electromagnetic Spectrum
Neas E Collins M Introduction to Microwave Sample Preparation Theory and Practice 1988 p 8
Schematic of a Microwave
E= electric fieldH= magnetic field= wavelength (122 cm for 2450 MHz)c= speed of light (300000 kms)
Microwaves Application in Heating Food
1946 Original patent (P L Spencer)1947 First commercial oven1955 Home models1967 Desktop model1975 US sales exceed gas ranges1976 60 of US households havemicrowave ovens
Spectrum Electromagnetic
bull Electric field component
bull Responsible for dielectric heating
bull Dipolar polarization
bull Conduction
bull Magnetic field component
Microwaves ndash Dipolar Rotationbull Polar molecules have intermolecular forces which give any motion of the
molecule some inertia
bull Under a very high frequency electric field the polar molecule will attempt to follow the field but intermolecular inertia stops any significant motion before the field has reversed and no net motion results
bull If the frequency of field oscillation is very low then the molecules will be polarized uniformly and no random motion results
bull In the intermediate case the frequency of the field will be such that the molecules will be almost but not quite able to keep in phase with the field polarity
bull In this case the random motion resulting as molecules jostle to attempt in vain to follow the field provides strong agitation and intense heating of the sample
bull At 245 GHz the field oscillates 49 x 109 timess which can lead to heating
rates of 10 degC per second when powerful waves are used
MW Heating Mechanism
Alternating electric field Withhigh frequency
NoconstraintContinuous electric field
Two mechanisms Dipolar rotation polarizationIonic Conduction mechanism
Microwave Dielectric HeatingMechanisms
Dipolar PolarizationMechanism
Conduction Mechanism
Dipolar molecules try toalign to an oscillating fieldby rotation
Ions in solution will moveby the applied electricfield
Mingos D M P et al Chem Soc Rev 1991 20 1 and 1998 27 213
Microwave vs Oil-bath Heating
J-S Schanche Mol Diversity 2003 7 293wwwpersonalchemistry-com wwwbiotagecom
Conventional Heating byConduction
ConductiveheatHeating byconvectioncurrentsSlow andenergyinefficientprocess
temperature on the outside surface isin excess of the boiling point of liquid
Direct Heating by MicrowaveIrradiation
bullSolventreagent absorbs MW energybull Vessel wall transparent to MWbullDirect in-core heatingbullInstant on-off
Inverted temperature gradients
Molecular Speeds
Molecular Speeds
Microwave Ovens
Cooking Chemistry Cooking Food
Household MW ovens
The Use of Microwave Ovens for Rapid Organic Synthesis R Gedye et al Tetrahedron Lett 1986 27 279
Publications on MW-AssistedOrganic Synthesis
7 Synthetic Journals JOrgChemOrgLettTetrahedron LettTetrahedron SynthCommun Synlett SynthesisAll Journals (Full Text) Dedicated instruments only (Anton Paar Biotage CEM Milestone Prolabo)
Industrial Chemical Applications of Microwave Heating
Food Processing+ Defrosting+ Drying roasting baking+ Pasteurization
Drying Industry+ Wood fibers textiles+ Pharmaceuticals+ Brick concrete walls
Polymer Chemistry+ Rubber curing vulcanization+ Polymerization
CeramicsMaterials+ Alumina sintering+ Welding smelting gluing
Plasma+ SemiconductorsWaste Remediation+ Sewage treatment
Analytical Chemistry+ Digestion+ Extraction+ Ashing
Biochemistry Pathology+ Protein hydrolysis+ PCR proteomics+ Tissue fixation+ Histoprocessing
Medical+ Diathermy tumor detection+ Blood warming+ Sterilization (Anthrax)+ Drying of catheters
Books on Microwave-Assisted Synthesis
1048707 Fundamentals of Microwave Application1048707 Alternative Laboratory MicrowaveInstruments1048707 Chemistry Applications1048707 Biochemistry Applications1048707 Laboratory Microwave Safety
Hayes B LCEM PublishingMatthews NC2002
(ACS Professional Reference Book) H M Kingston S J Haswell (eds)
Microwaves in Organic and Medicinal ChemistryKappe C O and Stadler AWiley-VCH Weinheim 2005 ISBN 3-527-31210-2410 pages ca 1000 references
Books on Microwave-Assisted Synthesis
Lidstoumlm PTierney J P(Eds)BlackwellScientific2005
Loupy Andre (Ed)Wiley-VCH Weinheim 2003 ISBN 3-527-30514-9523 pages 2000 refs
Book (2 volumes) Wiley-VCHA Loupy editSecond Edition(2006) 22 Chapters
Astra Zeneca ResearchFoundation Kavitha PrintersBangalore India 2002azrefiastrazenecacom
Practical Microwave Synthesis for Organic Chemists - Strategies Instruments and Protocols
Edition - 2009 X 310 Pages Hardcover Monograph
Books on Microwave-Assisted Synthesis
Microwave Ovens
Monomodal instrument
Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005
Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia
Multimodal instrument
+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile
Monomodal Vs Multimodal
Monomodal Vs Multimodal
Thermal Effects
bullMore efficient energetic coupling of solvent with microwaves
promotes higher rate of temperature increase
bull Inverted heat transfer volumetric
bull ldquoHot spotsrdquo in monomode microwaves
bull Selective on properties of material (solvents catalysts
reagents intermediates products susceptors)
Recent Applications of Microwave-Assisted Synthesis-MAOS
Hydrolysis of benzamide
thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)
The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions
R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958
Solvent-free Reactions or Solid-Solid Reactions
ldquoNo reaction proceeds without solventrdquo
Aristotle
Solventless syntheses
Green chemistry enabled advancement
Solvent-free Organic Synthesis
Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed
i n t o a p o w e r f u l m e t h o d o l o g y a s i t
reduces the amount of toxic waste produced and therefore becomes less harmful to the
e n v i r o n m e n t
Solvent-free Organic Synthesis
bull Clean and efficient synthesis
bull Economic and environmental impact
bull Fast reaction kinetics
Best solvent is no solvent
Adolf von Baeyer
Synthesis of Indigo
Towardsbenign
synthesiswith
remarkableVersatility
G W V Cave C LRaston J L ScottChemCommun
2001 2159
Solid-State General Oxidation with with Urea H2O2 Complex
R S Varma and K P Naiker Org Letters 1999 1 189
Solvent-free Oxidative Preparation of Heterocycles
Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157
Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones
Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199
Solvent-free Reduction
F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245
Carbon-Carbon Bond Formation
Toda Tanada Iwata J Org Chem 1989 54 3007
Solventless Photo Coupling and Photo Rearangements
Y Ito S Endo J Am Chem Soc 1997 119 5974
Shin Keating Maribay J Am Chem Soc 1996 118 7626
Solvent - Free Condensation
Z Gross et al Org Letters 1999 1 599
Solid-State Preparationof Dumb-bell-shaped C120
Wang Komatsu Murata Shiro Nature 1997 387 583
Advantages of Solid Mineral Supports(Alumina Silica and Clay)
Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area
The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity
Solids are generally easier and safer to handle than liquids or gaseous reagents
Inexpensive recyclable and environmentally benign nature
Solid-supported Solventless Reactions
bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation
R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43
Supported ReactionsUsing Microwaves
E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945
Microwave-Assisted Deacetylationon Alumina
Varma et al J Chem Soc Perkin Trans 1 999 (1993)
Deprotection of Benzyl Esters viaMicrowave Thermolysis
A practical alternative to traditional catalytic hydrogenation
Varma et al Tetrahedron Lett 34 4603 (1993)
Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of
Carbonyl Compounds Using Microwaves
Varma Meshram Tetrahedron Lett 38 5427 (1997)
Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm
PersulfatendashClay using Microwave and Ultrasonic Irradiation
Varma Meshram Tetrahedron Lett 38 7973 (1997)
Solid Supported Solvent-freeOxidation under MW
Varma et al Tetrahedron Lett 1997 38 2043 and 7823
Solvent-free Reduction Using MW
Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction
Varma et al Tetrahedron Lett 1997 38 4337
Hydrodechlorination under continuous MW
Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)
Synthesis of Heterocyclic Compounds
Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)
Synthesis of Heterocyclic Compounds
Organometallic Reactions
Rearrangements
Rearrangements
INDOLIZINES
Heterocyclic systems 10- electronics
Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine
Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds
N
1
2
34567
8R2
R3
R1
Why interest for indolizinic products
Strong fluorescent properties luminiscent products luminiscent products
Potentially fluorescents marker Potentially laserldquoscintillatersrdquo
bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999
Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )
Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2
ldquoCalcium-entryrdquo blockers
Indolizines by irradiation with microwaves in MCR
RBr
O+
N
R1 R2+N
R2
R1
COR
AcOAl2O3 Mw
R=Ph p-Tolil Stiril
R1= H COOMeR2= COOEt COOMe
Asymmetric indolizines by irradiation with microwaves in MCR
R1
O
Cl+ R2
N NEtOOC
OOMe
Br BrN N
EtOOC
COR1
R2COR1
R2
OOMe
2 [Pd(PPh3)2Cl24 CuI
20 echiv Et3N THF tc 2h
R1=Ph 4-OMe-C6H4R2= Ph
U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003
A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new indolizines
[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical
II
IHH
COORCOOR
N C C
O
R2NCC
O
R1
(B)
(A)
R1
O
C C N R2
O
CCN
H H
ROOC COOR
R1
O
C C N R2
O
CCN
COOR COOR
ROOC COOR
2
2 ROOC C C COOR
R1
O
C CH N R2
O
CCHN
H H
N NCH CHC C
O O
R1 R2
- 2 HX TEAanhydrous solvents
X-
X-
N NCH2 CH2C C
O O
R1 R2
C C COORH
R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5
Y=H NO2 OCH3 CH3 Cl BrX=Br Cl
bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998
bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001
bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004
bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new substituted pyridinium-indolizines
Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate
COO NO2CHC
N NH3C
OR
I IN NH3C
OR
IN NH3C
OR
I
H
KFNMP
-HI
NMP
95oC 30 min
N NH3CO
RN NH3C
O
R
O OO
NO2
O
NO2
-2[H]-2[H]
II
I II
N NH3CO
R
O O
NO2
IN NH3C
O
R
O O
NO2
I
(9a-d)(10a-d)
(15a-d)
(A) (B)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
12
34
56
78 9
10
11
12 3
4
56
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Green chemistry
is aboutbull Waste Minimisation at Sourcebull Use of Catalysts in place of Reagentsbull Using Non-Toxic Reagentsbull Use of Renewable Resourcesbull Improved Atom Efficiencybull Use of Solvent Free or Recyclable Environmentally
Benign Solvent systems
Green Chemistry = Responsibility
Why is there no lsquoGreen Geologyrsquo or lsquoGreen Astronomyrsquo
Because chemistry is the science that introduces new substances into the world and we have a responsibility for their impact in the worldrdquo
- Ronald Breslow
Green Chemistry is also calledhellip A new approach to designing chemicals and chemical
transformations that are beneficial for human health and the environment
An innovative way to design molecules and chemical transformations for sustainability
Meeting the needs of the current generation without compromising the ability of future generations to meet their own needs
Benign by design
Pollution prevention at the molecular level
What is Green Chemistry
bull Green chemistry is the study of how to design chemical products and processes in ways that are sustainable and not harmful for humans and the environment
bull Three components catalysis solvents non-toxic
bull 12 principles of green chemistry
Green Chemistry Is About
Cost
Waste
Materials
Hazard
Risk
Energy
bull Chemistry is a very prominent part of our daily lives
bull Chemical developments also bring new environmental problems and harmful unexpected side effects which result in the need for lsquogreenerrsquo chemical products
bull A famous example is the pesticide DDT
Why do we need Green Chemistry
1 PreventionIt is better to prevent waste than to treat or clean up waste after it has been created
2 Atom EconomySynthetic methods should be designed to maximise the incorporation of all materialsused in the process into the final product
3 Less Hazardous Chemical SynthesisWherever practicable synthetic methods should be designed to use and generatesubstances that possess little or no toxicity to people or the environment
4 Designing Safer ChemicalsChemical products should be designed to effect their desired function while minimisingtheir toxicity
5 Safer Solvents and AuxiliariesThe use of auxiliary substances (eg solvents or separation agents) should be madeunnecessary whenever possible and innocuous when used
6 Design for Energy EfficiencyEnergy requirements of chemical processes should be recognised for their environmentaland economic impacts and should be minimised If possible synthetic methods should beconducted at ambient temperature and pressure
The 12 Principles of Green Chemistry (1-6)
The 12 Principles of Green Chemistry (7-12)
7 Use of Renewable FeedstocksA raw material or feedstock should be renewable rather than depleting whenever technically and economically practicable
8 Reduce DerivativesUnnecessary derivatization (use of blocking groups protectionde-protection and temporary modification of physicalchemical processes) should be minimised or avoided if possible because such steps require additional reagents and can generate waste
9 CatalysisCatalytic reagents (as selective as possible) are superior to stoichiometric reagents
10 Design for DegradationChemical products should be designed so that at the end of their function they break down into innocuous degradation products and do not persist in the environment
11 Real-time Analysis for Pollution PreventionAnalytical methodologies need to be further developed to allow for real-time in-process monitoring and control prior to the formation of hazardous substances
12 Inherently Safer Chemistry for Accident PreventionSubstances and the form of a substance used in a chemical process should be chosen to minimise the potential for chemical accidents including releases explosions and fires
What is ldquoGreenrdquoSustainable Kinder and gentler to people and the planet
Green Chemistry
The cost of usinghazardous materials
Conventional Heating vs Alternative Energy Source
Conventional Heating Bunsen burnerOil bathHeating mantleAlternative Energy SourcesMicrowaveUltrasoundSunlight UV Electonchemistry
Clean Chemical Synthesis UsingAlternative Reaction Methods
Alternative Energy SourcesMicrowaveUltrasoundSunlight UV
AlternativeReactionMediaSolvent-free Supercritical FluidsIonic LiquidsWaterPolyethylene glycol (PEG)Solvent free
Microwaves in Synthesis
bull While fire is now rarely used in synthetic chemistry it was not until Robert Bunsen invented the burner in 1855 that the energy from this heat source could be applied
bull There is some controversy about the origins of the microwave power cavity called the magnetron ndash the high-power generator of microwave power
The British were particularly forward-looking in deploying radar for air defense with a system called Chain Home which began operation in 1937
Originally operating at 22 MHz frequencies increased to 55 MHz 1921 was published by AW Hull the earliest description of the magnetron a
diode with a cylindrical anode1940 It was developed practically by Randall and Booth at the University of
Birmingham in England they verified their first microwave transmissions 500 W at 3 GHz
A prototype was brought to the United States in September of that year to define an agreement whereby United States industrial capability would undertake the development of microwave radar
1940 the Radiation Laboratory was established at the Massachusetts Institute of Technology to exploit microwave radar More than 40 types of tube would be produced particularly in the S-band (ie 300 MHz) The growth of microwave radar is linked with Raytheon Company and PL Spencer who found the key to mass production
History or how it all beganhellip
bull 1946 Dr Percy Spencer-the magnetron inventor he has found a variety of technical applications in the chemical and related industries since the 1950s in particular in the food-processing drying and polymer
bull surprisingly microwave heating has only been implemented in organic synthesis since the mid-1980s
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
History or how it all beganhellip
bull 1969 ldquo Carrying out chemical reactions using microwave energy rdquo JW Vanderhoff ndash Dow Chemical Company US 3432413
bull 1986 ldquoThe Use of Microwave Ovens for Rapid Organic Synthesisrdquo Gedye R N et alTetrahedron Lett 1986 27 279
bull 1986 ldquoApplication of Commercial Microwave Ovens to Organic Synthesisrdquo Giguere R J and Majetich G Tetrahedron Lett 1986 27 4945
Energy Use in ConventionalChemical Processes
Heating Stirring Piping
Transporting Cooling
Problem of Conventional Heating
You heat what you donrsquot want to heat
Solvents for reactions apparatus
heated up and cool it down
Double energy penalty without any
apparent ldquobenefitrdquo
Energy Consumptions
Three ways to get the reaction done but different energy bills to pay
Microwaves
bull MW reactors operate at 245 GHzbull Electric field oscillates at 49 x 109 timessec ndash
10oCsec heating rate
Electromagnetic Spectrum
Neas E Collins M Introduction to Microwave Sample Preparation Theory and Practice 1988 p 8
Schematic of a Microwave
E= electric fieldH= magnetic field= wavelength (122 cm for 2450 MHz)c= speed of light (300000 kms)
Microwaves Application in Heating Food
1946 Original patent (P L Spencer)1947 First commercial oven1955 Home models1967 Desktop model1975 US sales exceed gas ranges1976 60 of US households havemicrowave ovens
Spectrum Electromagnetic
bull Electric field component
bull Responsible for dielectric heating
bull Dipolar polarization
bull Conduction
bull Magnetic field component
Microwaves ndash Dipolar Rotationbull Polar molecules have intermolecular forces which give any motion of the
molecule some inertia
bull Under a very high frequency electric field the polar molecule will attempt to follow the field but intermolecular inertia stops any significant motion before the field has reversed and no net motion results
bull If the frequency of field oscillation is very low then the molecules will be polarized uniformly and no random motion results
bull In the intermediate case the frequency of the field will be such that the molecules will be almost but not quite able to keep in phase with the field polarity
bull In this case the random motion resulting as molecules jostle to attempt in vain to follow the field provides strong agitation and intense heating of the sample
bull At 245 GHz the field oscillates 49 x 109 timess which can lead to heating
rates of 10 degC per second when powerful waves are used
MW Heating Mechanism
Alternating electric field Withhigh frequency
NoconstraintContinuous electric field
Two mechanisms Dipolar rotation polarizationIonic Conduction mechanism
Microwave Dielectric HeatingMechanisms
Dipolar PolarizationMechanism
Conduction Mechanism
Dipolar molecules try toalign to an oscillating fieldby rotation
Ions in solution will moveby the applied electricfield
Mingos D M P et al Chem Soc Rev 1991 20 1 and 1998 27 213
Microwave vs Oil-bath Heating
J-S Schanche Mol Diversity 2003 7 293wwwpersonalchemistry-com wwwbiotagecom
Conventional Heating byConduction
ConductiveheatHeating byconvectioncurrentsSlow andenergyinefficientprocess
temperature on the outside surface isin excess of the boiling point of liquid
Direct Heating by MicrowaveIrradiation
bullSolventreagent absorbs MW energybull Vessel wall transparent to MWbullDirect in-core heatingbullInstant on-off
Inverted temperature gradients
Molecular Speeds
Molecular Speeds
Microwave Ovens
Cooking Chemistry Cooking Food
Household MW ovens
The Use of Microwave Ovens for Rapid Organic Synthesis R Gedye et al Tetrahedron Lett 1986 27 279
Publications on MW-AssistedOrganic Synthesis
7 Synthetic Journals JOrgChemOrgLettTetrahedron LettTetrahedron SynthCommun Synlett SynthesisAll Journals (Full Text) Dedicated instruments only (Anton Paar Biotage CEM Milestone Prolabo)
Industrial Chemical Applications of Microwave Heating
Food Processing+ Defrosting+ Drying roasting baking+ Pasteurization
Drying Industry+ Wood fibers textiles+ Pharmaceuticals+ Brick concrete walls
Polymer Chemistry+ Rubber curing vulcanization+ Polymerization
CeramicsMaterials+ Alumina sintering+ Welding smelting gluing
Plasma+ SemiconductorsWaste Remediation+ Sewage treatment
Analytical Chemistry+ Digestion+ Extraction+ Ashing
Biochemistry Pathology+ Protein hydrolysis+ PCR proteomics+ Tissue fixation+ Histoprocessing
Medical+ Diathermy tumor detection+ Blood warming+ Sterilization (Anthrax)+ Drying of catheters
Books on Microwave-Assisted Synthesis
1048707 Fundamentals of Microwave Application1048707 Alternative Laboratory MicrowaveInstruments1048707 Chemistry Applications1048707 Biochemistry Applications1048707 Laboratory Microwave Safety
Hayes B LCEM PublishingMatthews NC2002
(ACS Professional Reference Book) H M Kingston S J Haswell (eds)
Microwaves in Organic and Medicinal ChemistryKappe C O and Stadler AWiley-VCH Weinheim 2005 ISBN 3-527-31210-2410 pages ca 1000 references
Books on Microwave-Assisted Synthesis
Lidstoumlm PTierney J P(Eds)BlackwellScientific2005
Loupy Andre (Ed)Wiley-VCH Weinheim 2003 ISBN 3-527-30514-9523 pages 2000 refs
Book (2 volumes) Wiley-VCHA Loupy editSecond Edition(2006) 22 Chapters
Astra Zeneca ResearchFoundation Kavitha PrintersBangalore India 2002azrefiastrazenecacom
Practical Microwave Synthesis for Organic Chemists - Strategies Instruments and Protocols
Edition - 2009 X 310 Pages Hardcover Monograph
Books on Microwave-Assisted Synthesis
Microwave Ovens
Monomodal instrument
Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005
Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia
Multimodal instrument
+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile
Monomodal Vs Multimodal
Monomodal Vs Multimodal
Thermal Effects
bullMore efficient energetic coupling of solvent with microwaves
promotes higher rate of temperature increase
bull Inverted heat transfer volumetric
bull ldquoHot spotsrdquo in monomode microwaves
bull Selective on properties of material (solvents catalysts
reagents intermediates products susceptors)
Recent Applications of Microwave-Assisted Synthesis-MAOS
Hydrolysis of benzamide
thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)
The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions
R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958
Solvent-free Reactions or Solid-Solid Reactions
ldquoNo reaction proceeds without solventrdquo
Aristotle
Solventless syntheses
Green chemistry enabled advancement
Solvent-free Organic Synthesis
Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed
i n t o a p o w e r f u l m e t h o d o l o g y a s i t
reduces the amount of toxic waste produced and therefore becomes less harmful to the
e n v i r o n m e n t
Solvent-free Organic Synthesis
bull Clean and efficient synthesis
bull Economic and environmental impact
bull Fast reaction kinetics
Best solvent is no solvent
Adolf von Baeyer
Synthesis of Indigo
Towardsbenign
synthesiswith
remarkableVersatility
G W V Cave C LRaston J L ScottChemCommun
2001 2159
Solid-State General Oxidation with with Urea H2O2 Complex
R S Varma and K P Naiker Org Letters 1999 1 189
Solvent-free Oxidative Preparation of Heterocycles
Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157
Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones
Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199
Solvent-free Reduction
F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245
Carbon-Carbon Bond Formation
Toda Tanada Iwata J Org Chem 1989 54 3007
Solventless Photo Coupling and Photo Rearangements
Y Ito S Endo J Am Chem Soc 1997 119 5974
Shin Keating Maribay J Am Chem Soc 1996 118 7626
Solvent - Free Condensation
Z Gross et al Org Letters 1999 1 599
Solid-State Preparationof Dumb-bell-shaped C120
Wang Komatsu Murata Shiro Nature 1997 387 583
Advantages of Solid Mineral Supports(Alumina Silica and Clay)
Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area
The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity
Solids are generally easier and safer to handle than liquids or gaseous reagents
Inexpensive recyclable and environmentally benign nature
Solid-supported Solventless Reactions
bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation
R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43
Supported ReactionsUsing Microwaves
E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945
Microwave-Assisted Deacetylationon Alumina
Varma et al J Chem Soc Perkin Trans 1 999 (1993)
Deprotection of Benzyl Esters viaMicrowave Thermolysis
A practical alternative to traditional catalytic hydrogenation
Varma et al Tetrahedron Lett 34 4603 (1993)
Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of
Carbonyl Compounds Using Microwaves
Varma Meshram Tetrahedron Lett 38 5427 (1997)
Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm
PersulfatendashClay using Microwave and Ultrasonic Irradiation
Varma Meshram Tetrahedron Lett 38 7973 (1997)
Solid Supported Solvent-freeOxidation under MW
Varma et al Tetrahedron Lett 1997 38 2043 and 7823
Solvent-free Reduction Using MW
Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction
Varma et al Tetrahedron Lett 1997 38 4337
Hydrodechlorination under continuous MW
Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)
Synthesis of Heterocyclic Compounds
Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)
Synthesis of Heterocyclic Compounds
Organometallic Reactions
Rearrangements
Rearrangements
INDOLIZINES
Heterocyclic systems 10- electronics
Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine
Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds
N
1
2
34567
8R2
R3
R1
Why interest for indolizinic products
Strong fluorescent properties luminiscent products luminiscent products
Potentially fluorescents marker Potentially laserldquoscintillatersrdquo
bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999
Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )
Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2
ldquoCalcium-entryrdquo blockers
Indolizines by irradiation with microwaves in MCR
RBr
O+
N
R1 R2+N
R2
R1
COR
AcOAl2O3 Mw
R=Ph p-Tolil Stiril
R1= H COOMeR2= COOEt COOMe
Asymmetric indolizines by irradiation with microwaves in MCR
R1
O
Cl+ R2
N NEtOOC
OOMe
Br BrN N
EtOOC
COR1
R2COR1
R2
OOMe
2 [Pd(PPh3)2Cl24 CuI
20 echiv Et3N THF tc 2h
R1=Ph 4-OMe-C6H4R2= Ph
U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003
A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new indolizines
[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical
II
IHH
COORCOOR
N C C
O
R2NCC
O
R1
(B)
(A)
R1
O
C C N R2
O
CCN
H H
ROOC COOR
R1
O
C C N R2
O
CCN
COOR COOR
ROOC COOR
2
2 ROOC C C COOR
R1
O
C CH N R2
O
CCHN
H H
N NCH CHC C
O O
R1 R2
- 2 HX TEAanhydrous solvents
X-
X-
N NCH2 CH2C C
O O
R1 R2
C C COORH
R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5
Y=H NO2 OCH3 CH3 Cl BrX=Br Cl
bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998
bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001
bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004
bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new substituted pyridinium-indolizines
Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate
COO NO2CHC
N NH3C
OR
I IN NH3C
OR
IN NH3C
OR
I
H
KFNMP
-HI
NMP
95oC 30 min
N NH3CO
RN NH3C
O
R
O OO
NO2
O
NO2
-2[H]-2[H]
II
I II
N NH3CO
R
O O
NO2
IN NH3C
O
R
O O
NO2
I
(9a-d)(10a-d)
(15a-d)
(A) (B)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
12
34
56
78 9
10
11
12 3
4
56
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Green Chemistry = Responsibility
Why is there no lsquoGreen Geologyrsquo or lsquoGreen Astronomyrsquo
Because chemistry is the science that introduces new substances into the world and we have a responsibility for their impact in the worldrdquo
- Ronald Breslow
Green Chemistry is also calledhellip A new approach to designing chemicals and chemical
transformations that are beneficial for human health and the environment
An innovative way to design molecules and chemical transformations for sustainability
Meeting the needs of the current generation without compromising the ability of future generations to meet their own needs
Benign by design
Pollution prevention at the molecular level
What is Green Chemistry
bull Green chemistry is the study of how to design chemical products and processes in ways that are sustainable and not harmful for humans and the environment
bull Three components catalysis solvents non-toxic
bull 12 principles of green chemistry
Green Chemistry Is About
Cost
Waste
Materials
Hazard
Risk
Energy
bull Chemistry is a very prominent part of our daily lives
bull Chemical developments also bring new environmental problems and harmful unexpected side effects which result in the need for lsquogreenerrsquo chemical products
bull A famous example is the pesticide DDT
Why do we need Green Chemistry
1 PreventionIt is better to prevent waste than to treat or clean up waste after it has been created
2 Atom EconomySynthetic methods should be designed to maximise the incorporation of all materialsused in the process into the final product
3 Less Hazardous Chemical SynthesisWherever practicable synthetic methods should be designed to use and generatesubstances that possess little or no toxicity to people or the environment
4 Designing Safer ChemicalsChemical products should be designed to effect their desired function while minimisingtheir toxicity
5 Safer Solvents and AuxiliariesThe use of auxiliary substances (eg solvents or separation agents) should be madeunnecessary whenever possible and innocuous when used
6 Design for Energy EfficiencyEnergy requirements of chemical processes should be recognised for their environmentaland economic impacts and should be minimised If possible synthetic methods should beconducted at ambient temperature and pressure
The 12 Principles of Green Chemistry (1-6)
The 12 Principles of Green Chemistry (7-12)
7 Use of Renewable FeedstocksA raw material or feedstock should be renewable rather than depleting whenever technically and economically practicable
8 Reduce DerivativesUnnecessary derivatization (use of blocking groups protectionde-protection and temporary modification of physicalchemical processes) should be minimised or avoided if possible because such steps require additional reagents and can generate waste
9 CatalysisCatalytic reagents (as selective as possible) are superior to stoichiometric reagents
10 Design for DegradationChemical products should be designed so that at the end of their function they break down into innocuous degradation products and do not persist in the environment
11 Real-time Analysis for Pollution PreventionAnalytical methodologies need to be further developed to allow for real-time in-process monitoring and control prior to the formation of hazardous substances
12 Inherently Safer Chemistry for Accident PreventionSubstances and the form of a substance used in a chemical process should be chosen to minimise the potential for chemical accidents including releases explosions and fires
What is ldquoGreenrdquoSustainable Kinder and gentler to people and the planet
Green Chemistry
The cost of usinghazardous materials
Conventional Heating vs Alternative Energy Source
Conventional Heating Bunsen burnerOil bathHeating mantleAlternative Energy SourcesMicrowaveUltrasoundSunlight UV Electonchemistry
Clean Chemical Synthesis UsingAlternative Reaction Methods
Alternative Energy SourcesMicrowaveUltrasoundSunlight UV
AlternativeReactionMediaSolvent-free Supercritical FluidsIonic LiquidsWaterPolyethylene glycol (PEG)Solvent free
Microwaves in Synthesis
bull While fire is now rarely used in synthetic chemistry it was not until Robert Bunsen invented the burner in 1855 that the energy from this heat source could be applied
bull There is some controversy about the origins of the microwave power cavity called the magnetron ndash the high-power generator of microwave power
The British were particularly forward-looking in deploying radar for air defense with a system called Chain Home which began operation in 1937
Originally operating at 22 MHz frequencies increased to 55 MHz 1921 was published by AW Hull the earliest description of the magnetron a
diode with a cylindrical anode1940 It was developed practically by Randall and Booth at the University of
Birmingham in England they verified their first microwave transmissions 500 W at 3 GHz
A prototype was brought to the United States in September of that year to define an agreement whereby United States industrial capability would undertake the development of microwave radar
1940 the Radiation Laboratory was established at the Massachusetts Institute of Technology to exploit microwave radar More than 40 types of tube would be produced particularly in the S-band (ie 300 MHz) The growth of microwave radar is linked with Raytheon Company and PL Spencer who found the key to mass production
History or how it all beganhellip
bull 1946 Dr Percy Spencer-the magnetron inventor he has found a variety of technical applications in the chemical and related industries since the 1950s in particular in the food-processing drying and polymer
bull surprisingly microwave heating has only been implemented in organic synthesis since the mid-1980s
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
History or how it all beganhellip
bull 1969 ldquo Carrying out chemical reactions using microwave energy rdquo JW Vanderhoff ndash Dow Chemical Company US 3432413
bull 1986 ldquoThe Use of Microwave Ovens for Rapid Organic Synthesisrdquo Gedye R N et alTetrahedron Lett 1986 27 279
bull 1986 ldquoApplication of Commercial Microwave Ovens to Organic Synthesisrdquo Giguere R J and Majetich G Tetrahedron Lett 1986 27 4945
Energy Use in ConventionalChemical Processes
Heating Stirring Piping
Transporting Cooling
Problem of Conventional Heating
You heat what you donrsquot want to heat
Solvents for reactions apparatus
heated up and cool it down
Double energy penalty without any
apparent ldquobenefitrdquo
Energy Consumptions
Three ways to get the reaction done but different energy bills to pay
Microwaves
bull MW reactors operate at 245 GHzbull Electric field oscillates at 49 x 109 timessec ndash
10oCsec heating rate
Electromagnetic Spectrum
Neas E Collins M Introduction to Microwave Sample Preparation Theory and Practice 1988 p 8
Schematic of a Microwave
E= electric fieldH= magnetic field= wavelength (122 cm for 2450 MHz)c= speed of light (300000 kms)
Microwaves Application in Heating Food
1946 Original patent (P L Spencer)1947 First commercial oven1955 Home models1967 Desktop model1975 US sales exceed gas ranges1976 60 of US households havemicrowave ovens
Spectrum Electromagnetic
bull Electric field component
bull Responsible for dielectric heating
bull Dipolar polarization
bull Conduction
bull Magnetic field component
Microwaves ndash Dipolar Rotationbull Polar molecules have intermolecular forces which give any motion of the
molecule some inertia
bull Under a very high frequency electric field the polar molecule will attempt to follow the field but intermolecular inertia stops any significant motion before the field has reversed and no net motion results
bull If the frequency of field oscillation is very low then the molecules will be polarized uniformly and no random motion results
bull In the intermediate case the frequency of the field will be such that the molecules will be almost but not quite able to keep in phase with the field polarity
bull In this case the random motion resulting as molecules jostle to attempt in vain to follow the field provides strong agitation and intense heating of the sample
bull At 245 GHz the field oscillates 49 x 109 timess which can lead to heating
rates of 10 degC per second when powerful waves are used
MW Heating Mechanism
Alternating electric field Withhigh frequency
NoconstraintContinuous electric field
Two mechanisms Dipolar rotation polarizationIonic Conduction mechanism
Microwave Dielectric HeatingMechanisms
Dipolar PolarizationMechanism
Conduction Mechanism
Dipolar molecules try toalign to an oscillating fieldby rotation
Ions in solution will moveby the applied electricfield
Mingos D M P et al Chem Soc Rev 1991 20 1 and 1998 27 213
Microwave vs Oil-bath Heating
J-S Schanche Mol Diversity 2003 7 293wwwpersonalchemistry-com wwwbiotagecom
Conventional Heating byConduction
ConductiveheatHeating byconvectioncurrentsSlow andenergyinefficientprocess
temperature on the outside surface isin excess of the boiling point of liquid
Direct Heating by MicrowaveIrradiation
bullSolventreagent absorbs MW energybull Vessel wall transparent to MWbullDirect in-core heatingbullInstant on-off
Inverted temperature gradients
Molecular Speeds
Molecular Speeds
Microwave Ovens
Cooking Chemistry Cooking Food
Household MW ovens
The Use of Microwave Ovens for Rapid Organic Synthesis R Gedye et al Tetrahedron Lett 1986 27 279
Publications on MW-AssistedOrganic Synthesis
7 Synthetic Journals JOrgChemOrgLettTetrahedron LettTetrahedron SynthCommun Synlett SynthesisAll Journals (Full Text) Dedicated instruments only (Anton Paar Biotage CEM Milestone Prolabo)
Industrial Chemical Applications of Microwave Heating
Food Processing+ Defrosting+ Drying roasting baking+ Pasteurization
Drying Industry+ Wood fibers textiles+ Pharmaceuticals+ Brick concrete walls
Polymer Chemistry+ Rubber curing vulcanization+ Polymerization
CeramicsMaterials+ Alumina sintering+ Welding smelting gluing
Plasma+ SemiconductorsWaste Remediation+ Sewage treatment
Analytical Chemistry+ Digestion+ Extraction+ Ashing
Biochemistry Pathology+ Protein hydrolysis+ PCR proteomics+ Tissue fixation+ Histoprocessing
Medical+ Diathermy tumor detection+ Blood warming+ Sterilization (Anthrax)+ Drying of catheters
Books on Microwave-Assisted Synthesis
1048707 Fundamentals of Microwave Application1048707 Alternative Laboratory MicrowaveInstruments1048707 Chemistry Applications1048707 Biochemistry Applications1048707 Laboratory Microwave Safety
Hayes B LCEM PublishingMatthews NC2002
(ACS Professional Reference Book) H M Kingston S J Haswell (eds)
Microwaves in Organic and Medicinal ChemistryKappe C O and Stadler AWiley-VCH Weinheim 2005 ISBN 3-527-31210-2410 pages ca 1000 references
Books on Microwave-Assisted Synthesis
Lidstoumlm PTierney J P(Eds)BlackwellScientific2005
Loupy Andre (Ed)Wiley-VCH Weinheim 2003 ISBN 3-527-30514-9523 pages 2000 refs
Book (2 volumes) Wiley-VCHA Loupy editSecond Edition(2006) 22 Chapters
Astra Zeneca ResearchFoundation Kavitha PrintersBangalore India 2002azrefiastrazenecacom
Practical Microwave Synthesis for Organic Chemists - Strategies Instruments and Protocols
Edition - 2009 X 310 Pages Hardcover Monograph
Books on Microwave-Assisted Synthesis
Microwave Ovens
Monomodal instrument
Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005
Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia
Multimodal instrument
+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile
Monomodal Vs Multimodal
Monomodal Vs Multimodal
Thermal Effects
bullMore efficient energetic coupling of solvent with microwaves
promotes higher rate of temperature increase
bull Inverted heat transfer volumetric
bull ldquoHot spotsrdquo in monomode microwaves
bull Selective on properties of material (solvents catalysts
reagents intermediates products susceptors)
Recent Applications of Microwave-Assisted Synthesis-MAOS
Hydrolysis of benzamide
thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)
The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions
R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958
Solvent-free Reactions or Solid-Solid Reactions
ldquoNo reaction proceeds without solventrdquo
Aristotle
Solventless syntheses
Green chemistry enabled advancement
Solvent-free Organic Synthesis
Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed
i n t o a p o w e r f u l m e t h o d o l o g y a s i t
reduces the amount of toxic waste produced and therefore becomes less harmful to the
e n v i r o n m e n t
Solvent-free Organic Synthesis
bull Clean and efficient synthesis
bull Economic and environmental impact
bull Fast reaction kinetics
Best solvent is no solvent
Adolf von Baeyer
Synthesis of Indigo
Towardsbenign
synthesiswith
remarkableVersatility
G W V Cave C LRaston J L ScottChemCommun
2001 2159
Solid-State General Oxidation with with Urea H2O2 Complex
R S Varma and K P Naiker Org Letters 1999 1 189
Solvent-free Oxidative Preparation of Heterocycles
Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157
Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones
Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199
Solvent-free Reduction
F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245
Carbon-Carbon Bond Formation
Toda Tanada Iwata J Org Chem 1989 54 3007
Solventless Photo Coupling and Photo Rearangements
Y Ito S Endo J Am Chem Soc 1997 119 5974
Shin Keating Maribay J Am Chem Soc 1996 118 7626
Solvent - Free Condensation
Z Gross et al Org Letters 1999 1 599
Solid-State Preparationof Dumb-bell-shaped C120
Wang Komatsu Murata Shiro Nature 1997 387 583
Advantages of Solid Mineral Supports(Alumina Silica and Clay)
Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area
The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity
Solids are generally easier and safer to handle than liquids or gaseous reagents
Inexpensive recyclable and environmentally benign nature
Solid-supported Solventless Reactions
bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation
R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43
Supported ReactionsUsing Microwaves
E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945
Microwave-Assisted Deacetylationon Alumina
Varma et al J Chem Soc Perkin Trans 1 999 (1993)
Deprotection of Benzyl Esters viaMicrowave Thermolysis
A practical alternative to traditional catalytic hydrogenation
Varma et al Tetrahedron Lett 34 4603 (1993)
Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of
Carbonyl Compounds Using Microwaves
Varma Meshram Tetrahedron Lett 38 5427 (1997)
Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm
PersulfatendashClay using Microwave and Ultrasonic Irradiation
Varma Meshram Tetrahedron Lett 38 7973 (1997)
Solid Supported Solvent-freeOxidation under MW
Varma et al Tetrahedron Lett 1997 38 2043 and 7823
Solvent-free Reduction Using MW
Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction
Varma et al Tetrahedron Lett 1997 38 4337
Hydrodechlorination under continuous MW
Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)
Synthesis of Heterocyclic Compounds
Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)
Synthesis of Heterocyclic Compounds
Organometallic Reactions
Rearrangements
Rearrangements
INDOLIZINES
Heterocyclic systems 10- electronics
Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine
Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds
N
1
2
34567
8R2
R3
R1
Why interest for indolizinic products
Strong fluorescent properties luminiscent products luminiscent products
Potentially fluorescents marker Potentially laserldquoscintillatersrdquo
bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999
Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )
Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2
ldquoCalcium-entryrdquo blockers
Indolizines by irradiation with microwaves in MCR
RBr
O+
N
R1 R2+N
R2
R1
COR
AcOAl2O3 Mw
R=Ph p-Tolil Stiril
R1= H COOMeR2= COOEt COOMe
Asymmetric indolizines by irradiation with microwaves in MCR
R1
O
Cl+ R2
N NEtOOC
OOMe
Br BrN N
EtOOC
COR1
R2COR1
R2
OOMe
2 [Pd(PPh3)2Cl24 CuI
20 echiv Et3N THF tc 2h
R1=Ph 4-OMe-C6H4R2= Ph
U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003
A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new indolizines
[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical
II
IHH
COORCOOR
N C C
O
R2NCC
O
R1
(B)
(A)
R1
O
C C N R2
O
CCN
H H
ROOC COOR
R1
O
C C N R2
O
CCN
COOR COOR
ROOC COOR
2
2 ROOC C C COOR
R1
O
C CH N R2
O
CCHN
H H
N NCH CHC C
O O
R1 R2
- 2 HX TEAanhydrous solvents
X-
X-
N NCH2 CH2C C
O O
R1 R2
C C COORH
R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5
Y=H NO2 OCH3 CH3 Cl BrX=Br Cl
bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998
bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001
bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004
bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new substituted pyridinium-indolizines
Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate
COO NO2CHC
N NH3C
OR
I IN NH3C
OR
IN NH3C
OR
I
H
KFNMP
-HI
NMP
95oC 30 min
N NH3CO
RN NH3C
O
R
O OO
NO2
O
NO2
-2[H]-2[H]
II
I II
N NH3CO
R
O O
NO2
IN NH3C
O
R
O O
NO2
I
(9a-d)(10a-d)
(15a-d)
(A) (B)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
12
34
56
78 9
10
11
12 3
4
56
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Green Chemistry is also calledhellip A new approach to designing chemicals and chemical
transformations that are beneficial for human health and the environment
An innovative way to design molecules and chemical transformations for sustainability
Meeting the needs of the current generation without compromising the ability of future generations to meet their own needs
Benign by design
Pollution prevention at the molecular level
What is Green Chemistry
bull Green chemistry is the study of how to design chemical products and processes in ways that are sustainable and not harmful for humans and the environment
bull Three components catalysis solvents non-toxic
bull 12 principles of green chemistry
Green Chemistry Is About
Cost
Waste
Materials
Hazard
Risk
Energy
bull Chemistry is a very prominent part of our daily lives
bull Chemical developments also bring new environmental problems and harmful unexpected side effects which result in the need for lsquogreenerrsquo chemical products
bull A famous example is the pesticide DDT
Why do we need Green Chemistry
1 PreventionIt is better to prevent waste than to treat or clean up waste after it has been created
2 Atom EconomySynthetic methods should be designed to maximise the incorporation of all materialsused in the process into the final product
3 Less Hazardous Chemical SynthesisWherever practicable synthetic methods should be designed to use and generatesubstances that possess little or no toxicity to people or the environment
4 Designing Safer ChemicalsChemical products should be designed to effect their desired function while minimisingtheir toxicity
5 Safer Solvents and AuxiliariesThe use of auxiliary substances (eg solvents or separation agents) should be madeunnecessary whenever possible and innocuous when used
6 Design for Energy EfficiencyEnergy requirements of chemical processes should be recognised for their environmentaland economic impacts and should be minimised If possible synthetic methods should beconducted at ambient temperature and pressure
The 12 Principles of Green Chemistry (1-6)
The 12 Principles of Green Chemistry (7-12)
7 Use of Renewable FeedstocksA raw material or feedstock should be renewable rather than depleting whenever technically and economically practicable
8 Reduce DerivativesUnnecessary derivatization (use of blocking groups protectionde-protection and temporary modification of physicalchemical processes) should be minimised or avoided if possible because such steps require additional reagents and can generate waste
9 CatalysisCatalytic reagents (as selective as possible) are superior to stoichiometric reagents
10 Design for DegradationChemical products should be designed so that at the end of their function they break down into innocuous degradation products and do not persist in the environment
11 Real-time Analysis for Pollution PreventionAnalytical methodologies need to be further developed to allow for real-time in-process monitoring and control prior to the formation of hazardous substances
12 Inherently Safer Chemistry for Accident PreventionSubstances and the form of a substance used in a chemical process should be chosen to minimise the potential for chemical accidents including releases explosions and fires
What is ldquoGreenrdquoSustainable Kinder and gentler to people and the planet
Green Chemistry
The cost of usinghazardous materials
Conventional Heating vs Alternative Energy Source
Conventional Heating Bunsen burnerOil bathHeating mantleAlternative Energy SourcesMicrowaveUltrasoundSunlight UV Electonchemistry
Clean Chemical Synthesis UsingAlternative Reaction Methods
Alternative Energy SourcesMicrowaveUltrasoundSunlight UV
AlternativeReactionMediaSolvent-free Supercritical FluidsIonic LiquidsWaterPolyethylene glycol (PEG)Solvent free
Microwaves in Synthesis
bull While fire is now rarely used in synthetic chemistry it was not until Robert Bunsen invented the burner in 1855 that the energy from this heat source could be applied
bull There is some controversy about the origins of the microwave power cavity called the magnetron ndash the high-power generator of microwave power
The British were particularly forward-looking in deploying radar for air defense with a system called Chain Home which began operation in 1937
Originally operating at 22 MHz frequencies increased to 55 MHz 1921 was published by AW Hull the earliest description of the magnetron a
diode with a cylindrical anode1940 It was developed practically by Randall and Booth at the University of
Birmingham in England they verified their first microwave transmissions 500 W at 3 GHz
A prototype was brought to the United States in September of that year to define an agreement whereby United States industrial capability would undertake the development of microwave radar
1940 the Radiation Laboratory was established at the Massachusetts Institute of Technology to exploit microwave radar More than 40 types of tube would be produced particularly in the S-band (ie 300 MHz) The growth of microwave radar is linked with Raytheon Company and PL Spencer who found the key to mass production
History or how it all beganhellip
bull 1946 Dr Percy Spencer-the magnetron inventor he has found a variety of technical applications in the chemical and related industries since the 1950s in particular in the food-processing drying and polymer
bull surprisingly microwave heating has only been implemented in organic synthesis since the mid-1980s
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
History or how it all beganhellip
bull 1969 ldquo Carrying out chemical reactions using microwave energy rdquo JW Vanderhoff ndash Dow Chemical Company US 3432413
bull 1986 ldquoThe Use of Microwave Ovens for Rapid Organic Synthesisrdquo Gedye R N et alTetrahedron Lett 1986 27 279
bull 1986 ldquoApplication of Commercial Microwave Ovens to Organic Synthesisrdquo Giguere R J and Majetich G Tetrahedron Lett 1986 27 4945
Energy Use in ConventionalChemical Processes
Heating Stirring Piping
Transporting Cooling
Problem of Conventional Heating
You heat what you donrsquot want to heat
Solvents for reactions apparatus
heated up and cool it down
Double energy penalty without any
apparent ldquobenefitrdquo
Energy Consumptions
Three ways to get the reaction done but different energy bills to pay
Microwaves
bull MW reactors operate at 245 GHzbull Electric field oscillates at 49 x 109 timessec ndash
10oCsec heating rate
Electromagnetic Spectrum
Neas E Collins M Introduction to Microwave Sample Preparation Theory and Practice 1988 p 8
Schematic of a Microwave
E= electric fieldH= magnetic field= wavelength (122 cm for 2450 MHz)c= speed of light (300000 kms)
Microwaves Application in Heating Food
1946 Original patent (P L Spencer)1947 First commercial oven1955 Home models1967 Desktop model1975 US sales exceed gas ranges1976 60 of US households havemicrowave ovens
Spectrum Electromagnetic
bull Electric field component
bull Responsible for dielectric heating
bull Dipolar polarization
bull Conduction
bull Magnetic field component
Microwaves ndash Dipolar Rotationbull Polar molecules have intermolecular forces which give any motion of the
molecule some inertia
bull Under a very high frequency electric field the polar molecule will attempt to follow the field but intermolecular inertia stops any significant motion before the field has reversed and no net motion results
bull If the frequency of field oscillation is very low then the molecules will be polarized uniformly and no random motion results
bull In the intermediate case the frequency of the field will be such that the molecules will be almost but not quite able to keep in phase with the field polarity
bull In this case the random motion resulting as molecules jostle to attempt in vain to follow the field provides strong agitation and intense heating of the sample
bull At 245 GHz the field oscillates 49 x 109 timess which can lead to heating
rates of 10 degC per second when powerful waves are used
MW Heating Mechanism
Alternating electric field Withhigh frequency
NoconstraintContinuous electric field
Two mechanisms Dipolar rotation polarizationIonic Conduction mechanism
Microwave Dielectric HeatingMechanisms
Dipolar PolarizationMechanism
Conduction Mechanism
Dipolar molecules try toalign to an oscillating fieldby rotation
Ions in solution will moveby the applied electricfield
Mingos D M P et al Chem Soc Rev 1991 20 1 and 1998 27 213
Microwave vs Oil-bath Heating
J-S Schanche Mol Diversity 2003 7 293wwwpersonalchemistry-com wwwbiotagecom
Conventional Heating byConduction
ConductiveheatHeating byconvectioncurrentsSlow andenergyinefficientprocess
temperature on the outside surface isin excess of the boiling point of liquid
Direct Heating by MicrowaveIrradiation
bullSolventreagent absorbs MW energybull Vessel wall transparent to MWbullDirect in-core heatingbullInstant on-off
Inverted temperature gradients
Molecular Speeds
Molecular Speeds
Microwave Ovens
Cooking Chemistry Cooking Food
Household MW ovens
The Use of Microwave Ovens for Rapid Organic Synthesis R Gedye et al Tetrahedron Lett 1986 27 279
Publications on MW-AssistedOrganic Synthesis
7 Synthetic Journals JOrgChemOrgLettTetrahedron LettTetrahedron SynthCommun Synlett SynthesisAll Journals (Full Text) Dedicated instruments only (Anton Paar Biotage CEM Milestone Prolabo)
Industrial Chemical Applications of Microwave Heating
Food Processing+ Defrosting+ Drying roasting baking+ Pasteurization
Drying Industry+ Wood fibers textiles+ Pharmaceuticals+ Brick concrete walls
Polymer Chemistry+ Rubber curing vulcanization+ Polymerization
CeramicsMaterials+ Alumina sintering+ Welding smelting gluing
Plasma+ SemiconductorsWaste Remediation+ Sewage treatment
Analytical Chemistry+ Digestion+ Extraction+ Ashing
Biochemistry Pathology+ Protein hydrolysis+ PCR proteomics+ Tissue fixation+ Histoprocessing
Medical+ Diathermy tumor detection+ Blood warming+ Sterilization (Anthrax)+ Drying of catheters
Books on Microwave-Assisted Synthesis
1048707 Fundamentals of Microwave Application1048707 Alternative Laboratory MicrowaveInstruments1048707 Chemistry Applications1048707 Biochemistry Applications1048707 Laboratory Microwave Safety
Hayes B LCEM PublishingMatthews NC2002
(ACS Professional Reference Book) H M Kingston S J Haswell (eds)
Microwaves in Organic and Medicinal ChemistryKappe C O and Stadler AWiley-VCH Weinheim 2005 ISBN 3-527-31210-2410 pages ca 1000 references
Books on Microwave-Assisted Synthesis
Lidstoumlm PTierney J P(Eds)BlackwellScientific2005
Loupy Andre (Ed)Wiley-VCH Weinheim 2003 ISBN 3-527-30514-9523 pages 2000 refs
Book (2 volumes) Wiley-VCHA Loupy editSecond Edition(2006) 22 Chapters
Astra Zeneca ResearchFoundation Kavitha PrintersBangalore India 2002azrefiastrazenecacom
Practical Microwave Synthesis for Organic Chemists - Strategies Instruments and Protocols
Edition - 2009 X 310 Pages Hardcover Monograph
Books on Microwave-Assisted Synthesis
Microwave Ovens
Monomodal instrument
Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005
Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia
Multimodal instrument
+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile
Monomodal Vs Multimodal
Monomodal Vs Multimodal
Thermal Effects
bullMore efficient energetic coupling of solvent with microwaves
promotes higher rate of temperature increase
bull Inverted heat transfer volumetric
bull ldquoHot spotsrdquo in monomode microwaves
bull Selective on properties of material (solvents catalysts
reagents intermediates products susceptors)
Recent Applications of Microwave-Assisted Synthesis-MAOS
Hydrolysis of benzamide
thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)
The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions
R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958
Solvent-free Reactions or Solid-Solid Reactions
ldquoNo reaction proceeds without solventrdquo
Aristotle
Solventless syntheses
Green chemistry enabled advancement
Solvent-free Organic Synthesis
Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed
i n t o a p o w e r f u l m e t h o d o l o g y a s i t
reduces the amount of toxic waste produced and therefore becomes less harmful to the
e n v i r o n m e n t
Solvent-free Organic Synthesis
bull Clean and efficient synthesis
bull Economic and environmental impact
bull Fast reaction kinetics
Best solvent is no solvent
Adolf von Baeyer
Synthesis of Indigo
Towardsbenign
synthesiswith
remarkableVersatility
G W V Cave C LRaston J L ScottChemCommun
2001 2159
Solid-State General Oxidation with with Urea H2O2 Complex
R S Varma and K P Naiker Org Letters 1999 1 189
Solvent-free Oxidative Preparation of Heterocycles
Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157
Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones
Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199
Solvent-free Reduction
F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245
Carbon-Carbon Bond Formation
Toda Tanada Iwata J Org Chem 1989 54 3007
Solventless Photo Coupling and Photo Rearangements
Y Ito S Endo J Am Chem Soc 1997 119 5974
Shin Keating Maribay J Am Chem Soc 1996 118 7626
Solvent - Free Condensation
Z Gross et al Org Letters 1999 1 599
Solid-State Preparationof Dumb-bell-shaped C120
Wang Komatsu Murata Shiro Nature 1997 387 583
Advantages of Solid Mineral Supports(Alumina Silica and Clay)
Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area
The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity
Solids are generally easier and safer to handle than liquids or gaseous reagents
Inexpensive recyclable and environmentally benign nature
Solid-supported Solventless Reactions
bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation
R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43
Supported ReactionsUsing Microwaves
E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945
Microwave-Assisted Deacetylationon Alumina
Varma et al J Chem Soc Perkin Trans 1 999 (1993)
Deprotection of Benzyl Esters viaMicrowave Thermolysis
A practical alternative to traditional catalytic hydrogenation
Varma et al Tetrahedron Lett 34 4603 (1993)
Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of
Carbonyl Compounds Using Microwaves
Varma Meshram Tetrahedron Lett 38 5427 (1997)
Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm
PersulfatendashClay using Microwave and Ultrasonic Irradiation
Varma Meshram Tetrahedron Lett 38 7973 (1997)
Solid Supported Solvent-freeOxidation under MW
Varma et al Tetrahedron Lett 1997 38 2043 and 7823
Solvent-free Reduction Using MW
Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction
Varma et al Tetrahedron Lett 1997 38 4337
Hydrodechlorination under continuous MW
Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)
Synthesis of Heterocyclic Compounds
Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)
Synthesis of Heterocyclic Compounds
Organometallic Reactions
Rearrangements
Rearrangements
INDOLIZINES
Heterocyclic systems 10- electronics
Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine
Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds
N
1
2
34567
8R2
R3
R1
Why interest for indolizinic products
Strong fluorescent properties luminiscent products luminiscent products
Potentially fluorescents marker Potentially laserldquoscintillatersrdquo
bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999
Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )
Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2
ldquoCalcium-entryrdquo blockers
Indolizines by irradiation with microwaves in MCR
RBr
O+
N
R1 R2+N
R2
R1
COR
AcOAl2O3 Mw
R=Ph p-Tolil Stiril
R1= H COOMeR2= COOEt COOMe
Asymmetric indolizines by irradiation with microwaves in MCR
R1
O
Cl+ R2
N NEtOOC
OOMe
Br BrN N
EtOOC
COR1
R2COR1
R2
OOMe
2 [Pd(PPh3)2Cl24 CuI
20 echiv Et3N THF tc 2h
R1=Ph 4-OMe-C6H4R2= Ph
U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003
A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new indolizines
[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical
II
IHH
COORCOOR
N C C
O
R2NCC
O
R1
(B)
(A)
R1
O
C C N R2
O
CCN
H H
ROOC COOR
R1
O
C C N R2
O
CCN
COOR COOR
ROOC COOR
2
2 ROOC C C COOR
R1
O
C CH N R2
O
CCHN
H H
N NCH CHC C
O O
R1 R2
- 2 HX TEAanhydrous solvents
X-
X-
N NCH2 CH2C C
O O
R1 R2
C C COORH
R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5
Y=H NO2 OCH3 CH3 Cl BrX=Br Cl
bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998
bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001
bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004
bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new substituted pyridinium-indolizines
Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate
COO NO2CHC
N NH3C
OR
I IN NH3C
OR
IN NH3C
OR
I
H
KFNMP
-HI
NMP
95oC 30 min
N NH3CO
RN NH3C
O
R
O OO
NO2
O
NO2
-2[H]-2[H]
II
I II
N NH3CO
R
O O
NO2
IN NH3C
O
R
O O
NO2
I
(9a-d)(10a-d)
(15a-d)
(A) (B)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
12
34
56
78 9
10
11
12 3
4
56
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
What is Green Chemistry
bull Green chemistry is the study of how to design chemical products and processes in ways that are sustainable and not harmful for humans and the environment
bull Three components catalysis solvents non-toxic
bull 12 principles of green chemistry
Green Chemistry Is About
Cost
Waste
Materials
Hazard
Risk
Energy
bull Chemistry is a very prominent part of our daily lives
bull Chemical developments also bring new environmental problems and harmful unexpected side effects which result in the need for lsquogreenerrsquo chemical products
bull A famous example is the pesticide DDT
Why do we need Green Chemistry
1 PreventionIt is better to prevent waste than to treat or clean up waste after it has been created
2 Atom EconomySynthetic methods should be designed to maximise the incorporation of all materialsused in the process into the final product
3 Less Hazardous Chemical SynthesisWherever practicable synthetic methods should be designed to use and generatesubstances that possess little or no toxicity to people or the environment
4 Designing Safer ChemicalsChemical products should be designed to effect their desired function while minimisingtheir toxicity
5 Safer Solvents and AuxiliariesThe use of auxiliary substances (eg solvents or separation agents) should be madeunnecessary whenever possible and innocuous when used
6 Design for Energy EfficiencyEnergy requirements of chemical processes should be recognised for their environmentaland economic impacts and should be minimised If possible synthetic methods should beconducted at ambient temperature and pressure
The 12 Principles of Green Chemistry (1-6)
The 12 Principles of Green Chemistry (7-12)
7 Use of Renewable FeedstocksA raw material or feedstock should be renewable rather than depleting whenever technically and economically practicable
8 Reduce DerivativesUnnecessary derivatization (use of blocking groups protectionde-protection and temporary modification of physicalchemical processes) should be minimised or avoided if possible because such steps require additional reagents and can generate waste
9 CatalysisCatalytic reagents (as selective as possible) are superior to stoichiometric reagents
10 Design for DegradationChemical products should be designed so that at the end of their function they break down into innocuous degradation products and do not persist in the environment
11 Real-time Analysis for Pollution PreventionAnalytical methodologies need to be further developed to allow for real-time in-process monitoring and control prior to the formation of hazardous substances
12 Inherently Safer Chemistry for Accident PreventionSubstances and the form of a substance used in a chemical process should be chosen to minimise the potential for chemical accidents including releases explosions and fires
What is ldquoGreenrdquoSustainable Kinder and gentler to people and the planet
Green Chemistry
The cost of usinghazardous materials
Conventional Heating vs Alternative Energy Source
Conventional Heating Bunsen burnerOil bathHeating mantleAlternative Energy SourcesMicrowaveUltrasoundSunlight UV Electonchemistry
Clean Chemical Synthesis UsingAlternative Reaction Methods
Alternative Energy SourcesMicrowaveUltrasoundSunlight UV
AlternativeReactionMediaSolvent-free Supercritical FluidsIonic LiquidsWaterPolyethylene glycol (PEG)Solvent free
Microwaves in Synthesis
bull While fire is now rarely used in synthetic chemistry it was not until Robert Bunsen invented the burner in 1855 that the energy from this heat source could be applied
bull There is some controversy about the origins of the microwave power cavity called the magnetron ndash the high-power generator of microwave power
The British were particularly forward-looking in deploying radar for air defense with a system called Chain Home which began operation in 1937
Originally operating at 22 MHz frequencies increased to 55 MHz 1921 was published by AW Hull the earliest description of the magnetron a
diode with a cylindrical anode1940 It was developed practically by Randall and Booth at the University of
Birmingham in England they verified their first microwave transmissions 500 W at 3 GHz
A prototype was brought to the United States in September of that year to define an agreement whereby United States industrial capability would undertake the development of microwave radar
1940 the Radiation Laboratory was established at the Massachusetts Institute of Technology to exploit microwave radar More than 40 types of tube would be produced particularly in the S-band (ie 300 MHz) The growth of microwave radar is linked with Raytheon Company and PL Spencer who found the key to mass production
History or how it all beganhellip
bull 1946 Dr Percy Spencer-the magnetron inventor he has found a variety of technical applications in the chemical and related industries since the 1950s in particular in the food-processing drying and polymer
bull surprisingly microwave heating has only been implemented in organic synthesis since the mid-1980s
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
History or how it all beganhellip
bull 1969 ldquo Carrying out chemical reactions using microwave energy rdquo JW Vanderhoff ndash Dow Chemical Company US 3432413
bull 1986 ldquoThe Use of Microwave Ovens for Rapid Organic Synthesisrdquo Gedye R N et alTetrahedron Lett 1986 27 279
bull 1986 ldquoApplication of Commercial Microwave Ovens to Organic Synthesisrdquo Giguere R J and Majetich G Tetrahedron Lett 1986 27 4945
Energy Use in ConventionalChemical Processes
Heating Stirring Piping
Transporting Cooling
Problem of Conventional Heating
You heat what you donrsquot want to heat
Solvents for reactions apparatus
heated up and cool it down
Double energy penalty without any
apparent ldquobenefitrdquo
Energy Consumptions
Three ways to get the reaction done but different energy bills to pay
Microwaves
bull MW reactors operate at 245 GHzbull Electric field oscillates at 49 x 109 timessec ndash
10oCsec heating rate
Electromagnetic Spectrum
Neas E Collins M Introduction to Microwave Sample Preparation Theory and Practice 1988 p 8
Schematic of a Microwave
E= electric fieldH= magnetic field= wavelength (122 cm for 2450 MHz)c= speed of light (300000 kms)
Microwaves Application in Heating Food
1946 Original patent (P L Spencer)1947 First commercial oven1955 Home models1967 Desktop model1975 US sales exceed gas ranges1976 60 of US households havemicrowave ovens
Spectrum Electromagnetic
bull Electric field component
bull Responsible for dielectric heating
bull Dipolar polarization
bull Conduction
bull Magnetic field component
Microwaves ndash Dipolar Rotationbull Polar molecules have intermolecular forces which give any motion of the
molecule some inertia
bull Under a very high frequency electric field the polar molecule will attempt to follow the field but intermolecular inertia stops any significant motion before the field has reversed and no net motion results
bull If the frequency of field oscillation is very low then the molecules will be polarized uniformly and no random motion results
bull In the intermediate case the frequency of the field will be such that the molecules will be almost but not quite able to keep in phase with the field polarity
bull In this case the random motion resulting as molecules jostle to attempt in vain to follow the field provides strong agitation and intense heating of the sample
bull At 245 GHz the field oscillates 49 x 109 timess which can lead to heating
rates of 10 degC per second when powerful waves are used
MW Heating Mechanism
Alternating electric field Withhigh frequency
NoconstraintContinuous electric field
Two mechanisms Dipolar rotation polarizationIonic Conduction mechanism
Microwave Dielectric HeatingMechanisms
Dipolar PolarizationMechanism
Conduction Mechanism
Dipolar molecules try toalign to an oscillating fieldby rotation
Ions in solution will moveby the applied electricfield
Mingos D M P et al Chem Soc Rev 1991 20 1 and 1998 27 213
Microwave vs Oil-bath Heating
J-S Schanche Mol Diversity 2003 7 293wwwpersonalchemistry-com wwwbiotagecom
Conventional Heating byConduction
ConductiveheatHeating byconvectioncurrentsSlow andenergyinefficientprocess
temperature on the outside surface isin excess of the boiling point of liquid
Direct Heating by MicrowaveIrradiation
bullSolventreagent absorbs MW energybull Vessel wall transparent to MWbullDirect in-core heatingbullInstant on-off
Inverted temperature gradients
Molecular Speeds
Molecular Speeds
Microwave Ovens
Cooking Chemistry Cooking Food
Household MW ovens
The Use of Microwave Ovens for Rapid Organic Synthesis R Gedye et al Tetrahedron Lett 1986 27 279
Publications on MW-AssistedOrganic Synthesis
7 Synthetic Journals JOrgChemOrgLettTetrahedron LettTetrahedron SynthCommun Synlett SynthesisAll Journals (Full Text) Dedicated instruments only (Anton Paar Biotage CEM Milestone Prolabo)
Industrial Chemical Applications of Microwave Heating
Food Processing+ Defrosting+ Drying roasting baking+ Pasteurization
Drying Industry+ Wood fibers textiles+ Pharmaceuticals+ Brick concrete walls
Polymer Chemistry+ Rubber curing vulcanization+ Polymerization
CeramicsMaterials+ Alumina sintering+ Welding smelting gluing
Plasma+ SemiconductorsWaste Remediation+ Sewage treatment
Analytical Chemistry+ Digestion+ Extraction+ Ashing
Biochemistry Pathology+ Protein hydrolysis+ PCR proteomics+ Tissue fixation+ Histoprocessing
Medical+ Diathermy tumor detection+ Blood warming+ Sterilization (Anthrax)+ Drying of catheters
Books on Microwave-Assisted Synthesis
1048707 Fundamentals of Microwave Application1048707 Alternative Laboratory MicrowaveInstruments1048707 Chemistry Applications1048707 Biochemistry Applications1048707 Laboratory Microwave Safety
Hayes B LCEM PublishingMatthews NC2002
(ACS Professional Reference Book) H M Kingston S J Haswell (eds)
Microwaves in Organic and Medicinal ChemistryKappe C O and Stadler AWiley-VCH Weinheim 2005 ISBN 3-527-31210-2410 pages ca 1000 references
Books on Microwave-Assisted Synthesis
Lidstoumlm PTierney J P(Eds)BlackwellScientific2005
Loupy Andre (Ed)Wiley-VCH Weinheim 2003 ISBN 3-527-30514-9523 pages 2000 refs
Book (2 volumes) Wiley-VCHA Loupy editSecond Edition(2006) 22 Chapters
Astra Zeneca ResearchFoundation Kavitha PrintersBangalore India 2002azrefiastrazenecacom
Practical Microwave Synthesis for Organic Chemists - Strategies Instruments and Protocols
Edition - 2009 X 310 Pages Hardcover Monograph
Books on Microwave-Assisted Synthesis
Microwave Ovens
Monomodal instrument
Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005
Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia
Multimodal instrument
+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile
Monomodal Vs Multimodal
Monomodal Vs Multimodal
Thermal Effects
bullMore efficient energetic coupling of solvent with microwaves
promotes higher rate of temperature increase
bull Inverted heat transfer volumetric
bull ldquoHot spotsrdquo in monomode microwaves
bull Selective on properties of material (solvents catalysts
reagents intermediates products susceptors)
Recent Applications of Microwave-Assisted Synthesis-MAOS
Hydrolysis of benzamide
thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)
The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions
R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958
Solvent-free Reactions or Solid-Solid Reactions
ldquoNo reaction proceeds without solventrdquo
Aristotle
Solventless syntheses
Green chemistry enabled advancement
Solvent-free Organic Synthesis
Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed
i n t o a p o w e r f u l m e t h o d o l o g y a s i t
reduces the amount of toxic waste produced and therefore becomes less harmful to the
e n v i r o n m e n t
Solvent-free Organic Synthesis
bull Clean and efficient synthesis
bull Economic and environmental impact
bull Fast reaction kinetics
Best solvent is no solvent
Adolf von Baeyer
Synthesis of Indigo
Towardsbenign
synthesiswith
remarkableVersatility
G W V Cave C LRaston J L ScottChemCommun
2001 2159
Solid-State General Oxidation with with Urea H2O2 Complex
R S Varma and K P Naiker Org Letters 1999 1 189
Solvent-free Oxidative Preparation of Heterocycles
Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157
Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones
Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199
Solvent-free Reduction
F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245
Carbon-Carbon Bond Formation
Toda Tanada Iwata J Org Chem 1989 54 3007
Solventless Photo Coupling and Photo Rearangements
Y Ito S Endo J Am Chem Soc 1997 119 5974
Shin Keating Maribay J Am Chem Soc 1996 118 7626
Solvent - Free Condensation
Z Gross et al Org Letters 1999 1 599
Solid-State Preparationof Dumb-bell-shaped C120
Wang Komatsu Murata Shiro Nature 1997 387 583
Advantages of Solid Mineral Supports(Alumina Silica and Clay)
Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area
The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity
Solids are generally easier and safer to handle than liquids or gaseous reagents
Inexpensive recyclable and environmentally benign nature
Solid-supported Solventless Reactions
bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation
R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43
Supported ReactionsUsing Microwaves
E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945
Microwave-Assisted Deacetylationon Alumina
Varma et al J Chem Soc Perkin Trans 1 999 (1993)
Deprotection of Benzyl Esters viaMicrowave Thermolysis
A practical alternative to traditional catalytic hydrogenation
Varma et al Tetrahedron Lett 34 4603 (1993)
Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of
Carbonyl Compounds Using Microwaves
Varma Meshram Tetrahedron Lett 38 5427 (1997)
Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm
PersulfatendashClay using Microwave and Ultrasonic Irradiation
Varma Meshram Tetrahedron Lett 38 7973 (1997)
Solid Supported Solvent-freeOxidation under MW
Varma et al Tetrahedron Lett 1997 38 2043 and 7823
Solvent-free Reduction Using MW
Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction
Varma et al Tetrahedron Lett 1997 38 4337
Hydrodechlorination under continuous MW
Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)
Synthesis of Heterocyclic Compounds
Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)
Synthesis of Heterocyclic Compounds
Organometallic Reactions
Rearrangements
Rearrangements
INDOLIZINES
Heterocyclic systems 10- electronics
Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine
Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds
N
1
2
34567
8R2
R3
R1
Why interest for indolizinic products
Strong fluorescent properties luminiscent products luminiscent products
Potentially fluorescents marker Potentially laserldquoscintillatersrdquo
bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999
Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )
Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2
ldquoCalcium-entryrdquo blockers
Indolizines by irradiation with microwaves in MCR
RBr
O+
N
R1 R2+N
R2
R1
COR
AcOAl2O3 Mw
R=Ph p-Tolil Stiril
R1= H COOMeR2= COOEt COOMe
Asymmetric indolizines by irradiation with microwaves in MCR
R1
O
Cl+ R2
N NEtOOC
OOMe
Br BrN N
EtOOC
COR1
R2COR1
R2
OOMe
2 [Pd(PPh3)2Cl24 CuI
20 echiv Et3N THF tc 2h
R1=Ph 4-OMe-C6H4R2= Ph
U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003
A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new indolizines
[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical
II
IHH
COORCOOR
N C C
O
R2NCC
O
R1
(B)
(A)
R1
O
C C N R2
O
CCN
H H
ROOC COOR
R1
O
C C N R2
O
CCN
COOR COOR
ROOC COOR
2
2 ROOC C C COOR
R1
O
C CH N R2
O
CCHN
H H
N NCH CHC C
O O
R1 R2
- 2 HX TEAanhydrous solvents
X-
X-
N NCH2 CH2C C
O O
R1 R2
C C COORH
R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5
Y=H NO2 OCH3 CH3 Cl BrX=Br Cl
bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998
bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001
bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004
bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new substituted pyridinium-indolizines
Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate
COO NO2CHC
N NH3C
OR
I IN NH3C
OR
IN NH3C
OR
I
H
KFNMP
-HI
NMP
95oC 30 min
N NH3CO
RN NH3C
O
R
O OO
NO2
O
NO2
-2[H]-2[H]
II
I II
N NH3CO
R
O O
NO2
IN NH3C
O
R
O O
NO2
I
(9a-d)(10a-d)
(15a-d)
(A) (B)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
12
34
56
78 9
10
11
12 3
4
56
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Green Chemistry Is About
Cost
Waste
Materials
Hazard
Risk
Energy
bull Chemistry is a very prominent part of our daily lives
bull Chemical developments also bring new environmental problems and harmful unexpected side effects which result in the need for lsquogreenerrsquo chemical products
bull A famous example is the pesticide DDT
Why do we need Green Chemistry
1 PreventionIt is better to prevent waste than to treat or clean up waste after it has been created
2 Atom EconomySynthetic methods should be designed to maximise the incorporation of all materialsused in the process into the final product
3 Less Hazardous Chemical SynthesisWherever practicable synthetic methods should be designed to use and generatesubstances that possess little or no toxicity to people or the environment
4 Designing Safer ChemicalsChemical products should be designed to effect their desired function while minimisingtheir toxicity
5 Safer Solvents and AuxiliariesThe use of auxiliary substances (eg solvents or separation agents) should be madeunnecessary whenever possible and innocuous when used
6 Design for Energy EfficiencyEnergy requirements of chemical processes should be recognised for their environmentaland economic impacts and should be minimised If possible synthetic methods should beconducted at ambient temperature and pressure
The 12 Principles of Green Chemistry (1-6)
The 12 Principles of Green Chemistry (7-12)
7 Use of Renewable FeedstocksA raw material or feedstock should be renewable rather than depleting whenever technically and economically practicable
8 Reduce DerivativesUnnecessary derivatization (use of blocking groups protectionde-protection and temporary modification of physicalchemical processes) should be minimised or avoided if possible because such steps require additional reagents and can generate waste
9 CatalysisCatalytic reagents (as selective as possible) are superior to stoichiometric reagents
10 Design for DegradationChemical products should be designed so that at the end of their function they break down into innocuous degradation products and do not persist in the environment
11 Real-time Analysis for Pollution PreventionAnalytical methodologies need to be further developed to allow for real-time in-process monitoring and control prior to the formation of hazardous substances
12 Inherently Safer Chemistry for Accident PreventionSubstances and the form of a substance used in a chemical process should be chosen to minimise the potential for chemical accidents including releases explosions and fires
What is ldquoGreenrdquoSustainable Kinder and gentler to people and the planet
Green Chemistry
The cost of usinghazardous materials
Conventional Heating vs Alternative Energy Source
Conventional Heating Bunsen burnerOil bathHeating mantleAlternative Energy SourcesMicrowaveUltrasoundSunlight UV Electonchemistry
Clean Chemical Synthesis UsingAlternative Reaction Methods
Alternative Energy SourcesMicrowaveUltrasoundSunlight UV
AlternativeReactionMediaSolvent-free Supercritical FluidsIonic LiquidsWaterPolyethylene glycol (PEG)Solvent free
Microwaves in Synthesis
bull While fire is now rarely used in synthetic chemistry it was not until Robert Bunsen invented the burner in 1855 that the energy from this heat source could be applied
bull There is some controversy about the origins of the microwave power cavity called the magnetron ndash the high-power generator of microwave power
The British were particularly forward-looking in deploying radar for air defense with a system called Chain Home which began operation in 1937
Originally operating at 22 MHz frequencies increased to 55 MHz 1921 was published by AW Hull the earliest description of the magnetron a
diode with a cylindrical anode1940 It was developed practically by Randall and Booth at the University of
Birmingham in England they verified their first microwave transmissions 500 W at 3 GHz
A prototype was brought to the United States in September of that year to define an agreement whereby United States industrial capability would undertake the development of microwave radar
1940 the Radiation Laboratory was established at the Massachusetts Institute of Technology to exploit microwave radar More than 40 types of tube would be produced particularly in the S-band (ie 300 MHz) The growth of microwave radar is linked with Raytheon Company and PL Spencer who found the key to mass production
History or how it all beganhellip
bull 1946 Dr Percy Spencer-the magnetron inventor he has found a variety of technical applications in the chemical and related industries since the 1950s in particular in the food-processing drying and polymer
bull surprisingly microwave heating has only been implemented in organic synthesis since the mid-1980s
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
History or how it all beganhellip
bull 1969 ldquo Carrying out chemical reactions using microwave energy rdquo JW Vanderhoff ndash Dow Chemical Company US 3432413
bull 1986 ldquoThe Use of Microwave Ovens for Rapid Organic Synthesisrdquo Gedye R N et alTetrahedron Lett 1986 27 279
bull 1986 ldquoApplication of Commercial Microwave Ovens to Organic Synthesisrdquo Giguere R J and Majetich G Tetrahedron Lett 1986 27 4945
Energy Use in ConventionalChemical Processes
Heating Stirring Piping
Transporting Cooling
Problem of Conventional Heating
You heat what you donrsquot want to heat
Solvents for reactions apparatus
heated up and cool it down
Double energy penalty without any
apparent ldquobenefitrdquo
Energy Consumptions
Three ways to get the reaction done but different energy bills to pay
Microwaves
bull MW reactors operate at 245 GHzbull Electric field oscillates at 49 x 109 timessec ndash
10oCsec heating rate
Electromagnetic Spectrum
Neas E Collins M Introduction to Microwave Sample Preparation Theory and Practice 1988 p 8
Schematic of a Microwave
E= electric fieldH= magnetic field= wavelength (122 cm for 2450 MHz)c= speed of light (300000 kms)
Microwaves Application in Heating Food
1946 Original patent (P L Spencer)1947 First commercial oven1955 Home models1967 Desktop model1975 US sales exceed gas ranges1976 60 of US households havemicrowave ovens
Spectrum Electromagnetic
bull Electric field component
bull Responsible for dielectric heating
bull Dipolar polarization
bull Conduction
bull Magnetic field component
Microwaves ndash Dipolar Rotationbull Polar molecules have intermolecular forces which give any motion of the
molecule some inertia
bull Under a very high frequency electric field the polar molecule will attempt to follow the field but intermolecular inertia stops any significant motion before the field has reversed and no net motion results
bull If the frequency of field oscillation is very low then the molecules will be polarized uniformly and no random motion results
bull In the intermediate case the frequency of the field will be such that the molecules will be almost but not quite able to keep in phase with the field polarity
bull In this case the random motion resulting as molecules jostle to attempt in vain to follow the field provides strong agitation and intense heating of the sample
bull At 245 GHz the field oscillates 49 x 109 timess which can lead to heating
rates of 10 degC per second when powerful waves are used
MW Heating Mechanism
Alternating electric field Withhigh frequency
NoconstraintContinuous electric field
Two mechanisms Dipolar rotation polarizationIonic Conduction mechanism
Microwave Dielectric HeatingMechanisms
Dipolar PolarizationMechanism
Conduction Mechanism
Dipolar molecules try toalign to an oscillating fieldby rotation
Ions in solution will moveby the applied electricfield
Mingos D M P et al Chem Soc Rev 1991 20 1 and 1998 27 213
Microwave vs Oil-bath Heating
J-S Schanche Mol Diversity 2003 7 293wwwpersonalchemistry-com wwwbiotagecom
Conventional Heating byConduction
ConductiveheatHeating byconvectioncurrentsSlow andenergyinefficientprocess
temperature on the outside surface isin excess of the boiling point of liquid
Direct Heating by MicrowaveIrradiation
bullSolventreagent absorbs MW energybull Vessel wall transparent to MWbullDirect in-core heatingbullInstant on-off
Inverted temperature gradients
Molecular Speeds
Molecular Speeds
Microwave Ovens
Cooking Chemistry Cooking Food
Household MW ovens
The Use of Microwave Ovens for Rapid Organic Synthesis R Gedye et al Tetrahedron Lett 1986 27 279
Publications on MW-AssistedOrganic Synthesis
7 Synthetic Journals JOrgChemOrgLettTetrahedron LettTetrahedron SynthCommun Synlett SynthesisAll Journals (Full Text) Dedicated instruments only (Anton Paar Biotage CEM Milestone Prolabo)
Industrial Chemical Applications of Microwave Heating
Food Processing+ Defrosting+ Drying roasting baking+ Pasteurization
Drying Industry+ Wood fibers textiles+ Pharmaceuticals+ Brick concrete walls
Polymer Chemistry+ Rubber curing vulcanization+ Polymerization
CeramicsMaterials+ Alumina sintering+ Welding smelting gluing
Plasma+ SemiconductorsWaste Remediation+ Sewage treatment
Analytical Chemistry+ Digestion+ Extraction+ Ashing
Biochemistry Pathology+ Protein hydrolysis+ PCR proteomics+ Tissue fixation+ Histoprocessing
Medical+ Diathermy tumor detection+ Blood warming+ Sterilization (Anthrax)+ Drying of catheters
Books on Microwave-Assisted Synthesis
1048707 Fundamentals of Microwave Application1048707 Alternative Laboratory MicrowaveInstruments1048707 Chemistry Applications1048707 Biochemistry Applications1048707 Laboratory Microwave Safety
Hayes B LCEM PublishingMatthews NC2002
(ACS Professional Reference Book) H M Kingston S J Haswell (eds)
Microwaves in Organic and Medicinal ChemistryKappe C O and Stadler AWiley-VCH Weinheim 2005 ISBN 3-527-31210-2410 pages ca 1000 references
Books on Microwave-Assisted Synthesis
Lidstoumlm PTierney J P(Eds)BlackwellScientific2005
Loupy Andre (Ed)Wiley-VCH Weinheim 2003 ISBN 3-527-30514-9523 pages 2000 refs
Book (2 volumes) Wiley-VCHA Loupy editSecond Edition(2006) 22 Chapters
Astra Zeneca ResearchFoundation Kavitha PrintersBangalore India 2002azrefiastrazenecacom
Practical Microwave Synthesis for Organic Chemists - Strategies Instruments and Protocols
Edition - 2009 X 310 Pages Hardcover Monograph
Books on Microwave-Assisted Synthesis
Microwave Ovens
Monomodal instrument
Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005
Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia
Multimodal instrument
+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile
Monomodal Vs Multimodal
Monomodal Vs Multimodal
Thermal Effects
bullMore efficient energetic coupling of solvent with microwaves
promotes higher rate of temperature increase
bull Inverted heat transfer volumetric
bull ldquoHot spotsrdquo in monomode microwaves
bull Selective on properties of material (solvents catalysts
reagents intermediates products susceptors)
Recent Applications of Microwave-Assisted Synthesis-MAOS
Hydrolysis of benzamide
thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)
The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions
R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958
Solvent-free Reactions or Solid-Solid Reactions
ldquoNo reaction proceeds without solventrdquo
Aristotle
Solventless syntheses
Green chemistry enabled advancement
Solvent-free Organic Synthesis
Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed
i n t o a p o w e r f u l m e t h o d o l o g y a s i t
reduces the amount of toxic waste produced and therefore becomes less harmful to the
e n v i r o n m e n t
Solvent-free Organic Synthesis
bull Clean and efficient synthesis
bull Economic and environmental impact
bull Fast reaction kinetics
Best solvent is no solvent
Adolf von Baeyer
Synthesis of Indigo
Towardsbenign
synthesiswith
remarkableVersatility
G W V Cave C LRaston J L ScottChemCommun
2001 2159
Solid-State General Oxidation with with Urea H2O2 Complex
R S Varma and K P Naiker Org Letters 1999 1 189
Solvent-free Oxidative Preparation of Heterocycles
Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157
Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones
Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199
Solvent-free Reduction
F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245
Carbon-Carbon Bond Formation
Toda Tanada Iwata J Org Chem 1989 54 3007
Solventless Photo Coupling and Photo Rearangements
Y Ito S Endo J Am Chem Soc 1997 119 5974
Shin Keating Maribay J Am Chem Soc 1996 118 7626
Solvent - Free Condensation
Z Gross et al Org Letters 1999 1 599
Solid-State Preparationof Dumb-bell-shaped C120
Wang Komatsu Murata Shiro Nature 1997 387 583
Advantages of Solid Mineral Supports(Alumina Silica and Clay)
Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area
The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity
Solids are generally easier and safer to handle than liquids or gaseous reagents
Inexpensive recyclable and environmentally benign nature
Solid-supported Solventless Reactions
bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation
R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43
Supported ReactionsUsing Microwaves
E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945
Microwave-Assisted Deacetylationon Alumina
Varma et al J Chem Soc Perkin Trans 1 999 (1993)
Deprotection of Benzyl Esters viaMicrowave Thermolysis
A practical alternative to traditional catalytic hydrogenation
Varma et al Tetrahedron Lett 34 4603 (1993)
Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of
Carbonyl Compounds Using Microwaves
Varma Meshram Tetrahedron Lett 38 5427 (1997)
Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm
PersulfatendashClay using Microwave and Ultrasonic Irradiation
Varma Meshram Tetrahedron Lett 38 7973 (1997)
Solid Supported Solvent-freeOxidation under MW
Varma et al Tetrahedron Lett 1997 38 2043 and 7823
Solvent-free Reduction Using MW
Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction
Varma et al Tetrahedron Lett 1997 38 4337
Hydrodechlorination under continuous MW
Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)
Synthesis of Heterocyclic Compounds
Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)
Synthesis of Heterocyclic Compounds
Organometallic Reactions
Rearrangements
Rearrangements
INDOLIZINES
Heterocyclic systems 10- electronics
Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine
Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds
N
1
2
34567
8R2
R3
R1
Why interest for indolizinic products
Strong fluorescent properties luminiscent products luminiscent products
Potentially fluorescents marker Potentially laserldquoscintillatersrdquo
bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999
Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )
Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2
ldquoCalcium-entryrdquo blockers
Indolizines by irradiation with microwaves in MCR
RBr
O+
N
R1 R2+N
R2
R1
COR
AcOAl2O3 Mw
R=Ph p-Tolil Stiril
R1= H COOMeR2= COOEt COOMe
Asymmetric indolizines by irradiation with microwaves in MCR
R1
O
Cl+ R2
N NEtOOC
OOMe
Br BrN N
EtOOC
COR1
R2COR1
R2
OOMe
2 [Pd(PPh3)2Cl24 CuI
20 echiv Et3N THF tc 2h
R1=Ph 4-OMe-C6H4R2= Ph
U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003
A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new indolizines
[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical
II
IHH
COORCOOR
N C C
O
R2NCC
O
R1
(B)
(A)
R1
O
C C N R2
O
CCN
H H
ROOC COOR
R1
O
C C N R2
O
CCN
COOR COOR
ROOC COOR
2
2 ROOC C C COOR
R1
O
C CH N R2
O
CCHN
H H
N NCH CHC C
O O
R1 R2
- 2 HX TEAanhydrous solvents
X-
X-
N NCH2 CH2C C
O O
R1 R2
C C COORH
R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5
Y=H NO2 OCH3 CH3 Cl BrX=Br Cl
bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998
bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001
bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004
bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new substituted pyridinium-indolizines
Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate
COO NO2CHC
N NH3C
OR
I IN NH3C
OR
IN NH3C
OR
I
H
KFNMP
-HI
NMP
95oC 30 min
N NH3CO
RN NH3C
O
R
O OO
NO2
O
NO2
-2[H]-2[H]
II
I II
N NH3CO
R
O O
NO2
IN NH3C
O
R
O O
NO2
I
(9a-d)(10a-d)
(15a-d)
(A) (B)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
12
34
56
78 9
10
11
12 3
4
56
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
bull Chemistry is a very prominent part of our daily lives
bull Chemical developments also bring new environmental problems and harmful unexpected side effects which result in the need for lsquogreenerrsquo chemical products
bull A famous example is the pesticide DDT
Why do we need Green Chemistry
1 PreventionIt is better to prevent waste than to treat or clean up waste after it has been created
2 Atom EconomySynthetic methods should be designed to maximise the incorporation of all materialsused in the process into the final product
3 Less Hazardous Chemical SynthesisWherever practicable synthetic methods should be designed to use and generatesubstances that possess little or no toxicity to people or the environment
4 Designing Safer ChemicalsChemical products should be designed to effect their desired function while minimisingtheir toxicity
5 Safer Solvents and AuxiliariesThe use of auxiliary substances (eg solvents or separation agents) should be madeunnecessary whenever possible and innocuous when used
6 Design for Energy EfficiencyEnergy requirements of chemical processes should be recognised for their environmentaland economic impacts and should be minimised If possible synthetic methods should beconducted at ambient temperature and pressure
The 12 Principles of Green Chemistry (1-6)
The 12 Principles of Green Chemistry (7-12)
7 Use of Renewable FeedstocksA raw material or feedstock should be renewable rather than depleting whenever technically and economically practicable
8 Reduce DerivativesUnnecessary derivatization (use of blocking groups protectionde-protection and temporary modification of physicalchemical processes) should be minimised or avoided if possible because such steps require additional reagents and can generate waste
9 CatalysisCatalytic reagents (as selective as possible) are superior to stoichiometric reagents
10 Design for DegradationChemical products should be designed so that at the end of their function they break down into innocuous degradation products and do not persist in the environment
11 Real-time Analysis for Pollution PreventionAnalytical methodologies need to be further developed to allow for real-time in-process monitoring and control prior to the formation of hazardous substances
12 Inherently Safer Chemistry for Accident PreventionSubstances and the form of a substance used in a chemical process should be chosen to minimise the potential for chemical accidents including releases explosions and fires
What is ldquoGreenrdquoSustainable Kinder and gentler to people and the planet
Green Chemistry
The cost of usinghazardous materials
Conventional Heating vs Alternative Energy Source
Conventional Heating Bunsen burnerOil bathHeating mantleAlternative Energy SourcesMicrowaveUltrasoundSunlight UV Electonchemistry
Clean Chemical Synthesis UsingAlternative Reaction Methods
Alternative Energy SourcesMicrowaveUltrasoundSunlight UV
AlternativeReactionMediaSolvent-free Supercritical FluidsIonic LiquidsWaterPolyethylene glycol (PEG)Solvent free
Microwaves in Synthesis
bull While fire is now rarely used in synthetic chemistry it was not until Robert Bunsen invented the burner in 1855 that the energy from this heat source could be applied
bull There is some controversy about the origins of the microwave power cavity called the magnetron ndash the high-power generator of microwave power
The British were particularly forward-looking in deploying radar for air defense with a system called Chain Home which began operation in 1937
Originally operating at 22 MHz frequencies increased to 55 MHz 1921 was published by AW Hull the earliest description of the magnetron a
diode with a cylindrical anode1940 It was developed practically by Randall and Booth at the University of
Birmingham in England they verified their first microwave transmissions 500 W at 3 GHz
A prototype was brought to the United States in September of that year to define an agreement whereby United States industrial capability would undertake the development of microwave radar
1940 the Radiation Laboratory was established at the Massachusetts Institute of Technology to exploit microwave radar More than 40 types of tube would be produced particularly in the S-band (ie 300 MHz) The growth of microwave radar is linked with Raytheon Company and PL Spencer who found the key to mass production
History or how it all beganhellip
bull 1946 Dr Percy Spencer-the magnetron inventor he has found a variety of technical applications in the chemical and related industries since the 1950s in particular in the food-processing drying and polymer
bull surprisingly microwave heating has only been implemented in organic synthesis since the mid-1980s
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
History or how it all beganhellip
bull 1969 ldquo Carrying out chemical reactions using microwave energy rdquo JW Vanderhoff ndash Dow Chemical Company US 3432413
bull 1986 ldquoThe Use of Microwave Ovens for Rapid Organic Synthesisrdquo Gedye R N et alTetrahedron Lett 1986 27 279
bull 1986 ldquoApplication of Commercial Microwave Ovens to Organic Synthesisrdquo Giguere R J and Majetich G Tetrahedron Lett 1986 27 4945
Energy Use in ConventionalChemical Processes
Heating Stirring Piping
Transporting Cooling
Problem of Conventional Heating
You heat what you donrsquot want to heat
Solvents for reactions apparatus
heated up and cool it down
Double energy penalty without any
apparent ldquobenefitrdquo
Energy Consumptions
Three ways to get the reaction done but different energy bills to pay
Microwaves
bull MW reactors operate at 245 GHzbull Electric field oscillates at 49 x 109 timessec ndash
10oCsec heating rate
Electromagnetic Spectrum
Neas E Collins M Introduction to Microwave Sample Preparation Theory and Practice 1988 p 8
Schematic of a Microwave
E= electric fieldH= magnetic field= wavelength (122 cm for 2450 MHz)c= speed of light (300000 kms)
Microwaves Application in Heating Food
1946 Original patent (P L Spencer)1947 First commercial oven1955 Home models1967 Desktop model1975 US sales exceed gas ranges1976 60 of US households havemicrowave ovens
Spectrum Electromagnetic
bull Electric field component
bull Responsible for dielectric heating
bull Dipolar polarization
bull Conduction
bull Magnetic field component
Microwaves ndash Dipolar Rotationbull Polar molecules have intermolecular forces which give any motion of the
molecule some inertia
bull Under a very high frequency electric field the polar molecule will attempt to follow the field but intermolecular inertia stops any significant motion before the field has reversed and no net motion results
bull If the frequency of field oscillation is very low then the molecules will be polarized uniformly and no random motion results
bull In the intermediate case the frequency of the field will be such that the molecules will be almost but not quite able to keep in phase with the field polarity
bull In this case the random motion resulting as molecules jostle to attempt in vain to follow the field provides strong agitation and intense heating of the sample
bull At 245 GHz the field oscillates 49 x 109 timess which can lead to heating
rates of 10 degC per second when powerful waves are used
MW Heating Mechanism
Alternating electric field Withhigh frequency
NoconstraintContinuous electric field
Two mechanisms Dipolar rotation polarizationIonic Conduction mechanism
Microwave Dielectric HeatingMechanisms
Dipolar PolarizationMechanism
Conduction Mechanism
Dipolar molecules try toalign to an oscillating fieldby rotation
Ions in solution will moveby the applied electricfield
Mingos D M P et al Chem Soc Rev 1991 20 1 and 1998 27 213
Microwave vs Oil-bath Heating
J-S Schanche Mol Diversity 2003 7 293wwwpersonalchemistry-com wwwbiotagecom
Conventional Heating byConduction
ConductiveheatHeating byconvectioncurrentsSlow andenergyinefficientprocess
temperature on the outside surface isin excess of the boiling point of liquid
Direct Heating by MicrowaveIrradiation
bullSolventreagent absorbs MW energybull Vessel wall transparent to MWbullDirect in-core heatingbullInstant on-off
Inverted temperature gradients
Molecular Speeds
Molecular Speeds
Microwave Ovens
Cooking Chemistry Cooking Food
Household MW ovens
The Use of Microwave Ovens for Rapid Organic Synthesis R Gedye et al Tetrahedron Lett 1986 27 279
Publications on MW-AssistedOrganic Synthesis
7 Synthetic Journals JOrgChemOrgLettTetrahedron LettTetrahedron SynthCommun Synlett SynthesisAll Journals (Full Text) Dedicated instruments only (Anton Paar Biotage CEM Milestone Prolabo)
Industrial Chemical Applications of Microwave Heating
Food Processing+ Defrosting+ Drying roasting baking+ Pasteurization
Drying Industry+ Wood fibers textiles+ Pharmaceuticals+ Brick concrete walls
Polymer Chemistry+ Rubber curing vulcanization+ Polymerization
CeramicsMaterials+ Alumina sintering+ Welding smelting gluing
Plasma+ SemiconductorsWaste Remediation+ Sewage treatment
Analytical Chemistry+ Digestion+ Extraction+ Ashing
Biochemistry Pathology+ Protein hydrolysis+ PCR proteomics+ Tissue fixation+ Histoprocessing
Medical+ Diathermy tumor detection+ Blood warming+ Sterilization (Anthrax)+ Drying of catheters
Books on Microwave-Assisted Synthesis
1048707 Fundamentals of Microwave Application1048707 Alternative Laboratory MicrowaveInstruments1048707 Chemistry Applications1048707 Biochemistry Applications1048707 Laboratory Microwave Safety
Hayes B LCEM PublishingMatthews NC2002
(ACS Professional Reference Book) H M Kingston S J Haswell (eds)
Microwaves in Organic and Medicinal ChemistryKappe C O and Stadler AWiley-VCH Weinheim 2005 ISBN 3-527-31210-2410 pages ca 1000 references
Books on Microwave-Assisted Synthesis
Lidstoumlm PTierney J P(Eds)BlackwellScientific2005
Loupy Andre (Ed)Wiley-VCH Weinheim 2003 ISBN 3-527-30514-9523 pages 2000 refs
Book (2 volumes) Wiley-VCHA Loupy editSecond Edition(2006) 22 Chapters
Astra Zeneca ResearchFoundation Kavitha PrintersBangalore India 2002azrefiastrazenecacom
Practical Microwave Synthesis for Organic Chemists - Strategies Instruments and Protocols
Edition - 2009 X 310 Pages Hardcover Monograph
Books on Microwave-Assisted Synthesis
Microwave Ovens
Monomodal instrument
Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005
Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia
Multimodal instrument
+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile
Monomodal Vs Multimodal
Monomodal Vs Multimodal
Thermal Effects
bullMore efficient energetic coupling of solvent with microwaves
promotes higher rate of temperature increase
bull Inverted heat transfer volumetric
bull ldquoHot spotsrdquo in monomode microwaves
bull Selective on properties of material (solvents catalysts
reagents intermediates products susceptors)
Recent Applications of Microwave-Assisted Synthesis-MAOS
Hydrolysis of benzamide
thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)
The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions
R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958
Solvent-free Reactions or Solid-Solid Reactions
ldquoNo reaction proceeds without solventrdquo
Aristotle
Solventless syntheses
Green chemistry enabled advancement
Solvent-free Organic Synthesis
Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed
i n t o a p o w e r f u l m e t h o d o l o g y a s i t
reduces the amount of toxic waste produced and therefore becomes less harmful to the
e n v i r o n m e n t
Solvent-free Organic Synthesis
bull Clean and efficient synthesis
bull Economic and environmental impact
bull Fast reaction kinetics
Best solvent is no solvent
Adolf von Baeyer
Synthesis of Indigo
Towardsbenign
synthesiswith
remarkableVersatility
G W V Cave C LRaston J L ScottChemCommun
2001 2159
Solid-State General Oxidation with with Urea H2O2 Complex
R S Varma and K P Naiker Org Letters 1999 1 189
Solvent-free Oxidative Preparation of Heterocycles
Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157
Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones
Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199
Solvent-free Reduction
F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245
Carbon-Carbon Bond Formation
Toda Tanada Iwata J Org Chem 1989 54 3007
Solventless Photo Coupling and Photo Rearangements
Y Ito S Endo J Am Chem Soc 1997 119 5974
Shin Keating Maribay J Am Chem Soc 1996 118 7626
Solvent - Free Condensation
Z Gross et al Org Letters 1999 1 599
Solid-State Preparationof Dumb-bell-shaped C120
Wang Komatsu Murata Shiro Nature 1997 387 583
Advantages of Solid Mineral Supports(Alumina Silica and Clay)
Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area
The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity
Solids are generally easier and safer to handle than liquids or gaseous reagents
Inexpensive recyclable and environmentally benign nature
Solid-supported Solventless Reactions
bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation
R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43
Supported ReactionsUsing Microwaves
E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945
Microwave-Assisted Deacetylationon Alumina
Varma et al J Chem Soc Perkin Trans 1 999 (1993)
Deprotection of Benzyl Esters viaMicrowave Thermolysis
A practical alternative to traditional catalytic hydrogenation
Varma et al Tetrahedron Lett 34 4603 (1993)
Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of
Carbonyl Compounds Using Microwaves
Varma Meshram Tetrahedron Lett 38 5427 (1997)
Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm
PersulfatendashClay using Microwave and Ultrasonic Irradiation
Varma Meshram Tetrahedron Lett 38 7973 (1997)
Solid Supported Solvent-freeOxidation under MW
Varma et al Tetrahedron Lett 1997 38 2043 and 7823
Solvent-free Reduction Using MW
Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction
Varma et al Tetrahedron Lett 1997 38 4337
Hydrodechlorination under continuous MW
Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)
Synthesis of Heterocyclic Compounds
Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)
Synthesis of Heterocyclic Compounds
Organometallic Reactions
Rearrangements
Rearrangements
INDOLIZINES
Heterocyclic systems 10- electronics
Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine
Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds
N
1
2
34567
8R2
R3
R1
Why interest for indolizinic products
Strong fluorescent properties luminiscent products luminiscent products
Potentially fluorescents marker Potentially laserldquoscintillatersrdquo
bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999
Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )
Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2
ldquoCalcium-entryrdquo blockers
Indolizines by irradiation with microwaves in MCR
RBr
O+
N
R1 R2+N
R2
R1
COR
AcOAl2O3 Mw
R=Ph p-Tolil Stiril
R1= H COOMeR2= COOEt COOMe
Asymmetric indolizines by irradiation with microwaves in MCR
R1
O
Cl+ R2
N NEtOOC
OOMe
Br BrN N
EtOOC
COR1
R2COR1
R2
OOMe
2 [Pd(PPh3)2Cl24 CuI
20 echiv Et3N THF tc 2h
R1=Ph 4-OMe-C6H4R2= Ph
U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003
A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new indolizines
[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical
II
IHH
COORCOOR
N C C
O
R2NCC
O
R1
(B)
(A)
R1
O
C C N R2
O
CCN
H H
ROOC COOR
R1
O
C C N R2
O
CCN
COOR COOR
ROOC COOR
2
2 ROOC C C COOR
R1
O
C CH N R2
O
CCHN
H H
N NCH CHC C
O O
R1 R2
- 2 HX TEAanhydrous solvents
X-
X-
N NCH2 CH2C C
O O
R1 R2
C C COORH
R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5
Y=H NO2 OCH3 CH3 Cl BrX=Br Cl
bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998
bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001
bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004
bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new substituted pyridinium-indolizines
Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate
COO NO2CHC
N NH3C
OR
I IN NH3C
OR
IN NH3C
OR
I
H
KFNMP
-HI
NMP
95oC 30 min
N NH3CO
RN NH3C
O
R
O OO
NO2
O
NO2
-2[H]-2[H]
II
I II
N NH3CO
R
O O
NO2
IN NH3C
O
R
O O
NO2
I
(9a-d)(10a-d)
(15a-d)
(A) (B)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
12
34
56
78 9
10
11
12 3
4
56
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
1 PreventionIt is better to prevent waste than to treat or clean up waste after it has been created
2 Atom EconomySynthetic methods should be designed to maximise the incorporation of all materialsused in the process into the final product
3 Less Hazardous Chemical SynthesisWherever practicable synthetic methods should be designed to use and generatesubstances that possess little or no toxicity to people or the environment
4 Designing Safer ChemicalsChemical products should be designed to effect their desired function while minimisingtheir toxicity
5 Safer Solvents and AuxiliariesThe use of auxiliary substances (eg solvents or separation agents) should be madeunnecessary whenever possible and innocuous when used
6 Design for Energy EfficiencyEnergy requirements of chemical processes should be recognised for their environmentaland economic impacts and should be minimised If possible synthetic methods should beconducted at ambient temperature and pressure
The 12 Principles of Green Chemistry (1-6)
The 12 Principles of Green Chemistry (7-12)
7 Use of Renewable FeedstocksA raw material or feedstock should be renewable rather than depleting whenever technically and economically practicable
8 Reduce DerivativesUnnecessary derivatization (use of blocking groups protectionde-protection and temporary modification of physicalchemical processes) should be minimised or avoided if possible because such steps require additional reagents and can generate waste
9 CatalysisCatalytic reagents (as selective as possible) are superior to stoichiometric reagents
10 Design for DegradationChemical products should be designed so that at the end of their function they break down into innocuous degradation products and do not persist in the environment
11 Real-time Analysis for Pollution PreventionAnalytical methodologies need to be further developed to allow for real-time in-process monitoring and control prior to the formation of hazardous substances
12 Inherently Safer Chemistry for Accident PreventionSubstances and the form of a substance used in a chemical process should be chosen to minimise the potential for chemical accidents including releases explosions and fires
What is ldquoGreenrdquoSustainable Kinder and gentler to people and the planet
Green Chemistry
The cost of usinghazardous materials
Conventional Heating vs Alternative Energy Source
Conventional Heating Bunsen burnerOil bathHeating mantleAlternative Energy SourcesMicrowaveUltrasoundSunlight UV Electonchemistry
Clean Chemical Synthesis UsingAlternative Reaction Methods
Alternative Energy SourcesMicrowaveUltrasoundSunlight UV
AlternativeReactionMediaSolvent-free Supercritical FluidsIonic LiquidsWaterPolyethylene glycol (PEG)Solvent free
Microwaves in Synthesis
bull While fire is now rarely used in synthetic chemistry it was not until Robert Bunsen invented the burner in 1855 that the energy from this heat source could be applied
bull There is some controversy about the origins of the microwave power cavity called the magnetron ndash the high-power generator of microwave power
The British were particularly forward-looking in deploying radar for air defense with a system called Chain Home which began operation in 1937
Originally operating at 22 MHz frequencies increased to 55 MHz 1921 was published by AW Hull the earliest description of the magnetron a
diode with a cylindrical anode1940 It was developed practically by Randall and Booth at the University of
Birmingham in England they verified their first microwave transmissions 500 W at 3 GHz
A prototype was brought to the United States in September of that year to define an agreement whereby United States industrial capability would undertake the development of microwave radar
1940 the Radiation Laboratory was established at the Massachusetts Institute of Technology to exploit microwave radar More than 40 types of tube would be produced particularly in the S-band (ie 300 MHz) The growth of microwave radar is linked with Raytheon Company and PL Spencer who found the key to mass production
History or how it all beganhellip
bull 1946 Dr Percy Spencer-the magnetron inventor he has found a variety of technical applications in the chemical and related industries since the 1950s in particular in the food-processing drying and polymer
bull surprisingly microwave heating has only been implemented in organic synthesis since the mid-1980s
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
History or how it all beganhellip
bull 1969 ldquo Carrying out chemical reactions using microwave energy rdquo JW Vanderhoff ndash Dow Chemical Company US 3432413
bull 1986 ldquoThe Use of Microwave Ovens for Rapid Organic Synthesisrdquo Gedye R N et alTetrahedron Lett 1986 27 279
bull 1986 ldquoApplication of Commercial Microwave Ovens to Organic Synthesisrdquo Giguere R J and Majetich G Tetrahedron Lett 1986 27 4945
Energy Use in ConventionalChemical Processes
Heating Stirring Piping
Transporting Cooling
Problem of Conventional Heating
You heat what you donrsquot want to heat
Solvents for reactions apparatus
heated up and cool it down
Double energy penalty without any
apparent ldquobenefitrdquo
Energy Consumptions
Three ways to get the reaction done but different energy bills to pay
Microwaves
bull MW reactors operate at 245 GHzbull Electric field oscillates at 49 x 109 timessec ndash
10oCsec heating rate
Electromagnetic Spectrum
Neas E Collins M Introduction to Microwave Sample Preparation Theory and Practice 1988 p 8
Schematic of a Microwave
E= electric fieldH= magnetic field= wavelength (122 cm for 2450 MHz)c= speed of light (300000 kms)
Microwaves Application in Heating Food
1946 Original patent (P L Spencer)1947 First commercial oven1955 Home models1967 Desktop model1975 US sales exceed gas ranges1976 60 of US households havemicrowave ovens
Spectrum Electromagnetic
bull Electric field component
bull Responsible for dielectric heating
bull Dipolar polarization
bull Conduction
bull Magnetic field component
Microwaves ndash Dipolar Rotationbull Polar molecules have intermolecular forces which give any motion of the
molecule some inertia
bull Under a very high frequency electric field the polar molecule will attempt to follow the field but intermolecular inertia stops any significant motion before the field has reversed and no net motion results
bull If the frequency of field oscillation is very low then the molecules will be polarized uniformly and no random motion results
bull In the intermediate case the frequency of the field will be such that the molecules will be almost but not quite able to keep in phase with the field polarity
bull In this case the random motion resulting as molecules jostle to attempt in vain to follow the field provides strong agitation and intense heating of the sample
bull At 245 GHz the field oscillates 49 x 109 timess which can lead to heating
rates of 10 degC per second when powerful waves are used
MW Heating Mechanism
Alternating electric field Withhigh frequency
NoconstraintContinuous electric field
Two mechanisms Dipolar rotation polarizationIonic Conduction mechanism
Microwave Dielectric HeatingMechanisms
Dipolar PolarizationMechanism
Conduction Mechanism
Dipolar molecules try toalign to an oscillating fieldby rotation
Ions in solution will moveby the applied electricfield
Mingos D M P et al Chem Soc Rev 1991 20 1 and 1998 27 213
Microwave vs Oil-bath Heating
J-S Schanche Mol Diversity 2003 7 293wwwpersonalchemistry-com wwwbiotagecom
Conventional Heating byConduction
ConductiveheatHeating byconvectioncurrentsSlow andenergyinefficientprocess
temperature on the outside surface isin excess of the boiling point of liquid
Direct Heating by MicrowaveIrradiation
bullSolventreagent absorbs MW energybull Vessel wall transparent to MWbullDirect in-core heatingbullInstant on-off
Inverted temperature gradients
Molecular Speeds
Molecular Speeds
Microwave Ovens
Cooking Chemistry Cooking Food
Household MW ovens
The Use of Microwave Ovens for Rapid Organic Synthesis R Gedye et al Tetrahedron Lett 1986 27 279
Publications on MW-AssistedOrganic Synthesis
7 Synthetic Journals JOrgChemOrgLettTetrahedron LettTetrahedron SynthCommun Synlett SynthesisAll Journals (Full Text) Dedicated instruments only (Anton Paar Biotage CEM Milestone Prolabo)
Industrial Chemical Applications of Microwave Heating
Food Processing+ Defrosting+ Drying roasting baking+ Pasteurization
Drying Industry+ Wood fibers textiles+ Pharmaceuticals+ Brick concrete walls
Polymer Chemistry+ Rubber curing vulcanization+ Polymerization
CeramicsMaterials+ Alumina sintering+ Welding smelting gluing
Plasma+ SemiconductorsWaste Remediation+ Sewage treatment
Analytical Chemistry+ Digestion+ Extraction+ Ashing
Biochemistry Pathology+ Protein hydrolysis+ PCR proteomics+ Tissue fixation+ Histoprocessing
Medical+ Diathermy tumor detection+ Blood warming+ Sterilization (Anthrax)+ Drying of catheters
Books on Microwave-Assisted Synthesis
1048707 Fundamentals of Microwave Application1048707 Alternative Laboratory MicrowaveInstruments1048707 Chemistry Applications1048707 Biochemistry Applications1048707 Laboratory Microwave Safety
Hayes B LCEM PublishingMatthews NC2002
(ACS Professional Reference Book) H M Kingston S J Haswell (eds)
Microwaves in Organic and Medicinal ChemistryKappe C O and Stadler AWiley-VCH Weinheim 2005 ISBN 3-527-31210-2410 pages ca 1000 references
Books on Microwave-Assisted Synthesis
Lidstoumlm PTierney J P(Eds)BlackwellScientific2005
Loupy Andre (Ed)Wiley-VCH Weinheim 2003 ISBN 3-527-30514-9523 pages 2000 refs
Book (2 volumes) Wiley-VCHA Loupy editSecond Edition(2006) 22 Chapters
Astra Zeneca ResearchFoundation Kavitha PrintersBangalore India 2002azrefiastrazenecacom
Practical Microwave Synthesis for Organic Chemists - Strategies Instruments and Protocols
Edition - 2009 X 310 Pages Hardcover Monograph
Books on Microwave-Assisted Synthesis
Microwave Ovens
Monomodal instrument
Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005
Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia
Multimodal instrument
+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile
Monomodal Vs Multimodal
Monomodal Vs Multimodal
Thermal Effects
bullMore efficient energetic coupling of solvent with microwaves
promotes higher rate of temperature increase
bull Inverted heat transfer volumetric
bull ldquoHot spotsrdquo in monomode microwaves
bull Selective on properties of material (solvents catalysts
reagents intermediates products susceptors)
Recent Applications of Microwave-Assisted Synthesis-MAOS
Hydrolysis of benzamide
thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)
The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions
R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958
Solvent-free Reactions or Solid-Solid Reactions
ldquoNo reaction proceeds without solventrdquo
Aristotle
Solventless syntheses
Green chemistry enabled advancement
Solvent-free Organic Synthesis
Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed
i n t o a p o w e r f u l m e t h o d o l o g y a s i t
reduces the amount of toxic waste produced and therefore becomes less harmful to the
e n v i r o n m e n t
Solvent-free Organic Synthesis
bull Clean and efficient synthesis
bull Economic and environmental impact
bull Fast reaction kinetics
Best solvent is no solvent
Adolf von Baeyer
Synthesis of Indigo
Towardsbenign
synthesiswith
remarkableVersatility
G W V Cave C LRaston J L ScottChemCommun
2001 2159
Solid-State General Oxidation with with Urea H2O2 Complex
R S Varma and K P Naiker Org Letters 1999 1 189
Solvent-free Oxidative Preparation of Heterocycles
Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157
Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones
Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199
Solvent-free Reduction
F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245
Carbon-Carbon Bond Formation
Toda Tanada Iwata J Org Chem 1989 54 3007
Solventless Photo Coupling and Photo Rearangements
Y Ito S Endo J Am Chem Soc 1997 119 5974
Shin Keating Maribay J Am Chem Soc 1996 118 7626
Solvent - Free Condensation
Z Gross et al Org Letters 1999 1 599
Solid-State Preparationof Dumb-bell-shaped C120
Wang Komatsu Murata Shiro Nature 1997 387 583
Advantages of Solid Mineral Supports(Alumina Silica and Clay)
Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area
The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity
Solids are generally easier and safer to handle than liquids or gaseous reagents
Inexpensive recyclable and environmentally benign nature
Solid-supported Solventless Reactions
bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation
R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43
Supported ReactionsUsing Microwaves
E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945
Microwave-Assisted Deacetylationon Alumina
Varma et al J Chem Soc Perkin Trans 1 999 (1993)
Deprotection of Benzyl Esters viaMicrowave Thermolysis
A practical alternative to traditional catalytic hydrogenation
Varma et al Tetrahedron Lett 34 4603 (1993)
Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of
Carbonyl Compounds Using Microwaves
Varma Meshram Tetrahedron Lett 38 5427 (1997)
Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm
PersulfatendashClay using Microwave and Ultrasonic Irradiation
Varma Meshram Tetrahedron Lett 38 7973 (1997)
Solid Supported Solvent-freeOxidation under MW
Varma et al Tetrahedron Lett 1997 38 2043 and 7823
Solvent-free Reduction Using MW
Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction
Varma et al Tetrahedron Lett 1997 38 4337
Hydrodechlorination under continuous MW
Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)
Synthesis of Heterocyclic Compounds
Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)
Synthesis of Heterocyclic Compounds
Organometallic Reactions
Rearrangements
Rearrangements
INDOLIZINES
Heterocyclic systems 10- electronics
Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine
Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds
N
1
2
34567
8R2
R3
R1
Why interest for indolizinic products
Strong fluorescent properties luminiscent products luminiscent products
Potentially fluorescents marker Potentially laserldquoscintillatersrdquo
bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999
Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )
Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2
ldquoCalcium-entryrdquo blockers
Indolizines by irradiation with microwaves in MCR
RBr
O+
N
R1 R2+N
R2
R1
COR
AcOAl2O3 Mw
R=Ph p-Tolil Stiril
R1= H COOMeR2= COOEt COOMe
Asymmetric indolizines by irradiation with microwaves in MCR
R1
O
Cl+ R2
N NEtOOC
OOMe
Br BrN N
EtOOC
COR1
R2COR1
R2
OOMe
2 [Pd(PPh3)2Cl24 CuI
20 echiv Et3N THF tc 2h
R1=Ph 4-OMe-C6H4R2= Ph
U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003
A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new indolizines
[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical
II
IHH
COORCOOR
N C C
O
R2NCC
O
R1
(B)
(A)
R1
O
C C N R2
O
CCN
H H
ROOC COOR
R1
O
C C N R2
O
CCN
COOR COOR
ROOC COOR
2
2 ROOC C C COOR
R1
O
C CH N R2
O
CCHN
H H
N NCH CHC C
O O
R1 R2
- 2 HX TEAanhydrous solvents
X-
X-
N NCH2 CH2C C
O O
R1 R2
C C COORH
R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5
Y=H NO2 OCH3 CH3 Cl BrX=Br Cl
bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998
bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001
bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004
bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new substituted pyridinium-indolizines
Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate
COO NO2CHC
N NH3C
OR
I IN NH3C
OR
IN NH3C
OR
I
H
KFNMP
-HI
NMP
95oC 30 min
N NH3CO
RN NH3C
O
R
O OO
NO2
O
NO2
-2[H]-2[H]
II
I II
N NH3CO
R
O O
NO2
IN NH3C
O
R
O O
NO2
I
(9a-d)(10a-d)
(15a-d)
(A) (B)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
12
34
56
78 9
10
11
12 3
4
56
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
The 12 Principles of Green Chemistry (7-12)
7 Use of Renewable FeedstocksA raw material or feedstock should be renewable rather than depleting whenever technically and economically practicable
8 Reduce DerivativesUnnecessary derivatization (use of blocking groups protectionde-protection and temporary modification of physicalchemical processes) should be minimised or avoided if possible because such steps require additional reagents and can generate waste
9 CatalysisCatalytic reagents (as selective as possible) are superior to stoichiometric reagents
10 Design for DegradationChemical products should be designed so that at the end of their function they break down into innocuous degradation products and do not persist in the environment
11 Real-time Analysis for Pollution PreventionAnalytical methodologies need to be further developed to allow for real-time in-process monitoring and control prior to the formation of hazardous substances
12 Inherently Safer Chemistry for Accident PreventionSubstances and the form of a substance used in a chemical process should be chosen to minimise the potential for chemical accidents including releases explosions and fires
What is ldquoGreenrdquoSustainable Kinder and gentler to people and the planet
Green Chemistry
The cost of usinghazardous materials
Conventional Heating vs Alternative Energy Source
Conventional Heating Bunsen burnerOil bathHeating mantleAlternative Energy SourcesMicrowaveUltrasoundSunlight UV Electonchemistry
Clean Chemical Synthesis UsingAlternative Reaction Methods
Alternative Energy SourcesMicrowaveUltrasoundSunlight UV
AlternativeReactionMediaSolvent-free Supercritical FluidsIonic LiquidsWaterPolyethylene glycol (PEG)Solvent free
Microwaves in Synthesis
bull While fire is now rarely used in synthetic chemistry it was not until Robert Bunsen invented the burner in 1855 that the energy from this heat source could be applied
bull There is some controversy about the origins of the microwave power cavity called the magnetron ndash the high-power generator of microwave power
The British were particularly forward-looking in deploying radar for air defense with a system called Chain Home which began operation in 1937
Originally operating at 22 MHz frequencies increased to 55 MHz 1921 was published by AW Hull the earliest description of the magnetron a
diode with a cylindrical anode1940 It was developed practically by Randall and Booth at the University of
Birmingham in England they verified their first microwave transmissions 500 W at 3 GHz
A prototype was brought to the United States in September of that year to define an agreement whereby United States industrial capability would undertake the development of microwave radar
1940 the Radiation Laboratory was established at the Massachusetts Institute of Technology to exploit microwave radar More than 40 types of tube would be produced particularly in the S-band (ie 300 MHz) The growth of microwave radar is linked with Raytheon Company and PL Spencer who found the key to mass production
History or how it all beganhellip
bull 1946 Dr Percy Spencer-the magnetron inventor he has found a variety of technical applications in the chemical and related industries since the 1950s in particular in the food-processing drying and polymer
bull surprisingly microwave heating has only been implemented in organic synthesis since the mid-1980s
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
History or how it all beganhellip
bull 1969 ldquo Carrying out chemical reactions using microwave energy rdquo JW Vanderhoff ndash Dow Chemical Company US 3432413
bull 1986 ldquoThe Use of Microwave Ovens for Rapid Organic Synthesisrdquo Gedye R N et alTetrahedron Lett 1986 27 279
bull 1986 ldquoApplication of Commercial Microwave Ovens to Organic Synthesisrdquo Giguere R J and Majetich G Tetrahedron Lett 1986 27 4945
Energy Use in ConventionalChemical Processes
Heating Stirring Piping
Transporting Cooling
Problem of Conventional Heating
You heat what you donrsquot want to heat
Solvents for reactions apparatus
heated up and cool it down
Double energy penalty without any
apparent ldquobenefitrdquo
Energy Consumptions
Three ways to get the reaction done but different energy bills to pay
Microwaves
bull MW reactors operate at 245 GHzbull Electric field oscillates at 49 x 109 timessec ndash
10oCsec heating rate
Electromagnetic Spectrum
Neas E Collins M Introduction to Microwave Sample Preparation Theory and Practice 1988 p 8
Schematic of a Microwave
E= electric fieldH= magnetic field= wavelength (122 cm for 2450 MHz)c= speed of light (300000 kms)
Microwaves Application in Heating Food
1946 Original patent (P L Spencer)1947 First commercial oven1955 Home models1967 Desktop model1975 US sales exceed gas ranges1976 60 of US households havemicrowave ovens
Spectrum Electromagnetic
bull Electric field component
bull Responsible for dielectric heating
bull Dipolar polarization
bull Conduction
bull Magnetic field component
Microwaves ndash Dipolar Rotationbull Polar molecules have intermolecular forces which give any motion of the
molecule some inertia
bull Under a very high frequency electric field the polar molecule will attempt to follow the field but intermolecular inertia stops any significant motion before the field has reversed and no net motion results
bull If the frequency of field oscillation is very low then the molecules will be polarized uniformly and no random motion results
bull In the intermediate case the frequency of the field will be such that the molecules will be almost but not quite able to keep in phase with the field polarity
bull In this case the random motion resulting as molecules jostle to attempt in vain to follow the field provides strong agitation and intense heating of the sample
bull At 245 GHz the field oscillates 49 x 109 timess which can lead to heating
rates of 10 degC per second when powerful waves are used
MW Heating Mechanism
Alternating electric field Withhigh frequency
NoconstraintContinuous electric field
Two mechanisms Dipolar rotation polarizationIonic Conduction mechanism
Microwave Dielectric HeatingMechanisms
Dipolar PolarizationMechanism
Conduction Mechanism
Dipolar molecules try toalign to an oscillating fieldby rotation
Ions in solution will moveby the applied electricfield
Mingos D M P et al Chem Soc Rev 1991 20 1 and 1998 27 213
Microwave vs Oil-bath Heating
J-S Schanche Mol Diversity 2003 7 293wwwpersonalchemistry-com wwwbiotagecom
Conventional Heating byConduction
ConductiveheatHeating byconvectioncurrentsSlow andenergyinefficientprocess
temperature on the outside surface isin excess of the boiling point of liquid
Direct Heating by MicrowaveIrradiation
bullSolventreagent absorbs MW energybull Vessel wall transparent to MWbullDirect in-core heatingbullInstant on-off
Inverted temperature gradients
Molecular Speeds
Molecular Speeds
Microwave Ovens
Cooking Chemistry Cooking Food
Household MW ovens
The Use of Microwave Ovens for Rapid Organic Synthesis R Gedye et al Tetrahedron Lett 1986 27 279
Publications on MW-AssistedOrganic Synthesis
7 Synthetic Journals JOrgChemOrgLettTetrahedron LettTetrahedron SynthCommun Synlett SynthesisAll Journals (Full Text) Dedicated instruments only (Anton Paar Biotage CEM Milestone Prolabo)
Industrial Chemical Applications of Microwave Heating
Food Processing+ Defrosting+ Drying roasting baking+ Pasteurization
Drying Industry+ Wood fibers textiles+ Pharmaceuticals+ Brick concrete walls
Polymer Chemistry+ Rubber curing vulcanization+ Polymerization
CeramicsMaterials+ Alumina sintering+ Welding smelting gluing
Plasma+ SemiconductorsWaste Remediation+ Sewage treatment
Analytical Chemistry+ Digestion+ Extraction+ Ashing
Biochemistry Pathology+ Protein hydrolysis+ PCR proteomics+ Tissue fixation+ Histoprocessing
Medical+ Diathermy tumor detection+ Blood warming+ Sterilization (Anthrax)+ Drying of catheters
Books on Microwave-Assisted Synthesis
1048707 Fundamentals of Microwave Application1048707 Alternative Laboratory MicrowaveInstruments1048707 Chemistry Applications1048707 Biochemistry Applications1048707 Laboratory Microwave Safety
Hayes B LCEM PublishingMatthews NC2002
(ACS Professional Reference Book) H M Kingston S J Haswell (eds)
Microwaves in Organic and Medicinal ChemistryKappe C O and Stadler AWiley-VCH Weinheim 2005 ISBN 3-527-31210-2410 pages ca 1000 references
Books on Microwave-Assisted Synthesis
Lidstoumlm PTierney J P(Eds)BlackwellScientific2005
Loupy Andre (Ed)Wiley-VCH Weinheim 2003 ISBN 3-527-30514-9523 pages 2000 refs
Book (2 volumes) Wiley-VCHA Loupy editSecond Edition(2006) 22 Chapters
Astra Zeneca ResearchFoundation Kavitha PrintersBangalore India 2002azrefiastrazenecacom
Practical Microwave Synthesis for Organic Chemists - Strategies Instruments and Protocols
Edition - 2009 X 310 Pages Hardcover Monograph
Books on Microwave-Assisted Synthesis
Microwave Ovens
Monomodal instrument
Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005
Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia
Multimodal instrument
+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile
Monomodal Vs Multimodal
Monomodal Vs Multimodal
Thermal Effects
bullMore efficient energetic coupling of solvent with microwaves
promotes higher rate of temperature increase
bull Inverted heat transfer volumetric
bull ldquoHot spotsrdquo in monomode microwaves
bull Selective on properties of material (solvents catalysts
reagents intermediates products susceptors)
Recent Applications of Microwave-Assisted Synthesis-MAOS
Hydrolysis of benzamide
thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)
The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions
R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958
Solvent-free Reactions or Solid-Solid Reactions
ldquoNo reaction proceeds without solventrdquo
Aristotle
Solventless syntheses
Green chemistry enabled advancement
Solvent-free Organic Synthesis
Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed
i n t o a p o w e r f u l m e t h o d o l o g y a s i t
reduces the amount of toxic waste produced and therefore becomes less harmful to the
e n v i r o n m e n t
Solvent-free Organic Synthesis
bull Clean and efficient synthesis
bull Economic and environmental impact
bull Fast reaction kinetics
Best solvent is no solvent
Adolf von Baeyer
Synthesis of Indigo
Towardsbenign
synthesiswith
remarkableVersatility
G W V Cave C LRaston J L ScottChemCommun
2001 2159
Solid-State General Oxidation with with Urea H2O2 Complex
R S Varma and K P Naiker Org Letters 1999 1 189
Solvent-free Oxidative Preparation of Heterocycles
Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157
Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones
Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199
Solvent-free Reduction
F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245
Carbon-Carbon Bond Formation
Toda Tanada Iwata J Org Chem 1989 54 3007
Solventless Photo Coupling and Photo Rearangements
Y Ito S Endo J Am Chem Soc 1997 119 5974
Shin Keating Maribay J Am Chem Soc 1996 118 7626
Solvent - Free Condensation
Z Gross et al Org Letters 1999 1 599
Solid-State Preparationof Dumb-bell-shaped C120
Wang Komatsu Murata Shiro Nature 1997 387 583
Advantages of Solid Mineral Supports(Alumina Silica and Clay)
Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area
The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity
Solids are generally easier and safer to handle than liquids or gaseous reagents
Inexpensive recyclable and environmentally benign nature
Solid-supported Solventless Reactions
bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation
R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43
Supported ReactionsUsing Microwaves
E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945
Microwave-Assisted Deacetylationon Alumina
Varma et al J Chem Soc Perkin Trans 1 999 (1993)
Deprotection of Benzyl Esters viaMicrowave Thermolysis
A practical alternative to traditional catalytic hydrogenation
Varma et al Tetrahedron Lett 34 4603 (1993)
Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of
Carbonyl Compounds Using Microwaves
Varma Meshram Tetrahedron Lett 38 5427 (1997)
Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm
PersulfatendashClay using Microwave and Ultrasonic Irradiation
Varma Meshram Tetrahedron Lett 38 7973 (1997)
Solid Supported Solvent-freeOxidation under MW
Varma et al Tetrahedron Lett 1997 38 2043 and 7823
Solvent-free Reduction Using MW
Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction
Varma et al Tetrahedron Lett 1997 38 4337
Hydrodechlorination under continuous MW
Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)
Synthesis of Heterocyclic Compounds
Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)
Synthesis of Heterocyclic Compounds
Organometallic Reactions
Rearrangements
Rearrangements
INDOLIZINES
Heterocyclic systems 10- electronics
Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine
Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds
N
1
2
34567
8R2
R3
R1
Why interest for indolizinic products
Strong fluorescent properties luminiscent products luminiscent products
Potentially fluorescents marker Potentially laserldquoscintillatersrdquo
bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999
Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )
Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2
ldquoCalcium-entryrdquo blockers
Indolizines by irradiation with microwaves in MCR
RBr
O+
N
R1 R2+N
R2
R1
COR
AcOAl2O3 Mw
R=Ph p-Tolil Stiril
R1= H COOMeR2= COOEt COOMe
Asymmetric indolizines by irradiation with microwaves in MCR
R1
O
Cl+ R2
N NEtOOC
OOMe
Br BrN N
EtOOC
COR1
R2COR1
R2
OOMe
2 [Pd(PPh3)2Cl24 CuI
20 echiv Et3N THF tc 2h
R1=Ph 4-OMe-C6H4R2= Ph
U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003
A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new indolizines
[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical
II
IHH
COORCOOR
N C C
O
R2NCC
O
R1
(B)
(A)
R1
O
C C N R2
O
CCN
H H
ROOC COOR
R1
O
C C N R2
O
CCN
COOR COOR
ROOC COOR
2
2 ROOC C C COOR
R1
O
C CH N R2
O
CCHN
H H
N NCH CHC C
O O
R1 R2
- 2 HX TEAanhydrous solvents
X-
X-
N NCH2 CH2C C
O O
R1 R2
C C COORH
R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5
Y=H NO2 OCH3 CH3 Cl BrX=Br Cl
bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998
bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001
bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004
bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new substituted pyridinium-indolizines
Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate
COO NO2CHC
N NH3C
OR
I IN NH3C
OR
IN NH3C
OR
I
H
KFNMP
-HI
NMP
95oC 30 min
N NH3CO
RN NH3C
O
R
O OO
NO2
O
NO2
-2[H]-2[H]
II
I II
N NH3CO
R
O O
NO2
IN NH3C
O
R
O O
NO2
I
(9a-d)(10a-d)
(15a-d)
(A) (B)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
12
34
56
78 9
10
11
12 3
4
56
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
What is ldquoGreenrdquoSustainable Kinder and gentler to people and the planet
Green Chemistry
The cost of usinghazardous materials
Conventional Heating vs Alternative Energy Source
Conventional Heating Bunsen burnerOil bathHeating mantleAlternative Energy SourcesMicrowaveUltrasoundSunlight UV Electonchemistry
Clean Chemical Synthesis UsingAlternative Reaction Methods
Alternative Energy SourcesMicrowaveUltrasoundSunlight UV
AlternativeReactionMediaSolvent-free Supercritical FluidsIonic LiquidsWaterPolyethylene glycol (PEG)Solvent free
Microwaves in Synthesis
bull While fire is now rarely used in synthetic chemistry it was not until Robert Bunsen invented the burner in 1855 that the energy from this heat source could be applied
bull There is some controversy about the origins of the microwave power cavity called the magnetron ndash the high-power generator of microwave power
The British were particularly forward-looking in deploying radar for air defense with a system called Chain Home which began operation in 1937
Originally operating at 22 MHz frequencies increased to 55 MHz 1921 was published by AW Hull the earliest description of the magnetron a
diode with a cylindrical anode1940 It was developed practically by Randall and Booth at the University of
Birmingham in England they verified their first microwave transmissions 500 W at 3 GHz
A prototype was brought to the United States in September of that year to define an agreement whereby United States industrial capability would undertake the development of microwave radar
1940 the Radiation Laboratory was established at the Massachusetts Institute of Technology to exploit microwave radar More than 40 types of tube would be produced particularly in the S-band (ie 300 MHz) The growth of microwave radar is linked with Raytheon Company and PL Spencer who found the key to mass production
History or how it all beganhellip
bull 1946 Dr Percy Spencer-the magnetron inventor he has found a variety of technical applications in the chemical and related industries since the 1950s in particular in the food-processing drying and polymer
bull surprisingly microwave heating has only been implemented in organic synthesis since the mid-1980s
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
History or how it all beganhellip
bull 1969 ldquo Carrying out chemical reactions using microwave energy rdquo JW Vanderhoff ndash Dow Chemical Company US 3432413
bull 1986 ldquoThe Use of Microwave Ovens for Rapid Organic Synthesisrdquo Gedye R N et alTetrahedron Lett 1986 27 279
bull 1986 ldquoApplication of Commercial Microwave Ovens to Organic Synthesisrdquo Giguere R J and Majetich G Tetrahedron Lett 1986 27 4945
Energy Use in ConventionalChemical Processes
Heating Stirring Piping
Transporting Cooling
Problem of Conventional Heating
You heat what you donrsquot want to heat
Solvents for reactions apparatus
heated up and cool it down
Double energy penalty without any
apparent ldquobenefitrdquo
Energy Consumptions
Three ways to get the reaction done but different energy bills to pay
Microwaves
bull MW reactors operate at 245 GHzbull Electric field oscillates at 49 x 109 timessec ndash
10oCsec heating rate
Electromagnetic Spectrum
Neas E Collins M Introduction to Microwave Sample Preparation Theory and Practice 1988 p 8
Schematic of a Microwave
E= electric fieldH= magnetic field= wavelength (122 cm for 2450 MHz)c= speed of light (300000 kms)
Microwaves Application in Heating Food
1946 Original patent (P L Spencer)1947 First commercial oven1955 Home models1967 Desktop model1975 US sales exceed gas ranges1976 60 of US households havemicrowave ovens
Spectrum Electromagnetic
bull Electric field component
bull Responsible for dielectric heating
bull Dipolar polarization
bull Conduction
bull Magnetic field component
Microwaves ndash Dipolar Rotationbull Polar molecules have intermolecular forces which give any motion of the
molecule some inertia
bull Under a very high frequency electric field the polar molecule will attempt to follow the field but intermolecular inertia stops any significant motion before the field has reversed and no net motion results
bull If the frequency of field oscillation is very low then the molecules will be polarized uniformly and no random motion results
bull In the intermediate case the frequency of the field will be such that the molecules will be almost but not quite able to keep in phase with the field polarity
bull In this case the random motion resulting as molecules jostle to attempt in vain to follow the field provides strong agitation and intense heating of the sample
bull At 245 GHz the field oscillates 49 x 109 timess which can lead to heating
rates of 10 degC per second when powerful waves are used
MW Heating Mechanism
Alternating electric field Withhigh frequency
NoconstraintContinuous electric field
Two mechanisms Dipolar rotation polarizationIonic Conduction mechanism
Microwave Dielectric HeatingMechanisms
Dipolar PolarizationMechanism
Conduction Mechanism
Dipolar molecules try toalign to an oscillating fieldby rotation
Ions in solution will moveby the applied electricfield
Mingos D M P et al Chem Soc Rev 1991 20 1 and 1998 27 213
Microwave vs Oil-bath Heating
J-S Schanche Mol Diversity 2003 7 293wwwpersonalchemistry-com wwwbiotagecom
Conventional Heating byConduction
ConductiveheatHeating byconvectioncurrentsSlow andenergyinefficientprocess
temperature on the outside surface isin excess of the boiling point of liquid
Direct Heating by MicrowaveIrradiation
bullSolventreagent absorbs MW energybull Vessel wall transparent to MWbullDirect in-core heatingbullInstant on-off
Inverted temperature gradients
Molecular Speeds
Molecular Speeds
Microwave Ovens
Cooking Chemistry Cooking Food
Household MW ovens
The Use of Microwave Ovens for Rapid Organic Synthesis R Gedye et al Tetrahedron Lett 1986 27 279
Publications on MW-AssistedOrganic Synthesis
7 Synthetic Journals JOrgChemOrgLettTetrahedron LettTetrahedron SynthCommun Synlett SynthesisAll Journals (Full Text) Dedicated instruments only (Anton Paar Biotage CEM Milestone Prolabo)
Industrial Chemical Applications of Microwave Heating
Food Processing+ Defrosting+ Drying roasting baking+ Pasteurization
Drying Industry+ Wood fibers textiles+ Pharmaceuticals+ Brick concrete walls
Polymer Chemistry+ Rubber curing vulcanization+ Polymerization
CeramicsMaterials+ Alumina sintering+ Welding smelting gluing
Plasma+ SemiconductorsWaste Remediation+ Sewage treatment
Analytical Chemistry+ Digestion+ Extraction+ Ashing
Biochemistry Pathology+ Protein hydrolysis+ PCR proteomics+ Tissue fixation+ Histoprocessing
Medical+ Diathermy tumor detection+ Blood warming+ Sterilization (Anthrax)+ Drying of catheters
Books on Microwave-Assisted Synthesis
1048707 Fundamentals of Microwave Application1048707 Alternative Laboratory MicrowaveInstruments1048707 Chemistry Applications1048707 Biochemistry Applications1048707 Laboratory Microwave Safety
Hayes B LCEM PublishingMatthews NC2002
(ACS Professional Reference Book) H M Kingston S J Haswell (eds)
Microwaves in Organic and Medicinal ChemistryKappe C O and Stadler AWiley-VCH Weinheim 2005 ISBN 3-527-31210-2410 pages ca 1000 references
Books on Microwave-Assisted Synthesis
Lidstoumlm PTierney J P(Eds)BlackwellScientific2005
Loupy Andre (Ed)Wiley-VCH Weinheim 2003 ISBN 3-527-30514-9523 pages 2000 refs
Book (2 volumes) Wiley-VCHA Loupy editSecond Edition(2006) 22 Chapters
Astra Zeneca ResearchFoundation Kavitha PrintersBangalore India 2002azrefiastrazenecacom
Practical Microwave Synthesis for Organic Chemists - Strategies Instruments and Protocols
Edition - 2009 X 310 Pages Hardcover Monograph
Books on Microwave-Assisted Synthesis
Microwave Ovens
Monomodal instrument
Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005
Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia
Multimodal instrument
+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile
Monomodal Vs Multimodal
Monomodal Vs Multimodal
Thermal Effects
bullMore efficient energetic coupling of solvent with microwaves
promotes higher rate of temperature increase
bull Inverted heat transfer volumetric
bull ldquoHot spotsrdquo in monomode microwaves
bull Selective on properties of material (solvents catalysts
reagents intermediates products susceptors)
Recent Applications of Microwave-Assisted Synthesis-MAOS
Hydrolysis of benzamide
thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)
The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions
R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958
Solvent-free Reactions or Solid-Solid Reactions
ldquoNo reaction proceeds without solventrdquo
Aristotle
Solventless syntheses
Green chemistry enabled advancement
Solvent-free Organic Synthesis
Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed
i n t o a p o w e r f u l m e t h o d o l o g y a s i t
reduces the amount of toxic waste produced and therefore becomes less harmful to the
e n v i r o n m e n t
Solvent-free Organic Synthesis
bull Clean and efficient synthesis
bull Economic and environmental impact
bull Fast reaction kinetics
Best solvent is no solvent
Adolf von Baeyer
Synthesis of Indigo
Towardsbenign
synthesiswith
remarkableVersatility
G W V Cave C LRaston J L ScottChemCommun
2001 2159
Solid-State General Oxidation with with Urea H2O2 Complex
R S Varma and K P Naiker Org Letters 1999 1 189
Solvent-free Oxidative Preparation of Heterocycles
Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157
Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones
Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199
Solvent-free Reduction
F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245
Carbon-Carbon Bond Formation
Toda Tanada Iwata J Org Chem 1989 54 3007
Solventless Photo Coupling and Photo Rearangements
Y Ito S Endo J Am Chem Soc 1997 119 5974
Shin Keating Maribay J Am Chem Soc 1996 118 7626
Solvent - Free Condensation
Z Gross et al Org Letters 1999 1 599
Solid-State Preparationof Dumb-bell-shaped C120
Wang Komatsu Murata Shiro Nature 1997 387 583
Advantages of Solid Mineral Supports(Alumina Silica and Clay)
Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area
The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity
Solids are generally easier and safer to handle than liquids or gaseous reagents
Inexpensive recyclable and environmentally benign nature
Solid-supported Solventless Reactions
bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation
R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43
Supported ReactionsUsing Microwaves
E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945
Microwave-Assisted Deacetylationon Alumina
Varma et al J Chem Soc Perkin Trans 1 999 (1993)
Deprotection of Benzyl Esters viaMicrowave Thermolysis
A practical alternative to traditional catalytic hydrogenation
Varma et al Tetrahedron Lett 34 4603 (1993)
Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of
Carbonyl Compounds Using Microwaves
Varma Meshram Tetrahedron Lett 38 5427 (1997)
Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm
PersulfatendashClay using Microwave and Ultrasonic Irradiation
Varma Meshram Tetrahedron Lett 38 7973 (1997)
Solid Supported Solvent-freeOxidation under MW
Varma et al Tetrahedron Lett 1997 38 2043 and 7823
Solvent-free Reduction Using MW
Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction
Varma et al Tetrahedron Lett 1997 38 4337
Hydrodechlorination under continuous MW
Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)
Synthesis of Heterocyclic Compounds
Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)
Synthesis of Heterocyclic Compounds
Organometallic Reactions
Rearrangements
Rearrangements
INDOLIZINES
Heterocyclic systems 10- electronics
Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine
Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds
N
1
2
34567
8R2
R3
R1
Why interest for indolizinic products
Strong fluorescent properties luminiscent products luminiscent products
Potentially fluorescents marker Potentially laserldquoscintillatersrdquo
bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999
Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )
Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2
ldquoCalcium-entryrdquo blockers
Indolizines by irradiation with microwaves in MCR
RBr
O+
N
R1 R2+N
R2
R1
COR
AcOAl2O3 Mw
R=Ph p-Tolil Stiril
R1= H COOMeR2= COOEt COOMe
Asymmetric indolizines by irradiation with microwaves in MCR
R1
O
Cl+ R2
N NEtOOC
OOMe
Br BrN N
EtOOC
COR1
R2COR1
R2
OOMe
2 [Pd(PPh3)2Cl24 CuI
20 echiv Et3N THF tc 2h
R1=Ph 4-OMe-C6H4R2= Ph
U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003
A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new indolizines
[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical
II
IHH
COORCOOR
N C C
O
R2NCC
O
R1
(B)
(A)
R1
O
C C N R2
O
CCN
H H
ROOC COOR
R1
O
C C N R2
O
CCN
COOR COOR
ROOC COOR
2
2 ROOC C C COOR
R1
O
C CH N R2
O
CCHN
H H
N NCH CHC C
O O
R1 R2
- 2 HX TEAanhydrous solvents
X-
X-
N NCH2 CH2C C
O O
R1 R2
C C COORH
R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5
Y=H NO2 OCH3 CH3 Cl BrX=Br Cl
bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998
bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001
bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004
bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new substituted pyridinium-indolizines
Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate
COO NO2CHC
N NH3C
OR
I IN NH3C
OR
IN NH3C
OR
I
H
KFNMP
-HI
NMP
95oC 30 min
N NH3CO
RN NH3C
O
R
O OO
NO2
O
NO2
-2[H]-2[H]
II
I II
N NH3CO
R
O O
NO2
IN NH3C
O
R
O O
NO2
I
(9a-d)(10a-d)
(15a-d)
(A) (B)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
12
34
56
78 9
10
11
12 3
4
56
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Green Chemistry
The cost of usinghazardous materials
Conventional Heating vs Alternative Energy Source
Conventional Heating Bunsen burnerOil bathHeating mantleAlternative Energy SourcesMicrowaveUltrasoundSunlight UV Electonchemistry
Clean Chemical Synthesis UsingAlternative Reaction Methods
Alternative Energy SourcesMicrowaveUltrasoundSunlight UV
AlternativeReactionMediaSolvent-free Supercritical FluidsIonic LiquidsWaterPolyethylene glycol (PEG)Solvent free
Microwaves in Synthesis
bull While fire is now rarely used in synthetic chemistry it was not until Robert Bunsen invented the burner in 1855 that the energy from this heat source could be applied
bull There is some controversy about the origins of the microwave power cavity called the magnetron ndash the high-power generator of microwave power
The British were particularly forward-looking in deploying radar for air defense with a system called Chain Home which began operation in 1937
Originally operating at 22 MHz frequencies increased to 55 MHz 1921 was published by AW Hull the earliest description of the magnetron a
diode with a cylindrical anode1940 It was developed practically by Randall and Booth at the University of
Birmingham in England they verified their first microwave transmissions 500 W at 3 GHz
A prototype was brought to the United States in September of that year to define an agreement whereby United States industrial capability would undertake the development of microwave radar
1940 the Radiation Laboratory was established at the Massachusetts Institute of Technology to exploit microwave radar More than 40 types of tube would be produced particularly in the S-band (ie 300 MHz) The growth of microwave radar is linked with Raytheon Company and PL Spencer who found the key to mass production
History or how it all beganhellip
bull 1946 Dr Percy Spencer-the magnetron inventor he has found a variety of technical applications in the chemical and related industries since the 1950s in particular in the food-processing drying and polymer
bull surprisingly microwave heating has only been implemented in organic synthesis since the mid-1980s
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
History or how it all beganhellip
bull 1969 ldquo Carrying out chemical reactions using microwave energy rdquo JW Vanderhoff ndash Dow Chemical Company US 3432413
bull 1986 ldquoThe Use of Microwave Ovens for Rapid Organic Synthesisrdquo Gedye R N et alTetrahedron Lett 1986 27 279
bull 1986 ldquoApplication of Commercial Microwave Ovens to Organic Synthesisrdquo Giguere R J and Majetich G Tetrahedron Lett 1986 27 4945
Energy Use in ConventionalChemical Processes
Heating Stirring Piping
Transporting Cooling
Problem of Conventional Heating
You heat what you donrsquot want to heat
Solvents for reactions apparatus
heated up and cool it down
Double energy penalty without any
apparent ldquobenefitrdquo
Energy Consumptions
Three ways to get the reaction done but different energy bills to pay
Microwaves
bull MW reactors operate at 245 GHzbull Electric field oscillates at 49 x 109 timessec ndash
10oCsec heating rate
Electromagnetic Spectrum
Neas E Collins M Introduction to Microwave Sample Preparation Theory and Practice 1988 p 8
Schematic of a Microwave
E= electric fieldH= magnetic field= wavelength (122 cm for 2450 MHz)c= speed of light (300000 kms)
Microwaves Application in Heating Food
1946 Original patent (P L Spencer)1947 First commercial oven1955 Home models1967 Desktop model1975 US sales exceed gas ranges1976 60 of US households havemicrowave ovens
Spectrum Electromagnetic
bull Electric field component
bull Responsible for dielectric heating
bull Dipolar polarization
bull Conduction
bull Magnetic field component
Microwaves ndash Dipolar Rotationbull Polar molecules have intermolecular forces which give any motion of the
molecule some inertia
bull Under a very high frequency electric field the polar molecule will attempt to follow the field but intermolecular inertia stops any significant motion before the field has reversed and no net motion results
bull If the frequency of field oscillation is very low then the molecules will be polarized uniformly and no random motion results
bull In the intermediate case the frequency of the field will be such that the molecules will be almost but not quite able to keep in phase with the field polarity
bull In this case the random motion resulting as molecules jostle to attempt in vain to follow the field provides strong agitation and intense heating of the sample
bull At 245 GHz the field oscillates 49 x 109 timess which can lead to heating
rates of 10 degC per second when powerful waves are used
MW Heating Mechanism
Alternating electric field Withhigh frequency
NoconstraintContinuous electric field
Two mechanisms Dipolar rotation polarizationIonic Conduction mechanism
Microwave Dielectric HeatingMechanisms
Dipolar PolarizationMechanism
Conduction Mechanism
Dipolar molecules try toalign to an oscillating fieldby rotation
Ions in solution will moveby the applied electricfield
Mingos D M P et al Chem Soc Rev 1991 20 1 and 1998 27 213
Microwave vs Oil-bath Heating
J-S Schanche Mol Diversity 2003 7 293wwwpersonalchemistry-com wwwbiotagecom
Conventional Heating byConduction
ConductiveheatHeating byconvectioncurrentsSlow andenergyinefficientprocess
temperature on the outside surface isin excess of the boiling point of liquid
Direct Heating by MicrowaveIrradiation
bullSolventreagent absorbs MW energybull Vessel wall transparent to MWbullDirect in-core heatingbullInstant on-off
Inverted temperature gradients
Molecular Speeds
Molecular Speeds
Microwave Ovens
Cooking Chemistry Cooking Food
Household MW ovens
The Use of Microwave Ovens for Rapid Organic Synthesis R Gedye et al Tetrahedron Lett 1986 27 279
Publications on MW-AssistedOrganic Synthesis
7 Synthetic Journals JOrgChemOrgLettTetrahedron LettTetrahedron SynthCommun Synlett SynthesisAll Journals (Full Text) Dedicated instruments only (Anton Paar Biotage CEM Milestone Prolabo)
Industrial Chemical Applications of Microwave Heating
Food Processing+ Defrosting+ Drying roasting baking+ Pasteurization
Drying Industry+ Wood fibers textiles+ Pharmaceuticals+ Brick concrete walls
Polymer Chemistry+ Rubber curing vulcanization+ Polymerization
CeramicsMaterials+ Alumina sintering+ Welding smelting gluing
Plasma+ SemiconductorsWaste Remediation+ Sewage treatment
Analytical Chemistry+ Digestion+ Extraction+ Ashing
Biochemistry Pathology+ Protein hydrolysis+ PCR proteomics+ Tissue fixation+ Histoprocessing
Medical+ Diathermy tumor detection+ Blood warming+ Sterilization (Anthrax)+ Drying of catheters
Books on Microwave-Assisted Synthesis
1048707 Fundamentals of Microwave Application1048707 Alternative Laboratory MicrowaveInstruments1048707 Chemistry Applications1048707 Biochemistry Applications1048707 Laboratory Microwave Safety
Hayes B LCEM PublishingMatthews NC2002
(ACS Professional Reference Book) H M Kingston S J Haswell (eds)
Microwaves in Organic and Medicinal ChemistryKappe C O and Stadler AWiley-VCH Weinheim 2005 ISBN 3-527-31210-2410 pages ca 1000 references
Books on Microwave-Assisted Synthesis
Lidstoumlm PTierney J P(Eds)BlackwellScientific2005
Loupy Andre (Ed)Wiley-VCH Weinheim 2003 ISBN 3-527-30514-9523 pages 2000 refs
Book (2 volumes) Wiley-VCHA Loupy editSecond Edition(2006) 22 Chapters
Astra Zeneca ResearchFoundation Kavitha PrintersBangalore India 2002azrefiastrazenecacom
Practical Microwave Synthesis for Organic Chemists - Strategies Instruments and Protocols
Edition - 2009 X 310 Pages Hardcover Monograph
Books on Microwave-Assisted Synthesis
Microwave Ovens
Monomodal instrument
Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005
Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia
Multimodal instrument
+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile
Monomodal Vs Multimodal
Monomodal Vs Multimodal
Thermal Effects
bullMore efficient energetic coupling of solvent with microwaves
promotes higher rate of temperature increase
bull Inverted heat transfer volumetric
bull ldquoHot spotsrdquo in monomode microwaves
bull Selective on properties of material (solvents catalysts
reagents intermediates products susceptors)
Recent Applications of Microwave-Assisted Synthesis-MAOS
Hydrolysis of benzamide
thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)
The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions
R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958
Solvent-free Reactions or Solid-Solid Reactions
ldquoNo reaction proceeds without solventrdquo
Aristotle
Solventless syntheses
Green chemistry enabled advancement
Solvent-free Organic Synthesis
Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed
i n t o a p o w e r f u l m e t h o d o l o g y a s i t
reduces the amount of toxic waste produced and therefore becomes less harmful to the
e n v i r o n m e n t
Solvent-free Organic Synthesis
bull Clean and efficient synthesis
bull Economic and environmental impact
bull Fast reaction kinetics
Best solvent is no solvent
Adolf von Baeyer
Synthesis of Indigo
Towardsbenign
synthesiswith
remarkableVersatility
G W V Cave C LRaston J L ScottChemCommun
2001 2159
Solid-State General Oxidation with with Urea H2O2 Complex
R S Varma and K P Naiker Org Letters 1999 1 189
Solvent-free Oxidative Preparation of Heterocycles
Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157
Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones
Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199
Solvent-free Reduction
F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245
Carbon-Carbon Bond Formation
Toda Tanada Iwata J Org Chem 1989 54 3007
Solventless Photo Coupling and Photo Rearangements
Y Ito S Endo J Am Chem Soc 1997 119 5974
Shin Keating Maribay J Am Chem Soc 1996 118 7626
Solvent - Free Condensation
Z Gross et al Org Letters 1999 1 599
Solid-State Preparationof Dumb-bell-shaped C120
Wang Komatsu Murata Shiro Nature 1997 387 583
Advantages of Solid Mineral Supports(Alumina Silica and Clay)
Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area
The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity
Solids are generally easier and safer to handle than liquids or gaseous reagents
Inexpensive recyclable and environmentally benign nature
Solid-supported Solventless Reactions
bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation
R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43
Supported ReactionsUsing Microwaves
E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945
Microwave-Assisted Deacetylationon Alumina
Varma et al J Chem Soc Perkin Trans 1 999 (1993)
Deprotection of Benzyl Esters viaMicrowave Thermolysis
A practical alternative to traditional catalytic hydrogenation
Varma et al Tetrahedron Lett 34 4603 (1993)
Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of
Carbonyl Compounds Using Microwaves
Varma Meshram Tetrahedron Lett 38 5427 (1997)
Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm
PersulfatendashClay using Microwave and Ultrasonic Irradiation
Varma Meshram Tetrahedron Lett 38 7973 (1997)
Solid Supported Solvent-freeOxidation under MW
Varma et al Tetrahedron Lett 1997 38 2043 and 7823
Solvent-free Reduction Using MW
Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction
Varma et al Tetrahedron Lett 1997 38 4337
Hydrodechlorination under continuous MW
Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)
Synthesis of Heterocyclic Compounds
Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)
Synthesis of Heterocyclic Compounds
Organometallic Reactions
Rearrangements
Rearrangements
INDOLIZINES
Heterocyclic systems 10- electronics
Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine
Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds
N
1
2
34567
8R2
R3
R1
Why interest for indolizinic products
Strong fluorescent properties luminiscent products luminiscent products
Potentially fluorescents marker Potentially laserldquoscintillatersrdquo
bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999
Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )
Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2
ldquoCalcium-entryrdquo blockers
Indolizines by irradiation with microwaves in MCR
RBr
O+
N
R1 R2+N
R2
R1
COR
AcOAl2O3 Mw
R=Ph p-Tolil Stiril
R1= H COOMeR2= COOEt COOMe
Asymmetric indolizines by irradiation with microwaves in MCR
R1
O
Cl+ R2
N NEtOOC
OOMe
Br BrN N
EtOOC
COR1
R2COR1
R2
OOMe
2 [Pd(PPh3)2Cl24 CuI
20 echiv Et3N THF tc 2h
R1=Ph 4-OMe-C6H4R2= Ph
U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003
A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new indolizines
[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical
II
IHH
COORCOOR
N C C
O
R2NCC
O
R1
(B)
(A)
R1
O
C C N R2
O
CCN
H H
ROOC COOR
R1
O
C C N R2
O
CCN
COOR COOR
ROOC COOR
2
2 ROOC C C COOR
R1
O
C CH N R2
O
CCHN
H H
N NCH CHC C
O O
R1 R2
- 2 HX TEAanhydrous solvents
X-
X-
N NCH2 CH2C C
O O
R1 R2
C C COORH
R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5
Y=H NO2 OCH3 CH3 Cl BrX=Br Cl
bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998
bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001
bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004
bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new substituted pyridinium-indolizines
Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate
COO NO2CHC
N NH3C
OR
I IN NH3C
OR
IN NH3C
OR
I
H
KFNMP
-HI
NMP
95oC 30 min
N NH3CO
RN NH3C
O
R
O OO
NO2
O
NO2
-2[H]-2[H]
II
I II
N NH3CO
R
O O
NO2
IN NH3C
O
R
O O
NO2
I
(9a-d)(10a-d)
(15a-d)
(A) (B)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
12
34
56
78 9
10
11
12 3
4
56
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
The cost of usinghazardous materials
Conventional Heating vs Alternative Energy Source
Conventional Heating Bunsen burnerOil bathHeating mantleAlternative Energy SourcesMicrowaveUltrasoundSunlight UV Electonchemistry
Clean Chemical Synthesis UsingAlternative Reaction Methods
Alternative Energy SourcesMicrowaveUltrasoundSunlight UV
AlternativeReactionMediaSolvent-free Supercritical FluidsIonic LiquidsWaterPolyethylene glycol (PEG)Solvent free
Microwaves in Synthesis
bull While fire is now rarely used in synthetic chemistry it was not until Robert Bunsen invented the burner in 1855 that the energy from this heat source could be applied
bull There is some controversy about the origins of the microwave power cavity called the magnetron ndash the high-power generator of microwave power
The British were particularly forward-looking in deploying radar for air defense with a system called Chain Home which began operation in 1937
Originally operating at 22 MHz frequencies increased to 55 MHz 1921 was published by AW Hull the earliest description of the magnetron a
diode with a cylindrical anode1940 It was developed practically by Randall and Booth at the University of
Birmingham in England they verified their first microwave transmissions 500 W at 3 GHz
A prototype was brought to the United States in September of that year to define an agreement whereby United States industrial capability would undertake the development of microwave radar
1940 the Radiation Laboratory was established at the Massachusetts Institute of Technology to exploit microwave radar More than 40 types of tube would be produced particularly in the S-band (ie 300 MHz) The growth of microwave radar is linked with Raytheon Company and PL Spencer who found the key to mass production
History or how it all beganhellip
bull 1946 Dr Percy Spencer-the magnetron inventor he has found a variety of technical applications in the chemical and related industries since the 1950s in particular in the food-processing drying and polymer
bull surprisingly microwave heating has only been implemented in organic synthesis since the mid-1980s
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
History or how it all beganhellip
bull 1969 ldquo Carrying out chemical reactions using microwave energy rdquo JW Vanderhoff ndash Dow Chemical Company US 3432413
bull 1986 ldquoThe Use of Microwave Ovens for Rapid Organic Synthesisrdquo Gedye R N et alTetrahedron Lett 1986 27 279
bull 1986 ldquoApplication of Commercial Microwave Ovens to Organic Synthesisrdquo Giguere R J and Majetich G Tetrahedron Lett 1986 27 4945
Energy Use in ConventionalChemical Processes
Heating Stirring Piping
Transporting Cooling
Problem of Conventional Heating
You heat what you donrsquot want to heat
Solvents for reactions apparatus
heated up and cool it down
Double energy penalty without any
apparent ldquobenefitrdquo
Energy Consumptions
Three ways to get the reaction done but different energy bills to pay
Microwaves
bull MW reactors operate at 245 GHzbull Electric field oscillates at 49 x 109 timessec ndash
10oCsec heating rate
Electromagnetic Spectrum
Neas E Collins M Introduction to Microwave Sample Preparation Theory and Practice 1988 p 8
Schematic of a Microwave
E= electric fieldH= magnetic field= wavelength (122 cm for 2450 MHz)c= speed of light (300000 kms)
Microwaves Application in Heating Food
1946 Original patent (P L Spencer)1947 First commercial oven1955 Home models1967 Desktop model1975 US sales exceed gas ranges1976 60 of US households havemicrowave ovens
Spectrum Electromagnetic
bull Electric field component
bull Responsible for dielectric heating
bull Dipolar polarization
bull Conduction
bull Magnetic field component
Microwaves ndash Dipolar Rotationbull Polar molecules have intermolecular forces which give any motion of the
molecule some inertia
bull Under a very high frequency electric field the polar molecule will attempt to follow the field but intermolecular inertia stops any significant motion before the field has reversed and no net motion results
bull If the frequency of field oscillation is very low then the molecules will be polarized uniformly and no random motion results
bull In the intermediate case the frequency of the field will be such that the molecules will be almost but not quite able to keep in phase with the field polarity
bull In this case the random motion resulting as molecules jostle to attempt in vain to follow the field provides strong agitation and intense heating of the sample
bull At 245 GHz the field oscillates 49 x 109 timess which can lead to heating
rates of 10 degC per second when powerful waves are used
MW Heating Mechanism
Alternating electric field Withhigh frequency
NoconstraintContinuous electric field
Two mechanisms Dipolar rotation polarizationIonic Conduction mechanism
Microwave Dielectric HeatingMechanisms
Dipolar PolarizationMechanism
Conduction Mechanism
Dipolar molecules try toalign to an oscillating fieldby rotation
Ions in solution will moveby the applied electricfield
Mingos D M P et al Chem Soc Rev 1991 20 1 and 1998 27 213
Microwave vs Oil-bath Heating
J-S Schanche Mol Diversity 2003 7 293wwwpersonalchemistry-com wwwbiotagecom
Conventional Heating byConduction
ConductiveheatHeating byconvectioncurrentsSlow andenergyinefficientprocess
temperature on the outside surface isin excess of the boiling point of liquid
Direct Heating by MicrowaveIrradiation
bullSolventreagent absorbs MW energybull Vessel wall transparent to MWbullDirect in-core heatingbullInstant on-off
Inverted temperature gradients
Molecular Speeds
Molecular Speeds
Microwave Ovens
Cooking Chemistry Cooking Food
Household MW ovens
The Use of Microwave Ovens for Rapid Organic Synthesis R Gedye et al Tetrahedron Lett 1986 27 279
Publications on MW-AssistedOrganic Synthesis
7 Synthetic Journals JOrgChemOrgLettTetrahedron LettTetrahedron SynthCommun Synlett SynthesisAll Journals (Full Text) Dedicated instruments only (Anton Paar Biotage CEM Milestone Prolabo)
Industrial Chemical Applications of Microwave Heating
Food Processing+ Defrosting+ Drying roasting baking+ Pasteurization
Drying Industry+ Wood fibers textiles+ Pharmaceuticals+ Brick concrete walls
Polymer Chemistry+ Rubber curing vulcanization+ Polymerization
CeramicsMaterials+ Alumina sintering+ Welding smelting gluing
Plasma+ SemiconductorsWaste Remediation+ Sewage treatment
Analytical Chemistry+ Digestion+ Extraction+ Ashing
Biochemistry Pathology+ Protein hydrolysis+ PCR proteomics+ Tissue fixation+ Histoprocessing
Medical+ Diathermy tumor detection+ Blood warming+ Sterilization (Anthrax)+ Drying of catheters
Books on Microwave-Assisted Synthesis
1048707 Fundamentals of Microwave Application1048707 Alternative Laboratory MicrowaveInstruments1048707 Chemistry Applications1048707 Biochemistry Applications1048707 Laboratory Microwave Safety
Hayes B LCEM PublishingMatthews NC2002
(ACS Professional Reference Book) H M Kingston S J Haswell (eds)
Microwaves in Organic and Medicinal ChemistryKappe C O and Stadler AWiley-VCH Weinheim 2005 ISBN 3-527-31210-2410 pages ca 1000 references
Books on Microwave-Assisted Synthesis
Lidstoumlm PTierney J P(Eds)BlackwellScientific2005
Loupy Andre (Ed)Wiley-VCH Weinheim 2003 ISBN 3-527-30514-9523 pages 2000 refs
Book (2 volumes) Wiley-VCHA Loupy editSecond Edition(2006) 22 Chapters
Astra Zeneca ResearchFoundation Kavitha PrintersBangalore India 2002azrefiastrazenecacom
Practical Microwave Synthesis for Organic Chemists - Strategies Instruments and Protocols
Edition - 2009 X 310 Pages Hardcover Monograph
Books on Microwave-Assisted Synthesis
Microwave Ovens
Monomodal instrument
Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005
Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia
Multimodal instrument
+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile
Monomodal Vs Multimodal
Monomodal Vs Multimodal
Thermal Effects
bullMore efficient energetic coupling of solvent with microwaves
promotes higher rate of temperature increase
bull Inverted heat transfer volumetric
bull ldquoHot spotsrdquo in monomode microwaves
bull Selective on properties of material (solvents catalysts
reagents intermediates products susceptors)
Recent Applications of Microwave-Assisted Synthesis-MAOS
Hydrolysis of benzamide
thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)
The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions
R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958
Solvent-free Reactions or Solid-Solid Reactions
ldquoNo reaction proceeds without solventrdquo
Aristotle
Solventless syntheses
Green chemistry enabled advancement
Solvent-free Organic Synthesis
Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed
i n t o a p o w e r f u l m e t h o d o l o g y a s i t
reduces the amount of toxic waste produced and therefore becomes less harmful to the
e n v i r o n m e n t
Solvent-free Organic Synthesis
bull Clean and efficient synthesis
bull Economic and environmental impact
bull Fast reaction kinetics
Best solvent is no solvent
Adolf von Baeyer
Synthesis of Indigo
Towardsbenign
synthesiswith
remarkableVersatility
G W V Cave C LRaston J L ScottChemCommun
2001 2159
Solid-State General Oxidation with with Urea H2O2 Complex
R S Varma and K P Naiker Org Letters 1999 1 189
Solvent-free Oxidative Preparation of Heterocycles
Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157
Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones
Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199
Solvent-free Reduction
F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245
Carbon-Carbon Bond Formation
Toda Tanada Iwata J Org Chem 1989 54 3007
Solventless Photo Coupling and Photo Rearangements
Y Ito S Endo J Am Chem Soc 1997 119 5974
Shin Keating Maribay J Am Chem Soc 1996 118 7626
Solvent - Free Condensation
Z Gross et al Org Letters 1999 1 599
Solid-State Preparationof Dumb-bell-shaped C120
Wang Komatsu Murata Shiro Nature 1997 387 583
Advantages of Solid Mineral Supports(Alumina Silica and Clay)
Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area
The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity
Solids are generally easier and safer to handle than liquids or gaseous reagents
Inexpensive recyclable and environmentally benign nature
Solid-supported Solventless Reactions
bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation
R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43
Supported ReactionsUsing Microwaves
E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945
Microwave-Assisted Deacetylationon Alumina
Varma et al J Chem Soc Perkin Trans 1 999 (1993)
Deprotection of Benzyl Esters viaMicrowave Thermolysis
A practical alternative to traditional catalytic hydrogenation
Varma et al Tetrahedron Lett 34 4603 (1993)
Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of
Carbonyl Compounds Using Microwaves
Varma Meshram Tetrahedron Lett 38 5427 (1997)
Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm
PersulfatendashClay using Microwave and Ultrasonic Irradiation
Varma Meshram Tetrahedron Lett 38 7973 (1997)
Solid Supported Solvent-freeOxidation under MW
Varma et al Tetrahedron Lett 1997 38 2043 and 7823
Solvent-free Reduction Using MW
Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction
Varma et al Tetrahedron Lett 1997 38 4337
Hydrodechlorination under continuous MW
Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)
Synthesis of Heterocyclic Compounds
Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)
Synthesis of Heterocyclic Compounds
Organometallic Reactions
Rearrangements
Rearrangements
INDOLIZINES
Heterocyclic systems 10- electronics
Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine
Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds
N
1
2
34567
8R2
R3
R1
Why interest for indolizinic products
Strong fluorescent properties luminiscent products luminiscent products
Potentially fluorescents marker Potentially laserldquoscintillatersrdquo
bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999
Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )
Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2
ldquoCalcium-entryrdquo blockers
Indolizines by irradiation with microwaves in MCR
RBr
O+
N
R1 R2+N
R2
R1
COR
AcOAl2O3 Mw
R=Ph p-Tolil Stiril
R1= H COOMeR2= COOEt COOMe
Asymmetric indolizines by irradiation with microwaves in MCR
R1
O
Cl+ R2
N NEtOOC
OOMe
Br BrN N
EtOOC
COR1
R2COR1
R2
OOMe
2 [Pd(PPh3)2Cl24 CuI
20 echiv Et3N THF tc 2h
R1=Ph 4-OMe-C6H4R2= Ph
U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003
A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new indolizines
[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical
II
IHH
COORCOOR
N C C
O
R2NCC
O
R1
(B)
(A)
R1
O
C C N R2
O
CCN
H H
ROOC COOR
R1
O
C C N R2
O
CCN
COOR COOR
ROOC COOR
2
2 ROOC C C COOR
R1
O
C CH N R2
O
CCHN
H H
N NCH CHC C
O O
R1 R2
- 2 HX TEAanhydrous solvents
X-
X-
N NCH2 CH2C C
O O
R1 R2
C C COORH
R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5
Y=H NO2 OCH3 CH3 Cl BrX=Br Cl
bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998
bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001
bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004
bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new substituted pyridinium-indolizines
Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate
COO NO2CHC
N NH3C
OR
I IN NH3C
OR
IN NH3C
OR
I
H
KFNMP
-HI
NMP
95oC 30 min
N NH3CO
RN NH3C
O
R
O OO
NO2
O
NO2
-2[H]-2[H]
II
I II
N NH3CO
R
O O
NO2
IN NH3C
O
R
O O
NO2
I
(9a-d)(10a-d)
(15a-d)
(A) (B)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
12
34
56
78 9
10
11
12 3
4
56
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Conventional Heating vs Alternative Energy Source
Conventional Heating Bunsen burnerOil bathHeating mantleAlternative Energy SourcesMicrowaveUltrasoundSunlight UV Electonchemistry
Clean Chemical Synthesis UsingAlternative Reaction Methods
Alternative Energy SourcesMicrowaveUltrasoundSunlight UV
AlternativeReactionMediaSolvent-free Supercritical FluidsIonic LiquidsWaterPolyethylene glycol (PEG)Solvent free
Microwaves in Synthesis
bull While fire is now rarely used in synthetic chemistry it was not until Robert Bunsen invented the burner in 1855 that the energy from this heat source could be applied
bull There is some controversy about the origins of the microwave power cavity called the magnetron ndash the high-power generator of microwave power
The British were particularly forward-looking in deploying radar for air defense with a system called Chain Home which began operation in 1937
Originally operating at 22 MHz frequencies increased to 55 MHz 1921 was published by AW Hull the earliest description of the magnetron a
diode with a cylindrical anode1940 It was developed practically by Randall and Booth at the University of
Birmingham in England they verified their first microwave transmissions 500 W at 3 GHz
A prototype was brought to the United States in September of that year to define an agreement whereby United States industrial capability would undertake the development of microwave radar
1940 the Radiation Laboratory was established at the Massachusetts Institute of Technology to exploit microwave radar More than 40 types of tube would be produced particularly in the S-band (ie 300 MHz) The growth of microwave radar is linked with Raytheon Company and PL Spencer who found the key to mass production
History or how it all beganhellip
bull 1946 Dr Percy Spencer-the magnetron inventor he has found a variety of technical applications in the chemical and related industries since the 1950s in particular in the food-processing drying and polymer
bull surprisingly microwave heating has only been implemented in organic synthesis since the mid-1980s
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
History or how it all beganhellip
bull 1969 ldquo Carrying out chemical reactions using microwave energy rdquo JW Vanderhoff ndash Dow Chemical Company US 3432413
bull 1986 ldquoThe Use of Microwave Ovens for Rapid Organic Synthesisrdquo Gedye R N et alTetrahedron Lett 1986 27 279
bull 1986 ldquoApplication of Commercial Microwave Ovens to Organic Synthesisrdquo Giguere R J and Majetich G Tetrahedron Lett 1986 27 4945
Energy Use in ConventionalChemical Processes
Heating Stirring Piping
Transporting Cooling
Problem of Conventional Heating
You heat what you donrsquot want to heat
Solvents for reactions apparatus
heated up and cool it down
Double energy penalty without any
apparent ldquobenefitrdquo
Energy Consumptions
Three ways to get the reaction done but different energy bills to pay
Microwaves
bull MW reactors operate at 245 GHzbull Electric field oscillates at 49 x 109 timessec ndash
10oCsec heating rate
Electromagnetic Spectrum
Neas E Collins M Introduction to Microwave Sample Preparation Theory and Practice 1988 p 8
Schematic of a Microwave
E= electric fieldH= magnetic field= wavelength (122 cm for 2450 MHz)c= speed of light (300000 kms)
Microwaves Application in Heating Food
1946 Original patent (P L Spencer)1947 First commercial oven1955 Home models1967 Desktop model1975 US sales exceed gas ranges1976 60 of US households havemicrowave ovens
Spectrum Electromagnetic
bull Electric field component
bull Responsible for dielectric heating
bull Dipolar polarization
bull Conduction
bull Magnetic field component
Microwaves ndash Dipolar Rotationbull Polar molecules have intermolecular forces which give any motion of the
molecule some inertia
bull Under a very high frequency electric field the polar molecule will attempt to follow the field but intermolecular inertia stops any significant motion before the field has reversed and no net motion results
bull If the frequency of field oscillation is very low then the molecules will be polarized uniformly and no random motion results
bull In the intermediate case the frequency of the field will be such that the molecules will be almost but not quite able to keep in phase with the field polarity
bull In this case the random motion resulting as molecules jostle to attempt in vain to follow the field provides strong agitation and intense heating of the sample
bull At 245 GHz the field oscillates 49 x 109 timess which can lead to heating
rates of 10 degC per second when powerful waves are used
MW Heating Mechanism
Alternating electric field Withhigh frequency
NoconstraintContinuous electric field
Two mechanisms Dipolar rotation polarizationIonic Conduction mechanism
Microwave Dielectric HeatingMechanisms
Dipolar PolarizationMechanism
Conduction Mechanism
Dipolar molecules try toalign to an oscillating fieldby rotation
Ions in solution will moveby the applied electricfield
Mingos D M P et al Chem Soc Rev 1991 20 1 and 1998 27 213
Microwave vs Oil-bath Heating
J-S Schanche Mol Diversity 2003 7 293wwwpersonalchemistry-com wwwbiotagecom
Conventional Heating byConduction
ConductiveheatHeating byconvectioncurrentsSlow andenergyinefficientprocess
temperature on the outside surface isin excess of the boiling point of liquid
Direct Heating by MicrowaveIrradiation
bullSolventreagent absorbs MW energybull Vessel wall transparent to MWbullDirect in-core heatingbullInstant on-off
Inverted temperature gradients
Molecular Speeds
Molecular Speeds
Microwave Ovens
Cooking Chemistry Cooking Food
Household MW ovens
The Use of Microwave Ovens for Rapid Organic Synthesis R Gedye et al Tetrahedron Lett 1986 27 279
Publications on MW-AssistedOrganic Synthesis
7 Synthetic Journals JOrgChemOrgLettTetrahedron LettTetrahedron SynthCommun Synlett SynthesisAll Journals (Full Text) Dedicated instruments only (Anton Paar Biotage CEM Milestone Prolabo)
Industrial Chemical Applications of Microwave Heating
Food Processing+ Defrosting+ Drying roasting baking+ Pasteurization
Drying Industry+ Wood fibers textiles+ Pharmaceuticals+ Brick concrete walls
Polymer Chemistry+ Rubber curing vulcanization+ Polymerization
CeramicsMaterials+ Alumina sintering+ Welding smelting gluing
Plasma+ SemiconductorsWaste Remediation+ Sewage treatment
Analytical Chemistry+ Digestion+ Extraction+ Ashing
Biochemistry Pathology+ Protein hydrolysis+ PCR proteomics+ Tissue fixation+ Histoprocessing
Medical+ Diathermy tumor detection+ Blood warming+ Sterilization (Anthrax)+ Drying of catheters
Books on Microwave-Assisted Synthesis
1048707 Fundamentals of Microwave Application1048707 Alternative Laboratory MicrowaveInstruments1048707 Chemistry Applications1048707 Biochemistry Applications1048707 Laboratory Microwave Safety
Hayes B LCEM PublishingMatthews NC2002
(ACS Professional Reference Book) H M Kingston S J Haswell (eds)
Microwaves in Organic and Medicinal ChemistryKappe C O and Stadler AWiley-VCH Weinheim 2005 ISBN 3-527-31210-2410 pages ca 1000 references
Books on Microwave-Assisted Synthesis
Lidstoumlm PTierney J P(Eds)BlackwellScientific2005
Loupy Andre (Ed)Wiley-VCH Weinheim 2003 ISBN 3-527-30514-9523 pages 2000 refs
Book (2 volumes) Wiley-VCHA Loupy editSecond Edition(2006) 22 Chapters
Astra Zeneca ResearchFoundation Kavitha PrintersBangalore India 2002azrefiastrazenecacom
Practical Microwave Synthesis for Organic Chemists - Strategies Instruments and Protocols
Edition - 2009 X 310 Pages Hardcover Monograph
Books on Microwave-Assisted Synthesis
Microwave Ovens
Monomodal instrument
Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005
Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia
Multimodal instrument
+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile
Monomodal Vs Multimodal
Monomodal Vs Multimodal
Thermal Effects
bullMore efficient energetic coupling of solvent with microwaves
promotes higher rate of temperature increase
bull Inverted heat transfer volumetric
bull ldquoHot spotsrdquo in monomode microwaves
bull Selective on properties of material (solvents catalysts
reagents intermediates products susceptors)
Recent Applications of Microwave-Assisted Synthesis-MAOS
Hydrolysis of benzamide
thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)
The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions
R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958
Solvent-free Reactions or Solid-Solid Reactions
ldquoNo reaction proceeds without solventrdquo
Aristotle
Solventless syntheses
Green chemistry enabled advancement
Solvent-free Organic Synthesis
Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed
i n t o a p o w e r f u l m e t h o d o l o g y a s i t
reduces the amount of toxic waste produced and therefore becomes less harmful to the
e n v i r o n m e n t
Solvent-free Organic Synthesis
bull Clean and efficient synthesis
bull Economic and environmental impact
bull Fast reaction kinetics
Best solvent is no solvent
Adolf von Baeyer
Synthesis of Indigo
Towardsbenign
synthesiswith
remarkableVersatility
G W V Cave C LRaston J L ScottChemCommun
2001 2159
Solid-State General Oxidation with with Urea H2O2 Complex
R S Varma and K P Naiker Org Letters 1999 1 189
Solvent-free Oxidative Preparation of Heterocycles
Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157
Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones
Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199
Solvent-free Reduction
F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245
Carbon-Carbon Bond Formation
Toda Tanada Iwata J Org Chem 1989 54 3007
Solventless Photo Coupling and Photo Rearangements
Y Ito S Endo J Am Chem Soc 1997 119 5974
Shin Keating Maribay J Am Chem Soc 1996 118 7626
Solvent - Free Condensation
Z Gross et al Org Letters 1999 1 599
Solid-State Preparationof Dumb-bell-shaped C120
Wang Komatsu Murata Shiro Nature 1997 387 583
Advantages of Solid Mineral Supports(Alumina Silica and Clay)
Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area
The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity
Solids are generally easier and safer to handle than liquids or gaseous reagents
Inexpensive recyclable and environmentally benign nature
Solid-supported Solventless Reactions
bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation
R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43
Supported ReactionsUsing Microwaves
E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945
Microwave-Assisted Deacetylationon Alumina
Varma et al J Chem Soc Perkin Trans 1 999 (1993)
Deprotection of Benzyl Esters viaMicrowave Thermolysis
A practical alternative to traditional catalytic hydrogenation
Varma et al Tetrahedron Lett 34 4603 (1993)
Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of
Carbonyl Compounds Using Microwaves
Varma Meshram Tetrahedron Lett 38 5427 (1997)
Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm
PersulfatendashClay using Microwave and Ultrasonic Irradiation
Varma Meshram Tetrahedron Lett 38 7973 (1997)
Solid Supported Solvent-freeOxidation under MW
Varma et al Tetrahedron Lett 1997 38 2043 and 7823
Solvent-free Reduction Using MW
Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction
Varma et al Tetrahedron Lett 1997 38 4337
Hydrodechlorination under continuous MW
Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)
Synthesis of Heterocyclic Compounds
Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)
Synthesis of Heterocyclic Compounds
Organometallic Reactions
Rearrangements
Rearrangements
INDOLIZINES
Heterocyclic systems 10- electronics
Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine
Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds
N
1
2
34567
8R2
R3
R1
Why interest for indolizinic products
Strong fluorescent properties luminiscent products luminiscent products
Potentially fluorescents marker Potentially laserldquoscintillatersrdquo
bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999
Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )
Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2
ldquoCalcium-entryrdquo blockers
Indolizines by irradiation with microwaves in MCR
RBr
O+
N
R1 R2+N
R2
R1
COR
AcOAl2O3 Mw
R=Ph p-Tolil Stiril
R1= H COOMeR2= COOEt COOMe
Asymmetric indolizines by irradiation with microwaves in MCR
R1
O
Cl+ R2
N NEtOOC
OOMe
Br BrN N
EtOOC
COR1
R2COR1
R2
OOMe
2 [Pd(PPh3)2Cl24 CuI
20 echiv Et3N THF tc 2h
R1=Ph 4-OMe-C6H4R2= Ph
U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003
A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new indolizines
[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical
II
IHH
COORCOOR
N C C
O
R2NCC
O
R1
(B)
(A)
R1
O
C C N R2
O
CCN
H H
ROOC COOR
R1
O
C C N R2
O
CCN
COOR COOR
ROOC COOR
2
2 ROOC C C COOR
R1
O
C CH N R2
O
CCHN
H H
N NCH CHC C
O O
R1 R2
- 2 HX TEAanhydrous solvents
X-
X-
N NCH2 CH2C C
O O
R1 R2
C C COORH
R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5
Y=H NO2 OCH3 CH3 Cl BrX=Br Cl
bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998
bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001
bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004
bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new substituted pyridinium-indolizines
Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate
COO NO2CHC
N NH3C
OR
I IN NH3C
OR
IN NH3C
OR
I
H
KFNMP
-HI
NMP
95oC 30 min
N NH3CO
RN NH3C
O
R
O OO
NO2
O
NO2
-2[H]-2[H]
II
I II
N NH3CO
R
O O
NO2
IN NH3C
O
R
O O
NO2
I
(9a-d)(10a-d)
(15a-d)
(A) (B)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
12
34
56
78 9
10
11
12 3
4
56
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Clean Chemical Synthesis UsingAlternative Reaction Methods
Alternative Energy SourcesMicrowaveUltrasoundSunlight UV
AlternativeReactionMediaSolvent-free Supercritical FluidsIonic LiquidsWaterPolyethylene glycol (PEG)Solvent free
Microwaves in Synthesis
bull While fire is now rarely used in synthetic chemistry it was not until Robert Bunsen invented the burner in 1855 that the energy from this heat source could be applied
bull There is some controversy about the origins of the microwave power cavity called the magnetron ndash the high-power generator of microwave power
The British were particularly forward-looking in deploying radar for air defense with a system called Chain Home which began operation in 1937
Originally operating at 22 MHz frequencies increased to 55 MHz 1921 was published by AW Hull the earliest description of the magnetron a
diode with a cylindrical anode1940 It was developed practically by Randall and Booth at the University of
Birmingham in England they verified their first microwave transmissions 500 W at 3 GHz
A prototype was brought to the United States in September of that year to define an agreement whereby United States industrial capability would undertake the development of microwave radar
1940 the Radiation Laboratory was established at the Massachusetts Institute of Technology to exploit microwave radar More than 40 types of tube would be produced particularly in the S-band (ie 300 MHz) The growth of microwave radar is linked with Raytheon Company and PL Spencer who found the key to mass production
History or how it all beganhellip
bull 1946 Dr Percy Spencer-the magnetron inventor he has found a variety of technical applications in the chemical and related industries since the 1950s in particular in the food-processing drying and polymer
bull surprisingly microwave heating has only been implemented in organic synthesis since the mid-1980s
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
History or how it all beganhellip
bull 1969 ldquo Carrying out chemical reactions using microwave energy rdquo JW Vanderhoff ndash Dow Chemical Company US 3432413
bull 1986 ldquoThe Use of Microwave Ovens for Rapid Organic Synthesisrdquo Gedye R N et alTetrahedron Lett 1986 27 279
bull 1986 ldquoApplication of Commercial Microwave Ovens to Organic Synthesisrdquo Giguere R J and Majetich G Tetrahedron Lett 1986 27 4945
Energy Use in ConventionalChemical Processes
Heating Stirring Piping
Transporting Cooling
Problem of Conventional Heating
You heat what you donrsquot want to heat
Solvents for reactions apparatus
heated up and cool it down
Double energy penalty without any
apparent ldquobenefitrdquo
Energy Consumptions
Three ways to get the reaction done but different energy bills to pay
Microwaves
bull MW reactors operate at 245 GHzbull Electric field oscillates at 49 x 109 timessec ndash
10oCsec heating rate
Electromagnetic Spectrum
Neas E Collins M Introduction to Microwave Sample Preparation Theory and Practice 1988 p 8
Schematic of a Microwave
E= electric fieldH= magnetic field= wavelength (122 cm for 2450 MHz)c= speed of light (300000 kms)
Microwaves Application in Heating Food
1946 Original patent (P L Spencer)1947 First commercial oven1955 Home models1967 Desktop model1975 US sales exceed gas ranges1976 60 of US households havemicrowave ovens
Spectrum Electromagnetic
bull Electric field component
bull Responsible for dielectric heating
bull Dipolar polarization
bull Conduction
bull Magnetic field component
Microwaves ndash Dipolar Rotationbull Polar molecules have intermolecular forces which give any motion of the
molecule some inertia
bull Under a very high frequency electric field the polar molecule will attempt to follow the field but intermolecular inertia stops any significant motion before the field has reversed and no net motion results
bull If the frequency of field oscillation is very low then the molecules will be polarized uniformly and no random motion results
bull In the intermediate case the frequency of the field will be such that the molecules will be almost but not quite able to keep in phase with the field polarity
bull In this case the random motion resulting as molecules jostle to attempt in vain to follow the field provides strong agitation and intense heating of the sample
bull At 245 GHz the field oscillates 49 x 109 timess which can lead to heating
rates of 10 degC per second when powerful waves are used
MW Heating Mechanism
Alternating electric field Withhigh frequency
NoconstraintContinuous electric field
Two mechanisms Dipolar rotation polarizationIonic Conduction mechanism
Microwave Dielectric HeatingMechanisms
Dipolar PolarizationMechanism
Conduction Mechanism
Dipolar molecules try toalign to an oscillating fieldby rotation
Ions in solution will moveby the applied electricfield
Mingos D M P et al Chem Soc Rev 1991 20 1 and 1998 27 213
Microwave vs Oil-bath Heating
J-S Schanche Mol Diversity 2003 7 293wwwpersonalchemistry-com wwwbiotagecom
Conventional Heating byConduction
ConductiveheatHeating byconvectioncurrentsSlow andenergyinefficientprocess
temperature on the outside surface isin excess of the boiling point of liquid
Direct Heating by MicrowaveIrradiation
bullSolventreagent absorbs MW energybull Vessel wall transparent to MWbullDirect in-core heatingbullInstant on-off
Inverted temperature gradients
Molecular Speeds
Molecular Speeds
Microwave Ovens
Cooking Chemistry Cooking Food
Household MW ovens
The Use of Microwave Ovens for Rapid Organic Synthesis R Gedye et al Tetrahedron Lett 1986 27 279
Publications on MW-AssistedOrganic Synthesis
7 Synthetic Journals JOrgChemOrgLettTetrahedron LettTetrahedron SynthCommun Synlett SynthesisAll Journals (Full Text) Dedicated instruments only (Anton Paar Biotage CEM Milestone Prolabo)
Industrial Chemical Applications of Microwave Heating
Food Processing+ Defrosting+ Drying roasting baking+ Pasteurization
Drying Industry+ Wood fibers textiles+ Pharmaceuticals+ Brick concrete walls
Polymer Chemistry+ Rubber curing vulcanization+ Polymerization
CeramicsMaterials+ Alumina sintering+ Welding smelting gluing
Plasma+ SemiconductorsWaste Remediation+ Sewage treatment
Analytical Chemistry+ Digestion+ Extraction+ Ashing
Biochemistry Pathology+ Protein hydrolysis+ PCR proteomics+ Tissue fixation+ Histoprocessing
Medical+ Diathermy tumor detection+ Blood warming+ Sterilization (Anthrax)+ Drying of catheters
Books on Microwave-Assisted Synthesis
1048707 Fundamentals of Microwave Application1048707 Alternative Laboratory MicrowaveInstruments1048707 Chemistry Applications1048707 Biochemistry Applications1048707 Laboratory Microwave Safety
Hayes B LCEM PublishingMatthews NC2002
(ACS Professional Reference Book) H M Kingston S J Haswell (eds)
Microwaves in Organic and Medicinal ChemistryKappe C O and Stadler AWiley-VCH Weinheim 2005 ISBN 3-527-31210-2410 pages ca 1000 references
Books on Microwave-Assisted Synthesis
Lidstoumlm PTierney J P(Eds)BlackwellScientific2005
Loupy Andre (Ed)Wiley-VCH Weinheim 2003 ISBN 3-527-30514-9523 pages 2000 refs
Book (2 volumes) Wiley-VCHA Loupy editSecond Edition(2006) 22 Chapters
Astra Zeneca ResearchFoundation Kavitha PrintersBangalore India 2002azrefiastrazenecacom
Practical Microwave Synthesis for Organic Chemists - Strategies Instruments and Protocols
Edition - 2009 X 310 Pages Hardcover Monograph
Books on Microwave-Assisted Synthesis
Microwave Ovens
Monomodal instrument
Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005
Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia
Multimodal instrument
+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile
Monomodal Vs Multimodal
Monomodal Vs Multimodal
Thermal Effects
bullMore efficient energetic coupling of solvent with microwaves
promotes higher rate of temperature increase
bull Inverted heat transfer volumetric
bull ldquoHot spotsrdquo in monomode microwaves
bull Selective on properties of material (solvents catalysts
reagents intermediates products susceptors)
Recent Applications of Microwave-Assisted Synthesis-MAOS
Hydrolysis of benzamide
thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)
The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions
R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958
Solvent-free Reactions or Solid-Solid Reactions
ldquoNo reaction proceeds without solventrdquo
Aristotle
Solventless syntheses
Green chemistry enabled advancement
Solvent-free Organic Synthesis
Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed
i n t o a p o w e r f u l m e t h o d o l o g y a s i t
reduces the amount of toxic waste produced and therefore becomes less harmful to the
e n v i r o n m e n t
Solvent-free Organic Synthesis
bull Clean and efficient synthesis
bull Economic and environmental impact
bull Fast reaction kinetics
Best solvent is no solvent
Adolf von Baeyer
Synthesis of Indigo
Towardsbenign
synthesiswith
remarkableVersatility
G W V Cave C LRaston J L ScottChemCommun
2001 2159
Solid-State General Oxidation with with Urea H2O2 Complex
R S Varma and K P Naiker Org Letters 1999 1 189
Solvent-free Oxidative Preparation of Heterocycles
Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157
Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones
Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199
Solvent-free Reduction
F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245
Carbon-Carbon Bond Formation
Toda Tanada Iwata J Org Chem 1989 54 3007
Solventless Photo Coupling and Photo Rearangements
Y Ito S Endo J Am Chem Soc 1997 119 5974
Shin Keating Maribay J Am Chem Soc 1996 118 7626
Solvent - Free Condensation
Z Gross et al Org Letters 1999 1 599
Solid-State Preparationof Dumb-bell-shaped C120
Wang Komatsu Murata Shiro Nature 1997 387 583
Advantages of Solid Mineral Supports(Alumina Silica and Clay)
Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area
The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity
Solids are generally easier and safer to handle than liquids or gaseous reagents
Inexpensive recyclable and environmentally benign nature
Solid-supported Solventless Reactions
bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation
R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43
Supported ReactionsUsing Microwaves
E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945
Microwave-Assisted Deacetylationon Alumina
Varma et al J Chem Soc Perkin Trans 1 999 (1993)
Deprotection of Benzyl Esters viaMicrowave Thermolysis
A practical alternative to traditional catalytic hydrogenation
Varma et al Tetrahedron Lett 34 4603 (1993)
Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of
Carbonyl Compounds Using Microwaves
Varma Meshram Tetrahedron Lett 38 5427 (1997)
Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm
PersulfatendashClay using Microwave and Ultrasonic Irradiation
Varma Meshram Tetrahedron Lett 38 7973 (1997)
Solid Supported Solvent-freeOxidation under MW
Varma et al Tetrahedron Lett 1997 38 2043 and 7823
Solvent-free Reduction Using MW
Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction
Varma et al Tetrahedron Lett 1997 38 4337
Hydrodechlorination under continuous MW
Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)
Synthesis of Heterocyclic Compounds
Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)
Synthesis of Heterocyclic Compounds
Organometallic Reactions
Rearrangements
Rearrangements
INDOLIZINES
Heterocyclic systems 10- electronics
Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine
Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds
N
1
2
34567
8R2
R3
R1
Why interest for indolizinic products
Strong fluorescent properties luminiscent products luminiscent products
Potentially fluorescents marker Potentially laserldquoscintillatersrdquo
bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999
Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )
Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2
ldquoCalcium-entryrdquo blockers
Indolizines by irradiation with microwaves in MCR
RBr
O+
N
R1 R2+N
R2
R1
COR
AcOAl2O3 Mw
R=Ph p-Tolil Stiril
R1= H COOMeR2= COOEt COOMe
Asymmetric indolizines by irradiation with microwaves in MCR
R1
O
Cl+ R2
N NEtOOC
OOMe
Br BrN N
EtOOC
COR1
R2COR1
R2
OOMe
2 [Pd(PPh3)2Cl24 CuI
20 echiv Et3N THF tc 2h
R1=Ph 4-OMe-C6H4R2= Ph
U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003
A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new indolizines
[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical
II
IHH
COORCOOR
N C C
O
R2NCC
O
R1
(B)
(A)
R1
O
C C N R2
O
CCN
H H
ROOC COOR
R1
O
C C N R2
O
CCN
COOR COOR
ROOC COOR
2
2 ROOC C C COOR
R1
O
C CH N R2
O
CCHN
H H
N NCH CHC C
O O
R1 R2
- 2 HX TEAanhydrous solvents
X-
X-
N NCH2 CH2C C
O O
R1 R2
C C COORH
R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5
Y=H NO2 OCH3 CH3 Cl BrX=Br Cl
bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998
bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001
bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004
bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new substituted pyridinium-indolizines
Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate
COO NO2CHC
N NH3C
OR
I IN NH3C
OR
IN NH3C
OR
I
H
KFNMP
-HI
NMP
95oC 30 min
N NH3CO
RN NH3C
O
R
O OO
NO2
O
NO2
-2[H]-2[H]
II
I II
N NH3CO
R
O O
NO2
IN NH3C
O
R
O O
NO2
I
(9a-d)(10a-d)
(15a-d)
(A) (B)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
12
34
56
78 9
10
11
12 3
4
56
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Microwaves in Synthesis
bull While fire is now rarely used in synthetic chemistry it was not until Robert Bunsen invented the burner in 1855 that the energy from this heat source could be applied
bull There is some controversy about the origins of the microwave power cavity called the magnetron ndash the high-power generator of microwave power
The British were particularly forward-looking in deploying radar for air defense with a system called Chain Home which began operation in 1937
Originally operating at 22 MHz frequencies increased to 55 MHz 1921 was published by AW Hull the earliest description of the magnetron a
diode with a cylindrical anode1940 It was developed practically by Randall and Booth at the University of
Birmingham in England they verified their first microwave transmissions 500 W at 3 GHz
A prototype was brought to the United States in September of that year to define an agreement whereby United States industrial capability would undertake the development of microwave radar
1940 the Radiation Laboratory was established at the Massachusetts Institute of Technology to exploit microwave radar More than 40 types of tube would be produced particularly in the S-band (ie 300 MHz) The growth of microwave radar is linked with Raytheon Company and PL Spencer who found the key to mass production
History or how it all beganhellip
bull 1946 Dr Percy Spencer-the magnetron inventor he has found a variety of technical applications in the chemical and related industries since the 1950s in particular in the food-processing drying and polymer
bull surprisingly microwave heating has only been implemented in organic synthesis since the mid-1980s
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
History or how it all beganhellip
bull 1969 ldquo Carrying out chemical reactions using microwave energy rdquo JW Vanderhoff ndash Dow Chemical Company US 3432413
bull 1986 ldquoThe Use of Microwave Ovens for Rapid Organic Synthesisrdquo Gedye R N et alTetrahedron Lett 1986 27 279
bull 1986 ldquoApplication of Commercial Microwave Ovens to Organic Synthesisrdquo Giguere R J and Majetich G Tetrahedron Lett 1986 27 4945
Energy Use in ConventionalChemical Processes
Heating Stirring Piping
Transporting Cooling
Problem of Conventional Heating
You heat what you donrsquot want to heat
Solvents for reactions apparatus
heated up and cool it down
Double energy penalty without any
apparent ldquobenefitrdquo
Energy Consumptions
Three ways to get the reaction done but different energy bills to pay
Microwaves
bull MW reactors operate at 245 GHzbull Electric field oscillates at 49 x 109 timessec ndash
10oCsec heating rate
Electromagnetic Spectrum
Neas E Collins M Introduction to Microwave Sample Preparation Theory and Practice 1988 p 8
Schematic of a Microwave
E= electric fieldH= magnetic field= wavelength (122 cm for 2450 MHz)c= speed of light (300000 kms)
Microwaves Application in Heating Food
1946 Original patent (P L Spencer)1947 First commercial oven1955 Home models1967 Desktop model1975 US sales exceed gas ranges1976 60 of US households havemicrowave ovens
Spectrum Electromagnetic
bull Electric field component
bull Responsible for dielectric heating
bull Dipolar polarization
bull Conduction
bull Magnetic field component
Microwaves ndash Dipolar Rotationbull Polar molecules have intermolecular forces which give any motion of the
molecule some inertia
bull Under a very high frequency electric field the polar molecule will attempt to follow the field but intermolecular inertia stops any significant motion before the field has reversed and no net motion results
bull If the frequency of field oscillation is very low then the molecules will be polarized uniformly and no random motion results
bull In the intermediate case the frequency of the field will be such that the molecules will be almost but not quite able to keep in phase with the field polarity
bull In this case the random motion resulting as molecules jostle to attempt in vain to follow the field provides strong agitation and intense heating of the sample
bull At 245 GHz the field oscillates 49 x 109 timess which can lead to heating
rates of 10 degC per second when powerful waves are used
MW Heating Mechanism
Alternating electric field Withhigh frequency
NoconstraintContinuous electric field
Two mechanisms Dipolar rotation polarizationIonic Conduction mechanism
Microwave Dielectric HeatingMechanisms
Dipolar PolarizationMechanism
Conduction Mechanism
Dipolar molecules try toalign to an oscillating fieldby rotation
Ions in solution will moveby the applied electricfield
Mingos D M P et al Chem Soc Rev 1991 20 1 and 1998 27 213
Microwave vs Oil-bath Heating
J-S Schanche Mol Diversity 2003 7 293wwwpersonalchemistry-com wwwbiotagecom
Conventional Heating byConduction
ConductiveheatHeating byconvectioncurrentsSlow andenergyinefficientprocess
temperature on the outside surface isin excess of the boiling point of liquid
Direct Heating by MicrowaveIrradiation
bullSolventreagent absorbs MW energybull Vessel wall transparent to MWbullDirect in-core heatingbullInstant on-off
Inverted temperature gradients
Molecular Speeds
Molecular Speeds
Microwave Ovens
Cooking Chemistry Cooking Food
Household MW ovens
The Use of Microwave Ovens for Rapid Organic Synthesis R Gedye et al Tetrahedron Lett 1986 27 279
Publications on MW-AssistedOrganic Synthesis
7 Synthetic Journals JOrgChemOrgLettTetrahedron LettTetrahedron SynthCommun Synlett SynthesisAll Journals (Full Text) Dedicated instruments only (Anton Paar Biotage CEM Milestone Prolabo)
Industrial Chemical Applications of Microwave Heating
Food Processing+ Defrosting+ Drying roasting baking+ Pasteurization
Drying Industry+ Wood fibers textiles+ Pharmaceuticals+ Brick concrete walls
Polymer Chemistry+ Rubber curing vulcanization+ Polymerization
CeramicsMaterials+ Alumina sintering+ Welding smelting gluing
Plasma+ SemiconductorsWaste Remediation+ Sewage treatment
Analytical Chemistry+ Digestion+ Extraction+ Ashing
Biochemistry Pathology+ Protein hydrolysis+ PCR proteomics+ Tissue fixation+ Histoprocessing
Medical+ Diathermy tumor detection+ Blood warming+ Sterilization (Anthrax)+ Drying of catheters
Books on Microwave-Assisted Synthesis
1048707 Fundamentals of Microwave Application1048707 Alternative Laboratory MicrowaveInstruments1048707 Chemistry Applications1048707 Biochemistry Applications1048707 Laboratory Microwave Safety
Hayes B LCEM PublishingMatthews NC2002
(ACS Professional Reference Book) H M Kingston S J Haswell (eds)
Microwaves in Organic and Medicinal ChemistryKappe C O and Stadler AWiley-VCH Weinheim 2005 ISBN 3-527-31210-2410 pages ca 1000 references
Books on Microwave-Assisted Synthesis
Lidstoumlm PTierney J P(Eds)BlackwellScientific2005
Loupy Andre (Ed)Wiley-VCH Weinheim 2003 ISBN 3-527-30514-9523 pages 2000 refs
Book (2 volumes) Wiley-VCHA Loupy editSecond Edition(2006) 22 Chapters
Astra Zeneca ResearchFoundation Kavitha PrintersBangalore India 2002azrefiastrazenecacom
Practical Microwave Synthesis for Organic Chemists - Strategies Instruments and Protocols
Edition - 2009 X 310 Pages Hardcover Monograph
Books on Microwave-Assisted Synthesis
Microwave Ovens
Monomodal instrument
Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005
Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia
Multimodal instrument
+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile
Monomodal Vs Multimodal
Monomodal Vs Multimodal
Thermal Effects
bullMore efficient energetic coupling of solvent with microwaves
promotes higher rate of temperature increase
bull Inverted heat transfer volumetric
bull ldquoHot spotsrdquo in monomode microwaves
bull Selective on properties of material (solvents catalysts
reagents intermediates products susceptors)
Recent Applications of Microwave-Assisted Synthesis-MAOS
Hydrolysis of benzamide
thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)
The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions
R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958
Solvent-free Reactions or Solid-Solid Reactions
ldquoNo reaction proceeds without solventrdquo
Aristotle
Solventless syntheses
Green chemistry enabled advancement
Solvent-free Organic Synthesis
Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed
i n t o a p o w e r f u l m e t h o d o l o g y a s i t
reduces the amount of toxic waste produced and therefore becomes less harmful to the
e n v i r o n m e n t
Solvent-free Organic Synthesis
bull Clean and efficient synthesis
bull Economic and environmental impact
bull Fast reaction kinetics
Best solvent is no solvent
Adolf von Baeyer
Synthesis of Indigo
Towardsbenign
synthesiswith
remarkableVersatility
G W V Cave C LRaston J L ScottChemCommun
2001 2159
Solid-State General Oxidation with with Urea H2O2 Complex
R S Varma and K P Naiker Org Letters 1999 1 189
Solvent-free Oxidative Preparation of Heterocycles
Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157
Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones
Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199
Solvent-free Reduction
F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245
Carbon-Carbon Bond Formation
Toda Tanada Iwata J Org Chem 1989 54 3007
Solventless Photo Coupling and Photo Rearangements
Y Ito S Endo J Am Chem Soc 1997 119 5974
Shin Keating Maribay J Am Chem Soc 1996 118 7626
Solvent - Free Condensation
Z Gross et al Org Letters 1999 1 599
Solid-State Preparationof Dumb-bell-shaped C120
Wang Komatsu Murata Shiro Nature 1997 387 583
Advantages of Solid Mineral Supports(Alumina Silica and Clay)
Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area
The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity
Solids are generally easier and safer to handle than liquids or gaseous reagents
Inexpensive recyclable and environmentally benign nature
Solid-supported Solventless Reactions
bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation
R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43
Supported ReactionsUsing Microwaves
E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945
Microwave-Assisted Deacetylationon Alumina
Varma et al J Chem Soc Perkin Trans 1 999 (1993)
Deprotection of Benzyl Esters viaMicrowave Thermolysis
A practical alternative to traditional catalytic hydrogenation
Varma et al Tetrahedron Lett 34 4603 (1993)
Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of
Carbonyl Compounds Using Microwaves
Varma Meshram Tetrahedron Lett 38 5427 (1997)
Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm
PersulfatendashClay using Microwave and Ultrasonic Irradiation
Varma Meshram Tetrahedron Lett 38 7973 (1997)
Solid Supported Solvent-freeOxidation under MW
Varma et al Tetrahedron Lett 1997 38 2043 and 7823
Solvent-free Reduction Using MW
Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction
Varma et al Tetrahedron Lett 1997 38 4337
Hydrodechlorination under continuous MW
Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)
Synthesis of Heterocyclic Compounds
Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)
Synthesis of Heterocyclic Compounds
Organometallic Reactions
Rearrangements
Rearrangements
INDOLIZINES
Heterocyclic systems 10- electronics
Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine
Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds
N
1
2
34567
8R2
R3
R1
Why interest for indolizinic products
Strong fluorescent properties luminiscent products luminiscent products
Potentially fluorescents marker Potentially laserldquoscintillatersrdquo
bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999
Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )
Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2
ldquoCalcium-entryrdquo blockers
Indolizines by irradiation with microwaves in MCR
RBr
O+
N
R1 R2+N
R2
R1
COR
AcOAl2O3 Mw
R=Ph p-Tolil Stiril
R1= H COOMeR2= COOEt COOMe
Asymmetric indolizines by irradiation with microwaves in MCR
R1
O
Cl+ R2
N NEtOOC
OOMe
Br BrN N
EtOOC
COR1
R2COR1
R2
OOMe
2 [Pd(PPh3)2Cl24 CuI
20 echiv Et3N THF tc 2h
R1=Ph 4-OMe-C6H4R2= Ph
U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003
A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new indolizines
[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical
II
IHH
COORCOOR
N C C
O
R2NCC
O
R1
(B)
(A)
R1
O
C C N R2
O
CCN
H H
ROOC COOR
R1
O
C C N R2
O
CCN
COOR COOR
ROOC COOR
2
2 ROOC C C COOR
R1
O
C CH N R2
O
CCHN
H H
N NCH CHC C
O O
R1 R2
- 2 HX TEAanhydrous solvents
X-
X-
N NCH2 CH2C C
O O
R1 R2
C C COORH
R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5
Y=H NO2 OCH3 CH3 Cl BrX=Br Cl
bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998
bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001
bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004
bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new substituted pyridinium-indolizines
Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate
COO NO2CHC
N NH3C
OR
I IN NH3C
OR
IN NH3C
OR
I
H
KFNMP
-HI
NMP
95oC 30 min
N NH3CO
RN NH3C
O
R
O OO
NO2
O
NO2
-2[H]-2[H]
II
I II
N NH3CO
R
O O
NO2
IN NH3C
O
R
O O
NO2
I
(9a-d)(10a-d)
(15a-d)
(A) (B)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
12
34
56
78 9
10
11
12 3
4
56
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
bull While fire is now rarely used in synthetic chemistry it was not until Robert Bunsen invented the burner in 1855 that the energy from this heat source could be applied
bull There is some controversy about the origins of the microwave power cavity called the magnetron ndash the high-power generator of microwave power
The British were particularly forward-looking in deploying radar for air defense with a system called Chain Home which began operation in 1937
Originally operating at 22 MHz frequencies increased to 55 MHz 1921 was published by AW Hull the earliest description of the magnetron a
diode with a cylindrical anode1940 It was developed practically by Randall and Booth at the University of
Birmingham in England they verified their first microwave transmissions 500 W at 3 GHz
A prototype was brought to the United States in September of that year to define an agreement whereby United States industrial capability would undertake the development of microwave radar
1940 the Radiation Laboratory was established at the Massachusetts Institute of Technology to exploit microwave radar More than 40 types of tube would be produced particularly in the S-band (ie 300 MHz) The growth of microwave radar is linked with Raytheon Company and PL Spencer who found the key to mass production
History or how it all beganhellip
bull 1946 Dr Percy Spencer-the magnetron inventor he has found a variety of technical applications in the chemical and related industries since the 1950s in particular in the food-processing drying and polymer
bull surprisingly microwave heating has only been implemented in organic synthesis since the mid-1980s
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
History or how it all beganhellip
bull 1969 ldquo Carrying out chemical reactions using microwave energy rdquo JW Vanderhoff ndash Dow Chemical Company US 3432413
bull 1986 ldquoThe Use of Microwave Ovens for Rapid Organic Synthesisrdquo Gedye R N et alTetrahedron Lett 1986 27 279
bull 1986 ldquoApplication of Commercial Microwave Ovens to Organic Synthesisrdquo Giguere R J and Majetich G Tetrahedron Lett 1986 27 4945
Energy Use in ConventionalChemical Processes
Heating Stirring Piping
Transporting Cooling
Problem of Conventional Heating
You heat what you donrsquot want to heat
Solvents for reactions apparatus
heated up and cool it down
Double energy penalty without any
apparent ldquobenefitrdquo
Energy Consumptions
Three ways to get the reaction done but different energy bills to pay
Microwaves
bull MW reactors operate at 245 GHzbull Electric field oscillates at 49 x 109 timessec ndash
10oCsec heating rate
Electromagnetic Spectrum
Neas E Collins M Introduction to Microwave Sample Preparation Theory and Practice 1988 p 8
Schematic of a Microwave
E= electric fieldH= magnetic field= wavelength (122 cm for 2450 MHz)c= speed of light (300000 kms)
Microwaves Application in Heating Food
1946 Original patent (P L Spencer)1947 First commercial oven1955 Home models1967 Desktop model1975 US sales exceed gas ranges1976 60 of US households havemicrowave ovens
Spectrum Electromagnetic
bull Electric field component
bull Responsible for dielectric heating
bull Dipolar polarization
bull Conduction
bull Magnetic field component
Microwaves ndash Dipolar Rotationbull Polar molecules have intermolecular forces which give any motion of the
molecule some inertia
bull Under a very high frequency electric field the polar molecule will attempt to follow the field but intermolecular inertia stops any significant motion before the field has reversed and no net motion results
bull If the frequency of field oscillation is very low then the molecules will be polarized uniformly and no random motion results
bull In the intermediate case the frequency of the field will be such that the molecules will be almost but not quite able to keep in phase with the field polarity
bull In this case the random motion resulting as molecules jostle to attempt in vain to follow the field provides strong agitation and intense heating of the sample
bull At 245 GHz the field oscillates 49 x 109 timess which can lead to heating
rates of 10 degC per second when powerful waves are used
MW Heating Mechanism
Alternating electric field Withhigh frequency
NoconstraintContinuous electric field
Two mechanisms Dipolar rotation polarizationIonic Conduction mechanism
Microwave Dielectric HeatingMechanisms
Dipolar PolarizationMechanism
Conduction Mechanism
Dipolar molecules try toalign to an oscillating fieldby rotation
Ions in solution will moveby the applied electricfield
Mingos D M P et al Chem Soc Rev 1991 20 1 and 1998 27 213
Microwave vs Oil-bath Heating
J-S Schanche Mol Diversity 2003 7 293wwwpersonalchemistry-com wwwbiotagecom
Conventional Heating byConduction
ConductiveheatHeating byconvectioncurrentsSlow andenergyinefficientprocess
temperature on the outside surface isin excess of the boiling point of liquid
Direct Heating by MicrowaveIrradiation
bullSolventreagent absorbs MW energybull Vessel wall transparent to MWbullDirect in-core heatingbullInstant on-off
Inverted temperature gradients
Molecular Speeds
Molecular Speeds
Microwave Ovens
Cooking Chemistry Cooking Food
Household MW ovens
The Use of Microwave Ovens for Rapid Organic Synthesis R Gedye et al Tetrahedron Lett 1986 27 279
Publications on MW-AssistedOrganic Synthesis
7 Synthetic Journals JOrgChemOrgLettTetrahedron LettTetrahedron SynthCommun Synlett SynthesisAll Journals (Full Text) Dedicated instruments only (Anton Paar Biotage CEM Milestone Prolabo)
Industrial Chemical Applications of Microwave Heating
Food Processing+ Defrosting+ Drying roasting baking+ Pasteurization
Drying Industry+ Wood fibers textiles+ Pharmaceuticals+ Brick concrete walls
Polymer Chemistry+ Rubber curing vulcanization+ Polymerization
CeramicsMaterials+ Alumina sintering+ Welding smelting gluing
Plasma+ SemiconductorsWaste Remediation+ Sewage treatment
Analytical Chemistry+ Digestion+ Extraction+ Ashing
Biochemistry Pathology+ Protein hydrolysis+ PCR proteomics+ Tissue fixation+ Histoprocessing
Medical+ Diathermy tumor detection+ Blood warming+ Sterilization (Anthrax)+ Drying of catheters
Books on Microwave-Assisted Synthesis
1048707 Fundamentals of Microwave Application1048707 Alternative Laboratory MicrowaveInstruments1048707 Chemistry Applications1048707 Biochemistry Applications1048707 Laboratory Microwave Safety
Hayes B LCEM PublishingMatthews NC2002
(ACS Professional Reference Book) H M Kingston S J Haswell (eds)
Microwaves in Organic and Medicinal ChemistryKappe C O and Stadler AWiley-VCH Weinheim 2005 ISBN 3-527-31210-2410 pages ca 1000 references
Books on Microwave-Assisted Synthesis
Lidstoumlm PTierney J P(Eds)BlackwellScientific2005
Loupy Andre (Ed)Wiley-VCH Weinheim 2003 ISBN 3-527-30514-9523 pages 2000 refs
Book (2 volumes) Wiley-VCHA Loupy editSecond Edition(2006) 22 Chapters
Astra Zeneca ResearchFoundation Kavitha PrintersBangalore India 2002azrefiastrazenecacom
Practical Microwave Synthesis for Organic Chemists - Strategies Instruments and Protocols
Edition - 2009 X 310 Pages Hardcover Monograph
Books on Microwave-Assisted Synthesis
Microwave Ovens
Monomodal instrument
Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005
Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia
Multimodal instrument
+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile
Monomodal Vs Multimodal
Monomodal Vs Multimodal
Thermal Effects
bullMore efficient energetic coupling of solvent with microwaves
promotes higher rate of temperature increase
bull Inverted heat transfer volumetric
bull ldquoHot spotsrdquo in monomode microwaves
bull Selective on properties of material (solvents catalysts
reagents intermediates products susceptors)
Recent Applications of Microwave-Assisted Synthesis-MAOS
Hydrolysis of benzamide
thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)
The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions
R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958
Solvent-free Reactions or Solid-Solid Reactions
ldquoNo reaction proceeds without solventrdquo
Aristotle
Solventless syntheses
Green chemistry enabled advancement
Solvent-free Organic Synthesis
Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed
i n t o a p o w e r f u l m e t h o d o l o g y a s i t
reduces the amount of toxic waste produced and therefore becomes less harmful to the
e n v i r o n m e n t
Solvent-free Organic Synthesis
bull Clean and efficient synthesis
bull Economic and environmental impact
bull Fast reaction kinetics
Best solvent is no solvent
Adolf von Baeyer
Synthesis of Indigo
Towardsbenign
synthesiswith
remarkableVersatility
G W V Cave C LRaston J L ScottChemCommun
2001 2159
Solid-State General Oxidation with with Urea H2O2 Complex
R S Varma and K P Naiker Org Letters 1999 1 189
Solvent-free Oxidative Preparation of Heterocycles
Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157
Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones
Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199
Solvent-free Reduction
F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245
Carbon-Carbon Bond Formation
Toda Tanada Iwata J Org Chem 1989 54 3007
Solventless Photo Coupling and Photo Rearangements
Y Ito S Endo J Am Chem Soc 1997 119 5974
Shin Keating Maribay J Am Chem Soc 1996 118 7626
Solvent - Free Condensation
Z Gross et al Org Letters 1999 1 599
Solid-State Preparationof Dumb-bell-shaped C120
Wang Komatsu Murata Shiro Nature 1997 387 583
Advantages of Solid Mineral Supports(Alumina Silica and Clay)
Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area
The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity
Solids are generally easier and safer to handle than liquids or gaseous reagents
Inexpensive recyclable and environmentally benign nature
Solid-supported Solventless Reactions
bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation
R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43
Supported ReactionsUsing Microwaves
E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945
Microwave-Assisted Deacetylationon Alumina
Varma et al J Chem Soc Perkin Trans 1 999 (1993)
Deprotection of Benzyl Esters viaMicrowave Thermolysis
A practical alternative to traditional catalytic hydrogenation
Varma et al Tetrahedron Lett 34 4603 (1993)
Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of
Carbonyl Compounds Using Microwaves
Varma Meshram Tetrahedron Lett 38 5427 (1997)
Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm
PersulfatendashClay using Microwave and Ultrasonic Irradiation
Varma Meshram Tetrahedron Lett 38 7973 (1997)
Solid Supported Solvent-freeOxidation under MW
Varma et al Tetrahedron Lett 1997 38 2043 and 7823
Solvent-free Reduction Using MW
Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction
Varma et al Tetrahedron Lett 1997 38 4337
Hydrodechlorination under continuous MW
Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)
Synthesis of Heterocyclic Compounds
Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)
Synthesis of Heterocyclic Compounds
Organometallic Reactions
Rearrangements
Rearrangements
INDOLIZINES
Heterocyclic systems 10- electronics
Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine
Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds
N
1
2
34567
8R2
R3
R1
Why interest for indolizinic products
Strong fluorescent properties luminiscent products luminiscent products
Potentially fluorescents marker Potentially laserldquoscintillatersrdquo
bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999
Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )
Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2
ldquoCalcium-entryrdquo blockers
Indolizines by irradiation with microwaves in MCR
RBr
O+
N
R1 R2+N
R2
R1
COR
AcOAl2O3 Mw
R=Ph p-Tolil Stiril
R1= H COOMeR2= COOEt COOMe
Asymmetric indolizines by irradiation with microwaves in MCR
R1
O
Cl+ R2
N NEtOOC
OOMe
Br BrN N
EtOOC
COR1
R2COR1
R2
OOMe
2 [Pd(PPh3)2Cl24 CuI
20 echiv Et3N THF tc 2h
R1=Ph 4-OMe-C6H4R2= Ph
U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003
A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new indolizines
[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical
II
IHH
COORCOOR
N C C
O
R2NCC
O
R1
(B)
(A)
R1
O
C C N R2
O
CCN
H H
ROOC COOR
R1
O
C C N R2
O
CCN
COOR COOR
ROOC COOR
2
2 ROOC C C COOR
R1
O
C CH N R2
O
CCHN
H H
N NCH CHC C
O O
R1 R2
- 2 HX TEAanhydrous solvents
X-
X-
N NCH2 CH2C C
O O
R1 R2
C C COORH
R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5
Y=H NO2 OCH3 CH3 Cl BrX=Br Cl
bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998
bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001
bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004
bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new substituted pyridinium-indolizines
Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate
COO NO2CHC
N NH3C
OR
I IN NH3C
OR
IN NH3C
OR
I
H
KFNMP
-HI
NMP
95oC 30 min
N NH3CO
RN NH3C
O
R
O OO
NO2
O
NO2
-2[H]-2[H]
II
I II
N NH3CO
R
O O
NO2
IN NH3C
O
R
O O
NO2
I
(9a-d)(10a-d)
(15a-d)
(A) (B)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
12
34
56
78 9
10
11
12 3
4
56
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
bull 1946 Dr Percy Spencer-the magnetron inventor he has found a variety of technical applications in the chemical and related industries since the 1950s in particular in the food-processing drying and polymer
bull surprisingly microwave heating has only been implemented in organic synthesis since the mid-1980s
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
History or how it all beganhellip
bull 1969 ldquo Carrying out chemical reactions using microwave energy rdquo JW Vanderhoff ndash Dow Chemical Company US 3432413
bull 1986 ldquoThe Use of Microwave Ovens for Rapid Organic Synthesisrdquo Gedye R N et alTetrahedron Lett 1986 27 279
bull 1986 ldquoApplication of Commercial Microwave Ovens to Organic Synthesisrdquo Giguere R J and Majetich G Tetrahedron Lett 1986 27 4945
Energy Use in ConventionalChemical Processes
Heating Stirring Piping
Transporting Cooling
Problem of Conventional Heating
You heat what you donrsquot want to heat
Solvents for reactions apparatus
heated up and cool it down
Double energy penalty without any
apparent ldquobenefitrdquo
Energy Consumptions
Three ways to get the reaction done but different energy bills to pay
Microwaves
bull MW reactors operate at 245 GHzbull Electric field oscillates at 49 x 109 timessec ndash
10oCsec heating rate
Electromagnetic Spectrum
Neas E Collins M Introduction to Microwave Sample Preparation Theory and Practice 1988 p 8
Schematic of a Microwave
E= electric fieldH= magnetic field= wavelength (122 cm for 2450 MHz)c= speed of light (300000 kms)
Microwaves Application in Heating Food
1946 Original patent (P L Spencer)1947 First commercial oven1955 Home models1967 Desktop model1975 US sales exceed gas ranges1976 60 of US households havemicrowave ovens
Spectrum Electromagnetic
bull Electric field component
bull Responsible for dielectric heating
bull Dipolar polarization
bull Conduction
bull Magnetic field component
Microwaves ndash Dipolar Rotationbull Polar molecules have intermolecular forces which give any motion of the
molecule some inertia
bull Under a very high frequency electric field the polar molecule will attempt to follow the field but intermolecular inertia stops any significant motion before the field has reversed and no net motion results
bull If the frequency of field oscillation is very low then the molecules will be polarized uniformly and no random motion results
bull In the intermediate case the frequency of the field will be such that the molecules will be almost but not quite able to keep in phase with the field polarity
bull In this case the random motion resulting as molecules jostle to attempt in vain to follow the field provides strong agitation and intense heating of the sample
bull At 245 GHz the field oscillates 49 x 109 timess which can lead to heating
rates of 10 degC per second when powerful waves are used
MW Heating Mechanism
Alternating electric field Withhigh frequency
NoconstraintContinuous electric field
Two mechanisms Dipolar rotation polarizationIonic Conduction mechanism
Microwave Dielectric HeatingMechanisms
Dipolar PolarizationMechanism
Conduction Mechanism
Dipolar molecules try toalign to an oscillating fieldby rotation
Ions in solution will moveby the applied electricfield
Mingos D M P et al Chem Soc Rev 1991 20 1 and 1998 27 213
Microwave vs Oil-bath Heating
J-S Schanche Mol Diversity 2003 7 293wwwpersonalchemistry-com wwwbiotagecom
Conventional Heating byConduction
ConductiveheatHeating byconvectioncurrentsSlow andenergyinefficientprocess
temperature on the outside surface isin excess of the boiling point of liquid
Direct Heating by MicrowaveIrradiation
bullSolventreagent absorbs MW energybull Vessel wall transparent to MWbullDirect in-core heatingbullInstant on-off
Inverted temperature gradients
Molecular Speeds
Molecular Speeds
Microwave Ovens
Cooking Chemistry Cooking Food
Household MW ovens
The Use of Microwave Ovens for Rapid Organic Synthesis R Gedye et al Tetrahedron Lett 1986 27 279
Publications on MW-AssistedOrganic Synthesis
7 Synthetic Journals JOrgChemOrgLettTetrahedron LettTetrahedron SynthCommun Synlett SynthesisAll Journals (Full Text) Dedicated instruments only (Anton Paar Biotage CEM Milestone Prolabo)
Industrial Chemical Applications of Microwave Heating
Food Processing+ Defrosting+ Drying roasting baking+ Pasteurization
Drying Industry+ Wood fibers textiles+ Pharmaceuticals+ Brick concrete walls
Polymer Chemistry+ Rubber curing vulcanization+ Polymerization
CeramicsMaterials+ Alumina sintering+ Welding smelting gluing
Plasma+ SemiconductorsWaste Remediation+ Sewage treatment
Analytical Chemistry+ Digestion+ Extraction+ Ashing
Biochemistry Pathology+ Protein hydrolysis+ PCR proteomics+ Tissue fixation+ Histoprocessing
Medical+ Diathermy tumor detection+ Blood warming+ Sterilization (Anthrax)+ Drying of catheters
Books on Microwave-Assisted Synthesis
1048707 Fundamentals of Microwave Application1048707 Alternative Laboratory MicrowaveInstruments1048707 Chemistry Applications1048707 Biochemistry Applications1048707 Laboratory Microwave Safety
Hayes B LCEM PublishingMatthews NC2002
(ACS Professional Reference Book) H M Kingston S J Haswell (eds)
Microwaves in Organic and Medicinal ChemistryKappe C O and Stadler AWiley-VCH Weinheim 2005 ISBN 3-527-31210-2410 pages ca 1000 references
Books on Microwave-Assisted Synthesis
Lidstoumlm PTierney J P(Eds)BlackwellScientific2005
Loupy Andre (Ed)Wiley-VCH Weinheim 2003 ISBN 3-527-30514-9523 pages 2000 refs
Book (2 volumes) Wiley-VCHA Loupy editSecond Edition(2006) 22 Chapters
Astra Zeneca ResearchFoundation Kavitha PrintersBangalore India 2002azrefiastrazenecacom
Practical Microwave Synthesis for Organic Chemists - Strategies Instruments and Protocols
Edition - 2009 X 310 Pages Hardcover Monograph
Books on Microwave-Assisted Synthesis
Microwave Ovens
Monomodal instrument
Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005
Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia
Multimodal instrument
+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile
Monomodal Vs Multimodal
Monomodal Vs Multimodal
Thermal Effects
bullMore efficient energetic coupling of solvent with microwaves
promotes higher rate of temperature increase
bull Inverted heat transfer volumetric
bull ldquoHot spotsrdquo in monomode microwaves
bull Selective on properties of material (solvents catalysts
reagents intermediates products susceptors)
Recent Applications of Microwave-Assisted Synthesis-MAOS
Hydrolysis of benzamide
thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)
The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions
R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958
Solvent-free Reactions or Solid-Solid Reactions
ldquoNo reaction proceeds without solventrdquo
Aristotle
Solventless syntheses
Green chemistry enabled advancement
Solvent-free Organic Synthesis
Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed
i n t o a p o w e r f u l m e t h o d o l o g y a s i t
reduces the amount of toxic waste produced and therefore becomes less harmful to the
e n v i r o n m e n t
Solvent-free Organic Synthesis
bull Clean and efficient synthesis
bull Economic and environmental impact
bull Fast reaction kinetics
Best solvent is no solvent
Adolf von Baeyer
Synthesis of Indigo
Towardsbenign
synthesiswith
remarkableVersatility
G W V Cave C LRaston J L ScottChemCommun
2001 2159
Solid-State General Oxidation with with Urea H2O2 Complex
R S Varma and K P Naiker Org Letters 1999 1 189
Solvent-free Oxidative Preparation of Heterocycles
Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157
Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones
Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199
Solvent-free Reduction
F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245
Carbon-Carbon Bond Formation
Toda Tanada Iwata J Org Chem 1989 54 3007
Solventless Photo Coupling and Photo Rearangements
Y Ito S Endo J Am Chem Soc 1997 119 5974
Shin Keating Maribay J Am Chem Soc 1996 118 7626
Solvent - Free Condensation
Z Gross et al Org Letters 1999 1 599
Solid-State Preparationof Dumb-bell-shaped C120
Wang Komatsu Murata Shiro Nature 1997 387 583
Advantages of Solid Mineral Supports(Alumina Silica and Clay)
Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area
The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity
Solids are generally easier and safer to handle than liquids or gaseous reagents
Inexpensive recyclable and environmentally benign nature
Solid-supported Solventless Reactions
bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation
R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43
Supported ReactionsUsing Microwaves
E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945
Microwave-Assisted Deacetylationon Alumina
Varma et al J Chem Soc Perkin Trans 1 999 (1993)
Deprotection of Benzyl Esters viaMicrowave Thermolysis
A practical alternative to traditional catalytic hydrogenation
Varma et al Tetrahedron Lett 34 4603 (1993)
Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of
Carbonyl Compounds Using Microwaves
Varma Meshram Tetrahedron Lett 38 5427 (1997)
Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm
PersulfatendashClay using Microwave and Ultrasonic Irradiation
Varma Meshram Tetrahedron Lett 38 7973 (1997)
Solid Supported Solvent-freeOxidation under MW
Varma et al Tetrahedron Lett 1997 38 2043 and 7823
Solvent-free Reduction Using MW
Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction
Varma et al Tetrahedron Lett 1997 38 4337
Hydrodechlorination under continuous MW
Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)
Synthesis of Heterocyclic Compounds
Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)
Synthesis of Heterocyclic Compounds
Organometallic Reactions
Rearrangements
Rearrangements
INDOLIZINES
Heterocyclic systems 10- electronics
Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine
Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds
N
1
2
34567
8R2
R3
R1
Why interest for indolizinic products
Strong fluorescent properties luminiscent products luminiscent products
Potentially fluorescents marker Potentially laserldquoscintillatersrdquo
bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999
Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )
Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2
ldquoCalcium-entryrdquo blockers
Indolizines by irradiation with microwaves in MCR
RBr
O+
N
R1 R2+N
R2
R1
COR
AcOAl2O3 Mw
R=Ph p-Tolil Stiril
R1= H COOMeR2= COOEt COOMe
Asymmetric indolizines by irradiation with microwaves in MCR
R1
O
Cl+ R2
N NEtOOC
OOMe
Br BrN N
EtOOC
COR1
R2COR1
R2
OOMe
2 [Pd(PPh3)2Cl24 CuI
20 echiv Et3N THF tc 2h
R1=Ph 4-OMe-C6H4R2= Ph
U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003
A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new indolizines
[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical
II
IHH
COORCOOR
N C C
O
R2NCC
O
R1
(B)
(A)
R1
O
C C N R2
O
CCN
H H
ROOC COOR
R1
O
C C N R2
O
CCN
COOR COOR
ROOC COOR
2
2 ROOC C C COOR
R1
O
C CH N R2
O
CCHN
H H
N NCH CHC C
O O
R1 R2
- 2 HX TEAanhydrous solvents
X-
X-
N NCH2 CH2C C
O O
R1 R2
C C COORH
R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5
Y=H NO2 OCH3 CH3 Cl BrX=Br Cl
bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998
bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001
bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004
bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new substituted pyridinium-indolizines
Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate
COO NO2CHC
N NH3C
OR
I IN NH3C
OR
IN NH3C
OR
I
H
KFNMP
-HI
NMP
95oC 30 min
N NH3CO
RN NH3C
O
R
O OO
NO2
O
NO2
-2[H]-2[H]
II
I II
N NH3CO
R
O O
NO2
IN NH3C
O
R
O O
NO2
I
(9a-d)(10a-d)
(15a-d)
(A) (B)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
12
34
56
78 9
10
11
12 3
4
56
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
bull 1969 ldquo Carrying out chemical reactions using microwave energy rdquo JW Vanderhoff ndash Dow Chemical Company US 3432413
bull 1986 ldquoThe Use of Microwave Ovens for Rapid Organic Synthesisrdquo Gedye R N et alTetrahedron Lett 1986 27 279
bull 1986 ldquoApplication of Commercial Microwave Ovens to Organic Synthesisrdquo Giguere R J and Majetich G Tetrahedron Lett 1986 27 4945
Energy Use in ConventionalChemical Processes
Heating Stirring Piping
Transporting Cooling
Problem of Conventional Heating
You heat what you donrsquot want to heat
Solvents for reactions apparatus
heated up and cool it down
Double energy penalty without any
apparent ldquobenefitrdquo
Energy Consumptions
Three ways to get the reaction done but different energy bills to pay
Microwaves
bull MW reactors operate at 245 GHzbull Electric field oscillates at 49 x 109 timessec ndash
10oCsec heating rate
Electromagnetic Spectrum
Neas E Collins M Introduction to Microwave Sample Preparation Theory and Practice 1988 p 8
Schematic of a Microwave
E= electric fieldH= magnetic field= wavelength (122 cm for 2450 MHz)c= speed of light (300000 kms)
Microwaves Application in Heating Food
1946 Original patent (P L Spencer)1947 First commercial oven1955 Home models1967 Desktop model1975 US sales exceed gas ranges1976 60 of US households havemicrowave ovens
Spectrum Electromagnetic
bull Electric field component
bull Responsible for dielectric heating
bull Dipolar polarization
bull Conduction
bull Magnetic field component
Microwaves ndash Dipolar Rotationbull Polar molecules have intermolecular forces which give any motion of the
molecule some inertia
bull Under a very high frequency electric field the polar molecule will attempt to follow the field but intermolecular inertia stops any significant motion before the field has reversed and no net motion results
bull If the frequency of field oscillation is very low then the molecules will be polarized uniformly and no random motion results
bull In the intermediate case the frequency of the field will be such that the molecules will be almost but not quite able to keep in phase with the field polarity
bull In this case the random motion resulting as molecules jostle to attempt in vain to follow the field provides strong agitation and intense heating of the sample
bull At 245 GHz the field oscillates 49 x 109 timess which can lead to heating
rates of 10 degC per second when powerful waves are used
MW Heating Mechanism
Alternating electric field Withhigh frequency
NoconstraintContinuous electric field
Two mechanisms Dipolar rotation polarizationIonic Conduction mechanism
Microwave Dielectric HeatingMechanisms
Dipolar PolarizationMechanism
Conduction Mechanism
Dipolar molecules try toalign to an oscillating fieldby rotation
Ions in solution will moveby the applied electricfield
Mingos D M P et al Chem Soc Rev 1991 20 1 and 1998 27 213
Microwave vs Oil-bath Heating
J-S Schanche Mol Diversity 2003 7 293wwwpersonalchemistry-com wwwbiotagecom
Conventional Heating byConduction
ConductiveheatHeating byconvectioncurrentsSlow andenergyinefficientprocess
temperature on the outside surface isin excess of the boiling point of liquid
Direct Heating by MicrowaveIrradiation
bullSolventreagent absorbs MW energybull Vessel wall transparent to MWbullDirect in-core heatingbullInstant on-off
Inverted temperature gradients
Molecular Speeds
Molecular Speeds
Microwave Ovens
Cooking Chemistry Cooking Food
Household MW ovens
The Use of Microwave Ovens for Rapid Organic Synthesis R Gedye et al Tetrahedron Lett 1986 27 279
Publications on MW-AssistedOrganic Synthesis
7 Synthetic Journals JOrgChemOrgLettTetrahedron LettTetrahedron SynthCommun Synlett SynthesisAll Journals (Full Text) Dedicated instruments only (Anton Paar Biotage CEM Milestone Prolabo)
Industrial Chemical Applications of Microwave Heating
Food Processing+ Defrosting+ Drying roasting baking+ Pasteurization
Drying Industry+ Wood fibers textiles+ Pharmaceuticals+ Brick concrete walls
Polymer Chemistry+ Rubber curing vulcanization+ Polymerization
CeramicsMaterials+ Alumina sintering+ Welding smelting gluing
Plasma+ SemiconductorsWaste Remediation+ Sewage treatment
Analytical Chemistry+ Digestion+ Extraction+ Ashing
Biochemistry Pathology+ Protein hydrolysis+ PCR proteomics+ Tissue fixation+ Histoprocessing
Medical+ Diathermy tumor detection+ Blood warming+ Sterilization (Anthrax)+ Drying of catheters
Books on Microwave-Assisted Synthesis
1048707 Fundamentals of Microwave Application1048707 Alternative Laboratory MicrowaveInstruments1048707 Chemistry Applications1048707 Biochemistry Applications1048707 Laboratory Microwave Safety
Hayes B LCEM PublishingMatthews NC2002
(ACS Professional Reference Book) H M Kingston S J Haswell (eds)
Microwaves in Organic and Medicinal ChemistryKappe C O and Stadler AWiley-VCH Weinheim 2005 ISBN 3-527-31210-2410 pages ca 1000 references
Books on Microwave-Assisted Synthesis
Lidstoumlm PTierney J P(Eds)BlackwellScientific2005
Loupy Andre (Ed)Wiley-VCH Weinheim 2003 ISBN 3-527-30514-9523 pages 2000 refs
Book (2 volumes) Wiley-VCHA Loupy editSecond Edition(2006) 22 Chapters
Astra Zeneca ResearchFoundation Kavitha PrintersBangalore India 2002azrefiastrazenecacom
Practical Microwave Synthesis for Organic Chemists - Strategies Instruments and Protocols
Edition - 2009 X 310 Pages Hardcover Monograph
Books on Microwave-Assisted Synthesis
Microwave Ovens
Monomodal instrument
Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005
Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia
Multimodal instrument
+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile
Monomodal Vs Multimodal
Monomodal Vs Multimodal
Thermal Effects
bullMore efficient energetic coupling of solvent with microwaves
promotes higher rate of temperature increase
bull Inverted heat transfer volumetric
bull ldquoHot spotsrdquo in monomode microwaves
bull Selective on properties of material (solvents catalysts
reagents intermediates products susceptors)
Recent Applications of Microwave-Assisted Synthesis-MAOS
Hydrolysis of benzamide
thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)
The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions
R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958
Solvent-free Reactions or Solid-Solid Reactions
ldquoNo reaction proceeds without solventrdquo
Aristotle
Solventless syntheses
Green chemistry enabled advancement
Solvent-free Organic Synthesis
Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed
i n t o a p o w e r f u l m e t h o d o l o g y a s i t
reduces the amount of toxic waste produced and therefore becomes less harmful to the
e n v i r o n m e n t
Solvent-free Organic Synthesis
bull Clean and efficient synthesis
bull Economic and environmental impact
bull Fast reaction kinetics
Best solvent is no solvent
Adolf von Baeyer
Synthesis of Indigo
Towardsbenign
synthesiswith
remarkableVersatility
G W V Cave C LRaston J L ScottChemCommun
2001 2159
Solid-State General Oxidation with with Urea H2O2 Complex
R S Varma and K P Naiker Org Letters 1999 1 189
Solvent-free Oxidative Preparation of Heterocycles
Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157
Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones
Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199
Solvent-free Reduction
F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245
Carbon-Carbon Bond Formation
Toda Tanada Iwata J Org Chem 1989 54 3007
Solventless Photo Coupling and Photo Rearangements
Y Ito S Endo J Am Chem Soc 1997 119 5974
Shin Keating Maribay J Am Chem Soc 1996 118 7626
Solvent - Free Condensation
Z Gross et al Org Letters 1999 1 599
Solid-State Preparationof Dumb-bell-shaped C120
Wang Komatsu Murata Shiro Nature 1997 387 583
Advantages of Solid Mineral Supports(Alumina Silica and Clay)
Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area
The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity
Solids are generally easier and safer to handle than liquids or gaseous reagents
Inexpensive recyclable and environmentally benign nature
Solid-supported Solventless Reactions
bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation
R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43
Supported ReactionsUsing Microwaves
E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945
Microwave-Assisted Deacetylationon Alumina
Varma et al J Chem Soc Perkin Trans 1 999 (1993)
Deprotection of Benzyl Esters viaMicrowave Thermolysis
A practical alternative to traditional catalytic hydrogenation
Varma et al Tetrahedron Lett 34 4603 (1993)
Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of
Carbonyl Compounds Using Microwaves
Varma Meshram Tetrahedron Lett 38 5427 (1997)
Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm
PersulfatendashClay using Microwave and Ultrasonic Irradiation
Varma Meshram Tetrahedron Lett 38 7973 (1997)
Solid Supported Solvent-freeOxidation under MW
Varma et al Tetrahedron Lett 1997 38 2043 and 7823
Solvent-free Reduction Using MW
Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction
Varma et al Tetrahedron Lett 1997 38 4337
Hydrodechlorination under continuous MW
Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)
Synthesis of Heterocyclic Compounds
Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)
Synthesis of Heterocyclic Compounds
Organometallic Reactions
Rearrangements
Rearrangements
INDOLIZINES
Heterocyclic systems 10- electronics
Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine
Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds
N
1
2
34567
8R2
R3
R1
Why interest for indolizinic products
Strong fluorescent properties luminiscent products luminiscent products
Potentially fluorescents marker Potentially laserldquoscintillatersrdquo
bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999
Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )
Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2
ldquoCalcium-entryrdquo blockers
Indolizines by irradiation with microwaves in MCR
RBr
O+
N
R1 R2+N
R2
R1
COR
AcOAl2O3 Mw
R=Ph p-Tolil Stiril
R1= H COOMeR2= COOEt COOMe
Asymmetric indolizines by irradiation with microwaves in MCR
R1
O
Cl+ R2
N NEtOOC
OOMe
Br BrN N
EtOOC
COR1
R2COR1
R2
OOMe
2 [Pd(PPh3)2Cl24 CuI
20 echiv Et3N THF tc 2h
R1=Ph 4-OMe-C6H4R2= Ph
U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003
A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new indolizines
[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical
II
IHH
COORCOOR
N C C
O
R2NCC
O
R1
(B)
(A)
R1
O
C C N R2
O
CCN
H H
ROOC COOR
R1
O
C C N R2
O
CCN
COOR COOR
ROOC COOR
2
2 ROOC C C COOR
R1
O
C CH N R2
O
CCHN
H H
N NCH CHC C
O O
R1 R2
- 2 HX TEAanhydrous solvents
X-
X-
N NCH2 CH2C C
O O
R1 R2
C C COORH
R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5
Y=H NO2 OCH3 CH3 Cl BrX=Br Cl
bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998
bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001
bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004
bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new substituted pyridinium-indolizines
Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate
COO NO2CHC
N NH3C
OR
I IN NH3C
OR
IN NH3C
OR
I
H
KFNMP
-HI
NMP
95oC 30 min
N NH3CO
RN NH3C
O
R
O OO
NO2
O
NO2
-2[H]-2[H]
II
I II
N NH3CO
R
O O
NO2
IN NH3C
O
R
O O
NO2
I
(9a-d)(10a-d)
(15a-d)
(A) (B)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
12
34
56
78 9
10
11
12 3
4
56
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Energy Use in ConventionalChemical Processes
Heating Stirring Piping
Transporting Cooling
Problem of Conventional Heating
You heat what you donrsquot want to heat
Solvents for reactions apparatus
heated up and cool it down
Double energy penalty without any
apparent ldquobenefitrdquo
Energy Consumptions
Three ways to get the reaction done but different energy bills to pay
Microwaves
bull MW reactors operate at 245 GHzbull Electric field oscillates at 49 x 109 timessec ndash
10oCsec heating rate
Electromagnetic Spectrum
Neas E Collins M Introduction to Microwave Sample Preparation Theory and Practice 1988 p 8
Schematic of a Microwave
E= electric fieldH= magnetic field= wavelength (122 cm for 2450 MHz)c= speed of light (300000 kms)
Microwaves Application in Heating Food
1946 Original patent (P L Spencer)1947 First commercial oven1955 Home models1967 Desktop model1975 US sales exceed gas ranges1976 60 of US households havemicrowave ovens
Spectrum Electromagnetic
bull Electric field component
bull Responsible for dielectric heating
bull Dipolar polarization
bull Conduction
bull Magnetic field component
Microwaves ndash Dipolar Rotationbull Polar molecules have intermolecular forces which give any motion of the
molecule some inertia
bull Under a very high frequency electric field the polar molecule will attempt to follow the field but intermolecular inertia stops any significant motion before the field has reversed and no net motion results
bull If the frequency of field oscillation is very low then the molecules will be polarized uniformly and no random motion results
bull In the intermediate case the frequency of the field will be such that the molecules will be almost but not quite able to keep in phase with the field polarity
bull In this case the random motion resulting as molecules jostle to attempt in vain to follow the field provides strong agitation and intense heating of the sample
bull At 245 GHz the field oscillates 49 x 109 timess which can lead to heating
rates of 10 degC per second when powerful waves are used
MW Heating Mechanism
Alternating electric field Withhigh frequency
NoconstraintContinuous electric field
Two mechanisms Dipolar rotation polarizationIonic Conduction mechanism
Microwave Dielectric HeatingMechanisms
Dipolar PolarizationMechanism
Conduction Mechanism
Dipolar molecules try toalign to an oscillating fieldby rotation
Ions in solution will moveby the applied electricfield
Mingos D M P et al Chem Soc Rev 1991 20 1 and 1998 27 213
Microwave vs Oil-bath Heating
J-S Schanche Mol Diversity 2003 7 293wwwpersonalchemistry-com wwwbiotagecom
Conventional Heating byConduction
ConductiveheatHeating byconvectioncurrentsSlow andenergyinefficientprocess
temperature on the outside surface isin excess of the boiling point of liquid
Direct Heating by MicrowaveIrradiation
bullSolventreagent absorbs MW energybull Vessel wall transparent to MWbullDirect in-core heatingbullInstant on-off
Inverted temperature gradients
Molecular Speeds
Molecular Speeds
Microwave Ovens
Cooking Chemistry Cooking Food
Household MW ovens
The Use of Microwave Ovens for Rapid Organic Synthesis R Gedye et al Tetrahedron Lett 1986 27 279
Publications on MW-AssistedOrganic Synthesis
7 Synthetic Journals JOrgChemOrgLettTetrahedron LettTetrahedron SynthCommun Synlett SynthesisAll Journals (Full Text) Dedicated instruments only (Anton Paar Biotage CEM Milestone Prolabo)
Industrial Chemical Applications of Microwave Heating
Food Processing+ Defrosting+ Drying roasting baking+ Pasteurization
Drying Industry+ Wood fibers textiles+ Pharmaceuticals+ Brick concrete walls
Polymer Chemistry+ Rubber curing vulcanization+ Polymerization
CeramicsMaterials+ Alumina sintering+ Welding smelting gluing
Plasma+ SemiconductorsWaste Remediation+ Sewage treatment
Analytical Chemistry+ Digestion+ Extraction+ Ashing
Biochemistry Pathology+ Protein hydrolysis+ PCR proteomics+ Tissue fixation+ Histoprocessing
Medical+ Diathermy tumor detection+ Blood warming+ Sterilization (Anthrax)+ Drying of catheters
Books on Microwave-Assisted Synthesis
1048707 Fundamentals of Microwave Application1048707 Alternative Laboratory MicrowaveInstruments1048707 Chemistry Applications1048707 Biochemistry Applications1048707 Laboratory Microwave Safety
Hayes B LCEM PublishingMatthews NC2002
(ACS Professional Reference Book) H M Kingston S J Haswell (eds)
Microwaves in Organic and Medicinal ChemistryKappe C O and Stadler AWiley-VCH Weinheim 2005 ISBN 3-527-31210-2410 pages ca 1000 references
Books on Microwave-Assisted Synthesis
Lidstoumlm PTierney J P(Eds)BlackwellScientific2005
Loupy Andre (Ed)Wiley-VCH Weinheim 2003 ISBN 3-527-30514-9523 pages 2000 refs
Book (2 volumes) Wiley-VCHA Loupy editSecond Edition(2006) 22 Chapters
Astra Zeneca ResearchFoundation Kavitha PrintersBangalore India 2002azrefiastrazenecacom
Practical Microwave Synthesis for Organic Chemists - Strategies Instruments and Protocols
Edition - 2009 X 310 Pages Hardcover Monograph
Books on Microwave-Assisted Synthesis
Microwave Ovens
Monomodal instrument
Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005
Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia
Multimodal instrument
+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile
Monomodal Vs Multimodal
Monomodal Vs Multimodal
Thermal Effects
bullMore efficient energetic coupling of solvent with microwaves
promotes higher rate of temperature increase
bull Inverted heat transfer volumetric
bull ldquoHot spotsrdquo in monomode microwaves
bull Selective on properties of material (solvents catalysts
reagents intermediates products susceptors)
Recent Applications of Microwave-Assisted Synthesis-MAOS
Hydrolysis of benzamide
thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)
The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions
R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958
Solvent-free Reactions or Solid-Solid Reactions
ldquoNo reaction proceeds without solventrdquo
Aristotle
Solventless syntheses
Green chemistry enabled advancement
Solvent-free Organic Synthesis
Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed
i n t o a p o w e r f u l m e t h o d o l o g y a s i t
reduces the amount of toxic waste produced and therefore becomes less harmful to the
e n v i r o n m e n t
Solvent-free Organic Synthesis
bull Clean and efficient synthesis
bull Economic and environmental impact
bull Fast reaction kinetics
Best solvent is no solvent
Adolf von Baeyer
Synthesis of Indigo
Towardsbenign
synthesiswith
remarkableVersatility
G W V Cave C LRaston J L ScottChemCommun
2001 2159
Solid-State General Oxidation with with Urea H2O2 Complex
R S Varma and K P Naiker Org Letters 1999 1 189
Solvent-free Oxidative Preparation of Heterocycles
Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157
Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones
Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199
Solvent-free Reduction
F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245
Carbon-Carbon Bond Formation
Toda Tanada Iwata J Org Chem 1989 54 3007
Solventless Photo Coupling and Photo Rearangements
Y Ito S Endo J Am Chem Soc 1997 119 5974
Shin Keating Maribay J Am Chem Soc 1996 118 7626
Solvent - Free Condensation
Z Gross et al Org Letters 1999 1 599
Solid-State Preparationof Dumb-bell-shaped C120
Wang Komatsu Murata Shiro Nature 1997 387 583
Advantages of Solid Mineral Supports(Alumina Silica and Clay)
Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area
The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity
Solids are generally easier and safer to handle than liquids or gaseous reagents
Inexpensive recyclable and environmentally benign nature
Solid-supported Solventless Reactions
bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation
R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43
Supported ReactionsUsing Microwaves
E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945
Microwave-Assisted Deacetylationon Alumina
Varma et al J Chem Soc Perkin Trans 1 999 (1993)
Deprotection of Benzyl Esters viaMicrowave Thermolysis
A practical alternative to traditional catalytic hydrogenation
Varma et al Tetrahedron Lett 34 4603 (1993)
Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of
Carbonyl Compounds Using Microwaves
Varma Meshram Tetrahedron Lett 38 5427 (1997)
Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm
PersulfatendashClay using Microwave and Ultrasonic Irradiation
Varma Meshram Tetrahedron Lett 38 7973 (1997)
Solid Supported Solvent-freeOxidation under MW
Varma et al Tetrahedron Lett 1997 38 2043 and 7823
Solvent-free Reduction Using MW
Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction
Varma et al Tetrahedron Lett 1997 38 4337
Hydrodechlorination under continuous MW
Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)
Synthesis of Heterocyclic Compounds
Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)
Synthesis of Heterocyclic Compounds
Organometallic Reactions
Rearrangements
Rearrangements
INDOLIZINES
Heterocyclic systems 10- electronics
Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine
Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds
N
1
2
34567
8R2
R3
R1
Why interest for indolizinic products
Strong fluorescent properties luminiscent products luminiscent products
Potentially fluorescents marker Potentially laserldquoscintillatersrdquo
bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999
Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )
Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2
ldquoCalcium-entryrdquo blockers
Indolizines by irradiation with microwaves in MCR
RBr
O+
N
R1 R2+N
R2
R1
COR
AcOAl2O3 Mw
R=Ph p-Tolil Stiril
R1= H COOMeR2= COOEt COOMe
Asymmetric indolizines by irradiation with microwaves in MCR
R1
O
Cl+ R2
N NEtOOC
OOMe
Br BrN N
EtOOC
COR1
R2COR1
R2
OOMe
2 [Pd(PPh3)2Cl24 CuI
20 echiv Et3N THF tc 2h
R1=Ph 4-OMe-C6H4R2= Ph
U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003
A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new indolizines
[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical
II
IHH
COORCOOR
N C C
O
R2NCC
O
R1
(B)
(A)
R1
O
C C N R2
O
CCN
H H
ROOC COOR
R1
O
C C N R2
O
CCN
COOR COOR
ROOC COOR
2
2 ROOC C C COOR
R1
O
C CH N R2
O
CCHN
H H
N NCH CHC C
O O
R1 R2
- 2 HX TEAanhydrous solvents
X-
X-
N NCH2 CH2C C
O O
R1 R2
C C COORH
R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5
Y=H NO2 OCH3 CH3 Cl BrX=Br Cl
bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998
bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001
bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004
bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new substituted pyridinium-indolizines
Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate
COO NO2CHC
N NH3C
OR
I IN NH3C
OR
IN NH3C
OR
I
H
KFNMP
-HI
NMP
95oC 30 min
N NH3CO
RN NH3C
O
R
O OO
NO2
O
NO2
-2[H]-2[H]
II
I II
N NH3CO
R
O O
NO2
IN NH3C
O
R
O O
NO2
I
(9a-d)(10a-d)
(15a-d)
(A) (B)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
12
34
56
78 9
10
11
12 3
4
56
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Problem of Conventional Heating
You heat what you donrsquot want to heat
Solvents for reactions apparatus
heated up and cool it down
Double energy penalty without any
apparent ldquobenefitrdquo
Energy Consumptions
Three ways to get the reaction done but different energy bills to pay
Microwaves
bull MW reactors operate at 245 GHzbull Electric field oscillates at 49 x 109 timessec ndash
10oCsec heating rate
Electromagnetic Spectrum
Neas E Collins M Introduction to Microwave Sample Preparation Theory and Practice 1988 p 8
Schematic of a Microwave
E= electric fieldH= magnetic field= wavelength (122 cm for 2450 MHz)c= speed of light (300000 kms)
Microwaves Application in Heating Food
1946 Original patent (P L Spencer)1947 First commercial oven1955 Home models1967 Desktop model1975 US sales exceed gas ranges1976 60 of US households havemicrowave ovens
Spectrum Electromagnetic
bull Electric field component
bull Responsible for dielectric heating
bull Dipolar polarization
bull Conduction
bull Magnetic field component
Microwaves ndash Dipolar Rotationbull Polar molecules have intermolecular forces which give any motion of the
molecule some inertia
bull Under a very high frequency electric field the polar molecule will attempt to follow the field but intermolecular inertia stops any significant motion before the field has reversed and no net motion results
bull If the frequency of field oscillation is very low then the molecules will be polarized uniformly and no random motion results
bull In the intermediate case the frequency of the field will be such that the molecules will be almost but not quite able to keep in phase with the field polarity
bull In this case the random motion resulting as molecules jostle to attempt in vain to follow the field provides strong agitation and intense heating of the sample
bull At 245 GHz the field oscillates 49 x 109 timess which can lead to heating
rates of 10 degC per second when powerful waves are used
MW Heating Mechanism
Alternating electric field Withhigh frequency
NoconstraintContinuous electric field
Two mechanisms Dipolar rotation polarizationIonic Conduction mechanism
Microwave Dielectric HeatingMechanisms
Dipolar PolarizationMechanism
Conduction Mechanism
Dipolar molecules try toalign to an oscillating fieldby rotation
Ions in solution will moveby the applied electricfield
Mingos D M P et al Chem Soc Rev 1991 20 1 and 1998 27 213
Microwave vs Oil-bath Heating
J-S Schanche Mol Diversity 2003 7 293wwwpersonalchemistry-com wwwbiotagecom
Conventional Heating byConduction
ConductiveheatHeating byconvectioncurrentsSlow andenergyinefficientprocess
temperature on the outside surface isin excess of the boiling point of liquid
Direct Heating by MicrowaveIrradiation
bullSolventreagent absorbs MW energybull Vessel wall transparent to MWbullDirect in-core heatingbullInstant on-off
Inverted temperature gradients
Molecular Speeds
Molecular Speeds
Microwave Ovens
Cooking Chemistry Cooking Food
Household MW ovens
The Use of Microwave Ovens for Rapid Organic Synthesis R Gedye et al Tetrahedron Lett 1986 27 279
Publications on MW-AssistedOrganic Synthesis
7 Synthetic Journals JOrgChemOrgLettTetrahedron LettTetrahedron SynthCommun Synlett SynthesisAll Journals (Full Text) Dedicated instruments only (Anton Paar Biotage CEM Milestone Prolabo)
Industrial Chemical Applications of Microwave Heating
Food Processing+ Defrosting+ Drying roasting baking+ Pasteurization
Drying Industry+ Wood fibers textiles+ Pharmaceuticals+ Brick concrete walls
Polymer Chemistry+ Rubber curing vulcanization+ Polymerization
CeramicsMaterials+ Alumina sintering+ Welding smelting gluing
Plasma+ SemiconductorsWaste Remediation+ Sewage treatment
Analytical Chemistry+ Digestion+ Extraction+ Ashing
Biochemistry Pathology+ Protein hydrolysis+ PCR proteomics+ Tissue fixation+ Histoprocessing
Medical+ Diathermy tumor detection+ Blood warming+ Sterilization (Anthrax)+ Drying of catheters
Books on Microwave-Assisted Synthesis
1048707 Fundamentals of Microwave Application1048707 Alternative Laboratory MicrowaveInstruments1048707 Chemistry Applications1048707 Biochemistry Applications1048707 Laboratory Microwave Safety
Hayes B LCEM PublishingMatthews NC2002
(ACS Professional Reference Book) H M Kingston S J Haswell (eds)
Microwaves in Organic and Medicinal ChemistryKappe C O and Stadler AWiley-VCH Weinheim 2005 ISBN 3-527-31210-2410 pages ca 1000 references
Books on Microwave-Assisted Synthesis
Lidstoumlm PTierney J P(Eds)BlackwellScientific2005
Loupy Andre (Ed)Wiley-VCH Weinheim 2003 ISBN 3-527-30514-9523 pages 2000 refs
Book (2 volumes) Wiley-VCHA Loupy editSecond Edition(2006) 22 Chapters
Astra Zeneca ResearchFoundation Kavitha PrintersBangalore India 2002azrefiastrazenecacom
Practical Microwave Synthesis for Organic Chemists - Strategies Instruments and Protocols
Edition - 2009 X 310 Pages Hardcover Monograph
Books on Microwave-Assisted Synthesis
Microwave Ovens
Monomodal instrument
Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005
Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia
Multimodal instrument
+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile
Monomodal Vs Multimodal
Monomodal Vs Multimodal
Thermal Effects
bullMore efficient energetic coupling of solvent with microwaves
promotes higher rate of temperature increase
bull Inverted heat transfer volumetric
bull ldquoHot spotsrdquo in monomode microwaves
bull Selective on properties of material (solvents catalysts
reagents intermediates products susceptors)
Recent Applications of Microwave-Assisted Synthesis-MAOS
Hydrolysis of benzamide
thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)
The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions
R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958
Solvent-free Reactions or Solid-Solid Reactions
ldquoNo reaction proceeds without solventrdquo
Aristotle
Solventless syntheses
Green chemistry enabled advancement
Solvent-free Organic Synthesis
Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed
i n t o a p o w e r f u l m e t h o d o l o g y a s i t
reduces the amount of toxic waste produced and therefore becomes less harmful to the
e n v i r o n m e n t
Solvent-free Organic Synthesis
bull Clean and efficient synthesis
bull Economic and environmental impact
bull Fast reaction kinetics
Best solvent is no solvent
Adolf von Baeyer
Synthesis of Indigo
Towardsbenign
synthesiswith
remarkableVersatility
G W V Cave C LRaston J L ScottChemCommun
2001 2159
Solid-State General Oxidation with with Urea H2O2 Complex
R S Varma and K P Naiker Org Letters 1999 1 189
Solvent-free Oxidative Preparation of Heterocycles
Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157
Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones
Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199
Solvent-free Reduction
F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245
Carbon-Carbon Bond Formation
Toda Tanada Iwata J Org Chem 1989 54 3007
Solventless Photo Coupling and Photo Rearangements
Y Ito S Endo J Am Chem Soc 1997 119 5974
Shin Keating Maribay J Am Chem Soc 1996 118 7626
Solvent - Free Condensation
Z Gross et al Org Letters 1999 1 599
Solid-State Preparationof Dumb-bell-shaped C120
Wang Komatsu Murata Shiro Nature 1997 387 583
Advantages of Solid Mineral Supports(Alumina Silica and Clay)
Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area
The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity
Solids are generally easier and safer to handle than liquids or gaseous reagents
Inexpensive recyclable and environmentally benign nature
Solid-supported Solventless Reactions
bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation
R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43
Supported ReactionsUsing Microwaves
E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945
Microwave-Assisted Deacetylationon Alumina
Varma et al J Chem Soc Perkin Trans 1 999 (1993)
Deprotection of Benzyl Esters viaMicrowave Thermolysis
A practical alternative to traditional catalytic hydrogenation
Varma et al Tetrahedron Lett 34 4603 (1993)
Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of
Carbonyl Compounds Using Microwaves
Varma Meshram Tetrahedron Lett 38 5427 (1997)
Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm
PersulfatendashClay using Microwave and Ultrasonic Irradiation
Varma Meshram Tetrahedron Lett 38 7973 (1997)
Solid Supported Solvent-freeOxidation under MW
Varma et al Tetrahedron Lett 1997 38 2043 and 7823
Solvent-free Reduction Using MW
Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction
Varma et al Tetrahedron Lett 1997 38 4337
Hydrodechlorination under continuous MW
Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)
Synthesis of Heterocyclic Compounds
Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)
Synthesis of Heterocyclic Compounds
Organometallic Reactions
Rearrangements
Rearrangements
INDOLIZINES
Heterocyclic systems 10- electronics
Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine
Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds
N
1
2
34567
8R2
R3
R1
Why interest for indolizinic products
Strong fluorescent properties luminiscent products luminiscent products
Potentially fluorescents marker Potentially laserldquoscintillatersrdquo
bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999
Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )
Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2
ldquoCalcium-entryrdquo blockers
Indolizines by irradiation with microwaves in MCR
RBr
O+
N
R1 R2+N
R2
R1
COR
AcOAl2O3 Mw
R=Ph p-Tolil Stiril
R1= H COOMeR2= COOEt COOMe
Asymmetric indolizines by irradiation with microwaves in MCR
R1
O
Cl+ R2
N NEtOOC
OOMe
Br BrN N
EtOOC
COR1
R2COR1
R2
OOMe
2 [Pd(PPh3)2Cl24 CuI
20 echiv Et3N THF tc 2h
R1=Ph 4-OMe-C6H4R2= Ph
U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003
A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new indolizines
[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical
II
IHH
COORCOOR
N C C
O
R2NCC
O
R1
(B)
(A)
R1
O
C C N R2
O
CCN
H H
ROOC COOR
R1
O
C C N R2
O
CCN
COOR COOR
ROOC COOR
2
2 ROOC C C COOR
R1
O
C CH N R2
O
CCHN
H H
N NCH CHC C
O O
R1 R2
- 2 HX TEAanhydrous solvents
X-
X-
N NCH2 CH2C C
O O
R1 R2
C C COORH
R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5
Y=H NO2 OCH3 CH3 Cl BrX=Br Cl
bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998
bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001
bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004
bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new substituted pyridinium-indolizines
Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate
COO NO2CHC
N NH3C
OR
I IN NH3C
OR
IN NH3C
OR
I
H
KFNMP
-HI
NMP
95oC 30 min
N NH3CO
RN NH3C
O
R
O OO
NO2
O
NO2
-2[H]-2[H]
II
I II
N NH3CO
R
O O
NO2
IN NH3C
O
R
O O
NO2
I
(9a-d)(10a-d)
(15a-d)
(A) (B)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
12
34
56
78 9
10
11
12 3
4
56
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Energy Consumptions
Three ways to get the reaction done but different energy bills to pay
Microwaves
bull MW reactors operate at 245 GHzbull Electric field oscillates at 49 x 109 timessec ndash
10oCsec heating rate
Electromagnetic Spectrum
Neas E Collins M Introduction to Microwave Sample Preparation Theory and Practice 1988 p 8
Schematic of a Microwave
E= electric fieldH= magnetic field= wavelength (122 cm for 2450 MHz)c= speed of light (300000 kms)
Microwaves Application in Heating Food
1946 Original patent (P L Spencer)1947 First commercial oven1955 Home models1967 Desktop model1975 US sales exceed gas ranges1976 60 of US households havemicrowave ovens
Spectrum Electromagnetic
bull Electric field component
bull Responsible for dielectric heating
bull Dipolar polarization
bull Conduction
bull Magnetic field component
Microwaves ndash Dipolar Rotationbull Polar molecules have intermolecular forces which give any motion of the
molecule some inertia
bull Under a very high frequency electric field the polar molecule will attempt to follow the field but intermolecular inertia stops any significant motion before the field has reversed and no net motion results
bull If the frequency of field oscillation is very low then the molecules will be polarized uniformly and no random motion results
bull In the intermediate case the frequency of the field will be such that the molecules will be almost but not quite able to keep in phase with the field polarity
bull In this case the random motion resulting as molecules jostle to attempt in vain to follow the field provides strong agitation and intense heating of the sample
bull At 245 GHz the field oscillates 49 x 109 timess which can lead to heating
rates of 10 degC per second when powerful waves are used
MW Heating Mechanism
Alternating electric field Withhigh frequency
NoconstraintContinuous electric field
Two mechanisms Dipolar rotation polarizationIonic Conduction mechanism
Microwave Dielectric HeatingMechanisms
Dipolar PolarizationMechanism
Conduction Mechanism
Dipolar molecules try toalign to an oscillating fieldby rotation
Ions in solution will moveby the applied electricfield
Mingos D M P et al Chem Soc Rev 1991 20 1 and 1998 27 213
Microwave vs Oil-bath Heating
J-S Schanche Mol Diversity 2003 7 293wwwpersonalchemistry-com wwwbiotagecom
Conventional Heating byConduction
ConductiveheatHeating byconvectioncurrentsSlow andenergyinefficientprocess
temperature on the outside surface isin excess of the boiling point of liquid
Direct Heating by MicrowaveIrradiation
bullSolventreagent absorbs MW energybull Vessel wall transparent to MWbullDirect in-core heatingbullInstant on-off
Inverted temperature gradients
Molecular Speeds
Molecular Speeds
Microwave Ovens
Cooking Chemistry Cooking Food
Household MW ovens
The Use of Microwave Ovens for Rapid Organic Synthesis R Gedye et al Tetrahedron Lett 1986 27 279
Publications on MW-AssistedOrganic Synthesis
7 Synthetic Journals JOrgChemOrgLettTetrahedron LettTetrahedron SynthCommun Synlett SynthesisAll Journals (Full Text) Dedicated instruments only (Anton Paar Biotage CEM Milestone Prolabo)
Industrial Chemical Applications of Microwave Heating
Food Processing+ Defrosting+ Drying roasting baking+ Pasteurization
Drying Industry+ Wood fibers textiles+ Pharmaceuticals+ Brick concrete walls
Polymer Chemistry+ Rubber curing vulcanization+ Polymerization
CeramicsMaterials+ Alumina sintering+ Welding smelting gluing
Plasma+ SemiconductorsWaste Remediation+ Sewage treatment
Analytical Chemistry+ Digestion+ Extraction+ Ashing
Biochemistry Pathology+ Protein hydrolysis+ PCR proteomics+ Tissue fixation+ Histoprocessing
Medical+ Diathermy tumor detection+ Blood warming+ Sterilization (Anthrax)+ Drying of catheters
Books on Microwave-Assisted Synthesis
1048707 Fundamentals of Microwave Application1048707 Alternative Laboratory MicrowaveInstruments1048707 Chemistry Applications1048707 Biochemistry Applications1048707 Laboratory Microwave Safety
Hayes B LCEM PublishingMatthews NC2002
(ACS Professional Reference Book) H M Kingston S J Haswell (eds)
Microwaves in Organic and Medicinal ChemistryKappe C O and Stadler AWiley-VCH Weinheim 2005 ISBN 3-527-31210-2410 pages ca 1000 references
Books on Microwave-Assisted Synthesis
Lidstoumlm PTierney J P(Eds)BlackwellScientific2005
Loupy Andre (Ed)Wiley-VCH Weinheim 2003 ISBN 3-527-30514-9523 pages 2000 refs
Book (2 volumes) Wiley-VCHA Loupy editSecond Edition(2006) 22 Chapters
Astra Zeneca ResearchFoundation Kavitha PrintersBangalore India 2002azrefiastrazenecacom
Practical Microwave Synthesis for Organic Chemists - Strategies Instruments and Protocols
Edition - 2009 X 310 Pages Hardcover Monograph
Books on Microwave-Assisted Synthesis
Microwave Ovens
Monomodal instrument
Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005
Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia
Multimodal instrument
+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile
Monomodal Vs Multimodal
Monomodal Vs Multimodal
Thermal Effects
bullMore efficient energetic coupling of solvent with microwaves
promotes higher rate of temperature increase
bull Inverted heat transfer volumetric
bull ldquoHot spotsrdquo in monomode microwaves
bull Selective on properties of material (solvents catalysts
reagents intermediates products susceptors)
Recent Applications of Microwave-Assisted Synthesis-MAOS
Hydrolysis of benzamide
thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)
The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions
R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958
Solvent-free Reactions or Solid-Solid Reactions
ldquoNo reaction proceeds without solventrdquo
Aristotle
Solventless syntheses
Green chemistry enabled advancement
Solvent-free Organic Synthesis
Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed
i n t o a p o w e r f u l m e t h o d o l o g y a s i t
reduces the amount of toxic waste produced and therefore becomes less harmful to the
e n v i r o n m e n t
Solvent-free Organic Synthesis
bull Clean and efficient synthesis
bull Economic and environmental impact
bull Fast reaction kinetics
Best solvent is no solvent
Adolf von Baeyer
Synthesis of Indigo
Towardsbenign
synthesiswith
remarkableVersatility
G W V Cave C LRaston J L ScottChemCommun
2001 2159
Solid-State General Oxidation with with Urea H2O2 Complex
R S Varma and K P Naiker Org Letters 1999 1 189
Solvent-free Oxidative Preparation of Heterocycles
Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157
Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones
Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199
Solvent-free Reduction
F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245
Carbon-Carbon Bond Formation
Toda Tanada Iwata J Org Chem 1989 54 3007
Solventless Photo Coupling and Photo Rearangements
Y Ito S Endo J Am Chem Soc 1997 119 5974
Shin Keating Maribay J Am Chem Soc 1996 118 7626
Solvent - Free Condensation
Z Gross et al Org Letters 1999 1 599
Solid-State Preparationof Dumb-bell-shaped C120
Wang Komatsu Murata Shiro Nature 1997 387 583
Advantages of Solid Mineral Supports(Alumina Silica and Clay)
Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area
The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity
Solids are generally easier and safer to handle than liquids or gaseous reagents
Inexpensive recyclable and environmentally benign nature
Solid-supported Solventless Reactions
bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation
R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43
Supported ReactionsUsing Microwaves
E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945
Microwave-Assisted Deacetylationon Alumina
Varma et al J Chem Soc Perkin Trans 1 999 (1993)
Deprotection of Benzyl Esters viaMicrowave Thermolysis
A practical alternative to traditional catalytic hydrogenation
Varma et al Tetrahedron Lett 34 4603 (1993)
Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of
Carbonyl Compounds Using Microwaves
Varma Meshram Tetrahedron Lett 38 5427 (1997)
Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm
PersulfatendashClay using Microwave and Ultrasonic Irradiation
Varma Meshram Tetrahedron Lett 38 7973 (1997)
Solid Supported Solvent-freeOxidation under MW
Varma et al Tetrahedron Lett 1997 38 2043 and 7823
Solvent-free Reduction Using MW
Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction
Varma et al Tetrahedron Lett 1997 38 4337
Hydrodechlorination under continuous MW
Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)
Synthesis of Heterocyclic Compounds
Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)
Synthesis of Heterocyclic Compounds
Organometallic Reactions
Rearrangements
Rearrangements
INDOLIZINES
Heterocyclic systems 10- electronics
Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine
Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds
N
1
2
34567
8R2
R3
R1
Why interest for indolizinic products
Strong fluorescent properties luminiscent products luminiscent products
Potentially fluorescents marker Potentially laserldquoscintillatersrdquo
bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999
Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )
Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2
ldquoCalcium-entryrdquo blockers
Indolizines by irradiation with microwaves in MCR
RBr
O+
N
R1 R2+N
R2
R1
COR
AcOAl2O3 Mw
R=Ph p-Tolil Stiril
R1= H COOMeR2= COOEt COOMe
Asymmetric indolizines by irradiation with microwaves in MCR
R1
O
Cl+ R2
N NEtOOC
OOMe
Br BrN N
EtOOC
COR1
R2COR1
R2
OOMe
2 [Pd(PPh3)2Cl24 CuI
20 echiv Et3N THF tc 2h
R1=Ph 4-OMe-C6H4R2= Ph
U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003
A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new indolizines
[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical
II
IHH
COORCOOR
N C C
O
R2NCC
O
R1
(B)
(A)
R1
O
C C N R2
O
CCN
H H
ROOC COOR
R1
O
C C N R2
O
CCN
COOR COOR
ROOC COOR
2
2 ROOC C C COOR
R1
O
C CH N R2
O
CCHN
H H
N NCH CHC C
O O
R1 R2
- 2 HX TEAanhydrous solvents
X-
X-
N NCH2 CH2C C
O O
R1 R2
C C COORH
R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5
Y=H NO2 OCH3 CH3 Cl BrX=Br Cl
bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998
bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001
bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004
bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new substituted pyridinium-indolizines
Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate
COO NO2CHC
N NH3C
OR
I IN NH3C
OR
IN NH3C
OR
I
H
KFNMP
-HI
NMP
95oC 30 min
N NH3CO
RN NH3C
O
R
O OO
NO2
O
NO2
-2[H]-2[H]
II
I II
N NH3CO
R
O O
NO2
IN NH3C
O
R
O O
NO2
I
(9a-d)(10a-d)
(15a-d)
(A) (B)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
12
34
56
78 9
10
11
12 3
4
56
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Microwaves
bull MW reactors operate at 245 GHzbull Electric field oscillates at 49 x 109 timessec ndash
10oCsec heating rate
Electromagnetic Spectrum
Neas E Collins M Introduction to Microwave Sample Preparation Theory and Practice 1988 p 8
Schematic of a Microwave
E= electric fieldH= magnetic field= wavelength (122 cm for 2450 MHz)c= speed of light (300000 kms)
Microwaves Application in Heating Food
1946 Original patent (P L Spencer)1947 First commercial oven1955 Home models1967 Desktop model1975 US sales exceed gas ranges1976 60 of US households havemicrowave ovens
Spectrum Electromagnetic
bull Electric field component
bull Responsible for dielectric heating
bull Dipolar polarization
bull Conduction
bull Magnetic field component
Microwaves ndash Dipolar Rotationbull Polar molecules have intermolecular forces which give any motion of the
molecule some inertia
bull Under a very high frequency electric field the polar molecule will attempt to follow the field but intermolecular inertia stops any significant motion before the field has reversed and no net motion results
bull If the frequency of field oscillation is very low then the molecules will be polarized uniformly and no random motion results
bull In the intermediate case the frequency of the field will be such that the molecules will be almost but not quite able to keep in phase with the field polarity
bull In this case the random motion resulting as molecules jostle to attempt in vain to follow the field provides strong agitation and intense heating of the sample
bull At 245 GHz the field oscillates 49 x 109 timess which can lead to heating
rates of 10 degC per second when powerful waves are used
MW Heating Mechanism
Alternating electric field Withhigh frequency
NoconstraintContinuous electric field
Two mechanisms Dipolar rotation polarizationIonic Conduction mechanism
Microwave Dielectric HeatingMechanisms
Dipolar PolarizationMechanism
Conduction Mechanism
Dipolar molecules try toalign to an oscillating fieldby rotation
Ions in solution will moveby the applied electricfield
Mingos D M P et al Chem Soc Rev 1991 20 1 and 1998 27 213
Microwave vs Oil-bath Heating
J-S Schanche Mol Diversity 2003 7 293wwwpersonalchemistry-com wwwbiotagecom
Conventional Heating byConduction
ConductiveheatHeating byconvectioncurrentsSlow andenergyinefficientprocess
temperature on the outside surface isin excess of the boiling point of liquid
Direct Heating by MicrowaveIrradiation
bullSolventreagent absorbs MW energybull Vessel wall transparent to MWbullDirect in-core heatingbullInstant on-off
Inverted temperature gradients
Molecular Speeds
Molecular Speeds
Microwave Ovens
Cooking Chemistry Cooking Food
Household MW ovens
The Use of Microwave Ovens for Rapid Organic Synthesis R Gedye et al Tetrahedron Lett 1986 27 279
Publications on MW-AssistedOrganic Synthesis
7 Synthetic Journals JOrgChemOrgLettTetrahedron LettTetrahedron SynthCommun Synlett SynthesisAll Journals (Full Text) Dedicated instruments only (Anton Paar Biotage CEM Milestone Prolabo)
Industrial Chemical Applications of Microwave Heating
Food Processing+ Defrosting+ Drying roasting baking+ Pasteurization
Drying Industry+ Wood fibers textiles+ Pharmaceuticals+ Brick concrete walls
Polymer Chemistry+ Rubber curing vulcanization+ Polymerization
CeramicsMaterials+ Alumina sintering+ Welding smelting gluing
Plasma+ SemiconductorsWaste Remediation+ Sewage treatment
Analytical Chemistry+ Digestion+ Extraction+ Ashing
Biochemistry Pathology+ Protein hydrolysis+ PCR proteomics+ Tissue fixation+ Histoprocessing
Medical+ Diathermy tumor detection+ Blood warming+ Sterilization (Anthrax)+ Drying of catheters
Books on Microwave-Assisted Synthesis
1048707 Fundamentals of Microwave Application1048707 Alternative Laboratory MicrowaveInstruments1048707 Chemistry Applications1048707 Biochemistry Applications1048707 Laboratory Microwave Safety
Hayes B LCEM PublishingMatthews NC2002
(ACS Professional Reference Book) H M Kingston S J Haswell (eds)
Microwaves in Organic and Medicinal ChemistryKappe C O and Stadler AWiley-VCH Weinheim 2005 ISBN 3-527-31210-2410 pages ca 1000 references
Books on Microwave-Assisted Synthesis
Lidstoumlm PTierney J P(Eds)BlackwellScientific2005
Loupy Andre (Ed)Wiley-VCH Weinheim 2003 ISBN 3-527-30514-9523 pages 2000 refs
Book (2 volumes) Wiley-VCHA Loupy editSecond Edition(2006) 22 Chapters
Astra Zeneca ResearchFoundation Kavitha PrintersBangalore India 2002azrefiastrazenecacom
Practical Microwave Synthesis for Organic Chemists - Strategies Instruments and Protocols
Edition - 2009 X 310 Pages Hardcover Monograph
Books on Microwave-Assisted Synthesis
Microwave Ovens
Monomodal instrument
Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005
Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia
Multimodal instrument
+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile
Monomodal Vs Multimodal
Monomodal Vs Multimodal
Thermal Effects
bullMore efficient energetic coupling of solvent with microwaves
promotes higher rate of temperature increase
bull Inverted heat transfer volumetric
bull ldquoHot spotsrdquo in monomode microwaves
bull Selective on properties of material (solvents catalysts
reagents intermediates products susceptors)
Recent Applications of Microwave-Assisted Synthesis-MAOS
Hydrolysis of benzamide
thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)
The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions
R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958
Solvent-free Reactions or Solid-Solid Reactions
ldquoNo reaction proceeds without solventrdquo
Aristotle
Solventless syntheses
Green chemistry enabled advancement
Solvent-free Organic Synthesis
Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed
i n t o a p o w e r f u l m e t h o d o l o g y a s i t
reduces the amount of toxic waste produced and therefore becomes less harmful to the
e n v i r o n m e n t
Solvent-free Organic Synthesis
bull Clean and efficient synthesis
bull Economic and environmental impact
bull Fast reaction kinetics
Best solvent is no solvent
Adolf von Baeyer
Synthesis of Indigo
Towardsbenign
synthesiswith
remarkableVersatility
G W V Cave C LRaston J L ScottChemCommun
2001 2159
Solid-State General Oxidation with with Urea H2O2 Complex
R S Varma and K P Naiker Org Letters 1999 1 189
Solvent-free Oxidative Preparation of Heterocycles
Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157
Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones
Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199
Solvent-free Reduction
F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245
Carbon-Carbon Bond Formation
Toda Tanada Iwata J Org Chem 1989 54 3007
Solventless Photo Coupling and Photo Rearangements
Y Ito S Endo J Am Chem Soc 1997 119 5974
Shin Keating Maribay J Am Chem Soc 1996 118 7626
Solvent - Free Condensation
Z Gross et al Org Letters 1999 1 599
Solid-State Preparationof Dumb-bell-shaped C120
Wang Komatsu Murata Shiro Nature 1997 387 583
Advantages of Solid Mineral Supports(Alumina Silica and Clay)
Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area
The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity
Solids are generally easier and safer to handle than liquids or gaseous reagents
Inexpensive recyclable and environmentally benign nature
Solid-supported Solventless Reactions
bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation
R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43
Supported ReactionsUsing Microwaves
E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945
Microwave-Assisted Deacetylationon Alumina
Varma et al J Chem Soc Perkin Trans 1 999 (1993)
Deprotection of Benzyl Esters viaMicrowave Thermolysis
A practical alternative to traditional catalytic hydrogenation
Varma et al Tetrahedron Lett 34 4603 (1993)
Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of
Carbonyl Compounds Using Microwaves
Varma Meshram Tetrahedron Lett 38 5427 (1997)
Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm
PersulfatendashClay using Microwave and Ultrasonic Irradiation
Varma Meshram Tetrahedron Lett 38 7973 (1997)
Solid Supported Solvent-freeOxidation under MW
Varma et al Tetrahedron Lett 1997 38 2043 and 7823
Solvent-free Reduction Using MW
Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction
Varma et al Tetrahedron Lett 1997 38 4337
Hydrodechlorination under continuous MW
Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)
Synthesis of Heterocyclic Compounds
Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)
Synthesis of Heterocyclic Compounds
Organometallic Reactions
Rearrangements
Rearrangements
INDOLIZINES
Heterocyclic systems 10- electronics
Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine
Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds
N
1
2
34567
8R2
R3
R1
Why interest for indolizinic products
Strong fluorescent properties luminiscent products luminiscent products
Potentially fluorescents marker Potentially laserldquoscintillatersrdquo
bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999
Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )
Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2
ldquoCalcium-entryrdquo blockers
Indolizines by irradiation with microwaves in MCR
RBr
O+
N
R1 R2+N
R2
R1
COR
AcOAl2O3 Mw
R=Ph p-Tolil Stiril
R1= H COOMeR2= COOEt COOMe
Asymmetric indolizines by irradiation with microwaves in MCR
R1
O
Cl+ R2
N NEtOOC
OOMe
Br BrN N
EtOOC
COR1
R2COR1
R2
OOMe
2 [Pd(PPh3)2Cl24 CuI
20 echiv Et3N THF tc 2h
R1=Ph 4-OMe-C6H4R2= Ph
U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003
A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new indolizines
[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical
II
IHH
COORCOOR
N C C
O
R2NCC
O
R1
(B)
(A)
R1
O
C C N R2
O
CCN
H H
ROOC COOR
R1
O
C C N R2
O
CCN
COOR COOR
ROOC COOR
2
2 ROOC C C COOR
R1
O
C CH N R2
O
CCHN
H H
N NCH CHC C
O O
R1 R2
- 2 HX TEAanhydrous solvents
X-
X-
N NCH2 CH2C C
O O
R1 R2
C C COORH
R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5
Y=H NO2 OCH3 CH3 Cl BrX=Br Cl
bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998
bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001
bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004
bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new substituted pyridinium-indolizines
Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate
COO NO2CHC
N NH3C
OR
I IN NH3C
OR
IN NH3C
OR
I
H
KFNMP
-HI
NMP
95oC 30 min
N NH3CO
RN NH3C
O
R
O OO
NO2
O
NO2
-2[H]-2[H]
II
I II
N NH3CO
R
O O
NO2
IN NH3C
O
R
O O
NO2
I
(9a-d)(10a-d)
(15a-d)
(A) (B)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
12
34
56
78 9
10
11
12 3
4
56
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Electromagnetic Spectrum
Neas E Collins M Introduction to Microwave Sample Preparation Theory and Practice 1988 p 8
Schematic of a Microwave
E= electric fieldH= magnetic field= wavelength (122 cm for 2450 MHz)c= speed of light (300000 kms)
Microwaves Application in Heating Food
1946 Original patent (P L Spencer)1947 First commercial oven1955 Home models1967 Desktop model1975 US sales exceed gas ranges1976 60 of US households havemicrowave ovens
Spectrum Electromagnetic
bull Electric field component
bull Responsible for dielectric heating
bull Dipolar polarization
bull Conduction
bull Magnetic field component
Microwaves ndash Dipolar Rotationbull Polar molecules have intermolecular forces which give any motion of the
molecule some inertia
bull Under a very high frequency electric field the polar molecule will attempt to follow the field but intermolecular inertia stops any significant motion before the field has reversed and no net motion results
bull If the frequency of field oscillation is very low then the molecules will be polarized uniformly and no random motion results
bull In the intermediate case the frequency of the field will be such that the molecules will be almost but not quite able to keep in phase with the field polarity
bull In this case the random motion resulting as molecules jostle to attempt in vain to follow the field provides strong agitation and intense heating of the sample
bull At 245 GHz the field oscillates 49 x 109 timess which can lead to heating
rates of 10 degC per second when powerful waves are used
MW Heating Mechanism
Alternating electric field Withhigh frequency
NoconstraintContinuous electric field
Two mechanisms Dipolar rotation polarizationIonic Conduction mechanism
Microwave Dielectric HeatingMechanisms
Dipolar PolarizationMechanism
Conduction Mechanism
Dipolar molecules try toalign to an oscillating fieldby rotation
Ions in solution will moveby the applied electricfield
Mingos D M P et al Chem Soc Rev 1991 20 1 and 1998 27 213
Microwave vs Oil-bath Heating
J-S Schanche Mol Diversity 2003 7 293wwwpersonalchemistry-com wwwbiotagecom
Conventional Heating byConduction
ConductiveheatHeating byconvectioncurrentsSlow andenergyinefficientprocess
temperature on the outside surface isin excess of the boiling point of liquid
Direct Heating by MicrowaveIrradiation
bullSolventreagent absorbs MW energybull Vessel wall transparent to MWbullDirect in-core heatingbullInstant on-off
Inverted temperature gradients
Molecular Speeds
Molecular Speeds
Microwave Ovens
Cooking Chemistry Cooking Food
Household MW ovens
The Use of Microwave Ovens for Rapid Organic Synthesis R Gedye et al Tetrahedron Lett 1986 27 279
Publications on MW-AssistedOrganic Synthesis
7 Synthetic Journals JOrgChemOrgLettTetrahedron LettTetrahedron SynthCommun Synlett SynthesisAll Journals (Full Text) Dedicated instruments only (Anton Paar Biotage CEM Milestone Prolabo)
Industrial Chemical Applications of Microwave Heating
Food Processing+ Defrosting+ Drying roasting baking+ Pasteurization
Drying Industry+ Wood fibers textiles+ Pharmaceuticals+ Brick concrete walls
Polymer Chemistry+ Rubber curing vulcanization+ Polymerization
CeramicsMaterials+ Alumina sintering+ Welding smelting gluing
Plasma+ SemiconductorsWaste Remediation+ Sewage treatment
Analytical Chemistry+ Digestion+ Extraction+ Ashing
Biochemistry Pathology+ Protein hydrolysis+ PCR proteomics+ Tissue fixation+ Histoprocessing
Medical+ Diathermy tumor detection+ Blood warming+ Sterilization (Anthrax)+ Drying of catheters
Books on Microwave-Assisted Synthesis
1048707 Fundamentals of Microwave Application1048707 Alternative Laboratory MicrowaveInstruments1048707 Chemistry Applications1048707 Biochemistry Applications1048707 Laboratory Microwave Safety
Hayes B LCEM PublishingMatthews NC2002
(ACS Professional Reference Book) H M Kingston S J Haswell (eds)
Microwaves in Organic and Medicinal ChemistryKappe C O and Stadler AWiley-VCH Weinheim 2005 ISBN 3-527-31210-2410 pages ca 1000 references
Books on Microwave-Assisted Synthesis
Lidstoumlm PTierney J P(Eds)BlackwellScientific2005
Loupy Andre (Ed)Wiley-VCH Weinheim 2003 ISBN 3-527-30514-9523 pages 2000 refs
Book (2 volumes) Wiley-VCHA Loupy editSecond Edition(2006) 22 Chapters
Astra Zeneca ResearchFoundation Kavitha PrintersBangalore India 2002azrefiastrazenecacom
Practical Microwave Synthesis for Organic Chemists - Strategies Instruments and Protocols
Edition - 2009 X 310 Pages Hardcover Monograph
Books on Microwave-Assisted Synthesis
Microwave Ovens
Monomodal instrument
Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005
Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia
Multimodal instrument
+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile
Monomodal Vs Multimodal
Monomodal Vs Multimodal
Thermal Effects
bullMore efficient energetic coupling of solvent with microwaves
promotes higher rate of temperature increase
bull Inverted heat transfer volumetric
bull ldquoHot spotsrdquo in monomode microwaves
bull Selective on properties of material (solvents catalysts
reagents intermediates products susceptors)
Recent Applications of Microwave-Assisted Synthesis-MAOS
Hydrolysis of benzamide
thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)
The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions
R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958
Solvent-free Reactions or Solid-Solid Reactions
ldquoNo reaction proceeds without solventrdquo
Aristotle
Solventless syntheses
Green chemistry enabled advancement
Solvent-free Organic Synthesis
Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed
i n t o a p o w e r f u l m e t h o d o l o g y a s i t
reduces the amount of toxic waste produced and therefore becomes less harmful to the
e n v i r o n m e n t
Solvent-free Organic Synthesis
bull Clean and efficient synthesis
bull Economic and environmental impact
bull Fast reaction kinetics
Best solvent is no solvent
Adolf von Baeyer
Synthesis of Indigo
Towardsbenign
synthesiswith
remarkableVersatility
G W V Cave C LRaston J L ScottChemCommun
2001 2159
Solid-State General Oxidation with with Urea H2O2 Complex
R S Varma and K P Naiker Org Letters 1999 1 189
Solvent-free Oxidative Preparation of Heterocycles
Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157
Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones
Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199
Solvent-free Reduction
F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245
Carbon-Carbon Bond Formation
Toda Tanada Iwata J Org Chem 1989 54 3007
Solventless Photo Coupling and Photo Rearangements
Y Ito S Endo J Am Chem Soc 1997 119 5974
Shin Keating Maribay J Am Chem Soc 1996 118 7626
Solvent - Free Condensation
Z Gross et al Org Letters 1999 1 599
Solid-State Preparationof Dumb-bell-shaped C120
Wang Komatsu Murata Shiro Nature 1997 387 583
Advantages of Solid Mineral Supports(Alumina Silica and Clay)
Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area
The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity
Solids are generally easier and safer to handle than liquids or gaseous reagents
Inexpensive recyclable and environmentally benign nature
Solid-supported Solventless Reactions
bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation
R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43
Supported ReactionsUsing Microwaves
E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945
Microwave-Assisted Deacetylationon Alumina
Varma et al J Chem Soc Perkin Trans 1 999 (1993)
Deprotection of Benzyl Esters viaMicrowave Thermolysis
A practical alternative to traditional catalytic hydrogenation
Varma et al Tetrahedron Lett 34 4603 (1993)
Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of
Carbonyl Compounds Using Microwaves
Varma Meshram Tetrahedron Lett 38 5427 (1997)
Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm
PersulfatendashClay using Microwave and Ultrasonic Irradiation
Varma Meshram Tetrahedron Lett 38 7973 (1997)
Solid Supported Solvent-freeOxidation under MW
Varma et al Tetrahedron Lett 1997 38 2043 and 7823
Solvent-free Reduction Using MW
Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction
Varma et al Tetrahedron Lett 1997 38 4337
Hydrodechlorination under continuous MW
Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)
Synthesis of Heterocyclic Compounds
Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)
Synthesis of Heterocyclic Compounds
Organometallic Reactions
Rearrangements
Rearrangements
INDOLIZINES
Heterocyclic systems 10- electronics
Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine
Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds
N
1
2
34567
8R2
R3
R1
Why interest for indolizinic products
Strong fluorescent properties luminiscent products luminiscent products
Potentially fluorescents marker Potentially laserldquoscintillatersrdquo
bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999
Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )
Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2
ldquoCalcium-entryrdquo blockers
Indolizines by irradiation with microwaves in MCR
RBr
O+
N
R1 R2+N
R2
R1
COR
AcOAl2O3 Mw
R=Ph p-Tolil Stiril
R1= H COOMeR2= COOEt COOMe
Asymmetric indolizines by irradiation with microwaves in MCR
R1
O
Cl+ R2
N NEtOOC
OOMe
Br BrN N
EtOOC
COR1
R2COR1
R2
OOMe
2 [Pd(PPh3)2Cl24 CuI
20 echiv Et3N THF tc 2h
R1=Ph 4-OMe-C6H4R2= Ph
U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003
A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new indolizines
[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical
II
IHH
COORCOOR
N C C
O
R2NCC
O
R1
(B)
(A)
R1
O
C C N R2
O
CCN
H H
ROOC COOR
R1
O
C C N R2
O
CCN
COOR COOR
ROOC COOR
2
2 ROOC C C COOR
R1
O
C CH N R2
O
CCHN
H H
N NCH CHC C
O O
R1 R2
- 2 HX TEAanhydrous solvents
X-
X-
N NCH2 CH2C C
O O
R1 R2
C C COORH
R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5
Y=H NO2 OCH3 CH3 Cl BrX=Br Cl
bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998
bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001
bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004
bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new substituted pyridinium-indolizines
Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate
COO NO2CHC
N NH3C
OR
I IN NH3C
OR
IN NH3C
OR
I
H
KFNMP
-HI
NMP
95oC 30 min
N NH3CO
RN NH3C
O
R
O OO
NO2
O
NO2
-2[H]-2[H]
II
I II
N NH3CO
R
O O
NO2
IN NH3C
O
R
O O
NO2
I
(9a-d)(10a-d)
(15a-d)
(A) (B)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
12
34
56
78 9
10
11
12 3
4
56
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Schematic of a Microwave
E= electric fieldH= magnetic field= wavelength (122 cm for 2450 MHz)c= speed of light (300000 kms)
Microwaves Application in Heating Food
1946 Original patent (P L Spencer)1947 First commercial oven1955 Home models1967 Desktop model1975 US sales exceed gas ranges1976 60 of US households havemicrowave ovens
Spectrum Electromagnetic
bull Electric field component
bull Responsible for dielectric heating
bull Dipolar polarization
bull Conduction
bull Magnetic field component
Microwaves ndash Dipolar Rotationbull Polar molecules have intermolecular forces which give any motion of the
molecule some inertia
bull Under a very high frequency electric field the polar molecule will attempt to follow the field but intermolecular inertia stops any significant motion before the field has reversed and no net motion results
bull If the frequency of field oscillation is very low then the molecules will be polarized uniformly and no random motion results
bull In the intermediate case the frequency of the field will be such that the molecules will be almost but not quite able to keep in phase with the field polarity
bull In this case the random motion resulting as molecules jostle to attempt in vain to follow the field provides strong agitation and intense heating of the sample
bull At 245 GHz the field oscillates 49 x 109 timess which can lead to heating
rates of 10 degC per second when powerful waves are used
MW Heating Mechanism
Alternating electric field Withhigh frequency
NoconstraintContinuous electric field
Two mechanisms Dipolar rotation polarizationIonic Conduction mechanism
Microwave Dielectric HeatingMechanisms
Dipolar PolarizationMechanism
Conduction Mechanism
Dipolar molecules try toalign to an oscillating fieldby rotation
Ions in solution will moveby the applied electricfield
Mingos D M P et al Chem Soc Rev 1991 20 1 and 1998 27 213
Microwave vs Oil-bath Heating
J-S Schanche Mol Diversity 2003 7 293wwwpersonalchemistry-com wwwbiotagecom
Conventional Heating byConduction
ConductiveheatHeating byconvectioncurrentsSlow andenergyinefficientprocess
temperature on the outside surface isin excess of the boiling point of liquid
Direct Heating by MicrowaveIrradiation
bullSolventreagent absorbs MW energybull Vessel wall transparent to MWbullDirect in-core heatingbullInstant on-off
Inverted temperature gradients
Molecular Speeds
Molecular Speeds
Microwave Ovens
Cooking Chemistry Cooking Food
Household MW ovens
The Use of Microwave Ovens for Rapid Organic Synthesis R Gedye et al Tetrahedron Lett 1986 27 279
Publications on MW-AssistedOrganic Synthesis
7 Synthetic Journals JOrgChemOrgLettTetrahedron LettTetrahedron SynthCommun Synlett SynthesisAll Journals (Full Text) Dedicated instruments only (Anton Paar Biotage CEM Milestone Prolabo)
Industrial Chemical Applications of Microwave Heating
Food Processing+ Defrosting+ Drying roasting baking+ Pasteurization
Drying Industry+ Wood fibers textiles+ Pharmaceuticals+ Brick concrete walls
Polymer Chemistry+ Rubber curing vulcanization+ Polymerization
CeramicsMaterials+ Alumina sintering+ Welding smelting gluing
Plasma+ SemiconductorsWaste Remediation+ Sewage treatment
Analytical Chemistry+ Digestion+ Extraction+ Ashing
Biochemistry Pathology+ Protein hydrolysis+ PCR proteomics+ Tissue fixation+ Histoprocessing
Medical+ Diathermy tumor detection+ Blood warming+ Sterilization (Anthrax)+ Drying of catheters
Books on Microwave-Assisted Synthesis
1048707 Fundamentals of Microwave Application1048707 Alternative Laboratory MicrowaveInstruments1048707 Chemistry Applications1048707 Biochemistry Applications1048707 Laboratory Microwave Safety
Hayes B LCEM PublishingMatthews NC2002
(ACS Professional Reference Book) H M Kingston S J Haswell (eds)
Microwaves in Organic and Medicinal ChemistryKappe C O and Stadler AWiley-VCH Weinheim 2005 ISBN 3-527-31210-2410 pages ca 1000 references
Books on Microwave-Assisted Synthesis
Lidstoumlm PTierney J P(Eds)BlackwellScientific2005
Loupy Andre (Ed)Wiley-VCH Weinheim 2003 ISBN 3-527-30514-9523 pages 2000 refs
Book (2 volumes) Wiley-VCHA Loupy editSecond Edition(2006) 22 Chapters
Astra Zeneca ResearchFoundation Kavitha PrintersBangalore India 2002azrefiastrazenecacom
Practical Microwave Synthesis for Organic Chemists - Strategies Instruments and Protocols
Edition - 2009 X 310 Pages Hardcover Monograph
Books on Microwave-Assisted Synthesis
Microwave Ovens
Monomodal instrument
Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005
Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia
Multimodal instrument
+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile
Monomodal Vs Multimodal
Monomodal Vs Multimodal
Thermal Effects
bullMore efficient energetic coupling of solvent with microwaves
promotes higher rate of temperature increase
bull Inverted heat transfer volumetric
bull ldquoHot spotsrdquo in monomode microwaves
bull Selective on properties of material (solvents catalysts
reagents intermediates products susceptors)
Recent Applications of Microwave-Assisted Synthesis-MAOS
Hydrolysis of benzamide
thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)
The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions
R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958
Solvent-free Reactions or Solid-Solid Reactions
ldquoNo reaction proceeds without solventrdquo
Aristotle
Solventless syntheses
Green chemistry enabled advancement
Solvent-free Organic Synthesis
Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed
i n t o a p o w e r f u l m e t h o d o l o g y a s i t
reduces the amount of toxic waste produced and therefore becomes less harmful to the
e n v i r o n m e n t
Solvent-free Organic Synthesis
bull Clean and efficient synthesis
bull Economic and environmental impact
bull Fast reaction kinetics
Best solvent is no solvent
Adolf von Baeyer
Synthesis of Indigo
Towardsbenign
synthesiswith
remarkableVersatility
G W V Cave C LRaston J L ScottChemCommun
2001 2159
Solid-State General Oxidation with with Urea H2O2 Complex
R S Varma and K P Naiker Org Letters 1999 1 189
Solvent-free Oxidative Preparation of Heterocycles
Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157
Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones
Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199
Solvent-free Reduction
F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245
Carbon-Carbon Bond Formation
Toda Tanada Iwata J Org Chem 1989 54 3007
Solventless Photo Coupling and Photo Rearangements
Y Ito S Endo J Am Chem Soc 1997 119 5974
Shin Keating Maribay J Am Chem Soc 1996 118 7626
Solvent - Free Condensation
Z Gross et al Org Letters 1999 1 599
Solid-State Preparationof Dumb-bell-shaped C120
Wang Komatsu Murata Shiro Nature 1997 387 583
Advantages of Solid Mineral Supports(Alumina Silica and Clay)
Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area
The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity
Solids are generally easier and safer to handle than liquids or gaseous reagents
Inexpensive recyclable and environmentally benign nature
Solid-supported Solventless Reactions
bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation
R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43
Supported ReactionsUsing Microwaves
E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945
Microwave-Assisted Deacetylationon Alumina
Varma et al J Chem Soc Perkin Trans 1 999 (1993)
Deprotection of Benzyl Esters viaMicrowave Thermolysis
A practical alternative to traditional catalytic hydrogenation
Varma et al Tetrahedron Lett 34 4603 (1993)
Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of
Carbonyl Compounds Using Microwaves
Varma Meshram Tetrahedron Lett 38 5427 (1997)
Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm
PersulfatendashClay using Microwave and Ultrasonic Irradiation
Varma Meshram Tetrahedron Lett 38 7973 (1997)
Solid Supported Solvent-freeOxidation under MW
Varma et al Tetrahedron Lett 1997 38 2043 and 7823
Solvent-free Reduction Using MW
Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction
Varma et al Tetrahedron Lett 1997 38 4337
Hydrodechlorination under continuous MW
Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)
Synthesis of Heterocyclic Compounds
Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)
Synthesis of Heterocyclic Compounds
Organometallic Reactions
Rearrangements
Rearrangements
INDOLIZINES
Heterocyclic systems 10- electronics
Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine
Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds
N
1
2
34567
8R2
R3
R1
Why interest for indolizinic products
Strong fluorescent properties luminiscent products luminiscent products
Potentially fluorescents marker Potentially laserldquoscintillatersrdquo
bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999
Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )
Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2
ldquoCalcium-entryrdquo blockers
Indolizines by irradiation with microwaves in MCR
RBr
O+
N
R1 R2+N
R2
R1
COR
AcOAl2O3 Mw
R=Ph p-Tolil Stiril
R1= H COOMeR2= COOEt COOMe
Asymmetric indolizines by irradiation with microwaves in MCR
R1
O
Cl+ R2
N NEtOOC
OOMe
Br BrN N
EtOOC
COR1
R2COR1
R2
OOMe
2 [Pd(PPh3)2Cl24 CuI
20 echiv Et3N THF tc 2h
R1=Ph 4-OMe-C6H4R2= Ph
U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003
A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new indolizines
[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical
II
IHH
COORCOOR
N C C
O
R2NCC
O
R1
(B)
(A)
R1
O
C C N R2
O
CCN
H H
ROOC COOR
R1
O
C C N R2
O
CCN
COOR COOR
ROOC COOR
2
2 ROOC C C COOR
R1
O
C CH N R2
O
CCHN
H H
N NCH CHC C
O O
R1 R2
- 2 HX TEAanhydrous solvents
X-
X-
N NCH2 CH2C C
O O
R1 R2
C C COORH
R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5
Y=H NO2 OCH3 CH3 Cl BrX=Br Cl
bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998
bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001
bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004
bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new substituted pyridinium-indolizines
Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate
COO NO2CHC
N NH3C
OR
I IN NH3C
OR
IN NH3C
OR
I
H
KFNMP
-HI
NMP
95oC 30 min
N NH3CO
RN NH3C
O
R
O OO
NO2
O
NO2
-2[H]-2[H]
II
I II
N NH3CO
R
O O
NO2
IN NH3C
O
R
O O
NO2
I
(9a-d)(10a-d)
(15a-d)
(A) (B)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
12
34
56
78 9
10
11
12 3
4
56
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Microwaves Application in Heating Food
1946 Original patent (P L Spencer)1947 First commercial oven1955 Home models1967 Desktop model1975 US sales exceed gas ranges1976 60 of US households havemicrowave ovens
Spectrum Electromagnetic
bull Electric field component
bull Responsible for dielectric heating
bull Dipolar polarization
bull Conduction
bull Magnetic field component
Microwaves ndash Dipolar Rotationbull Polar molecules have intermolecular forces which give any motion of the
molecule some inertia
bull Under a very high frequency electric field the polar molecule will attempt to follow the field but intermolecular inertia stops any significant motion before the field has reversed and no net motion results
bull If the frequency of field oscillation is very low then the molecules will be polarized uniformly and no random motion results
bull In the intermediate case the frequency of the field will be such that the molecules will be almost but not quite able to keep in phase with the field polarity
bull In this case the random motion resulting as molecules jostle to attempt in vain to follow the field provides strong agitation and intense heating of the sample
bull At 245 GHz the field oscillates 49 x 109 timess which can lead to heating
rates of 10 degC per second when powerful waves are used
MW Heating Mechanism
Alternating electric field Withhigh frequency
NoconstraintContinuous electric field
Two mechanisms Dipolar rotation polarizationIonic Conduction mechanism
Microwave Dielectric HeatingMechanisms
Dipolar PolarizationMechanism
Conduction Mechanism
Dipolar molecules try toalign to an oscillating fieldby rotation
Ions in solution will moveby the applied electricfield
Mingos D M P et al Chem Soc Rev 1991 20 1 and 1998 27 213
Microwave vs Oil-bath Heating
J-S Schanche Mol Diversity 2003 7 293wwwpersonalchemistry-com wwwbiotagecom
Conventional Heating byConduction
ConductiveheatHeating byconvectioncurrentsSlow andenergyinefficientprocess
temperature on the outside surface isin excess of the boiling point of liquid
Direct Heating by MicrowaveIrradiation
bullSolventreagent absorbs MW energybull Vessel wall transparent to MWbullDirect in-core heatingbullInstant on-off
Inverted temperature gradients
Molecular Speeds
Molecular Speeds
Microwave Ovens
Cooking Chemistry Cooking Food
Household MW ovens
The Use of Microwave Ovens for Rapid Organic Synthesis R Gedye et al Tetrahedron Lett 1986 27 279
Publications on MW-AssistedOrganic Synthesis
7 Synthetic Journals JOrgChemOrgLettTetrahedron LettTetrahedron SynthCommun Synlett SynthesisAll Journals (Full Text) Dedicated instruments only (Anton Paar Biotage CEM Milestone Prolabo)
Industrial Chemical Applications of Microwave Heating
Food Processing+ Defrosting+ Drying roasting baking+ Pasteurization
Drying Industry+ Wood fibers textiles+ Pharmaceuticals+ Brick concrete walls
Polymer Chemistry+ Rubber curing vulcanization+ Polymerization
CeramicsMaterials+ Alumina sintering+ Welding smelting gluing
Plasma+ SemiconductorsWaste Remediation+ Sewage treatment
Analytical Chemistry+ Digestion+ Extraction+ Ashing
Biochemistry Pathology+ Protein hydrolysis+ PCR proteomics+ Tissue fixation+ Histoprocessing
Medical+ Diathermy tumor detection+ Blood warming+ Sterilization (Anthrax)+ Drying of catheters
Books on Microwave-Assisted Synthesis
1048707 Fundamentals of Microwave Application1048707 Alternative Laboratory MicrowaveInstruments1048707 Chemistry Applications1048707 Biochemistry Applications1048707 Laboratory Microwave Safety
Hayes B LCEM PublishingMatthews NC2002
(ACS Professional Reference Book) H M Kingston S J Haswell (eds)
Microwaves in Organic and Medicinal ChemistryKappe C O and Stadler AWiley-VCH Weinheim 2005 ISBN 3-527-31210-2410 pages ca 1000 references
Books on Microwave-Assisted Synthesis
Lidstoumlm PTierney J P(Eds)BlackwellScientific2005
Loupy Andre (Ed)Wiley-VCH Weinheim 2003 ISBN 3-527-30514-9523 pages 2000 refs
Book (2 volumes) Wiley-VCHA Loupy editSecond Edition(2006) 22 Chapters
Astra Zeneca ResearchFoundation Kavitha PrintersBangalore India 2002azrefiastrazenecacom
Practical Microwave Synthesis for Organic Chemists - Strategies Instruments and Protocols
Edition - 2009 X 310 Pages Hardcover Monograph
Books on Microwave-Assisted Synthesis
Microwave Ovens
Monomodal instrument
Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005
Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia
Multimodal instrument
+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile
Monomodal Vs Multimodal
Monomodal Vs Multimodal
Thermal Effects
bullMore efficient energetic coupling of solvent with microwaves
promotes higher rate of temperature increase
bull Inverted heat transfer volumetric
bull ldquoHot spotsrdquo in monomode microwaves
bull Selective on properties of material (solvents catalysts
reagents intermediates products susceptors)
Recent Applications of Microwave-Assisted Synthesis-MAOS
Hydrolysis of benzamide
thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)
The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions
R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958
Solvent-free Reactions or Solid-Solid Reactions
ldquoNo reaction proceeds without solventrdquo
Aristotle
Solventless syntheses
Green chemistry enabled advancement
Solvent-free Organic Synthesis
Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed
i n t o a p o w e r f u l m e t h o d o l o g y a s i t
reduces the amount of toxic waste produced and therefore becomes less harmful to the
e n v i r o n m e n t
Solvent-free Organic Synthesis
bull Clean and efficient synthesis
bull Economic and environmental impact
bull Fast reaction kinetics
Best solvent is no solvent
Adolf von Baeyer
Synthesis of Indigo
Towardsbenign
synthesiswith
remarkableVersatility
G W V Cave C LRaston J L ScottChemCommun
2001 2159
Solid-State General Oxidation with with Urea H2O2 Complex
R S Varma and K P Naiker Org Letters 1999 1 189
Solvent-free Oxidative Preparation of Heterocycles
Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157
Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones
Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199
Solvent-free Reduction
F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245
Carbon-Carbon Bond Formation
Toda Tanada Iwata J Org Chem 1989 54 3007
Solventless Photo Coupling and Photo Rearangements
Y Ito S Endo J Am Chem Soc 1997 119 5974
Shin Keating Maribay J Am Chem Soc 1996 118 7626
Solvent - Free Condensation
Z Gross et al Org Letters 1999 1 599
Solid-State Preparationof Dumb-bell-shaped C120
Wang Komatsu Murata Shiro Nature 1997 387 583
Advantages of Solid Mineral Supports(Alumina Silica and Clay)
Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area
The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity
Solids are generally easier and safer to handle than liquids or gaseous reagents
Inexpensive recyclable and environmentally benign nature
Solid-supported Solventless Reactions
bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation
R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43
Supported ReactionsUsing Microwaves
E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945
Microwave-Assisted Deacetylationon Alumina
Varma et al J Chem Soc Perkin Trans 1 999 (1993)
Deprotection of Benzyl Esters viaMicrowave Thermolysis
A practical alternative to traditional catalytic hydrogenation
Varma et al Tetrahedron Lett 34 4603 (1993)
Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of
Carbonyl Compounds Using Microwaves
Varma Meshram Tetrahedron Lett 38 5427 (1997)
Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm
PersulfatendashClay using Microwave and Ultrasonic Irradiation
Varma Meshram Tetrahedron Lett 38 7973 (1997)
Solid Supported Solvent-freeOxidation under MW
Varma et al Tetrahedron Lett 1997 38 2043 and 7823
Solvent-free Reduction Using MW
Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction
Varma et al Tetrahedron Lett 1997 38 4337
Hydrodechlorination under continuous MW
Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)
Synthesis of Heterocyclic Compounds
Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)
Synthesis of Heterocyclic Compounds
Organometallic Reactions
Rearrangements
Rearrangements
INDOLIZINES
Heterocyclic systems 10- electronics
Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine
Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds
N
1
2
34567
8R2
R3
R1
Why interest for indolizinic products
Strong fluorescent properties luminiscent products luminiscent products
Potentially fluorescents marker Potentially laserldquoscintillatersrdquo
bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999
Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )
Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2
ldquoCalcium-entryrdquo blockers
Indolizines by irradiation with microwaves in MCR
RBr
O+
N
R1 R2+N
R2
R1
COR
AcOAl2O3 Mw
R=Ph p-Tolil Stiril
R1= H COOMeR2= COOEt COOMe
Asymmetric indolizines by irradiation with microwaves in MCR
R1
O
Cl+ R2
N NEtOOC
OOMe
Br BrN N
EtOOC
COR1
R2COR1
R2
OOMe
2 [Pd(PPh3)2Cl24 CuI
20 echiv Et3N THF tc 2h
R1=Ph 4-OMe-C6H4R2= Ph
U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003
A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new indolizines
[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical
II
IHH
COORCOOR
N C C
O
R2NCC
O
R1
(B)
(A)
R1
O
C C N R2
O
CCN
H H
ROOC COOR
R1
O
C C N R2
O
CCN
COOR COOR
ROOC COOR
2
2 ROOC C C COOR
R1
O
C CH N R2
O
CCHN
H H
N NCH CHC C
O O
R1 R2
- 2 HX TEAanhydrous solvents
X-
X-
N NCH2 CH2C C
O O
R1 R2
C C COORH
R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5
Y=H NO2 OCH3 CH3 Cl BrX=Br Cl
bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998
bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001
bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004
bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new substituted pyridinium-indolizines
Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate
COO NO2CHC
N NH3C
OR
I IN NH3C
OR
IN NH3C
OR
I
H
KFNMP
-HI
NMP
95oC 30 min
N NH3CO
RN NH3C
O
R
O OO
NO2
O
NO2
-2[H]-2[H]
II
I II
N NH3CO
R
O O
NO2
IN NH3C
O
R
O O
NO2
I
(9a-d)(10a-d)
(15a-d)
(A) (B)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
12
34
56
78 9
10
11
12 3
4
56
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Spectrum Electromagnetic
bull Electric field component
bull Responsible for dielectric heating
bull Dipolar polarization
bull Conduction
bull Magnetic field component
Microwaves ndash Dipolar Rotationbull Polar molecules have intermolecular forces which give any motion of the
molecule some inertia
bull Under a very high frequency electric field the polar molecule will attempt to follow the field but intermolecular inertia stops any significant motion before the field has reversed and no net motion results
bull If the frequency of field oscillation is very low then the molecules will be polarized uniformly and no random motion results
bull In the intermediate case the frequency of the field will be such that the molecules will be almost but not quite able to keep in phase with the field polarity
bull In this case the random motion resulting as molecules jostle to attempt in vain to follow the field provides strong agitation and intense heating of the sample
bull At 245 GHz the field oscillates 49 x 109 timess which can lead to heating
rates of 10 degC per second when powerful waves are used
MW Heating Mechanism
Alternating electric field Withhigh frequency
NoconstraintContinuous electric field
Two mechanisms Dipolar rotation polarizationIonic Conduction mechanism
Microwave Dielectric HeatingMechanisms
Dipolar PolarizationMechanism
Conduction Mechanism
Dipolar molecules try toalign to an oscillating fieldby rotation
Ions in solution will moveby the applied electricfield
Mingos D M P et al Chem Soc Rev 1991 20 1 and 1998 27 213
Microwave vs Oil-bath Heating
J-S Schanche Mol Diversity 2003 7 293wwwpersonalchemistry-com wwwbiotagecom
Conventional Heating byConduction
ConductiveheatHeating byconvectioncurrentsSlow andenergyinefficientprocess
temperature on the outside surface isin excess of the boiling point of liquid
Direct Heating by MicrowaveIrradiation
bullSolventreagent absorbs MW energybull Vessel wall transparent to MWbullDirect in-core heatingbullInstant on-off
Inverted temperature gradients
Molecular Speeds
Molecular Speeds
Microwave Ovens
Cooking Chemistry Cooking Food
Household MW ovens
The Use of Microwave Ovens for Rapid Organic Synthesis R Gedye et al Tetrahedron Lett 1986 27 279
Publications on MW-AssistedOrganic Synthesis
7 Synthetic Journals JOrgChemOrgLettTetrahedron LettTetrahedron SynthCommun Synlett SynthesisAll Journals (Full Text) Dedicated instruments only (Anton Paar Biotage CEM Milestone Prolabo)
Industrial Chemical Applications of Microwave Heating
Food Processing+ Defrosting+ Drying roasting baking+ Pasteurization
Drying Industry+ Wood fibers textiles+ Pharmaceuticals+ Brick concrete walls
Polymer Chemistry+ Rubber curing vulcanization+ Polymerization
CeramicsMaterials+ Alumina sintering+ Welding smelting gluing
Plasma+ SemiconductorsWaste Remediation+ Sewage treatment
Analytical Chemistry+ Digestion+ Extraction+ Ashing
Biochemistry Pathology+ Protein hydrolysis+ PCR proteomics+ Tissue fixation+ Histoprocessing
Medical+ Diathermy tumor detection+ Blood warming+ Sterilization (Anthrax)+ Drying of catheters
Books on Microwave-Assisted Synthesis
1048707 Fundamentals of Microwave Application1048707 Alternative Laboratory MicrowaveInstruments1048707 Chemistry Applications1048707 Biochemistry Applications1048707 Laboratory Microwave Safety
Hayes B LCEM PublishingMatthews NC2002
(ACS Professional Reference Book) H M Kingston S J Haswell (eds)
Microwaves in Organic and Medicinal ChemistryKappe C O and Stadler AWiley-VCH Weinheim 2005 ISBN 3-527-31210-2410 pages ca 1000 references
Books on Microwave-Assisted Synthesis
Lidstoumlm PTierney J P(Eds)BlackwellScientific2005
Loupy Andre (Ed)Wiley-VCH Weinheim 2003 ISBN 3-527-30514-9523 pages 2000 refs
Book (2 volumes) Wiley-VCHA Loupy editSecond Edition(2006) 22 Chapters
Astra Zeneca ResearchFoundation Kavitha PrintersBangalore India 2002azrefiastrazenecacom
Practical Microwave Synthesis for Organic Chemists - Strategies Instruments and Protocols
Edition - 2009 X 310 Pages Hardcover Monograph
Books on Microwave-Assisted Synthesis
Microwave Ovens
Monomodal instrument
Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005
Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia
Multimodal instrument
+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile
Monomodal Vs Multimodal
Monomodal Vs Multimodal
Thermal Effects
bullMore efficient energetic coupling of solvent with microwaves
promotes higher rate of temperature increase
bull Inverted heat transfer volumetric
bull ldquoHot spotsrdquo in monomode microwaves
bull Selective on properties of material (solvents catalysts
reagents intermediates products susceptors)
Recent Applications of Microwave-Assisted Synthesis-MAOS
Hydrolysis of benzamide
thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)
The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions
R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958
Solvent-free Reactions or Solid-Solid Reactions
ldquoNo reaction proceeds without solventrdquo
Aristotle
Solventless syntheses
Green chemistry enabled advancement
Solvent-free Organic Synthesis
Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed
i n t o a p o w e r f u l m e t h o d o l o g y a s i t
reduces the amount of toxic waste produced and therefore becomes less harmful to the
e n v i r o n m e n t
Solvent-free Organic Synthesis
bull Clean and efficient synthesis
bull Economic and environmental impact
bull Fast reaction kinetics
Best solvent is no solvent
Adolf von Baeyer
Synthesis of Indigo
Towardsbenign
synthesiswith
remarkableVersatility
G W V Cave C LRaston J L ScottChemCommun
2001 2159
Solid-State General Oxidation with with Urea H2O2 Complex
R S Varma and K P Naiker Org Letters 1999 1 189
Solvent-free Oxidative Preparation of Heterocycles
Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157
Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones
Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199
Solvent-free Reduction
F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245
Carbon-Carbon Bond Formation
Toda Tanada Iwata J Org Chem 1989 54 3007
Solventless Photo Coupling and Photo Rearangements
Y Ito S Endo J Am Chem Soc 1997 119 5974
Shin Keating Maribay J Am Chem Soc 1996 118 7626
Solvent - Free Condensation
Z Gross et al Org Letters 1999 1 599
Solid-State Preparationof Dumb-bell-shaped C120
Wang Komatsu Murata Shiro Nature 1997 387 583
Advantages of Solid Mineral Supports(Alumina Silica and Clay)
Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area
The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity
Solids are generally easier and safer to handle than liquids or gaseous reagents
Inexpensive recyclable and environmentally benign nature
Solid-supported Solventless Reactions
bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation
R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43
Supported ReactionsUsing Microwaves
E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945
Microwave-Assisted Deacetylationon Alumina
Varma et al J Chem Soc Perkin Trans 1 999 (1993)
Deprotection of Benzyl Esters viaMicrowave Thermolysis
A practical alternative to traditional catalytic hydrogenation
Varma et al Tetrahedron Lett 34 4603 (1993)
Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of
Carbonyl Compounds Using Microwaves
Varma Meshram Tetrahedron Lett 38 5427 (1997)
Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm
PersulfatendashClay using Microwave and Ultrasonic Irradiation
Varma Meshram Tetrahedron Lett 38 7973 (1997)
Solid Supported Solvent-freeOxidation under MW
Varma et al Tetrahedron Lett 1997 38 2043 and 7823
Solvent-free Reduction Using MW
Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction
Varma et al Tetrahedron Lett 1997 38 4337
Hydrodechlorination under continuous MW
Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)
Synthesis of Heterocyclic Compounds
Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)
Synthesis of Heterocyclic Compounds
Organometallic Reactions
Rearrangements
Rearrangements
INDOLIZINES
Heterocyclic systems 10- electronics
Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine
Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds
N
1
2
34567
8R2
R3
R1
Why interest for indolizinic products
Strong fluorescent properties luminiscent products luminiscent products
Potentially fluorescents marker Potentially laserldquoscintillatersrdquo
bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999
Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )
Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2
ldquoCalcium-entryrdquo blockers
Indolizines by irradiation with microwaves in MCR
RBr
O+
N
R1 R2+N
R2
R1
COR
AcOAl2O3 Mw
R=Ph p-Tolil Stiril
R1= H COOMeR2= COOEt COOMe
Asymmetric indolizines by irradiation with microwaves in MCR
R1
O
Cl+ R2
N NEtOOC
OOMe
Br BrN N
EtOOC
COR1
R2COR1
R2
OOMe
2 [Pd(PPh3)2Cl24 CuI
20 echiv Et3N THF tc 2h
R1=Ph 4-OMe-C6H4R2= Ph
U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003
A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new indolizines
[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical
II
IHH
COORCOOR
N C C
O
R2NCC
O
R1
(B)
(A)
R1
O
C C N R2
O
CCN
H H
ROOC COOR
R1
O
C C N R2
O
CCN
COOR COOR
ROOC COOR
2
2 ROOC C C COOR
R1
O
C CH N R2
O
CCHN
H H
N NCH CHC C
O O
R1 R2
- 2 HX TEAanhydrous solvents
X-
X-
N NCH2 CH2C C
O O
R1 R2
C C COORH
R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5
Y=H NO2 OCH3 CH3 Cl BrX=Br Cl
bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998
bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001
bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004
bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new substituted pyridinium-indolizines
Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate
COO NO2CHC
N NH3C
OR
I IN NH3C
OR
IN NH3C
OR
I
H
KFNMP
-HI
NMP
95oC 30 min
N NH3CO
RN NH3C
O
R
O OO
NO2
O
NO2
-2[H]-2[H]
II
I II
N NH3CO
R
O O
NO2
IN NH3C
O
R
O O
NO2
I
(9a-d)(10a-d)
(15a-d)
(A) (B)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
12
34
56
78 9
10
11
12 3
4
56
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Microwaves ndash Dipolar Rotationbull Polar molecules have intermolecular forces which give any motion of the
molecule some inertia
bull Under a very high frequency electric field the polar molecule will attempt to follow the field but intermolecular inertia stops any significant motion before the field has reversed and no net motion results
bull If the frequency of field oscillation is very low then the molecules will be polarized uniformly and no random motion results
bull In the intermediate case the frequency of the field will be such that the molecules will be almost but not quite able to keep in phase with the field polarity
bull In this case the random motion resulting as molecules jostle to attempt in vain to follow the field provides strong agitation and intense heating of the sample
bull At 245 GHz the field oscillates 49 x 109 timess which can lead to heating
rates of 10 degC per second when powerful waves are used
MW Heating Mechanism
Alternating electric field Withhigh frequency
NoconstraintContinuous electric field
Two mechanisms Dipolar rotation polarizationIonic Conduction mechanism
Microwave Dielectric HeatingMechanisms
Dipolar PolarizationMechanism
Conduction Mechanism
Dipolar molecules try toalign to an oscillating fieldby rotation
Ions in solution will moveby the applied electricfield
Mingos D M P et al Chem Soc Rev 1991 20 1 and 1998 27 213
Microwave vs Oil-bath Heating
J-S Schanche Mol Diversity 2003 7 293wwwpersonalchemistry-com wwwbiotagecom
Conventional Heating byConduction
ConductiveheatHeating byconvectioncurrentsSlow andenergyinefficientprocess
temperature on the outside surface isin excess of the boiling point of liquid
Direct Heating by MicrowaveIrradiation
bullSolventreagent absorbs MW energybull Vessel wall transparent to MWbullDirect in-core heatingbullInstant on-off
Inverted temperature gradients
Molecular Speeds
Molecular Speeds
Microwave Ovens
Cooking Chemistry Cooking Food
Household MW ovens
The Use of Microwave Ovens for Rapid Organic Synthesis R Gedye et al Tetrahedron Lett 1986 27 279
Publications on MW-AssistedOrganic Synthesis
7 Synthetic Journals JOrgChemOrgLettTetrahedron LettTetrahedron SynthCommun Synlett SynthesisAll Journals (Full Text) Dedicated instruments only (Anton Paar Biotage CEM Milestone Prolabo)
Industrial Chemical Applications of Microwave Heating
Food Processing+ Defrosting+ Drying roasting baking+ Pasteurization
Drying Industry+ Wood fibers textiles+ Pharmaceuticals+ Brick concrete walls
Polymer Chemistry+ Rubber curing vulcanization+ Polymerization
CeramicsMaterials+ Alumina sintering+ Welding smelting gluing
Plasma+ SemiconductorsWaste Remediation+ Sewage treatment
Analytical Chemistry+ Digestion+ Extraction+ Ashing
Biochemistry Pathology+ Protein hydrolysis+ PCR proteomics+ Tissue fixation+ Histoprocessing
Medical+ Diathermy tumor detection+ Blood warming+ Sterilization (Anthrax)+ Drying of catheters
Books on Microwave-Assisted Synthesis
1048707 Fundamentals of Microwave Application1048707 Alternative Laboratory MicrowaveInstruments1048707 Chemistry Applications1048707 Biochemistry Applications1048707 Laboratory Microwave Safety
Hayes B LCEM PublishingMatthews NC2002
(ACS Professional Reference Book) H M Kingston S J Haswell (eds)
Microwaves in Organic and Medicinal ChemistryKappe C O and Stadler AWiley-VCH Weinheim 2005 ISBN 3-527-31210-2410 pages ca 1000 references
Books on Microwave-Assisted Synthesis
Lidstoumlm PTierney J P(Eds)BlackwellScientific2005
Loupy Andre (Ed)Wiley-VCH Weinheim 2003 ISBN 3-527-30514-9523 pages 2000 refs
Book (2 volumes) Wiley-VCHA Loupy editSecond Edition(2006) 22 Chapters
Astra Zeneca ResearchFoundation Kavitha PrintersBangalore India 2002azrefiastrazenecacom
Practical Microwave Synthesis for Organic Chemists - Strategies Instruments and Protocols
Edition - 2009 X 310 Pages Hardcover Monograph
Books on Microwave-Assisted Synthesis
Microwave Ovens
Monomodal instrument
Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005
Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia
Multimodal instrument
+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile
Monomodal Vs Multimodal
Monomodal Vs Multimodal
Thermal Effects
bullMore efficient energetic coupling of solvent with microwaves
promotes higher rate of temperature increase
bull Inverted heat transfer volumetric
bull ldquoHot spotsrdquo in monomode microwaves
bull Selective on properties of material (solvents catalysts
reagents intermediates products susceptors)
Recent Applications of Microwave-Assisted Synthesis-MAOS
Hydrolysis of benzamide
thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)
The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions
R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958
Solvent-free Reactions or Solid-Solid Reactions
ldquoNo reaction proceeds without solventrdquo
Aristotle
Solventless syntheses
Green chemistry enabled advancement
Solvent-free Organic Synthesis
Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed
i n t o a p o w e r f u l m e t h o d o l o g y a s i t
reduces the amount of toxic waste produced and therefore becomes less harmful to the
e n v i r o n m e n t
Solvent-free Organic Synthesis
bull Clean and efficient synthesis
bull Economic and environmental impact
bull Fast reaction kinetics
Best solvent is no solvent
Adolf von Baeyer
Synthesis of Indigo
Towardsbenign
synthesiswith
remarkableVersatility
G W V Cave C LRaston J L ScottChemCommun
2001 2159
Solid-State General Oxidation with with Urea H2O2 Complex
R S Varma and K P Naiker Org Letters 1999 1 189
Solvent-free Oxidative Preparation of Heterocycles
Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157
Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones
Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199
Solvent-free Reduction
F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245
Carbon-Carbon Bond Formation
Toda Tanada Iwata J Org Chem 1989 54 3007
Solventless Photo Coupling and Photo Rearangements
Y Ito S Endo J Am Chem Soc 1997 119 5974
Shin Keating Maribay J Am Chem Soc 1996 118 7626
Solvent - Free Condensation
Z Gross et al Org Letters 1999 1 599
Solid-State Preparationof Dumb-bell-shaped C120
Wang Komatsu Murata Shiro Nature 1997 387 583
Advantages of Solid Mineral Supports(Alumina Silica and Clay)
Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area
The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity
Solids are generally easier and safer to handle than liquids or gaseous reagents
Inexpensive recyclable and environmentally benign nature
Solid-supported Solventless Reactions
bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation
R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43
Supported ReactionsUsing Microwaves
E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945
Microwave-Assisted Deacetylationon Alumina
Varma et al J Chem Soc Perkin Trans 1 999 (1993)
Deprotection of Benzyl Esters viaMicrowave Thermolysis
A practical alternative to traditional catalytic hydrogenation
Varma et al Tetrahedron Lett 34 4603 (1993)
Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of
Carbonyl Compounds Using Microwaves
Varma Meshram Tetrahedron Lett 38 5427 (1997)
Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm
PersulfatendashClay using Microwave and Ultrasonic Irradiation
Varma Meshram Tetrahedron Lett 38 7973 (1997)
Solid Supported Solvent-freeOxidation under MW
Varma et al Tetrahedron Lett 1997 38 2043 and 7823
Solvent-free Reduction Using MW
Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction
Varma et al Tetrahedron Lett 1997 38 4337
Hydrodechlorination under continuous MW
Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)
Synthesis of Heterocyclic Compounds
Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)
Synthesis of Heterocyclic Compounds
Organometallic Reactions
Rearrangements
Rearrangements
INDOLIZINES
Heterocyclic systems 10- electronics
Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine
Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds
N
1
2
34567
8R2
R3
R1
Why interest for indolizinic products
Strong fluorescent properties luminiscent products luminiscent products
Potentially fluorescents marker Potentially laserldquoscintillatersrdquo
bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999
Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )
Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2
ldquoCalcium-entryrdquo blockers
Indolizines by irradiation with microwaves in MCR
RBr
O+
N
R1 R2+N
R2
R1
COR
AcOAl2O3 Mw
R=Ph p-Tolil Stiril
R1= H COOMeR2= COOEt COOMe
Asymmetric indolizines by irradiation with microwaves in MCR
R1
O
Cl+ R2
N NEtOOC
OOMe
Br BrN N
EtOOC
COR1
R2COR1
R2
OOMe
2 [Pd(PPh3)2Cl24 CuI
20 echiv Et3N THF tc 2h
R1=Ph 4-OMe-C6H4R2= Ph
U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003
A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new indolizines
[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical
II
IHH
COORCOOR
N C C
O
R2NCC
O
R1
(B)
(A)
R1
O
C C N R2
O
CCN
H H
ROOC COOR
R1
O
C C N R2
O
CCN
COOR COOR
ROOC COOR
2
2 ROOC C C COOR
R1
O
C CH N R2
O
CCHN
H H
N NCH CHC C
O O
R1 R2
- 2 HX TEAanhydrous solvents
X-
X-
N NCH2 CH2C C
O O
R1 R2
C C COORH
R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5
Y=H NO2 OCH3 CH3 Cl BrX=Br Cl
bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998
bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001
bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004
bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new substituted pyridinium-indolizines
Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate
COO NO2CHC
N NH3C
OR
I IN NH3C
OR
IN NH3C
OR
I
H
KFNMP
-HI
NMP
95oC 30 min
N NH3CO
RN NH3C
O
R
O OO
NO2
O
NO2
-2[H]-2[H]
II
I II
N NH3CO
R
O O
NO2
IN NH3C
O
R
O O
NO2
I
(9a-d)(10a-d)
(15a-d)
(A) (B)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
12
34
56
78 9
10
11
12 3
4
56
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
MW Heating Mechanism
Alternating electric field Withhigh frequency
NoconstraintContinuous electric field
Two mechanisms Dipolar rotation polarizationIonic Conduction mechanism
Microwave Dielectric HeatingMechanisms
Dipolar PolarizationMechanism
Conduction Mechanism
Dipolar molecules try toalign to an oscillating fieldby rotation
Ions in solution will moveby the applied electricfield
Mingos D M P et al Chem Soc Rev 1991 20 1 and 1998 27 213
Microwave vs Oil-bath Heating
J-S Schanche Mol Diversity 2003 7 293wwwpersonalchemistry-com wwwbiotagecom
Conventional Heating byConduction
ConductiveheatHeating byconvectioncurrentsSlow andenergyinefficientprocess
temperature on the outside surface isin excess of the boiling point of liquid
Direct Heating by MicrowaveIrradiation
bullSolventreagent absorbs MW energybull Vessel wall transparent to MWbullDirect in-core heatingbullInstant on-off
Inverted temperature gradients
Molecular Speeds
Molecular Speeds
Microwave Ovens
Cooking Chemistry Cooking Food
Household MW ovens
The Use of Microwave Ovens for Rapid Organic Synthesis R Gedye et al Tetrahedron Lett 1986 27 279
Publications on MW-AssistedOrganic Synthesis
7 Synthetic Journals JOrgChemOrgLettTetrahedron LettTetrahedron SynthCommun Synlett SynthesisAll Journals (Full Text) Dedicated instruments only (Anton Paar Biotage CEM Milestone Prolabo)
Industrial Chemical Applications of Microwave Heating
Food Processing+ Defrosting+ Drying roasting baking+ Pasteurization
Drying Industry+ Wood fibers textiles+ Pharmaceuticals+ Brick concrete walls
Polymer Chemistry+ Rubber curing vulcanization+ Polymerization
CeramicsMaterials+ Alumina sintering+ Welding smelting gluing
Plasma+ SemiconductorsWaste Remediation+ Sewage treatment
Analytical Chemistry+ Digestion+ Extraction+ Ashing
Biochemistry Pathology+ Protein hydrolysis+ PCR proteomics+ Tissue fixation+ Histoprocessing
Medical+ Diathermy tumor detection+ Blood warming+ Sterilization (Anthrax)+ Drying of catheters
Books on Microwave-Assisted Synthesis
1048707 Fundamentals of Microwave Application1048707 Alternative Laboratory MicrowaveInstruments1048707 Chemistry Applications1048707 Biochemistry Applications1048707 Laboratory Microwave Safety
Hayes B LCEM PublishingMatthews NC2002
(ACS Professional Reference Book) H M Kingston S J Haswell (eds)
Microwaves in Organic and Medicinal ChemistryKappe C O and Stadler AWiley-VCH Weinheim 2005 ISBN 3-527-31210-2410 pages ca 1000 references
Books on Microwave-Assisted Synthesis
Lidstoumlm PTierney J P(Eds)BlackwellScientific2005
Loupy Andre (Ed)Wiley-VCH Weinheim 2003 ISBN 3-527-30514-9523 pages 2000 refs
Book (2 volumes) Wiley-VCHA Loupy editSecond Edition(2006) 22 Chapters
Astra Zeneca ResearchFoundation Kavitha PrintersBangalore India 2002azrefiastrazenecacom
Practical Microwave Synthesis for Organic Chemists - Strategies Instruments and Protocols
Edition - 2009 X 310 Pages Hardcover Monograph
Books on Microwave-Assisted Synthesis
Microwave Ovens
Monomodal instrument
Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005
Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia
Multimodal instrument
+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile
Monomodal Vs Multimodal
Monomodal Vs Multimodal
Thermal Effects
bullMore efficient energetic coupling of solvent with microwaves
promotes higher rate of temperature increase
bull Inverted heat transfer volumetric
bull ldquoHot spotsrdquo in monomode microwaves
bull Selective on properties of material (solvents catalysts
reagents intermediates products susceptors)
Recent Applications of Microwave-Assisted Synthesis-MAOS
Hydrolysis of benzamide
thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)
The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions
R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958
Solvent-free Reactions or Solid-Solid Reactions
ldquoNo reaction proceeds without solventrdquo
Aristotle
Solventless syntheses
Green chemistry enabled advancement
Solvent-free Organic Synthesis
Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed
i n t o a p o w e r f u l m e t h o d o l o g y a s i t
reduces the amount of toxic waste produced and therefore becomes less harmful to the
e n v i r o n m e n t
Solvent-free Organic Synthesis
bull Clean and efficient synthesis
bull Economic and environmental impact
bull Fast reaction kinetics
Best solvent is no solvent
Adolf von Baeyer
Synthesis of Indigo
Towardsbenign
synthesiswith
remarkableVersatility
G W V Cave C LRaston J L ScottChemCommun
2001 2159
Solid-State General Oxidation with with Urea H2O2 Complex
R S Varma and K P Naiker Org Letters 1999 1 189
Solvent-free Oxidative Preparation of Heterocycles
Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157
Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones
Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199
Solvent-free Reduction
F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245
Carbon-Carbon Bond Formation
Toda Tanada Iwata J Org Chem 1989 54 3007
Solventless Photo Coupling and Photo Rearangements
Y Ito S Endo J Am Chem Soc 1997 119 5974
Shin Keating Maribay J Am Chem Soc 1996 118 7626
Solvent - Free Condensation
Z Gross et al Org Letters 1999 1 599
Solid-State Preparationof Dumb-bell-shaped C120
Wang Komatsu Murata Shiro Nature 1997 387 583
Advantages of Solid Mineral Supports(Alumina Silica and Clay)
Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area
The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity
Solids are generally easier and safer to handle than liquids or gaseous reagents
Inexpensive recyclable and environmentally benign nature
Solid-supported Solventless Reactions
bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation
R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43
Supported ReactionsUsing Microwaves
E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945
Microwave-Assisted Deacetylationon Alumina
Varma et al J Chem Soc Perkin Trans 1 999 (1993)
Deprotection of Benzyl Esters viaMicrowave Thermolysis
A practical alternative to traditional catalytic hydrogenation
Varma et al Tetrahedron Lett 34 4603 (1993)
Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of
Carbonyl Compounds Using Microwaves
Varma Meshram Tetrahedron Lett 38 5427 (1997)
Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm
PersulfatendashClay using Microwave and Ultrasonic Irradiation
Varma Meshram Tetrahedron Lett 38 7973 (1997)
Solid Supported Solvent-freeOxidation under MW
Varma et al Tetrahedron Lett 1997 38 2043 and 7823
Solvent-free Reduction Using MW
Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction
Varma et al Tetrahedron Lett 1997 38 4337
Hydrodechlorination under continuous MW
Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)
Synthesis of Heterocyclic Compounds
Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)
Synthesis of Heterocyclic Compounds
Organometallic Reactions
Rearrangements
Rearrangements
INDOLIZINES
Heterocyclic systems 10- electronics
Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine
Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds
N
1
2
34567
8R2
R3
R1
Why interest for indolizinic products
Strong fluorescent properties luminiscent products luminiscent products
Potentially fluorescents marker Potentially laserldquoscintillatersrdquo
bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999
Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )
Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2
ldquoCalcium-entryrdquo blockers
Indolizines by irradiation with microwaves in MCR
RBr
O+
N
R1 R2+N
R2
R1
COR
AcOAl2O3 Mw
R=Ph p-Tolil Stiril
R1= H COOMeR2= COOEt COOMe
Asymmetric indolizines by irradiation with microwaves in MCR
R1
O
Cl+ R2
N NEtOOC
OOMe
Br BrN N
EtOOC
COR1
R2COR1
R2
OOMe
2 [Pd(PPh3)2Cl24 CuI
20 echiv Et3N THF tc 2h
R1=Ph 4-OMe-C6H4R2= Ph
U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003
A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new indolizines
[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical
II
IHH
COORCOOR
N C C
O
R2NCC
O
R1
(B)
(A)
R1
O
C C N R2
O
CCN
H H
ROOC COOR
R1
O
C C N R2
O
CCN
COOR COOR
ROOC COOR
2
2 ROOC C C COOR
R1
O
C CH N R2
O
CCHN
H H
N NCH CHC C
O O
R1 R2
- 2 HX TEAanhydrous solvents
X-
X-
N NCH2 CH2C C
O O
R1 R2
C C COORH
R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5
Y=H NO2 OCH3 CH3 Cl BrX=Br Cl
bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998
bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001
bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004
bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new substituted pyridinium-indolizines
Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate
COO NO2CHC
N NH3C
OR
I IN NH3C
OR
IN NH3C
OR
I
H
KFNMP
-HI
NMP
95oC 30 min
N NH3CO
RN NH3C
O
R
O OO
NO2
O
NO2
-2[H]-2[H]
II
I II
N NH3CO
R
O O
NO2
IN NH3C
O
R
O O
NO2
I
(9a-d)(10a-d)
(15a-d)
(A) (B)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
12
34
56
78 9
10
11
12 3
4
56
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Microwave Dielectric HeatingMechanisms
Dipolar PolarizationMechanism
Conduction Mechanism
Dipolar molecules try toalign to an oscillating fieldby rotation
Ions in solution will moveby the applied electricfield
Mingos D M P et al Chem Soc Rev 1991 20 1 and 1998 27 213
Microwave vs Oil-bath Heating
J-S Schanche Mol Diversity 2003 7 293wwwpersonalchemistry-com wwwbiotagecom
Conventional Heating byConduction
ConductiveheatHeating byconvectioncurrentsSlow andenergyinefficientprocess
temperature on the outside surface isin excess of the boiling point of liquid
Direct Heating by MicrowaveIrradiation
bullSolventreagent absorbs MW energybull Vessel wall transparent to MWbullDirect in-core heatingbullInstant on-off
Inverted temperature gradients
Molecular Speeds
Molecular Speeds
Microwave Ovens
Cooking Chemistry Cooking Food
Household MW ovens
The Use of Microwave Ovens for Rapid Organic Synthesis R Gedye et al Tetrahedron Lett 1986 27 279
Publications on MW-AssistedOrganic Synthesis
7 Synthetic Journals JOrgChemOrgLettTetrahedron LettTetrahedron SynthCommun Synlett SynthesisAll Journals (Full Text) Dedicated instruments only (Anton Paar Biotage CEM Milestone Prolabo)
Industrial Chemical Applications of Microwave Heating
Food Processing+ Defrosting+ Drying roasting baking+ Pasteurization
Drying Industry+ Wood fibers textiles+ Pharmaceuticals+ Brick concrete walls
Polymer Chemistry+ Rubber curing vulcanization+ Polymerization
CeramicsMaterials+ Alumina sintering+ Welding smelting gluing
Plasma+ SemiconductorsWaste Remediation+ Sewage treatment
Analytical Chemistry+ Digestion+ Extraction+ Ashing
Biochemistry Pathology+ Protein hydrolysis+ PCR proteomics+ Tissue fixation+ Histoprocessing
Medical+ Diathermy tumor detection+ Blood warming+ Sterilization (Anthrax)+ Drying of catheters
Books on Microwave-Assisted Synthesis
1048707 Fundamentals of Microwave Application1048707 Alternative Laboratory MicrowaveInstruments1048707 Chemistry Applications1048707 Biochemistry Applications1048707 Laboratory Microwave Safety
Hayes B LCEM PublishingMatthews NC2002
(ACS Professional Reference Book) H M Kingston S J Haswell (eds)
Microwaves in Organic and Medicinal ChemistryKappe C O and Stadler AWiley-VCH Weinheim 2005 ISBN 3-527-31210-2410 pages ca 1000 references
Books on Microwave-Assisted Synthesis
Lidstoumlm PTierney J P(Eds)BlackwellScientific2005
Loupy Andre (Ed)Wiley-VCH Weinheim 2003 ISBN 3-527-30514-9523 pages 2000 refs
Book (2 volumes) Wiley-VCHA Loupy editSecond Edition(2006) 22 Chapters
Astra Zeneca ResearchFoundation Kavitha PrintersBangalore India 2002azrefiastrazenecacom
Practical Microwave Synthesis for Organic Chemists - Strategies Instruments and Protocols
Edition - 2009 X 310 Pages Hardcover Monograph
Books on Microwave-Assisted Synthesis
Microwave Ovens
Monomodal instrument
Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005
Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia
Multimodal instrument
+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile
Monomodal Vs Multimodal
Monomodal Vs Multimodal
Thermal Effects
bullMore efficient energetic coupling of solvent with microwaves
promotes higher rate of temperature increase
bull Inverted heat transfer volumetric
bull ldquoHot spotsrdquo in monomode microwaves
bull Selective on properties of material (solvents catalysts
reagents intermediates products susceptors)
Recent Applications of Microwave-Assisted Synthesis-MAOS
Hydrolysis of benzamide
thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)
The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions
R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958
Solvent-free Reactions or Solid-Solid Reactions
ldquoNo reaction proceeds without solventrdquo
Aristotle
Solventless syntheses
Green chemistry enabled advancement
Solvent-free Organic Synthesis
Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed
i n t o a p o w e r f u l m e t h o d o l o g y a s i t
reduces the amount of toxic waste produced and therefore becomes less harmful to the
e n v i r o n m e n t
Solvent-free Organic Synthesis
bull Clean and efficient synthesis
bull Economic and environmental impact
bull Fast reaction kinetics
Best solvent is no solvent
Adolf von Baeyer
Synthesis of Indigo
Towardsbenign
synthesiswith
remarkableVersatility
G W V Cave C LRaston J L ScottChemCommun
2001 2159
Solid-State General Oxidation with with Urea H2O2 Complex
R S Varma and K P Naiker Org Letters 1999 1 189
Solvent-free Oxidative Preparation of Heterocycles
Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157
Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones
Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199
Solvent-free Reduction
F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245
Carbon-Carbon Bond Formation
Toda Tanada Iwata J Org Chem 1989 54 3007
Solventless Photo Coupling and Photo Rearangements
Y Ito S Endo J Am Chem Soc 1997 119 5974
Shin Keating Maribay J Am Chem Soc 1996 118 7626
Solvent - Free Condensation
Z Gross et al Org Letters 1999 1 599
Solid-State Preparationof Dumb-bell-shaped C120
Wang Komatsu Murata Shiro Nature 1997 387 583
Advantages of Solid Mineral Supports(Alumina Silica and Clay)
Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area
The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity
Solids are generally easier and safer to handle than liquids or gaseous reagents
Inexpensive recyclable and environmentally benign nature
Solid-supported Solventless Reactions
bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation
R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43
Supported ReactionsUsing Microwaves
E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945
Microwave-Assisted Deacetylationon Alumina
Varma et al J Chem Soc Perkin Trans 1 999 (1993)
Deprotection of Benzyl Esters viaMicrowave Thermolysis
A practical alternative to traditional catalytic hydrogenation
Varma et al Tetrahedron Lett 34 4603 (1993)
Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of
Carbonyl Compounds Using Microwaves
Varma Meshram Tetrahedron Lett 38 5427 (1997)
Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm
PersulfatendashClay using Microwave and Ultrasonic Irradiation
Varma Meshram Tetrahedron Lett 38 7973 (1997)
Solid Supported Solvent-freeOxidation under MW
Varma et al Tetrahedron Lett 1997 38 2043 and 7823
Solvent-free Reduction Using MW
Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction
Varma et al Tetrahedron Lett 1997 38 4337
Hydrodechlorination under continuous MW
Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)
Synthesis of Heterocyclic Compounds
Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)
Synthesis of Heterocyclic Compounds
Organometallic Reactions
Rearrangements
Rearrangements
INDOLIZINES
Heterocyclic systems 10- electronics
Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine
Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds
N
1
2
34567
8R2
R3
R1
Why interest for indolizinic products
Strong fluorescent properties luminiscent products luminiscent products
Potentially fluorescents marker Potentially laserldquoscintillatersrdquo
bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999
Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )
Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2
ldquoCalcium-entryrdquo blockers
Indolizines by irradiation with microwaves in MCR
RBr
O+
N
R1 R2+N
R2
R1
COR
AcOAl2O3 Mw
R=Ph p-Tolil Stiril
R1= H COOMeR2= COOEt COOMe
Asymmetric indolizines by irradiation with microwaves in MCR
R1
O
Cl+ R2
N NEtOOC
OOMe
Br BrN N
EtOOC
COR1
R2COR1
R2
OOMe
2 [Pd(PPh3)2Cl24 CuI
20 echiv Et3N THF tc 2h
R1=Ph 4-OMe-C6H4R2= Ph
U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003
A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new indolizines
[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical
II
IHH
COORCOOR
N C C
O
R2NCC
O
R1
(B)
(A)
R1
O
C C N R2
O
CCN
H H
ROOC COOR
R1
O
C C N R2
O
CCN
COOR COOR
ROOC COOR
2
2 ROOC C C COOR
R1
O
C CH N R2
O
CCHN
H H
N NCH CHC C
O O
R1 R2
- 2 HX TEAanhydrous solvents
X-
X-
N NCH2 CH2C C
O O
R1 R2
C C COORH
R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5
Y=H NO2 OCH3 CH3 Cl BrX=Br Cl
bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998
bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001
bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004
bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new substituted pyridinium-indolizines
Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate
COO NO2CHC
N NH3C
OR
I IN NH3C
OR
IN NH3C
OR
I
H
KFNMP
-HI
NMP
95oC 30 min
N NH3CO
RN NH3C
O
R
O OO
NO2
O
NO2
-2[H]-2[H]
II
I II
N NH3CO
R
O O
NO2
IN NH3C
O
R
O O
NO2
I
(9a-d)(10a-d)
(15a-d)
(A) (B)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
12
34
56
78 9
10
11
12 3
4
56
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Microwave vs Oil-bath Heating
J-S Schanche Mol Diversity 2003 7 293wwwpersonalchemistry-com wwwbiotagecom
Conventional Heating byConduction
ConductiveheatHeating byconvectioncurrentsSlow andenergyinefficientprocess
temperature on the outside surface isin excess of the boiling point of liquid
Direct Heating by MicrowaveIrradiation
bullSolventreagent absorbs MW energybull Vessel wall transparent to MWbullDirect in-core heatingbullInstant on-off
Inverted temperature gradients
Molecular Speeds
Molecular Speeds
Microwave Ovens
Cooking Chemistry Cooking Food
Household MW ovens
The Use of Microwave Ovens for Rapid Organic Synthesis R Gedye et al Tetrahedron Lett 1986 27 279
Publications on MW-AssistedOrganic Synthesis
7 Synthetic Journals JOrgChemOrgLettTetrahedron LettTetrahedron SynthCommun Synlett SynthesisAll Journals (Full Text) Dedicated instruments only (Anton Paar Biotage CEM Milestone Prolabo)
Industrial Chemical Applications of Microwave Heating
Food Processing+ Defrosting+ Drying roasting baking+ Pasteurization
Drying Industry+ Wood fibers textiles+ Pharmaceuticals+ Brick concrete walls
Polymer Chemistry+ Rubber curing vulcanization+ Polymerization
CeramicsMaterials+ Alumina sintering+ Welding smelting gluing
Plasma+ SemiconductorsWaste Remediation+ Sewage treatment
Analytical Chemistry+ Digestion+ Extraction+ Ashing
Biochemistry Pathology+ Protein hydrolysis+ PCR proteomics+ Tissue fixation+ Histoprocessing
Medical+ Diathermy tumor detection+ Blood warming+ Sterilization (Anthrax)+ Drying of catheters
Books on Microwave-Assisted Synthesis
1048707 Fundamentals of Microwave Application1048707 Alternative Laboratory MicrowaveInstruments1048707 Chemistry Applications1048707 Biochemistry Applications1048707 Laboratory Microwave Safety
Hayes B LCEM PublishingMatthews NC2002
(ACS Professional Reference Book) H M Kingston S J Haswell (eds)
Microwaves in Organic and Medicinal ChemistryKappe C O and Stadler AWiley-VCH Weinheim 2005 ISBN 3-527-31210-2410 pages ca 1000 references
Books on Microwave-Assisted Synthesis
Lidstoumlm PTierney J P(Eds)BlackwellScientific2005
Loupy Andre (Ed)Wiley-VCH Weinheim 2003 ISBN 3-527-30514-9523 pages 2000 refs
Book (2 volumes) Wiley-VCHA Loupy editSecond Edition(2006) 22 Chapters
Astra Zeneca ResearchFoundation Kavitha PrintersBangalore India 2002azrefiastrazenecacom
Practical Microwave Synthesis for Organic Chemists - Strategies Instruments and Protocols
Edition - 2009 X 310 Pages Hardcover Monograph
Books on Microwave-Assisted Synthesis
Microwave Ovens
Monomodal instrument
Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005
Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia
Multimodal instrument
+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile
Monomodal Vs Multimodal
Monomodal Vs Multimodal
Thermal Effects
bullMore efficient energetic coupling of solvent with microwaves
promotes higher rate of temperature increase
bull Inverted heat transfer volumetric
bull ldquoHot spotsrdquo in monomode microwaves
bull Selective on properties of material (solvents catalysts
reagents intermediates products susceptors)
Recent Applications of Microwave-Assisted Synthesis-MAOS
Hydrolysis of benzamide
thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)
The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions
R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958
Solvent-free Reactions or Solid-Solid Reactions
ldquoNo reaction proceeds without solventrdquo
Aristotle
Solventless syntheses
Green chemistry enabled advancement
Solvent-free Organic Synthesis
Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed
i n t o a p o w e r f u l m e t h o d o l o g y a s i t
reduces the amount of toxic waste produced and therefore becomes less harmful to the
e n v i r o n m e n t
Solvent-free Organic Synthesis
bull Clean and efficient synthesis
bull Economic and environmental impact
bull Fast reaction kinetics
Best solvent is no solvent
Adolf von Baeyer
Synthesis of Indigo
Towardsbenign
synthesiswith
remarkableVersatility
G W V Cave C LRaston J L ScottChemCommun
2001 2159
Solid-State General Oxidation with with Urea H2O2 Complex
R S Varma and K P Naiker Org Letters 1999 1 189
Solvent-free Oxidative Preparation of Heterocycles
Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157
Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones
Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199
Solvent-free Reduction
F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245
Carbon-Carbon Bond Formation
Toda Tanada Iwata J Org Chem 1989 54 3007
Solventless Photo Coupling and Photo Rearangements
Y Ito S Endo J Am Chem Soc 1997 119 5974
Shin Keating Maribay J Am Chem Soc 1996 118 7626
Solvent - Free Condensation
Z Gross et al Org Letters 1999 1 599
Solid-State Preparationof Dumb-bell-shaped C120
Wang Komatsu Murata Shiro Nature 1997 387 583
Advantages of Solid Mineral Supports(Alumina Silica and Clay)
Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area
The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity
Solids are generally easier and safer to handle than liquids or gaseous reagents
Inexpensive recyclable and environmentally benign nature
Solid-supported Solventless Reactions
bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation
R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43
Supported ReactionsUsing Microwaves
E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945
Microwave-Assisted Deacetylationon Alumina
Varma et al J Chem Soc Perkin Trans 1 999 (1993)
Deprotection of Benzyl Esters viaMicrowave Thermolysis
A practical alternative to traditional catalytic hydrogenation
Varma et al Tetrahedron Lett 34 4603 (1993)
Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of
Carbonyl Compounds Using Microwaves
Varma Meshram Tetrahedron Lett 38 5427 (1997)
Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm
PersulfatendashClay using Microwave and Ultrasonic Irradiation
Varma Meshram Tetrahedron Lett 38 7973 (1997)
Solid Supported Solvent-freeOxidation under MW
Varma et al Tetrahedron Lett 1997 38 2043 and 7823
Solvent-free Reduction Using MW
Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction
Varma et al Tetrahedron Lett 1997 38 4337
Hydrodechlorination under continuous MW
Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)
Synthesis of Heterocyclic Compounds
Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)
Synthesis of Heterocyclic Compounds
Organometallic Reactions
Rearrangements
Rearrangements
INDOLIZINES
Heterocyclic systems 10- electronics
Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine
Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds
N
1
2
34567
8R2
R3
R1
Why interest for indolizinic products
Strong fluorescent properties luminiscent products luminiscent products
Potentially fluorescents marker Potentially laserldquoscintillatersrdquo
bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999
Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )
Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2
ldquoCalcium-entryrdquo blockers
Indolizines by irradiation with microwaves in MCR
RBr
O+
N
R1 R2+N
R2
R1
COR
AcOAl2O3 Mw
R=Ph p-Tolil Stiril
R1= H COOMeR2= COOEt COOMe
Asymmetric indolizines by irradiation with microwaves in MCR
R1
O
Cl+ R2
N NEtOOC
OOMe
Br BrN N
EtOOC
COR1
R2COR1
R2
OOMe
2 [Pd(PPh3)2Cl24 CuI
20 echiv Et3N THF tc 2h
R1=Ph 4-OMe-C6H4R2= Ph
U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003
A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new indolizines
[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical
II
IHH
COORCOOR
N C C
O
R2NCC
O
R1
(B)
(A)
R1
O
C C N R2
O
CCN
H H
ROOC COOR
R1
O
C C N R2
O
CCN
COOR COOR
ROOC COOR
2
2 ROOC C C COOR
R1
O
C CH N R2
O
CCHN
H H
N NCH CHC C
O O
R1 R2
- 2 HX TEAanhydrous solvents
X-
X-
N NCH2 CH2C C
O O
R1 R2
C C COORH
R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5
Y=H NO2 OCH3 CH3 Cl BrX=Br Cl
bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998
bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001
bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004
bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new substituted pyridinium-indolizines
Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate
COO NO2CHC
N NH3C
OR
I IN NH3C
OR
IN NH3C
OR
I
H
KFNMP
-HI
NMP
95oC 30 min
N NH3CO
RN NH3C
O
R
O OO
NO2
O
NO2
-2[H]-2[H]
II
I II
N NH3CO
R
O O
NO2
IN NH3C
O
R
O O
NO2
I
(9a-d)(10a-d)
(15a-d)
(A) (B)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
12
34
56
78 9
10
11
12 3
4
56
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Conventional Heating byConduction
ConductiveheatHeating byconvectioncurrentsSlow andenergyinefficientprocess
temperature on the outside surface isin excess of the boiling point of liquid
Direct Heating by MicrowaveIrradiation
bullSolventreagent absorbs MW energybull Vessel wall transparent to MWbullDirect in-core heatingbullInstant on-off
Inverted temperature gradients
Molecular Speeds
Molecular Speeds
Microwave Ovens
Cooking Chemistry Cooking Food
Household MW ovens
The Use of Microwave Ovens for Rapid Organic Synthesis R Gedye et al Tetrahedron Lett 1986 27 279
Publications on MW-AssistedOrganic Synthesis
7 Synthetic Journals JOrgChemOrgLettTetrahedron LettTetrahedron SynthCommun Synlett SynthesisAll Journals (Full Text) Dedicated instruments only (Anton Paar Biotage CEM Milestone Prolabo)
Industrial Chemical Applications of Microwave Heating
Food Processing+ Defrosting+ Drying roasting baking+ Pasteurization
Drying Industry+ Wood fibers textiles+ Pharmaceuticals+ Brick concrete walls
Polymer Chemistry+ Rubber curing vulcanization+ Polymerization
CeramicsMaterials+ Alumina sintering+ Welding smelting gluing
Plasma+ SemiconductorsWaste Remediation+ Sewage treatment
Analytical Chemistry+ Digestion+ Extraction+ Ashing
Biochemistry Pathology+ Protein hydrolysis+ PCR proteomics+ Tissue fixation+ Histoprocessing
Medical+ Diathermy tumor detection+ Blood warming+ Sterilization (Anthrax)+ Drying of catheters
Books on Microwave-Assisted Synthesis
1048707 Fundamentals of Microwave Application1048707 Alternative Laboratory MicrowaveInstruments1048707 Chemistry Applications1048707 Biochemistry Applications1048707 Laboratory Microwave Safety
Hayes B LCEM PublishingMatthews NC2002
(ACS Professional Reference Book) H M Kingston S J Haswell (eds)
Microwaves in Organic and Medicinal ChemistryKappe C O and Stadler AWiley-VCH Weinheim 2005 ISBN 3-527-31210-2410 pages ca 1000 references
Books on Microwave-Assisted Synthesis
Lidstoumlm PTierney J P(Eds)BlackwellScientific2005
Loupy Andre (Ed)Wiley-VCH Weinheim 2003 ISBN 3-527-30514-9523 pages 2000 refs
Book (2 volumes) Wiley-VCHA Loupy editSecond Edition(2006) 22 Chapters
Astra Zeneca ResearchFoundation Kavitha PrintersBangalore India 2002azrefiastrazenecacom
Practical Microwave Synthesis for Organic Chemists - Strategies Instruments and Protocols
Edition - 2009 X 310 Pages Hardcover Monograph
Books on Microwave-Assisted Synthesis
Microwave Ovens
Monomodal instrument
Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005
Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia
Multimodal instrument
+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile
Monomodal Vs Multimodal
Monomodal Vs Multimodal
Thermal Effects
bullMore efficient energetic coupling of solvent with microwaves
promotes higher rate of temperature increase
bull Inverted heat transfer volumetric
bull ldquoHot spotsrdquo in monomode microwaves
bull Selective on properties of material (solvents catalysts
reagents intermediates products susceptors)
Recent Applications of Microwave-Assisted Synthesis-MAOS
Hydrolysis of benzamide
thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)
The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions
R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958
Solvent-free Reactions or Solid-Solid Reactions
ldquoNo reaction proceeds without solventrdquo
Aristotle
Solventless syntheses
Green chemistry enabled advancement
Solvent-free Organic Synthesis
Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed
i n t o a p o w e r f u l m e t h o d o l o g y a s i t
reduces the amount of toxic waste produced and therefore becomes less harmful to the
e n v i r o n m e n t
Solvent-free Organic Synthesis
bull Clean and efficient synthesis
bull Economic and environmental impact
bull Fast reaction kinetics
Best solvent is no solvent
Adolf von Baeyer
Synthesis of Indigo
Towardsbenign
synthesiswith
remarkableVersatility
G W V Cave C LRaston J L ScottChemCommun
2001 2159
Solid-State General Oxidation with with Urea H2O2 Complex
R S Varma and K P Naiker Org Letters 1999 1 189
Solvent-free Oxidative Preparation of Heterocycles
Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157
Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones
Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199
Solvent-free Reduction
F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245
Carbon-Carbon Bond Formation
Toda Tanada Iwata J Org Chem 1989 54 3007
Solventless Photo Coupling and Photo Rearangements
Y Ito S Endo J Am Chem Soc 1997 119 5974
Shin Keating Maribay J Am Chem Soc 1996 118 7626
Solvent - Free Condensation
Z Gross et al Org Letters 1999 1 599
Solid-State Preparationof Dumb-bell-shaped C120
Wang Komatsu Murata Shiro Nature 1997 387 583
Advantages of Solid Mineral Supports(Alumina Silica and Clay)
Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area
The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity
Solids are generally easier and safer to handle than liquids or gaseous reagents
Inexpensive recyclable and environmentally benign nature
Solid-supported Solventless Reactions
bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation
R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43
Supported ReactionsUsing Microwaves
E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945
Microwave-Assisted Deacetylationon Alumina
Varma et al J Chem Soc Perkin Trans 1 999 (1993)
Deprotection of Benzyl Esters viaMicrowave Thermolysis
A practical alternative to traditional catalytic hydrogenation
Varma et al Tetrahedron Lett 34 4603 (1993)
Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of
Carbonyl Compounds Using Microwaves
Varma Meshram Tetrahedron Lett 38 5427 (1997)
Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm
PersulfatendashClay using Microwave and Ultrasonic Irradiation
Varma Meshram Tetrahedron Lett 38 7973 (1997)
Solid Supported Solvent-freeOxidation under MW
Varma et al Tetrahedron Lett 1997 38 2043 and 7823
Solvent-free Reduction Using MW
Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction
Varma et al Tetrahedron Lett 1997 38 4337
Hydrodechlorination under continuous MW
Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)
Synthesis of Heterocyclic Compounds
Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)
Synthesis of Heterocyclic Compounds
Organometallic Reactions
Rearrangements
Rearrangements
INDOLIZINES
Heterocyclic systems 10- electronics
Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine
Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds
N
1
2
34567
8R2
R3
R1
Why interest for indolizinic products
Strong fluorescent properties luminiscent products luminiscent products
Potentially fluorescents marker Potentially laserldquoscintillatersrdquo
bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999
Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )
Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2
ldquoCalcium-entryrdquo blockers
Indolizines by irradiation with microwaves in MCR
RBr
O+
N
R1 R2+N
R2
R1
COR
AcOAl2O3 Mw
R=Ph p-Tolil Stiril
R1= H COOMeR2= COOEt COOMe
Asymmetric indolizines by irradiation with microwaves in MCR
R1
O
Cl+ R2
N NEtOOC
OOMe
Br BrN N
EtOOC
COR1
R2COR1
R2
OOMe
2 [Pd(PPh3)2Cl24 CuI
20 echiv Et3N THF tc 2h
R1=Ph 4-OMe-C6H4R2= Ph
U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003
A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new indolizines
[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical
II
IHH
COORCOOR
N C C
O
R2NCC
O
R1
(B)
(A)
R1
O
C C N R2
O
CCN
H H
ROOC COOR
R1
O
C C N R2
O
CCN
COOR COOR
ROOC COOR
2
2 ROOC C C COOR
R1
O
C CH N R2
O
CCHN
H H
N NCH CHC C
O O
R1 R2
- 2 HX TEAanhydrous solvents
X-
X-
N NCH2 CH2C C
O O
R1 R2
C C COORH
R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5
Y=H NO2 OCH3 CH3 Cl BrX=Br Cl
bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998
bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001
bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004
bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new substituted pyridinium-indolizines
Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate
COO NO2CHC
N NH3C
OR
I IN NH3C
OR
IN NH3C
OR
I
H
KFNMP
-HI
NMP
95oC 30 min
N NH3CO
RN NH3C
O
R
O OO
NO2
O
NO2
-2[H]-2[H]
II
I II
N NH3CO
R
O O
NO2
IN NH3C
O
R
O O
NO2
I
(9a-d)(10a-d)
(15a-d)
(A) (B)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
12
34
56
78 9
10
11
12 3
4
56
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Direct Heating by MicrowaveIrradiation
bullSolventreagent absorbs MW energybull Vessel wall transparent to MWbullDirect in-core heatingbullInstant on-off
Inverted temperature gradients
Molecular Speeds
Molecular Speeds
Microwave Ovens
Cooking Chemistry Cooking Food
Household MW ovens
The Use of Microwave Ovens for Rapid Organic Synthesis R Gedye et al Tetrahedron Lett 1986 27 279
Publications on MW-AssistedOrganic Synthesis
7 Synthetic Journals JOrgChemOrgLettTetrahedron LettTetrahedron SynthCommun Synlett SynthesisAll Journals (Full Text) Dedicated instruments only (Anton Paar Biotage CEM Milestone Prolabo)
Industrial Chemical Applications of Microwave Heating
Food Processing+ Defrosting+ Drying roasting baking+ Pasteurization
Drying Industry+ Wood fibers textiles+ Pharmaceuticals+ Brick concrete walls
Polymer Chemistry+ Rubber curing vulcanization+ Polymerization
CeramicsMaterials+ Alumina sintering+ Welding smelting gluing
Plasma+ SemiconductorsWaste Remediation+ Sewage treatment
Analytical Chemistry+ Digestion+ Extraction+ Ashing
Biochemistry Pathology+ Protein hydrolysis+ PCR proteomics+ Tissue fixation+ Histoprocessing
Medical+ Diathermy tumor detection+ Blood warming+ Sterilization (Anthrax)+ Drying of catheters
Books on Microwave-Assisted Synthesis
1048707 Fundamentals of Microwave Application1048707 Alternative Laboratory MicrowaveInstruments1048707 Chemistry Applications1048707 Biochemistry Applications1048707 Laboratory Microwave Safety
Hayes B LCEM PublishingMatthews NC2002
(ACS Professional Reference Book) H M Kingston S J Haswell (eds)
Microwaves in Organic and Medicinal ChemistryKappe C O and Stadler AWiley-VCH Weinheim 2005 ISBN 3-527-31210-2410 pages ca 1000 references
Books on Microwave-Assisted Synthesis
Lidstoumlm PTierney J P(Eds)BlackwellScientific2005
Loupy Andre (Ed)Wiley-VCH Weinheim 2003 ISBN 3-527-30514-9523 pages 2000 refs
Book (2 volumes) Wiley-VCHA Loupy editSecond Edition(2006) 22 Chapters
Astra Zeneca ResearchFoundation Kavitha PrintersBangalore India 2002azrefiastrazenecacom
Practical Microwave Synthesis for Organic Chemists - Strategies Instruments and Protocols
Edition - 2009 X 310 Pages Hardcover Monograph
Books on Microwave-Assisted Synthesis
Microwave Ovens
Monomodal instrument
Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005
Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia
Multimodal instrument
+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile
Monomodal Vs Multimodal
Monomodal Vs Multimodal
Thermal Effects
bullMore efficient energetic coupling of solvent with microwaves
promotes higher rate of temperature increase
bull Inverted heat transfer volumetric
bull ldquoHot spotsrdquo in monomode microwaves
bull Selective on properties of material (solvents catalysts
reagents intermediates products susceptors)
Recent Applications of Microwave-Assisted Synthesis-MAOS
Hydrolysis of benzamide
thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)
The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions
R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958
Solvent-free Reactions or Solid-Solid Reactions
ldquoNo reaction proceeds without solventrdquo
Aristotle
Solventless syntheses
Green chemistry enabled advancement
Solvent-free Organic Synthesis
Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed
i n t o a p o w e r f u l m e t h o d o l o g y a s i t
reduces the amount of toxic waste produced and therefore becomes less harmful to the
e n v i r o n m e n t
Solvent-free Organic Synthesis
bull Clean and efficient synthesis
bull Economic and environmental impact
bull Fast reaction kinetics
Best solvent is no solvent
Adolf von Baeyer
Synthesis of Indigo
Towardsbenign
synthesiswith
remarkableVersatility
G W V Cave C LRaston J L ScottChemCommun
2001 2159
Solid-State General Oxidation with with Urea H2O2 Complex
R S Varma and K P Naiker Org Letters 1999 1 189
Solvent-free Oxidative Preparation of Heterocycles
Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157
Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones
Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199
Solvent-free Reduction
F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245
Carbon-Carbon Bond Formation
Toda Tanada Iwata J Org Chem 1989 54 3007
Solventless Photo Coupling and Photo Rearangements
Y Ito S Endo J Am Chem Soc 1997 119 5974
Shin Keating Maribay J Am Chem Soc 1996 118 7626
Solvent - Free Condensation
Z Gross et al Org Letters 1999 1 599
Solid-State Preparationof Dumb-bell-shaped C120
Wang Komatsu Murata Shiro Nature 1997 387 583
Advantages of Solid Mineral Supports(Alumina Silica and Clay)
Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area
The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity
Solids are generally easier and safer to handle than liquids or gaseous reagents
Inexpensive recyclable and environmentally benign nature
Solid-supported Solventless Reactions
bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation
R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43
Supported ReactionsUsing Microwaves
E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945
Microwave-Assisted Deacetylationon Alumina
Varma et al J Chem Soc Perkin Trans 1 999 (1993)
Deprotection of Benzyl Esters viaMicrowave Thermolysis
A practical alternative to traditional catalytic hydrogenation
Varma et al Tetrahedron Lett 34 4603 (1993)
Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of
Carbonyl Compounds Using Microwaves
Varma Meshram Tetrahedron Lett 38 5427 (1997)
Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm
PersulfatendashClay using Microwave and Ultrasonic Irradiation
Varma Meshram Tetrahedron Lett 38 7973 (1997)
Solid Supported Solvent-freeOxidation under MW
Varma et al Tetrahedron Lett 1997 38 2043 and 7823
Solvent-free Reduction Using MW
Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction
Varma et al Tetrahedron Lett 1997 38 4337
Hydrodechlorination under continuous MW
Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)
Synthesis of Heterocyclic Compounds
Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)
Synthesis of Heterocyclic Compounds
Organometallic Reactions
Rearrangements
Rearrangements
INDOLIZINES
Heterocyclic systems 10- electronics
Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine
Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds
N
1
2
34567
8R2
R3
R1
Why interest for indolizinic products
Strong fluorescent properties luminiscent products luminiscent products
Potentially fluorescents marker Potentially laserldquoscintillatersrdquo
bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999
Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )
Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2
ldquoCalcium-entryrdquo blockers
Indolizines by irradiation with microwaves in MCR
RBr
O+
N
R1 R2+N
R2
R1
COR
AcOAl2O3 Mw
R=Ph p-Tolil Stiril
R1= H COOMeR2= COOEt COOMe
Asymmetric indolizines by irradiation with microwaves in MCR
R1
O
Cl+ R2
N NEtOOC
OOMe
Br BrN N
EtOOC
COR1
R2COR1
R2
OOMe
2 [Pd(PPh3)2Cl24 CuI
20 echiv Et3N THF tc 2h
R1=Ph 4-OMe-C6H4R2= Ph
U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003
A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new indolizines
[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical
II
IHH
COORCOOR
N C C
O
R2NCC
O
R1
(B)
(A)
R1
O
C C N R2
O
CCN
H H
ROOC COOR
R1
O
C C N R2
O
CCN
COOR COOR
ROOC COOR
2
2 ROOC C C COOR
R1
O
C CH N R2
O
CCHN
H H
N NCH CHC C
O O
R1 R2
- 2 HX TEAanhydrous solvents
X-
X-
N NCH2 CH2C C
O O
R1 R2
C C COORH
R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5
Y=H NO2 OCH3 CH3 Cl BrX=Br Cl
bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998
bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001
bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004
bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new substituted pyridinium-indolizines
Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate
COO NO2CHC
N NH3C
OR
I IN NH3C
OR
IN NH3C
OR
I
H
KFNMP
-HI
NMP
95oC 30 min
N NH3CO
RN NH3C
O
R
O OO
NO2
O
NO2
-2[H]-2[H]
II
I II
N NH3CO
R
O O
NO2
IN NH3C
O
R
O O
NO2
I
(9a-d)(10a-d)
(15a-d)
(A) (B)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
12
34
56
78 9
10
11
12 3
4
56
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Molecular Speeds
Molecular Speeds
Microwave Ovens
Cooking Chemistry Cooking Food
Household MW ovens
The Use of Microwave Ovens for Rapid Organic Synthesis R Gedye et al Tetrahedron Lett 1986 27 279
Publications on MW-AssistedOrganic Synthesis
7 Synthetic Journals JOrgChemOrgLettTetrahedron LettTetrahedron SynthCommun Synlett SynthesisAll Journals (Full Text) Dedicated instruments only (Anton Paar Biotage CEM Milestone Prolabo)
Industrial Chemical Applications of Microwave Heating
Food Processing+ Defrosting+ Drying roasting baking+ Pasteurization
Drying Industry+ Wood fibers textiles+ Pharmaceuticals+ Brick concrete walls
Polymer Chemistry+ Rubber curing vulcanization+ Polymerization
CeramicsMaterials+ Alumina sintering+ Welding smelting gluing
Plasma+ SemiconductorsWaste Remediation+ Sewage treatment
Analytical Chemistry+ Digestion+ Extraction+ Ashing
Biochemistry Pathology+ Protein hydrolysis+ PCR proteomics+ Tissue fixation+ Histoprocessing
Medical+ Diathermy tumor detection+ Blood warming+ Sterilization (Anthrax)+ Drying of catheters
Books on Microwave-Assisted Synthesis
1048707 Fundamentals of Microwave Application1048707 Alternative Laboratory MicrowaveInstruments1048707 Chemistry Applications1048707 Biochemistry Applications1048707 Laboratory Microwave Safety
Hayes B LCEM PublishingMatthews NC2002
(ACS Professional Reference Book) H M Kingston S J Haswell (eds)
Microwaves in Organic and Medicinal ChemistryKappe C O and Stadler AWiley-VCH Weinheim 2005 ISBN 3-527-31210-2410 pages ca 1000 references
Books on Microwave-Assisted Synthesis
Lidstoumlm PTierney J P(Eds)BlackwellScientific2005
Loupy Andre (Ed)Wiley-VCH Weinheim 2003 ISBN 3-527-30514-9523 pages 2000 refs
Book (2 volumes) Wiley-VCHA Loupy editSecond Edition(2006) 22 Chapters
Astra Zeneca ResearchFoundation Kavitha PrintersBangalore India 2002azrefiastrazenecacom
Practical Microwave Synthesis for Organic Chemists - Strategies Instruments and Protocols
Edition - 2009 X 310 Pages Hardcover Monograph
Books on Microwave-Assisted Synthesis
Microwave Ovens
Monomodal instrument
Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005
Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia
Multimodal instrument
+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile
Monomodal Vs Multimodal
Monomodal Vs Multimodal
Thermal Effects
bullMore efficient energetic coupling of solvent with microwaves
promotes higher rate of temperature increase
bull Inverted heat transfer volumetric
bull ldquoHot spotsrdquo in monomode microwaves
bull Selective on properties of material (solvents catalysts
reagents intermediates products susceptors)
Recent Applications of Microwave-Assisted Synthesis-MAOS
Hydrolysis of benzamide
thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)
The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions
R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958
Solvent-free Reactions or Solid-Solid Reactions
ldquoNo reaction proceeds without solventrdquo
Aristotle
Solventless syntheses
Green chemistry enabled advancement
Solvent-free Organic Synthesis
Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed
i n t o a p o w e r f u l m e t h o d o l o g y a s i t
reduces the amount of toxic waste produced and therefore becomes less harmful to the
e n v i r o n m e n t
Solvent-free Organic Synthesis
bull Clean and efficient synthesis
bull Economic and environmental impact
bull Fast reaction kinetics
Best solvent is no solvent
Adolf von Baeyer
Synthesis of Indigo
Towardsbenign
synthesiswith
remarkableVersatility
G W V Cave C LRaston J L ScottChemCommun
2001 2159
Solid-State General Oxidation with with Urea H2O2 Complex
R S Varma and K P Naiker Org Letters 1999 1 189
Solvent-free Oxidative Preparation of Heterocycles
Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157
Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones
Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199
Solvent-free Reduction
F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245
Carbon-Carbon Bond Formation
Toda Tanada Iwata J Org Chem 1989 54 3007
Solventless Photo Coupling and Photo Rearangements
Y Ito S Endo J Am Chem Soc 1997 119 5974
Shin Keating Maribay J Am Chem Soc 1996 118 7626
Solvent - Free Condensation
Z Gross et al Org Letters 1999 1 599
Solid-State Preparationof Dumb-bell-shaped C120
Wang Komatsu Murata Shiro Nature 1997 387 583
Advantages of Solid Mineral Supports(Alumina Silica and Clay)
Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area
The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity
Solids are generally easier and safer to handle than liquids or gaseous reagents
Inexpensive recyclable and environmentally benign nature
Solid-supported Solventless Reactions
bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation
R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43
Supported ReactionsUsing Microwaves
E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945
Microwave-Assisted Deacetylationon Alumina
Varma et al J Chem Soc Perkin Trans 1 999 (1993)
Deprotection of Benzyl Esters viaMicrowave Thermolysis
A practical alternative to traditional catalytic hydrogenation
Varma et al Tetrahedron Lett 34 4603 (1993)
Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of
Carbonyl Compounds Using Microwaves
Varma Meshram Tetrahedron Lett 38 5427 (1997)
Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm
PersulfatendashClay using Microwave and Ultrasonic Irradiation
Varma Meshram Tetrahedron Lett 38 7973 (1997)
Solid Supported Solvent-freeOxidation under MW
Varma et al Tetrahedron Lett 1997 38 2043 and 7823
Solvent-free Reduction Using MW
Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction
Varma et al Tetrahedron Lett 1997 38 4337
Hydrodechlorination under continuous MW
Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)
Synthesis of Heterocyclic Compounds
Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)
Synthesis of Heterocyclic Compounds
Organometallic Reactions
Rearrangements
Rearrangements
INDOLIZINES
Heterocyclic systems 10- electronics
Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine
Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds
N
1
2
34567
8R2
R3
R1
Why interest for indolizinic products
Strong fluorescent properties luminiscent products luminiscent products
Potentially fluorescents marker Potentially laserldquoscintillatersrdquo
bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999
Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )
Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2
ldquoCalcium-entryrdquo blockers
Indolizines by irradiation with microwaves in MCR
RBr
O+
N
R1 R2+N
R2
R1
COR
AcOAl2O3 Mw
R=Ph p-Tolil Stiril
R1= H COOMeR2= COOEt COOMe
Asymmetric indolizines by irradiation with microwaves in MCR
R1
O
Cl+ R2
N NEtOOC
OOMe
Br BrN N
EtOOC
COR1
R2COR1
R2
OOMe
2 [Pd(PPh3)2Cl24 CuI
20 echiv Et3N THF tc 2h
R1=Ph 4-OMe-C6H4R2= Ph
U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003
A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new indolizines
[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical
II
IHH
COORCOOR
N C C
O
R2NCC
O
R1
(B)
(A)
R1
O
C C N R2
O
CCN
H H
ROOC COOR
R1
O
C C N R2
O
CCN
COOR COOR
ROOC COOR
2
2 ROOC C C COOR
R1
O
C CH N R2
O
CCHN
H H
N NCH CHC C
O O
R1 R2
- 2 HX TEAanhydrous solvents
X-
X-
N NCH2 CH2C C
O O
R1 R2
C C COORH
R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5
Y=H NO2 OCH3 CH3 Cl BrX=Br Cl
bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998
bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001
bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004
bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new substituted pyridinium-indolizines
Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate
COO NO2CHC
N NH3C
OR
I IN NH3C
OR
IN NH3C
OR
I
H
KFNMP
-HI
NMP
95oC 30 min
N NH3CO
RN NH3C
O
R
O OO
NO2
O
NO2
-2[H]-2[H]
II
I II
N NH3CO
R
O O
NO2
IN NH3C
O
R
O O
NO2
I
(9a-d)(10a-d)
(15a-d)
(A) (B)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
12
34
56
78 9
10
11
12 3
4
56
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Molecular Speeds
Microwave Ovens
Cooking Chemistry Cooking Food
Household MW ovens
The Use of Microwave Ovens for Rapid Organic Synthesis R Gedye et al Tetrahedron Lett 1986 27 279
Publications on MW-AssistedOrganic Synthesis
7 Synthetic Journals JOrgChemOrgLettTetrahedron LettTetrahedron SynthCommun Synlett SynthesisAll Journals (Full Text) Dedicated instruments only (Anton Paar Biotage CEM Milestone Prolabo)
Industrial Chemical Applications of Microwave Heating
Food Processing+ Defrosting+ Drying roasting baking+ Pasteurization
Drying Industry+ Wood fibers textiles+ Pharmaceuticals+ Brick concrete walls
Polymer Chemistry+ Rubber curing vulcanization+ Polymerization
CeramicsMaterials+ Alumina sintering+ Welding smelting gluing
Plasma+ SemiconductorsWaste Remediation+ Sewage treatment
Analytical Chemistry+ Digestion+ Extraction+ Ashing
Biochemistry Pathology+ Protein hydrolysis+ PCR proteomics+ Tissue fixation+ Histoprocessing
Medical+ Diathermy tumor detection+ Blood warming+ Sterilization (Anthrax)+ Drying of catheters
Books on Microwave-Assisted Synthesis
1048707 Fundamentals of Microwave Application1048707 Alternative Laboratory MicrowaveInstruments1048707 Chemistry Applications1048707 Biochemistry Applications1048707 Laboratory Microwave Safety
Hayes B LCEM PublishingMatthews NC2002
(ACS Professional Reference Book) H M Kingston S J Haswell (eds)
Microwaves in Organic and Medicinal ChemistryKappe C O and Stadler AWiley-VCH Weinheim 2005 ISBN 3-527-31210-2410 pages ca 1000 references
Books on Microwave-Assisted Synthesis
Lidstoumlm PTierney J P(Eds)BlackwellScientific2005
Loupy Andre (Ed)Wiley-VCH Weinheim 2003 ISBN 3-527-30514-9523 pages 2000 refs
Book (2 volumes) Wiley-VCHA Loupy editSecond Edition(2006) 22 Chapters
Astra Zeneca ResearchFoundation Kavitha PrintersBangalore India 2002azrefiastrazenecacom
Practical Microwave Synthesis for Organic Chemists - Strategies Instruments and Protocols
Edition - 2009 X 310 Pages Hardcover Monograph
Books on Microwave-Assisted Synthesis
Microwave Ovens
Monomodal instrument
Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005
Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia
Multimodal instrument
+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile
Monomodal Vs Multimodal
Monomodal Vs Multimodal
Thermal Effects
bullMore efficient energetic coupling of solvent with microwaves
promotes higher rate of temperature increase
bull Inverted heat transfer volumetric
bull ldquoHot spotsrdquo in monomode microwaves
bull Selective on properties of material (solvents catalysts
reagents intermediates products susceptors)
Recent Applications of Microwave-Assisted Synthesis-MAOS
Hydrolysis of benzamide
thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)
The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions
R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958
Solvent-free Reactions or Solid-Solid Reactions
ldquoNo reaction proceeds without solventrdquo
Aristotle
Solventless syntheses
Green chemistry enabled advancement
Solvent-free Organic Synthesis
Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed
i n t o a p o w e r f u l m e t h o d o l o g y a s i t
reduces the amount of toxic waste produced and therefore becomes less harmful to the
e n v i r o n m e n t
Solvent-free Organic Synthesis
bull Clean and efficient synthesis
bull Economic and environmental impact
bull Fast reaction kinetics
Best solvent is no solvent
Adolf von Baeyer
Synthesis of Indigo
Towardsbenign
synthesiswith
remarkableVersatility
G W V Cave C LRaston J L ScottChemCommun
2001 2159
Solid-State General Oxidation with with Urea H2O2 Complex
R S Varma and K P Naiker Org Letters 1999 1 189
Solvent-free Oxidative Preparation of Heterocycles
Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157
Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones
Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199
Solvent-free Reduction
F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245
Carbon-Carbon Bond Formation
Toda Tanada Iwata J Org Chem 1989 54 3007
Solventless Photo Coupling and Photo Rearangements
Y Ito S Endo J Am Chem Soc 1997 119 5974
Shin Keating Maribay J Am Chem Soc 1996 118 7626
Solvent - Free Condensation
Z Gross et al Org Letters 1999 1 599
Solid-State Preparationof Dumb-bell-shaped C120
Wang Komatsu Murata Shiro Nature 1997 387 583
Advantages of Solid Mineral Supports(Alumina Silica and Clay)
Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area
The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity
Solids are generally easier and safer to handle than liquids or gaseous reagents
Inexpensive recyclable and environmentally benign nature
Solid-supported Solventless Reactions
bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation
R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43
Supported ReactionsUsing Microwaves
E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945
Microwave-Assisted Deacetylationon Alumina
Varma et al J Chem Soc Perkin Trans 1 999 (1993)
Deprotection of Benzyl Esters viaMicrowave Thermolysis
A practical alternative to traditional catalytic hydrogenation
Varma et al Tetrahedron Lett 34 4603 (1993)
Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of
Carbonyl Compounds Using Microwaves
Varma Meshram Tetrahedron Lett 38 5427 (1997)
Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm
PersulfatendashClay using Microwave and Ultrasonic Irradiation
Varma Meshram Tetrahedron Lett 38 7973 (1997)
Solid Supported Solvent-freeOxidation under MW
Varma et al Tetrahedron Lett 1997 38 2043 and 7823
Solvent-free Reduction Using MW
Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction
Varma et al Tetrahedron Lett 1997 38 4337
Hydrodechlorination under continuous MW
Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)
Synthesis of Heterocyclic Compounds
Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)
Synthesis of Heterocyclic Compounds
Organometallic Reactions
Rearrangements
Rearrangements
INDOLIZINES
Heterocyclic systems 10- electronics
Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine
Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds
N
1
2
34567
8R2
R3
R1
Why interest for indolizinic products
Strong fluorescent properties luminiscent products luminiscent products
Potentially fluorescents marker Potentially laserldquoscintillatersrdquo
bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999
Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )
Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2
ldquoCalcium-entryrdquo blockers
Indolizines by irradiation with microwaves in MCR
RBr
O+
N
R1 R2+N
R2
R1
COR
AcOAl2O3 Mw
R=Ph p-Tolil Stiril
R1= H COOMeR2= COOEt COOMe
Asymmetric indolizines by irradiation with microwaves in MCR
R1
O
Cl+ R2
N NEtOOC
OOMe
Br BrN N
EtOOC
COR1
R2COR1
R2
OOMe
2 [Pd(PPh3)2Cl24 CuI
20 echiv Et3N THF tc 2h
R1=Ph 4-OMe-C6H4R2= Ph
U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003
A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new indolizines
[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical
II
IHH
COORCOOR
N C C
O
R2NCC
O
R1
(B)
(A)
R1
O
C C N R2
O
CCN
H H
ROOC COOR
R1
O
C C N R2
O
CCN
COOR COOR
ROOC COOR
2
2 ROOC C C COOR
R1
O
C CH N R2
O
CCHN
H H
N NCH CHC C
O O
R1 R2
- 2 HX TEAanhydrous solvents
X-
X-
N NCH2 CH2C C
O O
R1 R2
C C COORH
R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5
Y=H NO2 OCH3 CH3 Cl BrX=Br Cl
bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998
bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001
bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004
bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new substituted pyridinium-indolizines
Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate
COO NO2CHC
N NH3C
OR
I IN NH3C
OR
IN NH3C
OR
I
H
KFNMP
-HI
NMP
95oC 30 min
N NH3CO
RN NH3C
O
R
O OO
NO2
O
NO2
-2[H]-2[H]
II
I II
N NH3CO
R
O O
NO2
IN NH3C
O
R
O O
NO2
I
(9a-d)(10a-d)
(15a-d)
(A) (B)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
12
34
56
78 9
10
11
12 3
4
56
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Microwave Ovens
Cooking Chemistry Cooking Food
Household MW ovens
The Use of Microwave Ovens for Rapid Organic Synthesis R Gedye et al Tetrahedron Lett 1986 27 279
Publications on MW-AssistedOrganic Synthesis
7 Synthetic Journals JOrgChemOrgLettTetrahedron LettTetrahedron SynthCommun Synlett SynthesisAll Journals (Full Text) Dedicated instruments only (Anton Paar Biotage CEM Milestone Prolabo)
Industrial Chemical Applications of Microwave Heating
Food Processing+ Defrosting+ Drying roasting baking+ Pasteurization
Drying Industry+ Wood fibers textiles+ Pharmaceuticals+ Brick concrete walls
Polymer Chemistry+ Rubber curing vulcanization+ Polymerization
CeramicsMaterials+ Alumina sintering+ Welding smelting gluing
Plasma+ SemiconductorsWaste Remediation+ Sewage treatment
Analytical Chemistry+ Digestion+ Extraction+ Ashing
Biochemistry Pathology+ Protein hydrolysis+ PCR proteomics+ Tissue fixation+ Histoprocessing
Medical+ Diathermy tumor detection+ Blood warming+ Sterilization (Anthrax)+ Drying of catheters
Books on Microwave-Assisted Synthesis
1048707 Fundamentals of Microwave Application1048707 Alternative Laboratory MicrowaveInstruments1048707 Chemistry Applications1048707 Biochemistry Applications1048707 Laboratory Microwave Safety
Hayes B LCEM PublishingMatthews NC2002
(ACS Professional Reference Book) H M Kingston S J Haswell (eds)
Microwaves in Organic and Medicinal ChemistryKappe C O and Stadler AWiley-VCH Weinheim 2005 ISBN 3-527-31210-2410 pages ca 1000 references
Books on Microwave-Assisted Synthesis
Lidstoumlm PTierney J P(Eds)BlackwellScientific2005
Loupy Andre (Ed)Wiley-VCH Weinheim 2003 ISBN 3-527-30514-9523 pages 2000 refs
Book (2 volumes) Wiley-VCHA Loupy editSecond Edition(2006) 22 Chapters
Astra Zeneca ResearchFoundation Kavitha PrintersBangalore India 2002azrefiastrazenecacom
Practical Microwave Synthesis for Organic Chemists - Strategies Instruments and Protocols
Edition - 2009 X 310 Pages Hardcover Monograph
Books on Microwave-Assisted Synthesis
Microwave Ovens
Monomodal instrument
Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005
Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia
Multimodal instrument
+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile
Monomodal Vs Multimodal
Monomodal Vs Multimodal
Thermal Effects
bullMore efficient energetic coupling of solvent with microwaves
promotes higher rate of temperature increase
bull Inverted heat transfer volumetric
bull ldquoHot spotsrdquo in monomode microwaves
bull Selective on properties of material (solvents catalysts
reagents intermediates products susceptors)
Recent Applications of Microwave-Assisted Synthesis-MAOS
Hydrolysis of benzamide
thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)
The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions
R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958
Solvent-free Reactions or Solid-Solid Reactions
ldquoNo reaction proceeds without solventrdquo
Aristotle
Solventless syntheses
Green chemistry enabled advancement
Solvent-free Organic Synthesis
Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed
i n t o a p o w e r f u l m e t h o d o l o g y a s i t
reduces the amount of toxic waste produced and therefore becomes less harmful to the
e n v i r o n m e n t
Solvent-free Organic Synthesis
bull Clean and efficient synthesis
bull Economic and environmental impact
bull Fast reaction kinetics
Best solvent is no solvent
Adolf von Baeyer
Synthesis of Indigo
Towardsbenign
synthesiswith
remarkableVersatility
G W V Cave C LRaston J L ScottChemCommun
2001 2159
Solid-State General Oxidation with with Urea H2O2 Complex
R S Varma and K P Naiker Org Letters 1999 1 189
Solvent-free Oxidative Preparation of Heterocycles
Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157
Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones
Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199
Solvent-free Reduction
F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245
Carbon-Carbon Bond Formation
Toda Tanada Iwata J Org Chem 1989 54 3007
Solventless Photo Coupling and Photo Rearangements
Y Ito S Endo J Am Chem Soc 1997 119 5974
Shin Keating Maribay J Am Chem Soc 1996 118 7626
Solvent - Free Condensation
Z Gross et al Org Letters 1999 1 599
Solid-State Preparationof Dumb-bell-shaped C120
Wang Komatsu Murata Shiro Nature 1997 387 583
Advantages of Solid Mineral Supports(Alumina Silica and Clay)
Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area
The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity
Solids are generally easier and safer to handle than liquids or gaseous reagents
Inexpensive recyclable and environmentally benign nature
Solid-supported Solventless Reactions
bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation
R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43
Supported ReactionsUsing Microwaves
E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945
Microwave-Assisted Deacetylationon Alumina
Varma et al J Chem Soc Perkin Trans 1 999 (1993)
Deprotection of Benzyl Esters viaMicrowave Thermolysis
A practical alternative to traditional catalytic hydrogenation
Varma et al Tetrahedron Lett 34 4603 (1993)
Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of
Carbonyl Compounds Using Microwaves
Varma Meshram Tetrahedron Lett 38 5427 (1997)
Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm
PersulfatendashClay using Microwave and Ultrasonic Irradiation
Varma Meshram Tetrahedron Lett 38 7973 (1997)
Solid Supported Solvent-freeOxidation under MW
Varma et al Tetrahedron Lett 1997 38 2043 and 7823
Solvent-free Reduction Using MW
Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction
Varma et al Tetrahedron Lett 1997 38 4337
Hydrodechlorination under continuous MW
Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)
Synthesis of Heterocyclic Compounds
Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)
Synthesis of Heterocyclic Compounds
Organometallic Reactions
Rearrangements
Rearrangements
INDOLIZINES
Heterocyclic systems 10- electronics
Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine
Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds
N
1
2
34567
8R2
R3
R1
Why interest for indolizinic products
Strong fluorescent properties luminiscent products luminiscent products
Potentially fluorescents marker Potentially laserldquoscintillatersrdquo
bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999
Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )
Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2
ldquoCalcium-entryrdquo blockers
Indolizines by irradiation with microwaves in MCR
RBr
O+
N
R1 R2+N
R2
R1
COR
AcOAl2O3 Mw
R=Ph p-Tolil Stiril
R1= H COOMeR2= COOEt COOMe
Asymmetric indolizines by irradiation with microwaves in MCR
R1
O
Cl+ R2
N NEtOOC
OOMe
Br BrN N
EtOOC
COR1
R2COR1
R2
OOMe
2 [Pd(PPh3)2Cl24 CuI
20 echiv Et3N THF tc 2h
R1=Ph 4-OMe-C6H4R2= Ph
U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003
A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new indolizines
[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical
II
IHH
COORCOOR
N C C
O
R2NCC
O
R1
(B)
(A)
R1
O
C C N R2
O
CCN
H H
ROOC COOR
R1
O
C C N R2
O
CCN
COOR COOR
ROOC COOR
2
2 ROOC C C COOR
R1
O
C CH N R2
O
CCHN
H H
N NCH CHC C
O O
R1 R2
- 2 HX TEAanhydrous solvents
X-
X-
N NCH2 CH2C C
O O
R1 R2
C C COORH
R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5
Y=H NO2 OCH3 CH3 Cl BrX=Br Cl
bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998
bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001
bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004
bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new substituted pyridinium-indolizines
Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate
COO NO2CHC
N NH3C
OR
I IN NH3C
OR
IN NH3C
OR
I
H
KFNMP
-HI
NMP
95oC 30 min
N NH3CO
RN NH3C
O
R
O OO
NO2
O
NO2
-2[H]-2[H]
II
I II
N NH3CO
R
O O
NO2
IN NH3C
O
R
O O
NO2
I
(9a-d)(10a-d)
(15a-d)
(A) (B)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
12
34
56
78 9
10
11
12 3
4
56
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Publications on MW-AssistedOrganic Synthesis
7 Synthetic Journals JOrgChemOrgLettTetrahedron LettTetrahedron SynthCommun Synlett SynthesisAll Journals (Full Text) Dedicated instruments only (Anton Paar Biotage CEM Milestone Prolabo)
Industrial Chemical Applications of Microwave Heating
Food Processing+ Defrosting+ Drying roasting baking+ Pasteurization
Drying Industry+ Wood fibers textiles+ Pharmaceuticals+ Brick concrete walls
Polymer Chemistry+ Rubber curing vulcanization+ Polymerization
CeramicsMaterials+ Alumina sintering+ Welding smelting gluing
Plasma+ SemiconductorsWaste Remediation+ Sewage treatment
Analytical Chemistry+ Digestion+ Extraction+ Ashing
Biochemistry Pathology+ Protein hydrolysis+ PCR proteomics+ Tissue fixation+ Histoprocessing
Medical+ Diathermy tumor detection+ Blood warming+ Sterilization (Anthrax)+ Drying of catheters
Books on Microwave-Assisted Synthesis
1048707 Fundamentals of Microwave Application1048707 Alternative Laboratory MicrowaveInstruments1048707 Chemistry Applications1048707 Biochemistry Applications1048707 Laboratory Microwave Safety
Hayes B LCEM PublishingMatthews NC2002
(ACS Professional Reference Book) H M Kingston S J Haswell (eds)
Microwaves in Organic and Medicinal ChemistryKappe C O and Stadler AWiley-VCH Weinheim 2005 ISBN 3-527-31210-2410 pages ca 1000 references
Books on Microwave-Assisted Synthesis
Lidstoumlm PTierney J P(Eds)BlackwellScientific2005
Loupy Andre (Ed)Wiley-VCH Weinheim 2003 ISBN 3-527-30514-9523 pages 2000 refs
Book (2 volumes) Wiley-VCHA Loupy editSecond Edition(2006) 22 Chapters
Astra Zeneca ResearchFoundation Kavitha PrintersBangalore India 2002azrefiastrazenecacom
Practical Microwave Synthesis for Organic Chemists - Strategies Instruments and Protocols
Edition - 2009 X 310 Pages Hardcover Monograph
Books on Microwave-Assisted Synthesis
Microwave Ovens
Monomodal instrument
Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005
Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia
Multimodal instrument
+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile
Monomodal Vs Multimodal
Monomodal Vs Multimodal
Thermal Effects
bullMore efficient energetic coupling of solvent with microwaves
promotes higher rate of temperature increase
bull Inverted heat transfer volumetric
bull ldquoHot spotsrdquo in monomode microwaves
bull Selective on properties of material (solvents catalysts
reagents intermediates products susceptors)
Recent Applications of Microwave-Assisted Synthesis-MAOS
Hydrolysis of benzamide
thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)
The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions
R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958
Solvent-free Reactions or Solid-Solid Reactions
ldquoNo reaction proceeds without solventrdquo
Aristotle
Solventless syntheses
Green chemistry enabled advancement
Solvent-free Organic Synthesis
Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed
i n t o a p o w e r f u l m e t h o d o l o g y a s i t
reduces the amount of toxic waste produced and therefore becomes less harmful to the
e n v i r o n m e n t
Solvent-free Organic Synthesis
bull Clean and efficient synthesis
bull Economic and environmental impact
bull Fast reaction kinetics
Best solvent is no solvent
Adolf von Baeyer
Synthesis of Indigo
Towardsbenign
synthesiswith
remarkableVersatility
G W V Cave C LRaston J L ScottChemCommun
2001 2159
Solid-State General Oxidation with with Urea H2O2 Complex
R S Varma and K P Naiker Org Letters 1999 1 189
Solvent-free Oxidative Preparation of Heterocycles
Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157
Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones
Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199
Solvent-free Reduction
F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245
Carbon-Carbon Bond Formation
Toda Tanada Iwata J Org Chem 1989 54 3007
Solventless Photo Coupling and Photo Rearangements
Y Ito S Endo J Am Chem Soc 1997 119 5974
Shin Keating Maribay J Am Chem Soc 1996 118 7626
Solvent - Free Condensation
Z Gross et al Org Letters 1999 1 599
Solid-State Preparationof Dumb-bell-shaped C120
Wang Komatsu Murata Shiro Nature 1997 387 583
Advantages of Solid Mineral Supports(Alumina Silica and Clay)
Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area
The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity
Solids are generally easier and safer to handle than liquids or gaseous reagents
Inexpensive recyclable and environmentally benign nature
Solid-supported Solventless Reactions
bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation
R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43
Supported ReactionsUsing Microwaves
E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945
Microwave-Assisted Deacetylationon Alumina
Varma et al J Chem Soc Perkin Trans 1 999 (1993)
Deprotection of Benzyl Esters viaMicrowave Thermolysis
A practical alternative to traditional catalytic hydrogenation
Varma et al Tetrahedron Lett 34 4603 (1993)
Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of
Carbonyl Compounds Using Microwaves
Varma Meshram Tetrahedron Lett 38 5427 (1997)
Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm
PersulfatendashClay using Microwave and Ultrasonic Irradiation
Varma Meshram Tetrahedron Lett 38 7973 (1997)
Solid Supported Solvent-freeOxidation under MW
Varma et al Tetrahedron Lett 1997 38 2043 and 7823
Solvent-free Reduction Using MW
Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction
Varma et al Tetrahedron Lett 1997 38 4337
Hydrodechlorination under continuous MW
Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)
Synthesis of Heterocyclic Compounds
Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)
Synthesis of Heterocyclic Compounds
Organometallic Reactions
Rearrangements
Rearrangements
INDOLIZINES
Heterocyclic systems 10- electronics
Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine
Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds
N
1
2
34567
8R2
R3
R1
Why interest for indolizinic products
Strong fluorescent properties luminiscent products luminiscent products
Potentially fluorescents marker Potentially laserldquoscintillatersrdquo
bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999
Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )
Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2
ldquoCalcium-entryrdquo blockers
Indolizines by irradiation with microwaves in MCR
RBr
O+
N
R1 R2+N
R2
R1
COR
AcOAl2O3 Mw
R=Ph p-Tolil Stiril
R1= H COOMeR2= COOEt COOMe
Asymmetric indolizines by irradiation with microwaves in MCR
R1
O
Cl+ R2
N NEtOOC
OOMe
Br BrN N
EtOOC
COR1
R2COR1
R2
OOMe
2 [Pd(PPh3)2Cl24 CuI
20 echiv Et3N THF tc 2h
R1=Ph 4-OMe-C6H4R2= Ph
U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003
A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new indolizines
[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical
II
IHH
COORCOOR
N C C
O
R2NCC
O
R1
(B)
(A)
R1
O
C C N R2
O
CCN
H H
ROOC COOR
R1
O
C C N R2
O
CCN
COOR COOR
ROOC COOR
2
2 ROOC C C COOR
R1
O
C CH N R2
O
CCHN
H H
N NCH CHC C
O O
R1 R2
- 2 HX TEAanhydrous solvents
X-
X-
N NCH2 CH2C C
O O
R1 R2
C C COORH
R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5
Y=H NO2 OCH3 CH3 Cl BrX=Br Cl
bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998
bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001
bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004
bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new substituted pyridinium-indolizines
Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate
COO NO2CHC
N NH3C
OR
I IN NH3C
OR
IN NH3C
OR
I
H
KFNMP
-HI
NMP
95oC 30 min
N NH3CO
RN NH3C
O
R
O OO
NO2
O
NO2
-2[H]-2[H]
II
I II
N NH3CO
R
O O
NO2
IN NH3C
O
R
O O
NO2
I
(9a-d)(10a-d)
(15a-d)
(A) (B)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
12
34
56
78 9
10
11
12 3
4
56
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Industrial Chemical Applications of Microwave Heating
Food Processing+ Defrosting+ Drying roasting baking+ Pasteurization
Drying Industry+ Wood fibers textiles+ Pharmaceuticals+ Brick concrete walls
Polymer Chemistry+ Rubber curing vulcanization+ Polymerization
CeramicsMaterials+ Alumina sintering+ Welding smelting gluing
Plasma+ SemiconductorsWaste Remediation+ Sewage treatment
Analytical Chemistry+ Digestion+ Extraction+ Ashing
Biochemistry Pathology+ Protein hydrolysis+ PCR proteomics+ Tissue fixation+ Histoprocessing
Medical+ Diathermy tumor detection+ Blood warming+ Sterilization (Anthrax)+ Drying of catheters
Books on Microwave-Assisted Synthesis
1048707 Fundamentals of Microwave Application1048707 Alternative Laboratory MicrowaveInstruments1048707 Chemistry Applications1048707 Biochemistry Applications1048707 Laboratory Microwave Safety
Hayes B LCEM PublishingMatthews NC2002
(ACS Professional Reference Book) H M Kingston S J Haswell (eds)
Microwaves in Organic and Medicinal ChemistryKappe C O and Stadler AWiley-VCH Weinheim 2005 ISBN 3-527-31210-2410 pages ca 1000 references
Books on Microwave-Assisted Synthesis
Lidstoumlm PTierney J P(Eds)BlackwellScientific2005
Loupy Andre (Ed)Wiley-VCH Weinheim 2003 ISBN 3-527-30514-9523 pages 2000 refs
Book (2 volumes) Wiley-VCHA Loupy editSecond Edition(2006) 22 Chapters
Astra Zeneca ResearchFoundation Kavitha PrintersBangalore India 2002azrefiastrazenecacom
Practical Microwave Synthesis for Organic Chemists - Strategies Instruments and Protocols
Edition - 2009 X 310 Pages Hardcover Monograph
Books on Microwave-Assisted Synthesis
Microwave Ovens
Monomodal instrument
Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005
Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia
Multimodal instrument
+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile
Monomodal Vs Multimodal
Monomodal Vs Multimodal
Thermal Effects
bullMore efficient energetic coupling of solvent with microwaves
promotes higher rate of temperature increase
bull Inverted heat transfer volumetric
bull ldquoHot spotsrdquo in monomode microwaves
bull Selective on properties of material (solvents catalysts
reagents intermediates products susceptors)
Recent Applications of Microwave-Assisted Synthesis-MAOS
Hydrolysis of benzamide
thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)
The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions
R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958
Solvent-free Reactions or Solid-Solid Reactions
ldquoNo reaction proceeds without solventrdquo
Aristotle
Solventless syntheses
Green chemistry enabled advancement
Solvent-free Organic Synthesis
Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed
i n t o a p o w e r f u l m e t h o d o l o g y a s i t
reduces the amount of toxic waste produced and therefore becomes less harmful to the
e n v i r o n m e n t
Solvent-free Organic Synthesis
bull Clean and efficient synthesis
bull Economic and environmental impact
bull Fast reaction kinetics
Best solvent is no solvent
Adolf von Baeyer
Synthesis of Indigo
Towardsbenign
synthesiswith
remarkableVersatility
G W V Cave C LRaston J L ScottChemCommun
2001 2159
Solid-State General Oxidation with with Urea H2O2 Complex
R S Varma and K P Naiker Org Letters 1999 1 189
Solvent-free Oxidative Preparation of Heterocycles
Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157
Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones
Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199
Solvent-free Reduction
F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245
Carbon-Carbon Bond Formation
Toda Tanada Iwata J Org Chem 1989 54 3007
Solventless Photo Coupling and Photo Rearangements
Y Ito S Endo J Am Chem Soc 1997 119 5974
Shin Keating Maribay J Am Chem Soc 1996 118 7626
Solvent - Free Condensation
Z Gross et al Org Letters 1999 1 599
Solid-State Preparationof Dumb-bell-shaped C120
Wang Komatsu Murata Shiro Nature 1997 387 583
Advantages of Solid Mineral Supports(Alumina Silica and Clay)
Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area
The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity
Solids are generally easier and safer to handle than liquids or gaseous reagents
Inexpensive recyclable and environmentally benign nature
Solid-supported Solventless Reactions
bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation
R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43
Supported ReactionsUsing Microwaves
E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945
Microwave-Assisted Deacetylationon Alumina
Varma et al J Chem Soc Perkin Trans 1 999 (1993)
Deprotection of Benzyl Esters viaMicrowave Thermolysis
A practical alternative to traditional catalytic hydrogenation
Varma et al Tetrahedron Lett 34 4603 (1993)
Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of
Carbonyl Compounds Using Microwaves
Varma Meshram Tetrahedron Lett 38 5427 (1997)
Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm
PersulfatendashClay using Microwave and Ultrasonic Irradiation
Varma Meshram Tetrahedron Lett 38 7973 (1997)
Solid Supported Solvent-freeOxidation under MW
Varma et al Tetrahedron Lett 1997 38 2043 and 7823
Solvent-free Reduction Using MW
Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction
Varma et al Tetrahedron Lett 1997 38 4337
Hydrodechlorination under continuous MW
Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)
Synthesis of Heterocyclic Compounds
Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)
Synthesis of Heterocyclic Compounds
Organometallic Reactions
Rearrangements
Rearrangements
INDOLIZINES
Heterocyclic systems 10- electronics
Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine
Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds
N
1
2
34567
8R2
R3
R1
Why interest for indolizinic products
Strong fluorescent properties luminiscent products luminiscent products
Potentially fluorescents marker Potentially laserldquoscintillatersrdquo
bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999
Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )
Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2
ldquoCalcium-entryrdquo blockers
Indolizines by irradiation with microwaves in MCR
RBr
O+
N
R1 R2+N
R2
R1
COR
AcOAl2O3 Mw
R=Ph p-Tolil Stiril
R1= H COOMeR2= COOEt COOMe
Asymmetric indolizines by irradiation with microwaves in MCR
R1
O
Cl+ R2
N NEtOOC
OOMe
Br BrN N
EtOOC
COR1
R2COR1
R2
OOMe
2 [Pd(PPh3)2Cl24 CuI
20 echiv Et3N THF tc 2h
R1=Ph 4-OMe-C6H4R2= Ph
U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003
A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new indolizines
[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical
II
IHH
COORCOOR
N C C
O
R2NCC
O
R1
(B)
(A)
R1
O
C C N R2
O
CCN
H H
ROOC COOR
R1
O
C C N R2
O
CCN
COOR COOR
ROOC COOR
2
2 ROOC C C COOR
R1
O
C CH N R2
O
CCHN
H H
N NCH CHC C
O O
R1 R2
- 2 HX TEAanhydrous solvents
X-
X-
N NCH2 CH2C C
O O
R1 R2
C C COORH
R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5
Y=H NO2 OCH3 CH3 Cl BrX=Br Cl
bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998
bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001
bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004
bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new substituted pyridinium-indolizines
Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate
COO NO2CHC
N NH3C
OR
I IN NH3C
OR
IN NH3C
OR
I
H
KFNMP
-HI
NMP
95oC 30 min
N NH3CO
RN NH3C
O
R
O OO
NO2
O
NO2
-2[H]-2[H]
II
I II
N NH3CO
R
O O
NO2
IN NH3C
O
R
O O
NO2
I
(9a-d)(10a-d)
(15a-d)
(A) (B)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
12
34
56
78 9
10
11
12 3
4
56
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Books on Microwave-Assisted Synthesis
1048707 Fundamentals of Microwave Application1048707 Alternative Laboratory MicrowaveInstruments1048707 Chemistry Applications1048707 Biochemistry Applications1048707 Laboratory Microwave Safety
Hayes B LCEM PublishingMatthews NC2002
(ACS Professional Reference Book) H M Kingston S J Haswell (eds)
Microwaves in Organic and Medicinal ChemistryKappe C O and Stadler AWiley-VCH Weinheim 2005 ISBN 3-527-31210-2410 pages ca 1000 references
Books on Microwave-Assisted Synthesis
Lidstoumlm PTierney J P(Eds)BlackwellScientific2005
Loupy Andre (Ed)Wiley-VCH Weinheim 2003 ISBN 3-527-30514-9523 pages 2000 refs
Book (2 volumes) Wiley-VCHA Loupy editSecond Edition(2006) 22 Chapters
Astra Zeneca ResearchFoundation Kavitha PrintersBangalore India 2002azrefiastrazenecacom
Practical Microwave Synthesis for Organic Chemists - Strategies Instruments and Protocols
Edition - 2009 X 310 Pages Hardcover Monograph
Books on Microwave-Assisted Synthesis
Microwave Ovens
Monomodal instrument
Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005
Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia
Multimodal instrument
+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile
Monomodal Vs Multimodal
Monomodal Vs Multimodal
Thermal Effects
bullMore efficient energetic coupling of solvent with microwaves
promotes higher rate of temperature increase
bull Inverted heat transfer volumetric
bull ldquoHot spotsrdquo in monomode microwaves
bull Selective on properties of material (solvents catalysts
reagents intermediates products susceptors)
Recent Applications of Microwave-Assisted Synthesis-MAOS
Hydrolysis of benzamide
thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)
The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions
R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958
Solvent-free Reactions or Solid-Solid Reactions
ldquoNo reaction proceeds without solventrdquo
Aristotle
Solventless syntheses
Green chemistry enabled advancement
Solvent-free Organic Synthesis
Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed
i n t o a p o w e r f u l m e t h o d o l o g y a s i t
reduces the amount of toxic waste produced and therefore becomes less harmful to the
e n v i r o n m e n t
Solvent-free Organic Synthesis
bull Clean and efficient synthesis
bull Economic and environmental impact
bull Fast reaction kinetics
Best solvent is no solvent
Adolf von Baeyer
Synthesis of Indigo
Towardsbenign
synthesiswith
remarkableVersatility
G W V Cave C LRaston J L ScottChemCommun
2001 2159
Solid-State General Oxidation with with Urea H2O2 Complex
R S Varma and K P Naiker Org Letters 1999 1 189
Solvent-free Oxidative Preparation of Heterocycles
Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157
Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones
Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199
Solvent-free Reduction
F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245
Carbon-Carbon Bond Formation
Toda Tanada Iwata J Org Chem 1989 54 3007
Solventless Photo Coupling and Photo Rearangements
Y Ito S Endo J Am Chem Soc 1997 119 5974
Shin Keating Maribay J Am Chem Soc 1996 118 7626
Solvent - Free Condensation
Z Gross et al Org Letters 1999 1 599
Solid-State Preparationof Dumb-bell-shaped C120
Wang Komatsu Murata Shiro Nature 1997 387 583
Advantages of Solid Mineral Supports(Alumina Silica and Clay)
Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area
The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity
Solids are generally easier and safer to handle than liquids or gaseous reagents
Inexpensive recyclable and environmentally benign nature
Solid-supported Solventless Reactions
bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation
R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43
Supported ReactionsUsing Microwaves
E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945
Microwave-Assisted Deacetylationon Alumina
Varma et al J Chem Soc Perkin Trans 1 999 (1993)
Deprotection of Benzyl Esters viaMicrowave Thermolysis
A practical alternative to traditional catalytic hydrogenation
Varma et al Tetrahedron Lett 34 4603 (1993)
Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of
Carbonyl Compounds Using Microwaves
Varma Meshram Tetrahedron Lett 38 5427 (1997)
Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm
PersulfatendashClay using Microwave and Ultrasonic Irradiation
Varma Meshram Tetrahedron Lett 38 7973 (1997)
Solid Supported Solvent-freeOxidation under MW
Varma et al Tetrahedron Lett 1997 38 2043 and 7823
Solvent-free Reduction Using MW
Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction
Varma et al Tetrahedron Lett 1997 38 4337
Hydrodechlorination under continuous MW
Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)
Synthesis of Heterocyclic Compounds
Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)
Synthesis of Heterocyclic Compounds
Organometallic Reactions
Rearrangements
Rearrangements
INDOLIZINES
Heterocyclic systems 10- electronics
Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine
Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds
N
1
2
34567
8R2
R3
R1
Why interest for indolizinic products
Strong fluorescent properties luminiscent products luminiscent products
Potentially fluorescents marker Potentially laserldquoscintillatersrdquo
bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999
Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )
Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2
ldquoCalcium-entryrdquo blockers
Indolizines by irradiation with microwaves in MCR
RBr
O+
N
R1 R2+N
R2
R1
COR
AcOAl2O3 Mw
R=Ph p-Tolil Stiril
R1= H COOMeR2= COOEt COOMe
Asymmetric indolizines by irradiation with microwaves in MCR
R1
O
Cl+ R2
N NEtOOC
OOMe
Br BrN N
EtOOC
COR1
R2COR1
R2
OOMe
2 [Pd(PPh3)2Cl24 CuI
20 echiv Et3N THF tc 2h
R1=Ph 4-OMe-C6H4R2= Ph
U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003
A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new indolizines
[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical
II
IHH
COORCOOR
N C C
O
R2NCC
O
R1
(B)
(A)
R1
O
C C N R2
O
CCN
H H
ROOC COOR
R1
O
C C N R2
O
CCN
COOR COOR
ROOC COOR
2
2 ROOC C C COOR
R1
O
C CH N R2
O
CCHN
H H
N NCH CHC C
O O
R1 R2
- 2 HX TEAanhydrous solvents
X-
X-
N NCH2 CH2C C
O O
R1 R2
C C COORH
R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5
Y=H NO2 OCH3 CH3 Cl BrX=Br Cl
bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998
bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001
bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004
bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new substituted pyridinium-indolizines
Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate
COO NO2CHC
N NH3C
OR
I IN NH3C
OR
IN NH3C
OR
I
H
KFNMP
-HI
NMP
95oC 30 min
N NH3CO
RN NH3C
O
R
O OO
NO2
O
NO2
-2[H]-2[H]
II
I II
N NH3CO
R
O O
NO2
IN NH3C
O
R
O O
NO2
I
(9a-d)(10a-d)
(15a-d)
(A) (B)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
12
34
56
78 9
10
11
12 3
4
56
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Books on Microwave-Assisted Synthesis
Lidstoumlm PTierney J P(Eds)BlackwellScientific2005
Loupy Andre (Ed)Wiley-VCH Weinheim 2003 ISBN 3-527-30514-9523 pages 2000 refs
Book (2 volumes) Wiley-VCHA Loupy editSecond Edition(2006) 22 Chapters
Astra Zeneca ResearchFoundation Kavitha PrintersBangalore India 2002azrefiastrazenecacom
Practical Microwave Synthesis for Organic Chemists - Strategies Instruments and Protocols
Edition - 2009 X 310 Pages Hardcover Monograph
Books on Microwave-Assisted Synthesis
Microwave Ovens
Monomodal instrument
Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005
Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia
Multimodal instrument
+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile
Monomodal Vs Multimodal
Monomodal Vs Multimodal
Thermal Effects
bullMore efficient energetic coupling of solvent with microwaves
promotes higher rate of temperature increase
bull Inverted heat transfer volumetric
bull ldquoHot spotsrdquo in monomode microwaves
bull Selective on properties of material (solvents catalysts
reagents intermediates products susceptors)
Recent Applications of Microwave-Assisted Synthesis-MAOS
Hydrolysis of benzamide
thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)
The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions
R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958
Solvent-free Reactions or Solid-Solid Reactions
ldquoNo reaction proceeds without solventrdquo
Aristotle
Solventless syntheses
Green chemistry enabled advancement
Solvent-free Organic Synthesis
Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed
i n t o a p o w e r f u l m e t h o d o l o g y a s i t
reduces the amount of toxic waste produced and therefore becomes less harmful to the
e n v i r o n m e n t
Solvent-free Organic Synthesis
bull Clean and efficient synthesis
bull Economic and environmental impact
bull Fast reaction kinetics
Best solvent is no solvent
Adolf von Baeyer
Synthesis of Indigo
Towardsbenign
synthesiswith
remarkableVersatility
G W V Cave C LRaston J L ScottChemCommun
2001 2159
Solid-State General Oxidation with with Urea H2O2 Complex
R S Varma and K P Naiker Org Letters 1999 1 189
Solvent-free Oxidative Preparation of Heterocycles
Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157
Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones
Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199
Solvent-free Reduction
F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245
Carbon-Carbon Bond Formation
Toda Tanada Iwata J Org Chem 1989 54 3007
Solventless Photo Coupling and Photo Rearangements
Y Ito S Endo J Am Chem Soc 1997 119 5974
Shin Keating Maribay J Am Chem Soc 1996 118 7626
Solvent - Free Condensation
Z Gross et al Org Letters 1999 1 599
Solid-State Preparationof Dumb-bell-shaped C120
Wang Komatsu Murata Shiro Nature 1997 387 583
Advantages of Solid Mineral Supports(Alumina Silica and Clay)
Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area
The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity
Solids are generally easier and safer to handle than liquids or gaseous reagents
Inexpensive recyclable and environmentally benign nature
Solid-supported Solventless Reactions
bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation
R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43
Supported ReactionsUsing Microwaves
E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945
Microwave-Assisted Deacetylationon Alumina
Varma et al J Chem Soc Perkin Trans 1 999 (1993)
Deprotection of Benzyl Esters viaMicrowave Thermolysis
A practical alternative to traditional catalytic hydrogenation
Varma et al Tetrahedron Lett 34 4603 (1993)
Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of
Carbonyl Compounds Using Microwaves
Varma Meshram Tetrahedron Lett 38 5427 (1997)
Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm
PersulfatendashClay using Microwave and Ultrasonic Irradiation
Varma Meshram Tetrahedron Lett 38 7973 (1997)
Solid Supported Solvent-freeOxidation under MW
Varma et al Tetrahedron Lett 1997 38 2043 and 7823
Solvent-free Reduction Using MW
Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction
Varma et al Tetrahedron Lett 1997 38 4337
Hydrodechlorination under continuous MW
Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)
Synthesis of Heterocyclic Compounds
Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)
Synthesis of Heterocyclic Compounds
Organometallic Reactions
Rearrangements
Rearrangements
INDOLIZINES
Heterocyclic systems 10- electronics
Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine
Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds
N
1
2
34567
8R2
R3
R1
Why interest for indolizinic products
Strong fluorescent properties luminiscent products luminiscent products
Potentially fluorescents marker Potentially laserldquoscintillatersrdquo
bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999
Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )
Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2
ldquoCalcium-entryrdquo blockers
Indolizines by irradiation with microwaves in MCR
RBr
O+
N
R1 R2+N
R2
R1
COR
AcOAl2O3 Mw
R=Ph p-Tolil Stiril
R1= H COOMeR2= COOEt COOMe
Asymmetric indolizines by irradiation with microwaves in MCR
R1
O
Cl+ R2
N NEtOOC
OOMe
Br BrN N
EtOOC
COR1
R2COR1
R2
OOMe
2 [Pd(PPh3)2Cl24 CuI
20 echiv Et3N THF tc 2h
R1=Ph 4-OMe-C6H4R2= Ph
U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003
A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new indolizines
[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical
II
IHH
COORCOOR
N C C
O
R2NCC
O
R1
(B)
(A)
R1
O
C C N R2
O
CCN
H H
ROOC COOR
R1
O
C C N R2
O
CCN
COOR COOR
ROOC COOR
2
2 ROOC C C COOR
R1
O
C CH N R2
O
CCHN
H H
N NCH CHC C
O O
R1 R2
- 2 HX TEAanhydrous solvents
X-
X-
N NCH2 CH2C C
O O
R1 R2
C C COORH
R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5
Y=H NO2 OCH3 CH3 Cl BrX=Br Cl
bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998
bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001
bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004
bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new substituted pyridinium-indolizines
Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate
COO NO2CHC
N NH3C
OR
I IN NH3C
OR
IN NH3C
OR
I
H
KFNMP
-HI
NMP
95oC 30 min
N NH3CO
RN NH3C
O
R
O OO
NO2
O
NO2
-2[H]-2[H]
II
I II
N NH3CO
R
O O
NO2
IN NH3C
O
R
O O
NO2
I
(9a-d)(10a-d)
(15a-d)
(A) (B)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
12
34
56
78 9
10
11
12 3
4
56
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Astra Zeneca ResearchFoundation Kavitha PrintersBangalore India 2002azrefiastrazenecacom
Practical Microwave Synthesis for Organic Chemists - Strategies Instruments and Protocols
Edition - 2009 X 310 Pages Hardcover Monograph
Books on Microwave-Assisted Synthesis
Microwave Ovens
Monomodal instrument
Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005
Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia
Multimodal instrument
+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile
Monomodal Vs Multimodal
Monomodal Vs Multimodal
Thermal Effects
bullMore efficient energetic coupling of solvent with microwaves
promotes higher rate of temperature increase
bull Inverted heat transfer volumetric
bull ldquoHot spotsrdquo in monomode microwaves
bull Selective on properties of material (solvents catalysts
reagents intermediates products susceptors)
Recent Applications of Microwave-Assisted Synthesis-MAOS
Hydrolysis of benzamide
thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)
The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions
R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958
Solvent-free Reactions or Solid-Solid Reactions
ldquoNo reaction proceeds without solventrdquo
Aristotle
Solventless syntheses
Green chemistry enabled advancement
Solvent-free Organic Synthesis
Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed
i n t o a p o w e r f u l m e t h o d o l o g y a s i t
reduces the amount of toxic waste produced and therefore becomes less harmful to the
e n v i r o n m e n t
Solvent-free Organic Synthesis
bull Clean and efficient synthesis
bull Economic and environmental impact
bull Fast reaction kinetics
Best solvent is no solvent
Adolf von Baeyer
Synthesis of Indigo
Towardsbenign
synthesiswith
remarkableVersatility
G W V Cave C LRaston J L ScottChemCommun
2001 2159
Solid-State General Oxidation with with Urea H2O2 Complex
R S Varma and K P Naiker Org Letters 1999 1 189
Solvent-free Oxidative Preparation of Heterocycles
Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157
Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones
Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199
Solvent-free Reduction
F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245
Carbon-Carbon Bond Formation
Toda Tanada Iwata J Org Chem 1989 54 3007
Solventless Photo Coupling and Photo Rearangements
Y Ito S Endo J Am Chem Soc 1997 119 5974
Shin Keating Maribay J Am Chem Soc 1996 118 7626
Solvent - Free Condensation
Z Gross et al Org Letters 1999 1 599
Solid-State Preparationof Dumb-bell-shaped C120
Wang Komatsu Murata Shiro Nature 1997 387 583
Advantages of Solid Mineral Supports(Alumina Silica and Clay)
Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area
The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity
Solids are generally easier and safer to handle than liquids or gaseous reagents
Inexpensive recyclable and environmentally benign nature
Solid-supported Solventless Reactions
bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation
R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43
Supported ReactionsUsing Microwaves
E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945
Microwave-Assisted Deacetylationon Alumina
Varma et al J Chem Soc Perkin Trans 1 999 (1993)
Deprotection of Benzyl Esters viaMicrowave Thermolysis
A practical alternative to traditional catalytic hydrogenation
Varma et al Tetrahedron Lett 34 4603 (1993)
Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of
Carbonyl Compounds Using Microwaves
Varma Meshram Tetrahedron Lett 38 5427 (1997)
Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm
PersulfatendashClay using Microwave and Ultrasonic Irradiation
Varma Meshram Tetrahedron Lett 38 7973 (1997)
Solid Supported Solvent-freeOxidation under MW
Varma et al Tetrahedron Lett 1997 38 2043 and 7823
Solvent-free Reduction Using MW
Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction
Varma et al Tetrahedron Lett 1997 38 4337
Hydrodechlorination under continuous MW
Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)
Synthesis of Heterocyclic Compounds
Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)
Synthesis of Heterocyclic Compounds
Organometallic Reactions
Rearrangements
Rearrangements
INDOLIZINES
Heterocyclic systems 10- electronics
Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine
Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds
N
1
2
34567
8R2
R3
R1
Why interest for indolizinic products
Strong fluorescent properties luminiscent products luminiscent products
Potentially fluorescents marker Potentially laserldquoscintillatersrdquo
bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999
Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )
Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2
ldquoCalcium-entryrdquo blockers
Indolizines by irradiation with microwaves in MCR
RBr
O+
N
R1 R2+N
R2
R1
COR
AcOAl2O3 Mw
R=Ph p-Tolil Stiril
R1= H COOMeR2= COOEt COOMe
Asymmetric indolizines by irradiation with microwaves in MCR
R1
O
Cl+ R2
N NEtOOC
OOMe
Br BrN N
EtOOC
COR1
R2COR1
R2
OOMe
2 [Pd(PPh3)2Cl24 CuI
20 echiv Et3N THF tc 2h
R1=Ph 4-OMe-C6H4R2= Ph
U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003
A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new indolizines
[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical
II
IHH
COORCOOR
N C C
O
R2NCC
O
R1
(B)
(A)
R1
O
C C N R2
O
CCN
H H
ROOC COOR
R1
O
C C N R2
O
CCN
COOR COOR
ROOC COOR
2
2 ROOC C C COOR
R1
O
C CH N R2
O
CCHN
H H
N NCH CHC C
O O
R1 R2
- 2 HX TEAanhydrous solvents
X-
X-
N NCH2 CH2C C
O O
R1 R2
C C COORH
R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5
Y=H NO2 OCH3 CH3 Cl BrX=Br Cl
bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998
bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001
bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004
bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new substituted pyridinium-indolizines
Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate
COO NO2CHC
N NH3C
OR
I IN NH3C
OR
IN NH3C
OR
I
H
KFNMP
-HI
NMP
95oC 30 min
N NH3CO
RN NH3C
O
R
O OO
NO2
O
NO2
-2[H]-2[H]
II
I II
N NH3CO
R
O O
NO2
IN NH3C
O
R
O O
NO2
I
(9a-d)(10a-d)
(15a-d)
(A) (B)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
12
34
56
78 9
10
11
12 3
4
56
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Microwave Ovens
Monomodal instrument
Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005
Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia
Multimodal instrument
+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile
Monomodal Vs Multimodal
Monomodal Vs Multimodal
Thermal Effects
bullMore efficient energetic coupling of solvent with microwaves
promotes higher rate of temperature increase
bull Inverted heat transfer volumetric
bull ldquoHot spotsrdquo in monomode microwaves
bull Selective on properties of material (solvents catalysts
reagents intermediates products susceptors)
Recent Applications of Microwave-Assisted Synthesis-MAOS
Hydrolysis of benzamide
thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)
The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions
R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958
Solvent-free Reactions or Solid-Solid Reactions
ldquoNo reaction proceeds without solventrdquo
Aristotle
Solventless syntheses
Green chemistry enabled advancement
Solvent-free Organic Synthesis
Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed
i n t o a p o w e r f u l m e t h o d o l o g y a s i t
reduces the amount of toxic waste produced and therefore becomes less harmful to the
e n v i r o n m e n t
Solvent-free Organic Synthesis
bull Clean and efficient synthesis
bull Economic and environmental impact
bull Fast reaction kinetics
Best solvent is no solvent
Adolf von Baeyer
Synthesis of Indigo
Towardsbenign
synthesiswith
remarkableVersatility
G W V Cave C LRaston J L ScottChemCommun
2001 2159
Solid-State General Oxidation with with Urea H2O2 Complex
R S Varma and K P Naiker Org Letters 1999 1 189
Solvent-free Oxidative Preparation of Heterocycles
Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157
Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones
Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199
Solvent-free Reduction
F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245
Carbon-Carbon Bond Formation
Toda Tanada Iwata J Org Chem 1989 54 3007
Solventless Photo Coupling and Photo Rearangements
Y Ito S Endo J Am Chem Soc 1997 119 5974
Shin Keating Maribay J Am Chem Soc 1996 118 7626
Solvent - Free Condensation
Z Gross et al Org Letters 1999 1 599
Solid-State Preparationof Dumb-bell-shaped C120
Wang Komatsu Murata Shiro Nature 1997 387 583
Advantages of Solid Mineral Supports(Alumina Silica and Clay)
Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area
The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity
Solids are generally easier and safer to handle than liquids or gaseous reagents
Inexpensive recyclable and environmentally benign nature
Solid-supported Solventless Reactions
bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation
R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43
Supported ReactionsUsing Microwaves
E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945
Microwave-Assisted Deacetylationon Alumina
Varma et al J Chem Soc Perkin Trans 1 999 (1993)
Deprotection of Benzyl Esters viaMicrowave Thermolysis
A practical alternative to traditional catalytic hydrogenation
Varma et al Tetrahedron Lett 34 4603 (1993)
Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of
Carbonyl Compounds Using Microwaves
Varma Meshram Tetrahedron Lett 38 5427 (1997)
Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm
PersulfatendashClay using Microwave and Ultrasonic Irradiation
Varma Meshram Tetrahedron Lett 38 7973 (1997)
Solid Supported Solvent-freeOxidation under MW
Varma et al Tetrahedron Lett 1997 38 2043 and 7823
Solvent-free Reduction Using MW
Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction
Varma et al Tetrahedron Lett 1997 38 4337
Hydrodechlorination under continuous MW
Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)
Synthesis of Heterocyclic Compounds
Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)
Synthesis of Heterocyclic Compounds
Organometallic Reactions
Rearrangements
Rearrangements
INDOLIZINES
Heterocyclic systems 10- electronics
Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine
Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds
N
1
2
34567
8R2
R3
R1
Why interest for indolizinic products
Strong fluorescent properties luminiscent products luminiscent products
Potentially fluorescents marker Potentially laserldquoscintillatersrdquo
bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999
Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )
Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2
ldquoCalcium-entryrdquo blockers
Indolizines by irradiation with microwaves in MCR
RBr
O+
N
R1 R2+N
R2
R1
COR
AcOAl2O3 Mw
R=Ph p-Tolil Stiril
R1= H COOMeR2= COOEt COOMe
Asymmetric indolizines by irradiation with microwaves in MCR
R1
O
Cl+ R2
N NEtOOC
OOMe
Br BrN N
EtOOC
COR1
R2COR1
R2
OOMe
2 [Pd(PPh3)2Cl24 CuI
20 echiv Et3N THF tc 2h
R1=Ph 4-OMe-C6H4R2= Ph
U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003
A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new indolizines
[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical
II
IHH
COORCOOR
N C C
O
R2NCC
O
R1
(B)
(A)
R1
O
C C N R2
O
CCN
H H
ROOC COOR
R1
O
C C N R2
O
CCN
COOR COOR
ROOC COOR
2
2 ROOC C C COOR
R1
O
C CH N R2
O
CCHN
H H
N NCH CHC C
O O
R1 R2
- 2 HX TEAanhydrous solvents
X-
X-
N NCH2 CH2C C
O O
R1 R2
C C COORH
R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5
Y=H NO2 OCH3 CH3 Cl BrX=Br Cl
bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998
bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001
bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004
bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new substituted pyridinium-indolizines
Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate
COO NO2CHC
N NH3C
OR
I IN NH3C
OR
IN NH3C
OR
I
H
KFNMP
-HI
NMP
95oC 30 min
N NH3CO
RN NH3C
O
R
O OO
NO2
O
NO2
-2[H]-2[H]
II
I II
N NH3CO
R
O O
NO2
IN NH3C
O
R
O O
NO2
I
(9a-d)(10a-d)
(15a-d)
(A) (B)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
12
34
56
78 9
10
11
12 3
4
56
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Monomodal instrument
Images adapted from CO Kappe A Stadler Microwaves in Organic and Medicinal Chemistry Wiley 2005
Piccoli volumi processabili- Onde Stazionarie (Hot Spots)- Difficoltagrave nello Scale-up+ Alta densitagrave drsquoenergia
Multimodal instrument
+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile
Monomodal Vs Multimodal
Monomodal Vs Multimodal
Thermal Effects
bullMore efficient energetic coupling of solvent with microwaves
promotes higher rate of temperature increase
bull Inverted heat transfer volumetric
bull ldquoHot spotsrdquo in monomode microwaves
bull Selective on properties of material (solvents catalysts
reagents intermediates products susceptors)
Recent Applications of Microwave-Assisted Synthesis-MAOS
Hydrolysis of benzamide
thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)
The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions
R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958
Solvent-free Reactions or Solid-Solid Reactions
ldquoNo reaction proceeds without solventrdquo
Aristotle
Solventless syntheses
Green chemistry enabled advancement
Solvent-free Organic Synthesis
Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed
i n t o a p o w e r f u l m e t h o d o l o g y a s i t
reduces the amount of toxic waste produced and therefore becomes less harmful to the
e n v i r o n m e n t
Solvent-free Organic Synthesis
bull Clean and efficient synthesis
bull Economic and environmental impact
bull Fast reaction kinetics
Best solvent is no solvent
Adolf von Baeyer
Synthesis of Indigo
Towardsbenign
synthesiswith
remarkableVersatility
G W V Cave C LRaston J L ScottChemCommun
2001 2159
Solid-State General Oxidation with with Urea H2O2 Complex
R S Varma and K P Naiker Org Letters 1999 1 189
Solvent-free Oxidative Preparation of Heterocycles
Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157
Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones
Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199
Solvent-free Reduction
F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245
Carbon-Carbon Bond Formation
Toda Tanada Iwata J Org Chem 1989 54 3007
Solventless Photo Coupling and Photo Rearangements
Y Ito S Endo J Am Chem Soc 1997 119 5974
Shin Keating Maribay J Am Chem Soc 1996 118 7626
Solvent - Free Condensation
Z Gross et al Org Letters 1999 1 599
Solid-State Preparationof Dumb-bell-shaped C120
Wang Komatsu Murata Shiro Nature 1997 387 583
Advantages of Solid Mineral Supports(Alumina Silica and Clay)
Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area
The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity
Solids are generally easier and safer to handle than liquids or gaseous reagents
Inexpensive recyclable and environmentally benign nature
Solid-supported Solventless Reactions
bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation
R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43
Supported ReactionsUsing Microwaves
E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945
Microwave-Assisted Deacetylationon Alumina
Varma et al J Chem Soc Perkin Trans 1 999 (1993)
Deprotection of Benzyl Esters viaMicrowave Thermolysis
A practical alternative to traditional catalytic hydrogenation
Varma et al Tetrahedron Lett 34 4603 (1993)
Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of
Carbonyl Compounds Using Microwaves
Varma Meshram Tetrahedron Lett 38 5427 (1997)
Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm
PersulfatendashClay using Microwave and Ultrasonic Irradiation
Varma Meshram Tetrahedron Lett 38 7973 (1997)
Solid Supported Solvent-freeOxidation under MW
Varma et al Tetrahedron Lett 1997 38 2043 and 7823
Solvent-free Reduction Using MW
Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction
Varma et al Tetrahedron Lett 1997 38 4337
Hydrodechlorination under continuous MW
Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)
Synthesis of Heterocyclic Compounds
Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)
Synthesis of Heterocyclic Compounds
Organometallic Reactions
Rearrangements
Rearrangements
INDOLIZINES
Heterocyclic systems 10- electronics
Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine
Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds
N
1
2
34567
8R2
R3
R1
Why interest for indolizinic products
Strong fluorescent properties luminiscent products luminiscent products
Potentially fluorescents marker Potentially laserldquoscintillatersrdquo
bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999
Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )
Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2
ldquoCalcium-entryrdquo blockers
Indolizines by irradiation with microwaves in MCR
RBr
O+
N
R1 R2+N
R2
R1
COR
AcOAl2O3 Mw
R=Ph p-Tolil Stiril
R1= H COOMeR2= COOEt COOMe
Asymmetric indolizines by irradiation with microwaves in MCR
R1
O
Cl+ R2
N NEtOOC
OOMe
Br BrN N
EtOOC
COR1
R2COR1
R2
OOMe
2 [Pd(PPh3)2Cl24 CuI
20 echiv Et3N THF tc 2h
R1=Ph 4-OMe-C6H4R2= Ph
U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003
A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new indolizines
[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical
II
IHH
COORCOOR
N C C
O
R2NCC
O
R1
(B)
(A)
R1
O
C C N R2
O
CCN
H H
ROOC COOR
R1
O
C C N R2
O
CCN
COOR COOR
ROOC COOR
2
2 ROOC C C COOR
R1
O
C CH N R2
O
CCHN
H H
N NCH CHC C
O O
R1 R2
- 2 HX TEAanhydrous solvents
X-
X-
N NCH2 CH2C C
O O
R1 R2
C C COORH
R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5
Y=H NO2 OCH3 CH3 Cl BrX=Br Cl
bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998
bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001
bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004
bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new substituted pyridinium-indolizines
Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate
COO NO2CHC
N NH3C
OR
I IN NH3C
OR
IN NH3C
OR
I
H
KFNMP
-HI
NMP
95oC 30 min
N NH3CO
RN NH3C
O
R
O OO
NO2
O
NO2
-2[H]-2[H]
II
I II
N NH3CO
R
O O
NO2
IN NH3C
O
R
O O
NO2
I
(9a-d)(10a-d)
(15a-d)
(A) (B)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
12
34
56
78 9
10
11
12 3
4
56
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Multimodal instrument
+ Alta densitagrave drsquoenergia (maggior potenza disponibile)+ Maggiori volumi processabili (cavitagrave a MW piugrave grande)+ No Onde Stazionarie (No Hot-spots)+ Semplice Scale-up- Volume minimo processabile
Monomodal Vs Multimodal
Monomodal Vs Multimodal
Thermal Effects
bullMore efficient energetic coupling of solvent with microwaves
promotes higher rate of temperature increase
bull Inverted heat transfer volumetric
bull ldquoHot spotsrdquo in monomode microwaves
bull Selective on properties of material (solvents catalysts
reagents intermediates products susceptors)
Recent Applications of Microwave-Assisted Synthesis-MAOS
Hydrolysis of benzamide
thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)
The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions
R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958
Solvent-free Reactions or Solid-Solid Reactions
ldquoNo reaction proceeds without solventrdquo
Aristotle
Solventless syntheses
Green chemistry enabled advancement
Solvent-free Organic Synthesis
Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed
i n t o a p o w e r f u l m e t h o d o l o g y a s i t
reduces the amount of toxic waste produced and therefore becomes less harmful to the
e n v i r o n m e n t
Solvent-free Organic Synthesis
bull Clean and efficient synthesis
bull Economic and environmental impact
bull Fast reaction kinetics
Best solvent is no solvent
Adolf von Baeyer
Synthesis of Indigo
Towardsbenign
synthesiswith
remarkableVersatility
G W V Cave C LRaston J L ScottChemCommun
2001 2159
Solid-State General Oxidation with with Urea H2O2 Complex
R S Varma and K P Naiker Org Letters 1999 1 189
Solvent-free Oxidative Preparation of Heterocycles
Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157
Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones
Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199
Solvent-free Reduction
F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245
Carbon-Carbon Bond Formation
Toda Tanada Iwata J Org Chem 1989 54 3007
Solventless Photo Coupling and Photo Rearangements
Y Ito S Endo J Am Chem Soc 1997 119 5974
Shin Keating Maribay J Am Chem Soc 1996 118 7626
Solvent - Free Condensation
Z Gross et al Org Letters 1999 1 599
Solid-State Preparationof Dumb-bell-shaped C120
Wang Komatsu Murata Shiro Nature 1997 387 583
Advantages of Solid Mineral Supports(Alumina Silica and Clay)
Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area
The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity
Solids are generally easier and safer to handle than liquids or gaseous reagents
Inexpensive recyclable and environmentally benign nature
Solid-supported Solventless Reactions
bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation
R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43
Supported ReactionsUsing Microwaves
E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945
Microwave-Assisted Deacetylationon Alumina
Varma et al J Chem Soc Perkin Trans 1 999 (1993)
Deprotection of Benzyl Esters viaMicrowave Thermolysis
A practical alternative to traditional catalytic hydrogenation
Varma et al Tetrahedron Lett 34 4603 (1993)
Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of
Carbonyl Compounds Using Microwaves
Varma Meshram Tetrahedron Lett 38 5427 (1997)
Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm
PersulfatendashClay using Microwave and Ultrasonic Irradiation
Varma Meshram Tetrahedron Lett 38 7973 (1997)
Solid Supported Solvent-freeOxidation under MW
Varma et al Tetrahedron Lett 1997 38 2043 and 7823
Solvent-free Reduction Using MW
Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction
Varma et al Tetrahedron Lett 1997 38 4337
Hydrodechlorination under continuous MW
Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)
Synthesis of Heterocyclic Compounds
Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)
Synthesis of Heterocyclic Compounds
Organometallic Reactions
Rearrangements
Rearrangements
INDOLIZINES
Heterocyclic systems 10- electronics
Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine
Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds
N
1
2
34567
8R2
R3
R1
Why interest for indolizinic products
Strong fluorescent properties luminiscent products luminiscent products
Potentially fluorescents marker Potentially laserldquoscintillatersrdquo
bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999
Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )
Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2
ldquoCalcium-entryrdquo blockers
Indolizines by irradiation with microwaves in MCR
RBr
O+
N
R1 R2+N
R2
R1
COR
AcOAl2O3 Mw
R=Ph p-Tolil Stiril
R1= H COOMeR2= COOEt COOMe
Asymmetric indolizines by irradiation with microwaves in MCR
R1
O
Cl+ R2
N NEtOOC
OOMe
Br BrN N
EtOOC
COR1
R2COR1
R2
OOMe
2 [Pd(PPh3)2Cl24 CuI
20 echiv Et3N THF tc 2h
R1=Ph 4-OMe-C6H4R2= Ph
U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003
A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new indolizines
[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical
II
IHH
COORCOOR
N C C
O
R2NCC
O
R1
(B)
(A)
R1
O
C C N R2
O
CCN
H H
ROOC COOR
R1
O
C C N R2
O
CCN
COOR COOR
ROOC COOR
2
2 ROOC C C COOR
R1
O
C CH N R2
O
CCHN
H H
N NCH CHC C
O O
R1 R2
- 2 HX TEAanhydrous solvents
X-
X-
N NCH2 CH2C C
O O
R1 R2
C C COORH
R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5
Y=H NO2 OCH3 CH3 Cl BrX=Br Cl
bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998
bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001
bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004
bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new substituted pyridinium-indolizines
Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate
COO NO2CHC
N NH3C
OR
I IN NH3C
OR
IN NH3C
OR
I
H
KFNMP
-HI
NMP
95oC 30 min
N NH3CO
RN NH3C
O
R
O OO
NO2
O
NO2
-2[H]-2[H]
II
I II
N NH3CO
R
O O
NO2
IN NH3C
O
R
O O
NO2
I
(9a-d)(10a-d)
(15a-d)
(A) (B)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
12
34
56
78 9
10
11
12 3
4
56
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Monomodal Vs Multimodal
Monomodal Vs Multimodal
Thermal Effects
bullMore efficient energetic coupling of solvent with microwaves
promotes higher rate of temperature increase
bull Inverted heat transfer volumetric
bull ldquoHot spotsrdquo in monomode microwaves
bull Selective on properties of material (solvents catalysts
reagents intermediates products susceptors)
Recent Applications of Microwave-Assisted Synthesis-MAOS
Hydrolysis of benzamide
thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)
The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions
R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958
Solvent-free Reactions or Solid-Solid Reactions
ldquoNo reaction proceeds without solventrdquo
Aristotle
Solventless syntheses
Green chemistry enabled advancement
Solvent-free Organic Synthesis
Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed
i n t o a p o w e r f u l m e t h o d o l o g y a s i t
reduces the amount of toxic waste produced and therefore becomes less harmful to the
e n v i r o n m e n t
Solvent-free Organic Synthesis
bull Clean and efficient synthesis
bull Economic and environmental impact
bull Fast reaction kinetics
Best solvent is no solvent
Adolf von Baeyer
Synthesis of Indigo
Towardsbenign
synthesiswith
remarkableVersatility
G W V Cave C LRaston J L ScottChemCommun
2001 2159
Solid-State General Oxidation with with Urea H2O2 Complex
R S Varma and K P Naiker Org Letters 1999 1 189
Solvent-free Oxidative Preparation of Heterocycles
Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157
Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones
Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199
Solvent-free Reduction
F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245
Carbon-Carbon Bond Formation
Toda Tanada Iwata J Org Chem 1989 54 3007
Solventless Photo Coupling and Photo Rearangements
Y Ito S Endo J Am Chem Soc 1997 119 5974
Shin Keating Maribay J Am Chem Soc 1996 118 7626
Solvent - Free Condensation
Z Gross et al Org Letters 1999 1 599
Solid-State Preparationof Dumb-bell-shaped C120
Wang Komatsu Murata Shiro Nature 1997 387 583
Advantages of Solid Mineral Supports(Alumina Silica and Clay)
Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area
The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity
Solids are generally easier and safer to handle than liquids or gaseous reagents
Inexpensive recyclable and environmentally benign nature
Solid-supported Solventless Reactions
bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation
R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43
Supported ReactionsUsing Microwaves
E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945
Microwave-Assisted Deacetylationon Alumina
Varma et al J Chem Soc Perkin Trans 1 999 (1993)
Deprotection of Benzyl Esters viaMicrowave Thermolysis
A practical alternative to traditional catalytic hydrogenation
Varma et al Tetrahedron Lett 34 4603 (1993)
Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of
Carbonyl Compounds Using Microwaves
Varma Meshram Tetrahedron Lett 38 5427 (1997)
Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm
PersulfatendashClay using Microwave and Ultrasonic Irradiation
Varma Meshram Tetrahedron Lett 38 7973 (1997)
Solid Supported Solvent-freeOxidation under MW
Varma et al Tetrahedron Lett 1997 38 2043 and 7823
Solvent-free Reduction Using MW
Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction
Varma et al Tetrahedron Lett 1997 38 4337
Hydrodechlorination under continuous MW
Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)
Synthesis of Heterocyclic Compounds
Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)
Synthesis of Heterocyclic Compounds
Organometallic Reactions
Rearrangements
Rearrangements
INDOLIZINES
Heterocyclic systems 10- electronics
Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine
Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds
N
1
2
34567
8R2
R3
R1
Why interest for indolizinic products
Strong fluorescent properties luminiscent products luminiscent products
Potentially fluorescents marker Potentially laserldquoscintillatersrdquo
bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999
Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )
Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2
ldquoCalcium-entryrdquo blockers
Indolizines by irradiation with microwaves in MCR
RBr
O+
N
R1 R2+N
R2
R1
COR
AcOAl2O3 Mw
R=Ph p-Tolil Stiril
R1= H COOMeR2= COOEt COOMe
Asymmetric indolizines by irradiation with microwaves in MCR
R1
O
Cl+ R2
N NEtOOC
OOMe
Br BrN N
EtOOC
COR1
R2COR1
R2
OOMe
2 [Pd(PPh3)2Cl24 CuI
20 echiv Et3N THF tc 2h
R1=Ph 4-OMe-C6H4R2= Ph
U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003
A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new indolizines
[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical
II
IHH
COORCOOR
N C C
O
R2NCC
O
R1
(B)
(A)
R1
O
C C N R2
O
CCN
H H
ROOC COOR
R1
O
C C N R2
O
CCN
COOR COOR
ROOC COOR
2
2 ROOC C C COOR
R1
O
C CH N R2
O
CCHN
H H
N NCH CHC C
O O
R1 R2
- 2 HX TEAanhydrous solvents
X-
X-
N NCH2 CH2C C
O O
R1 R2
C C COORH
R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5
Y=H NO2 OCH3 CH3 Cl BrX=Br Cl
bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998
bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001
bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004
bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new substituted pyridinium-indolizines
Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate
COO NO2CHC
N NH3C
OR
I IN NH3C
OR
IN NH3C
OR
I
H
KFNMP
-HI
NMP
95oC 30 min
N NH3CO
RN NH3C
O
R
O OO
NO2
O
NO2
-2[H]-2[H]
II
I II
N NH3CO
R
O O
NO2
IN NH3C
O
R
O O
NO2
I
(9a-d)(10a-d)
(15a-d)
(A) (B)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
12
34
56
78 9
10
11
12 3
4
56
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Monomodal Vs Multimodal
Thermal Effects
bullMore efficient energetic coupling of solvent with microwaves
promotes higher rate of temperature increase
bull Inverted heat transfer volumetric
bull ldquoHot spotsrdquo in monomode microwaves
bull Selective on properties of material (solvents catalysts
reagents intermediates products susceptors)
Recent Applications of Microwave-Assisted Synthesis-MAOS
Hydrolysis of benzamide
thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)
The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions
R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958
Solvent-free Reactions or Solid-Solid Reactions
ldquoNo reaction proceeds without solventrdquo
Aristotle
Solventless syntheses
Green chemistry enabled advancement
Solvent-free Organic Synthesis
Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed
i n t o a p o w e r f u l m e t h o d o l o g y a s i t
reduces the amount of toxic waste produced and therefore becomes less harmful to the
e n v i r o n m e n t
Solvent-free Organic Synthesis
bull Clean and efficient synthesis
bull Economic and environmental impact
bull Fast reaction kinetics
Best solvent is no solvent
Adolf von Baeyer
Synthesis of Indigo
Towardsbenign
synthesiswith
remarkableVersatility
G W V Cave C LRaston J L ScottChemCommun
2001 2159
Solid-State General Oxidation with with Urea H2O2 Complex
R S Varma and K P Naiker Org Letters 1999 1 189
Solvent-free Oxidative Preparation of Heterocycles
Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157
Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones
Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199
Solvent-free Reduction
F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245
Carbon-Carbon Bond Formation
Toda Tanada Iwata J Org Chem 1989 54 3007
Solventless Photo Coupling and Photo Rearangements
Y Ito S Endo J Am Chem Soc 1997 119 5974
Shin Keating Maribay J Am Chem Soc 1996 118 7626
Solvent - Free Condensation
Z Gross et al Org Letters 1999 1 599
Solid-State Preparationof Dumb-bell-shaped C120
Wang Komatsu Murata Shiro Nature 1997 387 583
Advantages of Solid Mineral Supports(Alumina Silica and Clay)
Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area
The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity
Solids are generally easier and safer to handle than liquids or gaseous reagents
Inexpensive recyclable and environmentally benign nature
Solid-supported Solventless Reactions
bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation
R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43
Supported ReactionsUsing Microwaves
E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945
Microwave-Assisted Deacetylationon Alumina
Varma et al J Chem Soc Perkin Trans 1 999 (1993)
Deprotection of Benzyl Esters viaMicrowave Thermolysis
A practical alternative to traditional catalytic hydrogenation
Varma et al Tetrahedron Lett 34 4603 (1993)
Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of
Carbonyl Compounds Using Microwaves
Varma Meshram Tetrahedron Lett 38 5427 (1997)
Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm
PersulfatendashClay using Microwave and Ultrasonic Irradiation
Varma Meshram Tetrahedron Lett 38 7973 (1997)
Solid Supported Solvent-freeOxidation under MW
Varma et al Tetrahedron Lett 1997 38 2043 and 7823
Solvent-free Reduction Using MW
Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction
Varma et al Tetrahedron Lett 1997 38 4337
Hydrodechlorination under continuous MW
Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)
Synthesis of Heterocyclic Compounds
Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)
Synthesis of Heterocyclic Compounds
Organometallic Reactions
Rearrangements
Rearrangements
INDOLIZINES
Heterocyclic systems 10- electronics
Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine
Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds
N
1
2
34567
8R2
R3
R1
Why interest for indolizinic products
Strong fluorescent properties luminiscent products luminiscent products
Potentially fluorescents marker Potentially laserldquoscintillatersrdquo
bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999
Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )
Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2
ldquoCalcium-entryrdquo blockers
Indolizines by irradiation with microwaves in MCR
RBr
O+
N
R1 R2+N
R2
R1
COR
AcOAl2O3 Mw
R=Ph p-Tolil Stiril
R1= H COOMeR2= COOEt COOMe
Asymmetric indolizines by irradiation with microwaves in MCR
R1
O
Cl+ R2
N NEtOOC
OOMe
Br BrN N
EtOOC
COR1
R2COR1
R2
OOMe
2 [Pd(PPh3)2Cl24 CuI
20 echiv Et3N THF tc 2h
R1=Ph 4-OMe-C6H4R2= Ph
U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003
A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new indolizines
[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical
II
IHH
COORCOOR
N C C
O
R2NCC
O
R1
(B)
(A)
R1
O
C C N R2
O
CCN
H H
ROOC COOR
R1
O
C C N R2
O
CCN
COOR COOR
ROOC COOR
2
2 ROOC C C COOR
R1
O
C CH N R2
O
CCHN
H H
N NCH CHC C
O O
R1 R2
- 2 HX TEAanhydrous solvents
X-
X-
N NCH2 CH2C C
O O
R1 R2
C C COORH
R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5
Y=H NO2 OCH3 CH3 Cl BrX=Br Cl
bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998
bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001
bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004
bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new substituted pyridinium-indolizines
Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate
COO NO2CHC
N NH3C
OR
I IN NH3C
OR
IN NH3C
OR
I
H
KFNMP
-HI
NMP
95oC 30 min
N NH3CO
RN NH3C
O
R
O OO
NO2
O
NO2
-2[H]-2[H]
II
I II
N NH3CO
R
O O
NO2
IN NH3C
O
R
O O
NO2
I
(9a-d)(10a-d)
(15a-d)
(A) (B)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
12
34
56
78 9
10
11
12 3
4
56
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Thermal Effects
bullMore efficient energetic coupling of solvent with microwaves
promotes higher rate of temperature increase
bull Inverted heat transfer volumetric
bull ldquoHot spotsrdquo in monomode microwaves
bull Selective on properties of material (solvents catalysts
reagents intermediates products susceptors)
Recent Applications of Microwave-Assisted Synthesis-MAOS
Hydrolysis of benzamide
thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)
The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions
R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958
Solvent-free Reactions or Solid-Solid Reactions
ldquoNo reaction proceeds without solventrdquo
Aristotle
Solventless syntheses
Green chemistry enabled advancement
Solvent-free Organic Synthesis
Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed
i n t o a p o w e r f u l m e t h o d o l o g y a s i t
reduces the amount of toxic waste produced and therefore becomes less harmful to the
e n v i r o n m e n t
Solvent-free Organic Synthesis
bull Clean and efficient synthesis
bull Economic and environmental impact
bull Fast reaction kinetics
Best solvent is no solvent
Adolf von Baeyer
Synthesis of Indigo
Towardsbenign
synthesiswith
remarkableVersatility
G W V Cave C LRaston J L ScottChemCommun
2001 2159
Solid-State General Oxidation with with Urea H2O2 Complex
R S Varma and K P Naiker Org Letters 1999 1 189
Solvent-free Oxidative Preparation of Heterocycles
Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157
Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones
Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199
Solvent-free Reduction
F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245
Carbon-Carbon Bond Formation
Toda Tanada Iwata J Org Chem 1989 54 3007
Solventless Photo Coupling and Photo Rearangements
Y Ito S Endo J Am Chem Soc 1997 119 5974
Shin Keating Maribay J Am Chem Soc 1996 118 7626
Solvent - Free Condensation
Z Gross et al Org Letters 1999 1 599
Solid-State Preparationof Dumb-bell-shaped C120
Wang Komatsu Murata Shiro Nature 1997 387 583
Advantages of Solid Mineral Supports(Alumina Silica and Clay)
Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area
The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity
Solids are generally easier and safer to handle than liquids or gaseous reagents
Inexpensive recyclable and environmentally benign nature
Solid-supported Solventless Reactions
bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation
R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43
Supported ReactionsUsing Microwaves
E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945
Microwave-Assisted Deacetylationon Alumina
Varma et al J Chem Soc Perkin Trans 1 999 (1993)
Deprotection of Benzyl Esters viaMicrowave Thermolysis
A practical alternative to traditional catalytic hydrogenation
Varma et al Tetrahedron Lett 34 4603 (1993)
Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of
Carbonyl Compounds Using Microwaves
Varma Meshram Tetrahedron Lett 38 5427 (1997)
Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm
PersulfatendashClay using Microwave and Ultrasonic Irradiation
Varma Meshram Tetrahedron Lett 38 7973 (1997)
Solid Supported Solvent-freeOxidation under MW
Varma et al Tetrahedron Lett 1997 38 2043 and 7823
Solvent-free Reduction Using MW
Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction
Varma et al Tetrahedron Lett 1997 38 4337
Hydrodechlorination under continuous MW
Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)
Synthesis of Heterocyclic Compounds
Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)
Synthesis of Heterocyclic Compounds
Organometallic Reactions
Rearrangements
Rearrangements
INDOLIZINES
Heterocyclic systems 10- electronics
Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine
Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds
N
1
2
34567
8R2
R3
R1
Why interest for indolizinic products
Strong fluorescent properties luminiscent products luminiscent products
Potentially fluorescents marker Potentially laserldquoscintillatersrdquo
bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999
Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )
Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2
ldquoCalcium-entryrdquo blockers
Indolizines by irradiation with microwaves in MCR
RBr
O+
N
R1 R2+N
R2
R1
COR
AcOAl2O3 Mw
R=Ph p-Tolil Stiril
R1= H COOMeR2= COOEt COOMe
Asymmetric indolizines by irradiation with microwaves in MCR
R1
O
Cl+ R2
N NEtOOC
OOMe
Br BrN N
EtOOC
COR1
R2COR1
R2
OOMe
2 [Pd(PPh3)2Cl24 CuI
20 echiv Et3N THF tc 2h
R1=Ph 4-OMe-C6H4R2= Ph
U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003
A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new indolizines
[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical
II
IHH
COORCOOR
N C C
O
R2NCC
O
R1
(B)
(A)
R1
O
C C N R2
O
CCN
H H
ROOC COOR
R1
O
C C N R2
O
CCN
COOR COOR
ROOC COOR
2
2 ROOC C C COOR
R1
O
C CH N R2
O
CCHN
H H
N NCH CHC C
O O
R1 R2
- 2 HX TEAanhydrous solvents
X-
X-
N NCH2 CH2C C
O O
R1 R2
C C COORH
R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5
Y=H NO2 OCH3 CH3 Cl BrX=Br Cl
bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998
bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001
bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004
bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new substituted pyridinium-indolizines
Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate
COO NO2CHC
N NH3C
OR
I IN NH3C
OR
IN NH3C
OR
I
H
KFNMP
-HI
NMP
95oC 30 min
N NH3CO
RN NH3C
O
R
O OO
NO2
O
NO2
-2[H]-2[H]
II
I II
N NH3CO
R
O O
NO2
IN NH3C
O
R
O O
NO2
I
(9a-d)(10a-d)
(15a-d)
(A) (B)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
12
34
56
78 9
10
11
12 3
4
56
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Recent Applications of Microwave-Assisted Synthesis-MAOS
Hydrolysis of benzamide
thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)
The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions
R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958
Solvent-free Reactions or Solid-Solid Reactions
ldquoNo reaction proceeds without solventrdquo
Aristotle
Solventless syntheses
Green chemistry enabled advancement
Solvent-free Organic Synthesis
Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed
i n t o a p o w e r f u l m e t h o d o l o g y a s i t
reduces the amount of toxic waste produced and therefore becomes less harmful to the
e n v i r o n m e n t
Solvent-free Organic Synthesis
bull Clean and efficient synthesis
bull Economic and environmental impact
bull Fast reaction kinetics
Best solvent is no solvent
Adolf von Baeyer
Synthesis of Indigo
Towardsbenign
synthesiswith
remarkableVersatility
G W V Cave C LRaston J L ScottChemCommun
2001 2159
Solid-State General Oxidation with with Urea H2O2 Complex
R S Varma and K P Naiker Org Letters 1999 1 189
Solvent-free Oxidative Preparation of Heterocycles
Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157
Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones
Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199
Solvent-free Reduction
F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245
Carbon-Carbon Bond Formation
Toda Tanada Iwata J Org Chem 1989 54 3007
Solventless Photo Coupling and Photo Rearangements
Y Ito S Endo J Am Chem Soc 1997 119 5974
Shin Keating Maribay J Am Chem Soc 1996 118 7626
Solvent - Free Condensation
Z Gross et al Org Letters 1999 1 599
Solid-State Preparationof Dumb-bell-shaped C120
Wang Komatsu Murata Shiro Nature 1997 387 583
Advantages of Solid Mineral Supports(Alumina Silica and Clay)
Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area
The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity
Solids are generally easier and safer to handle than liquids or gaseous reagents
Inexpensive recyclable and environmentally benign nature
Solid-supported Solventless Reactions
bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation
R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43
Supported ReactionsUsing Microwaves
E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945
Microwave-Assisted Deacetylationon Alumina
Varma et al J Chem Soc Perkin Trans 1 999 (1993)
Deprotection of Benzyl Esters viaMicrowave Thermolysis
A practical alternative to traditional catalytic hydrogenation
Varma et al Tetrahedron Lett 34 4603 (1993)
Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of
Carbonyl Compounds Using Microwaves
Varma Meshram Tetrahedron Lett 38 5427 (1997)
Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm
PersulfatendashClay using Microwave and Ultrasonic Irradiation
Varma Meshram Tetrahedron Lett 38 7973 (1997)
Solid Supported Solvent-freeOxidation under MW
Varma et al Tetrahedron Lett 1997 38 2043 and 7823
Solvent-free Reduction Using MW
Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction
Varma et al Tetrahedron Lett 1997 38 4337
Hydrodechlorination under continuous MW
Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)
Synthesis of Heterocyclic Compounds
Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)
Synthesis of Heterocyclic Compounds
Organometallic Reactions
Rearrangements
Rearrangements
INDOLIZINES
Heterocyclic systems 10- electronics
Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine
Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds
N
1
2
34567
8R2
R3
R1
Why interest for indolizinic products
Strong fluorescent properties luminiscent products luminiscent products
Potentially fluorescents marker Potentially laserldquoscintillatersrdquo
bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999
Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )
Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2
ldquoCalcium-entryrdquo blockers
Indolizines by irradiation with microwaves in MCR
RBr
O+
N
R1 R2+N
R2
R1
COR
AcOAl2O3 Mw
R=Ph p-Tolil Stiril
R1= H COOMeR2= COOEt COOMe
Asymmetric indolizines by irradiation with microwaves in MCR
R1
O
Cl+ R2
N NEtOOC
OOMe
Br BrN N
EtOOC
COR1
R2COR1
R2
OOMe
2 [Pd(PPh3)2Cl24 CuI
20 echiv Et3N THF tc 2h
R1=Ph 4-OMe-C6H4R2= Ph
U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003
A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new indolizines
[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical
II
IHH
COORCOOR
N C C
O
R2NCC
O
R1
(B)
(A)
R1
O
C C N R2
O
CCN
H H
ROOC COOR
R1
O
C C N R2
O
CCN
COOR COOR
ROOC COOR
2
2 ROOC C C COOR
R1
O
C CH N R2
O
CCHN
H H
N NCH CHC C
O O
R1 R2
- 2 HX TEAanhydrous solvents
X-
X-
N NCH2 CH2C C
O O
R1 R2
C C COORH
R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5
Y=H NO2 OCH3 CH3 Cl BrX=Br Cl
bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998
bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001
bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004
bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new substituted pyridinium-indolizines
Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate
COO NO2CHC
N NH3C
OR
I IN NH3C
OR
IN NH3C
OR
I
H
KFNMP
-HI
NMP
95oC 30 min
N NH3CO
RN NH3C
O
R
O OO
NO2
O
NO2
-2[H]-2[H]
II
I II
N NH3CO
R
O O
NO2
IN NH3C
O
R
O O
NO2
I
(9a-d)(10a-d)
(15a-d)
(A) (B)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
12
34
56
78 9
10
11
12 3
4
56
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Hydrolysis of benzamide
thermal 1 h 90 yield (reflux)MW 10 min 99 yield (sealed vessel)
The first reports on the use of microwave heating to accelerate organic chemical transformations (MAOS) were published by the groups of Richard Gedye (and Raymond J GiguereGeorge Majetich in 1986 In those early days experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurements The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions
R Gedye F Smith K Westaway H Ali L Baldisera L Laberge J Rousell Tetrahedron Lett 1986 27 279ndash282 R J Giguere T L Bray S M DuncanG Majetich Tetrahedron Lett 1986 27 4945ndash4958
Solvent-free Reactions or Solid-Solid Reactions
ldquoNo reaction proceeds without solventrdquo
Aristotle
Solventless syntheses
Green chemistry enabled advancement
Solvent-free Organic Synthesis
Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed
i n t o a p o w e r f u l m e t h o d o l o g y a s i t
reduces the amount of toxic waste produced and therefore becomes less harmful to the
e n v i r o n m e n t
Solvent-free Organic Synthesis
bull Clean and efficient synthesis
bull Economic and environmental impact
bull Fast reaction kinetics
Best solvent is no solvent
Adolf von Baeyer
Synthesis of Indigo
Towardsbenign
synthesiswith
remarkableVersatility
G W V Cave C LRaston J L ScottChemCommun
2001 2159
Solid-State General Oxidation with with Urea H2O2 Complex
R S Varma and K P Naiker Org Letters 1999 1 189
Solvent-free Oxidative Preparation of Heterocycles
Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157
Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones
Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199
Solvent-free Reduction
F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245
Carbon-Carbon Bond Formation
Toda Tanada Iwata J Org Chem 1989 54 3007
Solventless Photo Coupling and Photo Rearangements
Y Ito S Endo J Am Chem Soc 1997 119 5974
Shin Keating Maribay J Am Chem Soc 1996 118 7626
Solvent - Free Condensation
Z Gross et al Org Letters 1999 1 599
Solid-State Preparationof Dumb-bell-shaped C120
Wang Komatsu Murata Shiro Nature 1997 387 583
Advantages of Solid Mineral Supports(Alumina Silica and Clay)
Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area
The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity
Solids are generally easier and safer to handle than liquids or gaseous reagents
Inexpensive recyclable and environmentally benign nature
Solid-supported Solventless Reactions
bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation
R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43
Supported ReactionsUsing Microwaves
E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945
Microwave-Assisted Deacetylationon Alumina
Varma et al J Chem Soc Perkin Trans 1 999 (1993)
Deprotection of Benzyl Esters viaMicrowave Thermolysis
A practical alternative to traditional catalytic hydrogenation
Varma et al Tetrahedron Lett 34 4603 (1993)
Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of
Carbonyl Compounds Using Microwaves
Varma Meshram Tetrahedron Lett 38 5427 (1997)
Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm
PersulfatendashClay using Microwave and Ultrasonic Irradiation
Varma Meshram Tetrahedron Lett 38 7973 (1997)
Solid Supported Solvent-freeOxidation under MW
Varma et al Tetrahedron Lett 1997 38 2043 and 7823
Solvent-free Reduction Using MW
Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction
Varma et al Tetrahedron Lett 1997 38 4337
Hydrodechlorination under continuous MW
Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)
Synthesis of Heterocyclic Compounds
Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)
Synthesis of Heterocyclic Compounds
Organometallic Reactions
Rearrangements
Rearrangements
INDOLIZINES
Heterocyclic systems 10- electronics
Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine
Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds
N
1
2
34567
8R2
R3
R1
Why interest for indolizinic products
Strong fluorescent properties luminiscent products luminiscent products
Potentially fluorescents marker Potentially laserldquoscintillatersrdquo
bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999
Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )
Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2
ldquoCalcium-entryrdquo blockers
Indolizines by irradiation with microwaves in MCR
RBr
O+
N
R1 R2+N
R2
R1
COR
AcOAl2O3 Mw
R=Ph p-Tolil Stiril
R1= H COOMeR2= COOEt COOMe
Asymmetric indolizines by irradiation with microwaves in MCR
R1
O
Cl+ R2
N NEtOOC
OOMe
Br BrN N
EtOOC
COR1
R2COR1
R2
OOMe
2 [Pd(PPh3)2Cl24 CuI
20 echiv Et3N THF tc 2h
R1=Ph 4-OMe-C6H4R2= Ph
U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003
A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new indolizines
[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical
II
IHH
COORCOOR
N C C
O
R2NCC
O
R1
(B)
(A)
R1
O
C C N R2
O
CCN
H H
ROOC COOR
R1
O
C C N R2
O
CCN
COOR COOR
ROOC COOR
2
2 ROOC C C COOR
R1
O
C CH N R2
O
CCHN
H H
N NCH CHC C
O O
R1 R2
- 2 HX TEAanhydrous solvents
X-
X-
N NCH2 CH2C C
O O
R1 R2
C C COORH
R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5
Y=H NO2 OCH3 CH3 Cl BrX=Br Cl
bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998
bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001
bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004
bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new substituted pyridinium-indolizines
Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate
COO NO2CHC
N NH3C
OR
I IN NH3C
OR
IN NH3C
OR
I
H
KFNMP
-HI
NMP
95oC 30 min
N NH3CO
RN NH3C
O
R
O OO
NO2
O
NO2
-2[H]-2[H]
II
I II
N NH3CO
R
O O
NO2
IN NH3C
O
R
O O
NO2
I
(9a-d)(10a-d)
(15a-d)
(A) (B)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
12
34
56
78 9
10
11
12 3
4
56
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Solvent-free Reactions or Solid-Solid Reactions
ldquoNo reaction proceeds without solventrdquo
Aristotle
Solventless syntheses
Green chemistry enabled advancement
Solvent-free Organic Synthesis
Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed
i n t o a p o w e r f u l m e t h o d o l o g y a s i t
reduces the amount of toxic waste produced and therefore becomes less harmful to the
e n v i r o n m e n t
Solvent-free Organic Synthesis
bull Clean and efficient synthesis
bull Economic and environmental impact
bull Fast reaction kinetics
Best solvent is no solvent
Adolf von Baeyer
Synthesis of Indigo
Towardsbenign
synthesiswith
remarkableVersatility
G W V Cave C LRaston J L ScottChemCommun
2001 2159
Solid-State General Oxidation with with Urea H2O2 Complex
R S Varma and K P Naiker Org Letters 1999 1 189
Solvent-free Oxidative Preparation of Heterocycles
Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157
Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones
Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199
Solvent-free Reduction
F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245
Carbon-Carbon Bond Formation
Toda Tanada Iwata J Org Chem 1989 54 3007
Solventless Photo Coupling and Photo Rearangements
Y Ito S Endo J Am Chem Soc 1997 119 5974
Shin Keating Maribay J Am Chem Soc 1996 118 7626
Solvent - Free Condensation
Z Gross et al Org Letters 1999 1 599
Solid-State Preparationof Dumb-bell-shaped C120
Wang Komatsu Murata Shiro Nature 1997 387 583
Advantages of Solid Mineral Supports(Alumina Silica and Clay)
Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area
The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity
Solids are generally easier and safer to handle than liquids or gaseous reagents
Inexpensive recyclable and environmentally benign nature
Solid-supported Solventless Reactions
bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation
R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43
Supported ReactionsUsing Microwaves
E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945
Microwave-Assisted Deacetylationon Alumina
Varma et al J Chem Soc Perkin Trans 1 999 (1993)
Deprotection of Benzyl Esters viaMicrowave Thermolysis
A practical alternative to traditional catalytic hydrogenation
Varma et al Tetrahedron Lett 34 4603 (1993)
Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of
Carbonyl Compounds Using Microwaves
Varma Meshram Tetrahedron Lett 38 5427 (1997)
Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm
PersulfatendashClay using Microwave and Ultrasonic Irradiation
Varma Meshram Tetrahedron Lett 38 7973 (1997)
Solid Supported Solvent-freeOxidation under MW
Varma et al Tetrahedron Lett 1997 38 2043 and 7823
Solvent-free Reduction Using MW
Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction
Varma et al Tetrahedron Lett 1997 38 4337
Hydrodechlorination under continuous MW
Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)
Synthesis of Heterocyclic Compounds
Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)
Synthesis of Heterocyclic Compounds
Organometallic Reactions
Rearrangements
Rearrangements
INDOLIZINES
Heterocyclic systems 10- electronics
Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine
Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds
N
1
2
34567
8R2
R3
R1
Why interest for indolizinic products
Strong fluorescent properties luminiscent products luminiscent products
Potentially fluorescents marker Potentially laserldquoscintillatersrdquo
bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999
Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )
Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2
ldquoCalcium-entryrdquo blockers
Indolizines by irradiation with microwaves in MCR
RBr
O+
N
R1 R2+N
R2
R1
COR
AcOAl2O3 Mw
R=Ph p-Tolil Stiril
R1= H COOMeR2= COOEt COOMe
Asymmetric indolizines by irradiation with microwaves in MCR
R1
O
Cl+ R2
N NEtOOC
OOMe
Br BrN N
EtOOC
COR1
R2COR1
R2
OOMe
2 [Pd(PPh3)2Cl24 CuI
20 echiv Et3N THF tc 2h
R1=Ph 4-OMe-C6H4R2= Ph
U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003
A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new indolizines
[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical
II
IHH
COORCOOR
N C C
O
R2NCC
O
R1
(B)
(A)
R1
O
C C N R2
O
CCN
H H
ROOC COOR
R1
O
C C N R2
O
CCN
COOR COOR
ROOC COOR
2
2 ROOC C C COOR
R1
O
C CH N R2
O
CCHN
H H
N NCH CHC C
O O
R1 R2
- 2 HX TEAanhydrous solvents
X-
X-
N NCH2 CH2C C
O O
R1 R2
C C COORH
R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5
Y=H NO2 OCH3 CH3 Cl BrX=Br Cl
bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998
bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001
bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004
bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new substituted pyridinium-indolizines
Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate
COO NO2CHC
N NH3C
OR
I IN NH3C
OR
IN NH3C
OR
I
H
KFNMP
-HI
NMP
95oC 30 min
N NH3CO
RN NH3C
O
R
O OO
NO2
O
NO2
-2[H]-2[H]
II
I II
N NH3CO
R
O O
NO2
IN NH3C
O
R
O O
NO2
I
(9a-d)(10a-d)
(15a-d)
(A) (B)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
12
34
56
78 9
10
11
12 3
4
56
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Solvent-free Organic Synthesis
Chemical Synthesis w i t h o u t t h e u s e o f solvents has developed
i n t o a p o w e r f u l m e t h o d o l o g y a s i t
reduces the amount of toxic waste produced and therefore becomes less harmful to the
e n v i r o n m e n t
Solvent-free Organic Synthesis
bull Clean and efficient synthesis
bull Economic and environmental impact
bull Fast reaction kinetics
Best solvent is no solvent
Adolf von Baeyer
Synthesis of Indigo
Towardsbenign
synthesiswith
remarkableVersatility
G W V Cave C LRaston J L ScottChemCommun
2001 2159
Solid-State General Oxidation with with Urea H2O2 Complex
R S Varma and K P Naiker Org Letters 1999 1 189
Solvent-free Oxidative Preparation of Heterocycles
Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157
Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones
Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199
Solvent-free Reduction
F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245
Carbon-Carbon Bond Formation
Toda Tanada Iwata J Org Chem 1989 54 3007
Solventless Photo Coupling and Photo Rearangements
Y Ito S Endo J Am Chem Soc 1997 119 5974
Shin Keating Maribay J Am Chem Soc 1996 118 7626
Solvent - Free Condensation
Z Gross et al Org Letters 1999 1 599
Solid-State Preparationof Dumb-bell-shaped C120
Wang Komatsu Murata Shiro Nature 1997 387 583
Advantages of Solid Mineral Supports(Alumina Silica and Clay)
Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area
The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity
Solids are generally easier and safer to handle than liquids or gaseous reagents
Inexpensive recyclable and environmentally benign nature
Solid-supported Solventless Reactions
bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation
R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43
Supported ReactionsUsing Microwaves
E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945
Microwave-Assisted Deacetylationon Alumina
Varma et al J Chem Soc Perkin Trans 1 999 (1993)
Deprotection of Benzyl Esters viaMicrowave Thermolysis
A practical alternative to traditional catalytic hydrogenation
Varma et al Tetrahedron Lett 34 4603 (1993)
Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of
Carbonyl Compounds Using Microwaves
Varma Meshram Tetrahedron Lett 38 5427 (1997)
Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm
PersulfatendashClay using Microwave and Ultrasonic Irradiation
Varma Meshram Tetrahedron Lett 38 7973 (1997)
Solid Supported Solvent-freeOxidation under MW
Varma et al Tetrahedron Lett 1997 38 2043 and 7823
Solvent-free Reduction Using MW
Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction
Varma et al Tetrahedron Lett 1997 38 4337
Hydrodechlorination under continuous MW
Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)
Synthesis of Heterocyclic Compounds
Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)
Synthesis of Heterocyclic Compounds
Organometallic Reactions
Rearrangements
Rearrangements
INDOLIZINES
Heterocyclic systems 10- electronics
Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine
Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds
N
1
2
34567
8R2
R3
R1
Why interest for indolizinic products
Strong fluorescent properties luminiscent products luminiscent products
Potentially fluorescents marker Potentially laserldquoscintillatersrdquo
bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999
Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )
Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2
ldquoCalcium-entryrdquo blockers
Indolizines by irradiation with microwaves in MCR
RBr
O+
N
R1 R2+N
R2
R1
COR
AcOAl2O3 Mw
R=Ph p-Tolil Stiril
R1= H COOMeR2= COOEt COOMe
Asymmetric indolizines by irradiation with microwaves in MCR
R1
O
Cl+ R2
N NEtOOC
OOMe
Br BrN N
EtOOC
COR1
R2COR1
R2
OOMe
2 [Pd(PPh3)2Cl24 CuI
20 echiv Et3N THF tc 2h
R1=Ph 4-OMe-C6H4R2= Ph
U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003
A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new indolizines
[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical
II
IHH
COORCOOR
N C C
O
R2NCC
O
R1
(B)
(A)
R1
O
C C N R2
O
CCN
H H
ROOC COOR
R1
O
C C N R2
O
CCN
COOR COOR
ROOC COOR
2
2 ROOC C C COOR
R1
O
C CH N R2
O
CCHN
H H
N NCH CHC C
O O
R1 R2
- 2 HX TEAanhydrous solvents
X-
X-
N NCH2 CH2C C
O O
R1 R2
C C COORH
R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5
Y=H NO2 OCH3 CH3 Cl BrX=Br Cl
bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998
bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001
bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004
bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new substituted pyridinium-indolizines
Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate
COO NO2CHC
N NH3C
OR
I IN NH3C
OR
IN NH3C
OR
I
H
KFNMP
-HI
NMP
95oC 30 min
N NH3CO
RN NH3C
O
R
O OO
NO2
O
NO2
-2[H]-2[H]
II
I II
N NH3CO
R
O O
NO2
IN NH3C
O
R
O O
NO2
I
(9a-d)(10a-d)
(15a-d)
(A) (B)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
12
34
56
78 9
10
11
12 3
4
56
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Solvent-free Organic Synthesis
bull Clean and efficient synthesis
bull Economic and environmental impact
bull Fast reaction kinetics
Best solvent is no solvent
Adolf von Baeyer
Synthesis of Indigo
Towardsbenign
synthesiswith
remarkableVersatility
G W V Cave C LRaston J L ScottChemCommun
2001 2159
Solid-State General Oxidation with with Urea H2O2 Complex
R S Varma and K P Naiker Org Letters 1999 1 189
Solvent-free Oxidative Preparation of Heterocycles
Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157
Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones
Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199
Solvent-free Reduction
F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245
Carbon-Carbon Bond Formation
Toda Tanada Iwata J Org Chem 1989 54 3007
Solventless Photo Coupling and Photo Rearangements
Y Ito S Endo J Am Chem Soc 1997 119 5974
Shin Keating Maribay J Am Chem Soc 1996 118 7626
Solvent - Free Condensation
Z Gross et al Org Letters 1999 1 599
Solid-State Preparationof Dumb-bell-shaped C120
Wang Komatsu Murata Shiro Nature 1997 387 583
Advantages of Solid Mineral Supports(Alumina Silica and Clay)
Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area
The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity
Solids are generally easier and safer to handle than liquids or gaseous reagents
Inexpensive recyclable and environmentally benign nature
Solid-supported Solventless Reactions
bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation
R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43
Supported ReactionsUsing Microwaves
E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945
Microwave-Assisted Deacetylationon Alumina
Varma et al J Chem Soc Perkin Trans 1 999 (1993)
Deprotection of Benzyl Esters viaMicrowave Thermolysis
A practical alternative to traditional catalytic hydrogenation
Varma et al Tetrahedron Lett 34 4603 (1993)
Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of
Carbonyl Compounds Using Microwaves
Varma Meshram Tetrahedron Lett 38 5427 (1997)
Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm
PersulfatendashClay using Microwave and Ultrasonic Irradiation
Varma Meshram Tetrahedron Lett 38 7973 (1997)
Solid Supported Solvent-freeOxidation under MW
Varma et al Tetrahedron Lett 1997 38 2043 and 7823
Solvent-free Reduction Using MW
Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction
Varma et al Tetrahedron Lett 1997 38 4337
Hydrodechlorination under continuous MW
Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)
Synthesis of Heterocyclic Compounds
Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)
Synthesis of Heterocyclic Compounds
Organometallic Reactions
Rearrangements
Rearrangements
INDOLIZINES
Heterocyclic systems 10- electronics
Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine
Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds
N
1
2
34567
8R2
R3
R1
Why interest for indolizinic products
Strong fluorescent properties luminiscent products luminiscent products
Potentially fluorescents marker Potentially laserldquoscintillatersrdquo
bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999
Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )
Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2
ldquoCalcium-entryrdquo blockers
Indolizines by irradiation with microwaves in MCR
RBr
O+
N
R1 R2+N
R2
R1
COR
AcOAl2O3 Mw
R=Ph p-Tolil Stiril
R1= H COOMeR2= COOEt COOMe
Asymmetric indolizines by irradiation with microwaves in MCR
R1
O
Cl+ R2
N NEtOOC
OOMe
Br BrN N
EtOOC
COR1
R2COR1
R2
OOMe
2 [Pd(PPh3)2Cl24 CuI
20 echiv Et3N THF tc 2h
R1=Ph 4-OMe-C6H4R2= Ph
U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003
A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new indolizines
[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical
II
IHH
COORCOOR
N C C
O
R2NCC
O
R1
(B)
(A)
R1
O
C C N R2
O
CCN
H H
ROOC COOR
R1
O
C C N R2
O
CCN
COOR COOR
ROOC COOR
2
2 ROOC C C COOR
R1
O
C CH N R2
O
CCHN
H H
N NCH CHC C
O O
R1 R2
- 2 HX TEAanhydrous solvents
X-
X-
N NCH2 CH2C C
O O
R1 R2
C C COORH
R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5
Y=H NO2 OCH3 CH3 Cl BrX=Br Cl
bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998
bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001
bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004
bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new substituted pyridinium-indolizines
Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate
COO NO2CHC
N NH3C
OR
I IN NH3C
OR
IN NH3C
OR
I
H
KFNMP
-HI
NMP
95oC 30 min
N NH3CO
RN NH3C
O
R
O OO
NO2
O
NO2
-2[H]-2[H]
II
I II
N NH3CO
R
O O
NO2
IN NH3C
O
R
O O
NO2
I
(9a-d)(10a-d)
(15a-d)
(A) (B)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
12
34
56
78 9
10
11
12 3
4
56
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Adolf von Baeyer
Synthesis of Indigo
Towardsbenign
synthesiswith
remarkableVersatility
G W V Cave C LRaston J L ScottChemCommun
2001 2159
Solid-State General Oxidation with with Urea H2O2 Complex
R S Varma and K P Naiker Org Letters 1999 1 189
Solvent-free Oxidative Preparation of Heterocycles
Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157
Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones
Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199
Solvent-free Reduction
F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245
Carbon-Carbon Bond Formation
Toda Tanada Iwata J Org Chem 1989 54 3007
Solventless Photo Coupling and Photo Rearangements
Y Ito S Endo J Am Chem Soc 1997 119 5974
Shin Keating Maribay J Am Chem Soc 1996 118 7626
Solvent - Free Condensation
Z Gross et al Org Letters 1999 1 599
Solid-State Preparationof Dumb-bell-shaped C120
Wang Komatsu Murata Shiro Nature 1997 387 583
Advantages of Solid Mineral Supports(Alumina Silica and Clay)
Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area
The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity
Solids are generally easier and safer to handle than liquids or gaseous reagents
Inexpensive recyclable and environmentally benign nature
Solid-supported Solventless Reactions
bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation
R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43
Supported ReactionsUsing Microwaves
E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945
Microwave-Assisted Deacetylationon Alumina
Varma et al J Chem Soc Perkin Trans 1 999 (1993)
Deprotection of Benzyl Esters viaMicrowave Thermolysis
A practical alternative to traditional catalytic hydrogenation
Varma et al Tetrahedron Lett 34 4603 (1993)
Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of
Carbonyl Compounds Using Microwaves
Varma Meshram Tetrahedron Lett 38 5427 (1997)
Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm
PersulfatendashClay using Microwave and Ultrasonic Irradiation
Varma Meshram Tetrahedron Lett 38 7973 (1997)
Solid Supported Solvent-freeOxidation under MW
Varma et al Tetrahedron Lett 1997 38 2043 and 7823
Solvent-free Reduction Using MW
Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction
Varma et al Tetrahedron Lett 1997 38 4337
Hydrodechlorination under continuous MW
Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)
Synthesis of Heterocyclic Compounds
Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)
Synthesis of Heterocyclic Compounds
Organometallic Reactions
Rearrangements
Rearrangements
INDOLIZINES
Heterocyclic systems 10- electronics
Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine
Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds
N
1
2
34567
8R2
R3
R1
Why interest for indolizinic products
Strong fluorescent properties luminiscent products luminiscent products
Potentially fluorescents marker Potentially laserldquoscintillatersrdquo
bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999
Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )
Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2
ldquoCalcium-entryrdquo blockers
Indolizines by irradiation with microwaves in MCR
RBr
O+
N
R1 R2+N
R2
R1
COR
AcOAl2O3 Mw
R=Ph p-Tolil Stiril
R1= H COOMeR2= COOEt COOMe
Asymmetric indolizines by irradiation with microwaves in MCR
R1
O
Cl+ R2
N NEtOOC
OOMe
Br BrN N
EtOOC
COR1
R2COR1
R2
OOMe
2 [Pd(PPh3)2Cl24 CuI
20 echiv Et3N THF tc 2h
R1=Ph 4-OMe-C6H4R2= Ph
U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003
A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new indolizines
[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical
II
IHH
COORCOOR
N C C
O
R2NCC
O
R1
(B)
(A)
R1
O
C C N R2
O
CCN
H H
ROOC COOR
R1
O
C C N R2
O
CCN
COOR COOR
ROOC COOR
2
2 ROOC C C COOR
R1
O
C CH N R2
O
CCHN
H H
N NCH CHC C
O O
R1 R2
- 2 HX TEAanhydrous solvents
X-
X-
N NCH2 CH2C C
O O
R1 R2
C C COORH
R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5
Y=H NO2 OCH3 CH3 Cl BrX=Br Cl
bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998
bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001
bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004
bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new substituted pyridinium-indolizines
Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate
COO NO2CHC
N NH3C
OR
I IN NH3C
OR
IN NH3C
OR
I
H
KFNMP
-HI
NMP
95oC 30 min
N NH3CO
RN NH3C
O
R
O OO
NO2
O
NO2
-2[H]-2[H]
II
I II
N NH3CO
R
O O
NO2
IN NH3C
O
R
O O
NO2
I
(9a-d)(10a-d)
(15a-d)
(A) (B)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
12
34
56
78 9
10
11
12 3
4
56
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Synthesis of Indigo
Towardsbenign
synthesiswith
remarkableVersatility
G W V Cave C LRaston J L ScottChemCommun
2001 2159
Solid-State General Oxidation with with Urea H2O2 Complex
R S Varma and K P Naiker Org Letters 1999 1 189
Solvent-free Oxidative Preparation of Heterocycles
Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157
Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones
Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199
Solvent-free Reduction
F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245
Carbon-Carbon Bond Formation
Toda Tanada Iwata J Org Chem 1989 54 3007
Solventless Photo Coupling and Photo Rearangements
Y Ito S Endo J Am Chem Soc 1997 119 5974
Shin Keating Maribay J Am Chem Soc 1996 118 7626
Solvent - Free Condensation
Z Gross et al Org Letters 1999 1 599
Solid-State Preparationof Dumb-bell-shaped C120
Wang Komatsu Murata Shiro Nature 1997 387 583
Advantages of Solid Mineral Supports(Alumina Silica and Clay)
Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area
The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity
Solids are generally easier and safer to handle than liquids or gaseous reagents
Inexpensive recyclable and environmentally benign nature
Solid-supported Solventless Reactions
bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation
R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43
Supported ReactionsUsing Microwaves
E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945
Microwave-Assisted Deacetylationon Alumina
Varma et al J Chem Soc Perkin Trans 1 999 (1993)
Deprotection of Benzyl Esters viaMicrowave Thermolysis
A practical alternative to traditional catalytic hydrogenation
Varma et al Tetrahedron Lett 34 4603 (1993)
Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of
Carbonyl Compounds Using Microwaves
Varma Meshram Tetrahedron Lett 38 5427 (1997)
Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm
PersulfatendashClay using Microwave and Ultrasonic Irradiation
Varma Meshram Tetrahedron Lett 38 7973 (1997)
Solid Supported Solvent-freeOxidation under MW
Varma et al Tetrahedron Lett 1997 38 2043 and 7823
Solvent-free Reduction Using MW
Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction
Varma et al Tetrahedron Lett 1997 38 4337
Hydrodechlorination under continuous MW
Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)
Synthesis of Heterocyclic Compounds
Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)
Synthesis of Heterocyclic Compounds
Organometallic Reactions
Rearrangements
Rearrangements
INDOLIZINES
Heterocyclic systems 10- electronics
Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine
Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds
N
1
2
34567
8R2
R3
R1
Why interest for indolizinic products
Strong fluorescent properties luminiscent products luminiscent products
Potentially fluorescents marker Potentially laserldquoscintillatersrdquo
bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999
Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )
Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2
ldquoCalcium-entryrdquo blockers
Indolizines by irradiation with microwaves in MCR
RBr
O+
N
R1 R2+N
R2
R1
COR
AcOAl2O3 Mw
R=Ph p-Tolil Stiril
R1= H COOMeR2= COOEt COOMe
Asymmetric indolizines by irradiation with microwaves in MCR
R1
O
Cl+ R2
N NEtOOC
OOMe
Br BrN N
EtOOC
COR1
R2COR1
R2
OOMe
2 [Pd(PPh3)2Cl24 CuI
20 echiv Et3N THF tc 2h
R1=Ph 4-OMe-C6H4R2= Ph
U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003
A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new indolizines
[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical
II
IHH
COORCOOR
N C C
O
R2NCC
O
R1
(B)
(A)
R1
O
C C N R2
O
CCN
H H
ROOC COOR
R1
O
C C N R2
O
CCN
COOR COOR
ROOC COOR
2
2 ROOC C C COOR
R1
O
C CH N R2
O
CCHN
H H
N NCH CHC C
O O
R1 R2
- 2 HX TEAanhydrous solvents
X-
X-
N NCH2 CH2C C
O O
R1 R2
C C COORH
R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5
Y=H NO2 OCH3 CH3 Cl BrX=Br Cl
bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998
bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001
bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004
bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new substituted pyridinium-indolizines
Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate
COO NO2CHC
N NH3C
OR
I IN NH3C
OR
IN NH3C
OR
I
H
KFNMP
-HI
NMP
95oC 30 min
N NH3CO
RN NH3C
O
R
O OO
NO2
O
NO2
-2[H]-2[H]
II
I II
N NH3CO
R
O O
NO2
IN NH3C
O
R
O O
NO2
I
(9a-d)(10a-d)
(15a-d)
(A) (B)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
12
34
56
78 9
10
11
12 3
4
56
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Towardsbenign
synthesiswith
remarkableVersatility
G W V Cave C LRaston J L ScottChemCommun
2001 2159
Solid-State General Oxidation with with Urea H2O2 Complex
R S Varma and K P Naiker Org Letters 1999 1 189
Solvent-free Oxidative Preparation of Heterocycles
Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157
Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones
Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199
Solvent-free Reduction
F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245
Carbon-Carbon Bond Formation
Toda Tanada Iwata J Org Chem 1989 54 3007
Solventless Photo Coupling and Photo Rearangements
Y Ito S Endo J Am Chem Soc 1997 119 5974
Shin Keating Maribay J Am Chem Soc 1996 118 7626
Solvent - Free Condensation
Z Gross et al Org Letters 1999 1 599
Solid-State Preparationof Dumb-bell-shaped C120
Wang Komatsu Murata Shiro Nature 1997 387 583
Advantages of Solid Mineral Supports(Alumina Silica and Clay)
Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area
The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity
Solids are generally easier and safer to handle than liquids or gaseous reagents
Inexpensive recyclable and environmentally benign nature
Solid-supported Solventless Reactions
bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation
R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43
Supported ReactionsUsing Microwaves
E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945
Microwave-Assisted Deacetylationon Alumina
Varma et al J Chem Soc Perkin Trans 1 999 (1993)
Deprotection of Benzyl Esters viaMicrowave Thermolysis
A practical alternative to traditional catalytic hydrogenation
Varma et al Tetrahedron Lett 34 4603 (1993)
Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of
Carbonyl Compounds Using Microwaves
Varma Meshram Tetrahedron Lett 38 5427 (1997)
Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm
PersulfatendashClay using Microwave and Ultrasonic Irradiation
Varma Meshram Tetrahedron Lett 38 7973 (1997)
Solid Supported Solvent-freeOxidation under MW
Varma et al Tetrahedron Lett 1997 38 2043 and 7823
Solvent-free Reduction Using MW
Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction
Varma et al Tetrahedron Lett 1997 38 4337
Hydrodechlorination under continuous MW
Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)
Synthesis of Heterocyclic Compounds
Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)
Synthesis of Heterocyclic Compounds
Organometallic Reactions
Rearrangements
Rearrangements
INDOLIZINES
Heterocyclic systems 10- electronics
Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine
Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds
N
1
2
34567
8R2
R3
R1
Why interest for indolizinic products
Strong fluorescent properties luminiscent products luminiscent products
Potentially fluorescents marker Potentially laserldquoscintillatersrdquo
bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999
Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )
Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2
ldquoCalcium-entryrdquo blockers
Indolizines by irradiation with microwaves in MCR
RBr
O+
N
R1 R2+N
R2
R1
COR
AcOAl2O3 Mw
R=Ph p-Tolil Stiril
R1= H COOMeR2= COOEt COOMe
Asymmetric indolizines by irradiation with microwaves in MCR
R1
O
Cl+ R2
N NEtOOC
OOMe
Br BrN N
EtOOC
COR1
R2COR1
R2
OOMe
2 [Pd(PPh3)2Cl24 CuI
20 echiv Et3N THF tc 2h
R1=Ph 4-OMe-C6H4R2= Ph
U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003
A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new indolizines
[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical
II
IHH
COORCOOR
N C C
O
R2NCC
O
R1
(B)
(A)
R1
O
C C N R2
O
CCN
H H
ROOC COOR
R1
O
C C N R2
O
CCN
COOR COOR
ROOC COOR
2
2 ROOC C C COOR
R1
O
C CH N R2
O
CCHN
H H
N NCH CHC C
O O
R1 R2
- 2 HX TEAanhydrous solvents
X-
X-
N NCH2 CH2C C
O O
R1 R2
C C COORH
R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5
Y=H NO2 OCH3 CH3 Cl BrX=Br Cl
bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998
bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001
bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004
bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new substituted pyridinium-indolizines
Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate
COO NO2CHC
N NH3C
OR
I IN NH3C
OR
IN NH3C
OR
I
H
KFNMP
-HI
NMP
95oC 30 min
N NH3CO
RN NH3C
O
R
O OO
NO2
O
NO2
-2[H]-2[H]
II
I II
N NH3CO
R
O O
NO2
IN NH3C
O
R
O O
NO2
I
(9a-d)(10a-d)
(15a-d)
(A) (B)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
12
34
56
78 9
10
11
12 3
4
56
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Solid-State General Oxidation with with Urea H2O2 Complex
R S Varma and K P Naiker Org Letters 1999 1 189
Solvent-free Oxidative Preparation of Heterocycles
Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157
Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones
Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199
Solvent-free Reduction
F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245
Carbon-Carbon Bond Formation
Toda Tanada Iwata J Org Chem 1989 54 3007
Solventless Photo Coupling and Photo Rearangements
Y Ito S Endo J Am Chem Soc 1997 119 5974
Shin Keating Maribay J Am Chem Soc 1996 118 7626
Solvent - Free Condensation
Z Gross et al Org Letters 1999 1 599
Solid-State Preparationof Dumb-bell-shaped C120
Wang Komatsu Murata Shiro Nature 1997 387 583
Advantages of Solid Mineral Supports(Alumina Silica and Clay)
Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area
The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity
Solids are generally easier and safer to handle than liquids or gaseous reagents
Inexpensive recyclable and environmentally benign nature
Solid-supported Solventless Reactions
bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation
R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43
Supported ReactionsUsing Microwaves
E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945
Microwave-Assisted Deacetylationon Alumina
Varma et al J Chem Soc Perkin Trans 1 999 (1993)
Deprotection of Benzyl Esters viaMicrowave Thermolysis
A practical alternative to traditional catalytic hydrogenation
Varma et al Tetrahedron Lett 34 4603 (1993)
Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of
Carbonyl Compounds Using Microwaves
Varma Meshram Tetrahedron Lett 38 5427 (1997)
Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm
PersulfatendashClay using Microwave and Ultrasonic Irradiation
Varma Meshram Tetrahedron Lett 38 7973 (1997)
Solid Supported Solvent-freeOxidation under MW
Varma et al Tetrahedron Lett 1997 38 2043 and 7823
Solvent-free Reduction Using MW
Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction
Varma et al Tetrahedron Lett 1997 38 4337
Hydrodechlorination under continuous MW
Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)
Synthesis of Heterocyclic Compounds
Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)
Synthesis of Heterocyclic Compounds
Organometallic Reactions
Rearrangements
Rearrangements
INDOLIZINES
Heterocyclic systems 10- electronics
Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine
Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds
N
1
2
34567
8R2
R3
R1
Why interest for indolizinic products
Strong fluorescent properties luminiscent products luminiscent products
Potentially fluorescents marker Potentially laserldquoscintillatersrdquo
bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999
Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )
Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2
ldquoCalcium-entryrdquo blockers
Indolizines by irradiation with microwaves in MCR
RBr
O+
N
R1 R2+N
R2
R1
COR
AcOAl2O3 Mw
R=Ph p-Tolil Stiril
R1= H COOMeR2= COOEt COOMe
Asymmetric indolizines by irradiation with microwaves in MCR
R1
O
Cl+ R2
N NEtOOC
OOMe
Br BrN N
EtOOC
COR1
R2COR1
R2
OOMe
2 [Pd(PPh3)2Cl24 CuI
20 echiv Et3N THF tc 2h
R1=Ph 4-OMe-C6H4R2= Ph
U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003
A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new indolizines
[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical
II
IHH
COORCOOR
N C C
O
R2NCC
O
R1
(B)
(A)
R1
O
C C N R2
O
CCN
H H
ROOC COOR
R1
O
C C N R2
O
CCN
COOR COOR
ROOC COOR
2
2 ROOC C C COOR
R1
O
C CH N R2
O
CCHN
H H
N NCH CHC C
O O
R1 R2
- 2 HX TEAanhydrous solvents
X-
X-
N NCH2 CH2C C
O O
R1 R2
C C COORH
R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5
Y=H NO2 OCH3 CH3 Cl BrX=Br Cl
bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998
bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001
bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004
bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new substituted pyridinium-indolizines
Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate
COO NO2CHC
N NH3C
OR
I IN NH3C
OR
IN NH3C
OR
I
H
KFNMP
-HI
NMP
95oC 30 min
N NH3CO
RN NH3C
O
R
O OO
NO2
O
NO2
-2[H]-2[H]
II
I II
N NH3CO
R
O O
NO2
IN NH3C
O
R
O O
NO2
I
(9a-d)(10a-d)
(15a-d)
(A) (B)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
12
34
56
78 9
10
11
12 3
4
56
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Solvent-free Oxidative Preparation of Heterocycles
Kumar Chandra Sekhar Dhillon Rao and VarmaGreen Chem 2004 6 156-157
Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones
Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199
Solvent-free Reduction
F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245
Carbon-Carbon Bond Formation
Toda Tanada Iwata J Org Chem 1989 54 3007
Solventless Photo Coupling and Photo Rearangements
Y Ito S Endo J Am Chem Soc 1997 119 5974
Shin Keating Maribay J Am Chem Soc 1996 118 7626
Solvent - Free Condensation
Z Gross et al Org Letters 1999 1 599
Solid-State Preparationof Dumb-bell-shaped C120
Wang Komatsu Murata Shiro Nature 1997 387 583
Advantages of Solid Mineral Supports(Alumina Silica and Clay)
Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area
The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity
Solids are generally easier and safer to handle than liquids or gaseous reagents
Inexpensive recyclable and environmentally benign nature
Solid-supported Solventless Reactions
bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation
R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43
Supported ReactionsUsing Microwaves
E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945
Microwave-Assisted Deacetylationon Alumina
Varma et al J Chem Soc Perkin Trans 1 999 (1993)
Deprotection of Benzyl Esters viaMicrowave Thermolysis
A practical alternative to traditional catalytic hydrogenation
Varma et al Tetrahedron Lett 34 4603 (1993)
Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of
Carbonyl Compounds Using Microwaves
Varma Meshram Tetrahedron Lett 38 5427 (1997)
Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm
PersulfatendashClay using Microwave and Ultrasonic Irradiation
Varma Meshram Tetrahedron Lett 38 7973 (1997)
Solid Supported Solvent-freeOxidation under MW
Varma et al Tetrahedron Lett 1997 38 2043 and 7823
Solvent-free Reduction Using MW
Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction
Varma et al Tetrahedron Lett 1997 38 4337
Hydrodechlorination under continuous MW
Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)
Synthesis of Heterocyclic Compounds
Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)
Synthesis of Heterocyclic Compounds
Organometallic Reactions
Rearrangements
Rearrangements
INDOLIZINES
Heterocyclic systems 10- electronics
Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine
Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds
N
1
2
34567
8R2
R3
R1
Why interest for indolizinic products
Strong fluorescent properties luminiscent products luminiscent products
Potentially fluorescents marker Potentially laserldquoscintillatersrdquo
bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999
Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )
Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2
ldquoCalcium-entryrdquo blockers
Indolizines by irradiation with microwaves in MCR
RBr
O+
N
R1 R2+N
R2
R1
COR
AcOAl2O3 Mw
R=Ph p-Tolil Stiril
R1= H COOMeR2= COOEt COOMe
Asymmetric indolizines by irradiation with microwaves in MCR
R1
O
Cl+ R2
N NEtOOC
OOMe
Br BrN N
EtOOC
COR1
R2COR1
R2
OOMe
2 [Pd(PPh3)2Cl24 CuI
20 echiv Et3N THF tc 2h
R1=Ph 4-OMe-C6H4R2= Ph
U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003
A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new indolizines
[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical
II
IHH
COORCOOR
N C C
O
R2NCC
O
R1
(B)
(A)
R1
O
C C N R2
O
CCN
H H
ROOC COOR
R1
O
C C N R2
O
CCN
COOR COOR
ROOC COOR
2
2 ROOC C C COOR
R1
O
C CH N R2
O
CCHN
H H
N NCH CHC C
O O
R1 R2
- 2 HX TEAanhydrous solvents
X-
X-
N NCH2 CH2C C
O O
R1 R2
C C COORH
R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5
Y=H NO2 OCH3 CH3 Cl BrX=Br Cl
bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998
bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001
bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004
bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new substituted pyridinium-indolizines
Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate
COO NO2CHC
N NH3C
OR
I IN NH3C
OR
IN NH3C
OR
I
H
KFNMP
-HI
NMP
95oC 30 min
N NH3CO
RN NH3C
O
R
O OO
NO2
O
NO2
-2[H]-2[H]
II
I II
N NH3CO
R
O O
NO2
IN NH3C
O
R
O O
NO2
I
(9a-d)(10a-d)
(15a-d)
(A) (B)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
12
34
56
78 9
10
11
12 3
4
56
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Solvent-free Synthesis of szlig-Keto Keto Sulfones Ketones
Kumar Sundaree Rao and VarmaTetrahedron Letters 2006 47 4197-4199
Solvent-free Reduction
F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245
Carbon-Carbon Bond Formation
Toda Tanada Iwata J Org Chem 1989 54 3007
Solventless Photo Coupling and Photo Rearangements
Y Ito S Endo J Am Chem Soc 1997 119 5974
Shin Keating Maribay J Am Chem Soc 1996 118 7626
Solvent - Free Condensation
Z Gross et al Org Letters 1999 1 599
Solid-State Preparationof Dumb-bell-shaped C120
Wang Komatsu Murata Shiro Nature 1997 387 583
Advantages of Solid Mineral Supports(Alumina Silica and Clay)
Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area
The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity
Solids are generally easier and safer to handle than liquids or gaseous reagents
Inexpensive recyclable and environmentally benign nature
Solid-supported Solventless Reactions
bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation
R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43
Supported ReactionsUsing Microwaves
E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945
Microwave-Assisted Deacetylationon Alumina
Varma et al J Chem Soc Perkin Trans 1 999 (1993)
Deprotection of Benzyl Esters viaMicrowave Thermolysis
A practical alternative to traditional catalytic hydrogenation
Varma et al Tetrahedron Lett 34 4603 (1993)
Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of
Carbonyl Compounds Using Microwaves
Varma Meshram Tetrahedron Lett 38 5427 (1997)
Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm
PersulfatendashClay using Microwave and Ultrasonic Irradiation
Varma Meshram Tetrahedron Lett 38 7973 (1997)
Solid Supported Solvent-freeOxidation under MW
Varma et al Tetrahedron Lett 1997 38 2043 and 7823
Solvent-free Reduction Using MW
Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction
Varma et al Tetrahedron Lett 1997 38 4337
Hydrodechlorination under continuous MW
Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)
Synthesis of Heterocyclic Compounds
Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)
Synthesis of Heterocyclic Compounds
Organometallic Reactions
Rearrangements
Rearrangements
INDOLIZINES
Heterocyclic systems 10- electronics
Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine
Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds
N
1
2
34567
8R2
R3
R1
Why interest for indolizinic products
Strong fluorescent properties luminiscent products luminiscent products
Potentially fluorescents marker Potentially laserldquoscintillatersrdquo
bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999
Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )
Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2
ldquoCalcium-entryrdquo blockers
Indolizines by irradiation with microwaves in MCR
RBr
O+
N
R1 R2+N
R2
R1
COR
AcOAl2O3 Mw
R=Ph p-Tolil Stiril
R1= H COOMeR2= COOEt COOMe
Asymmetric indolizines by irradiation with microwaves in MCR
R1
O
Cl+ R2
N NEtOOC
OOMe
Br BrN N
EtOOC
COR1
R2COR1
R2
OOMe
2 [Pd(PPh3)2Cl24 CuI
20 echiv Et3N THF tc 2h
R1=Ph 4-OMe-C6H4R2= Ph
U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003
A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new indolizines
[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical
II
IHH
COORCOOR
N C C
O
R2NCC
O
R1
(B)
(A)
R1
O
C C N R2
O
CCN
H H
ROOC COOR
R1
O
C C N R2
O
CCN
COOR COOR
ROOC COOR
2
2 ROOC C C COOR
R1
O
C CH N R2
O
CCHN
H H
N NCH CHC C
O O
R1 R2
- 2 HX TEAanhydrous solvents
X-
X-
N NCH2 CH2C C
O O
R1 R2
C C COORH
R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5
Y=H NO2 OCH3 CH3 Cl BrX=Br Cl
bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998
bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001
bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004
bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new substituted pyridinium-indolizines
Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate
COO NO2CHC
N NH3C
OR
I IN NH3C
OR
IN NH3C
OR
I
H
KFNMP
-HI
NMP
95oC 30 min
N NH3CO
RN NH3C
O
R
O OO
NO2
O
NO2
-2[H]-2[H]
II
I II
N NH3CO
R
O O
NO2
IN NH3C
O
R
O O
NO2
I
(9a-d)(10a-d)
(15a-d)
(A) (B)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
12
34
56
78 9
10
11
12 3
4
56
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Solvent-free Reduction
F Toda et al Angew Chem Int Ed Engl 1989 28 320and Chem Commun 1989 1245
Carbon-Carbon Bond Formation
Toda Tanada Iwata J Org Chem 1989 54 3007
Solventless Photo Coupling and Photo Rearangements
Y Ito S Endo J Am Chem Soc 1997 119 5974
Shin Keating Maribay J Am Chem Soc 1996 118 7626
Solvent - Free Condensation
Z Gross et al Org Letters 1999 1 599
Solid-State Preparationof Dumb-bell-shaped C120
Wang Komatsu Murata Shiro Nature 1997 387 583
Advantages of Solid Mineral Supports(Alumina Silica and Clay)
Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area
The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity
Solids are generally easier and safer to handle than liquids or gaseous reagents
Inexpensive recyclable and environmentally benign nature
Solid-supported Solventless Reactions
bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation
R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43
Supported ReactionsUsing Microwaves
E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945
Microwave-Assisted Deacetylationon Alumina
Varma et al J Chem Soc Perkin Trans 1 999 (1993)
Deprotection of Benzyl Esters viaMicrowave Thermolysis
A practical alternative to traditional catalytic hydrogenation
Varma et al Tetrahedron Lett 34 4603 (1993)
Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of
Carbonyl Compounds Using Microwaves
Varma Meshram Tetrahedron Lett 38 5427 (1997)
Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm
PersulfatendashClay using Microwave and Ultrasonic Irradiation
Varma Meshram Tetrahedron Lett 38 7973 (1997)
Solid Supported Solvent-freeOxidation under MW
Varma et al Tetrahedron Lett 1997 38 2043 and 7823
Solvent-free Reduction Using MW
Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction
Varma et al Tetrahedron Lett 1997 38 4337
Hydrodechlorination under continuous MW
Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)
Synthesis of Heterocyclic Compounds
Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)
Synthesis of Heterocyclic Compounds
Organometallic Reactions
Rearrangements
Rearrangements
INDOLIZINES
Heterocyclic systems 10- electronics
Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine
Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds
N
1
2
34567
8R2
R3
R1
Why interest for indolizinic products
Strong fluorescent properties luminiscent products luminiscent products
Potentially fluorescents marker Potentially laserldquoscintillatersrdquo
bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999
Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )
Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2
ldquoCalcium-entryrdquo blockers
Indolizines by irradiation with microwaves in MCR
RBr
O+
N
R1 R2+N
R2
R1
COR
AcOAl2O3 Mw
R=Ph p-Tolil Stiril
R1= H COOMeR2= COOEt COOMe
Asymmetric indolizines by irradiation with microwaves in MCR
R1
O
Cl+ R2
N NEtOOC
OOMe
Br BrN N
EtOOC
COR1
R2COR1
R2
OOMe
2 [Pd(PPh3)2Cl24 CuI
20 echiv Et3N THF tc 2h
R1=Ph 4-OMe-C6H4R2= Ph
U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003
A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new indolizines
[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical
II
IHH
COORCOOR
N C C
O
R2NCC
O
R1
(B)
(A)
R1
O
C C N R2
O
CCN
H H
ROOC COOR
R1
O
C C N R2
O
CCN
COOR COOR
ROOC COOR
2
2 ROOC C C COOR
R1
O
C CH N R2
O
CCHN
H H
N NCH CHC C
O O
R1 R2
- 2 HX TEAanhydrous solvents
X-
X-
N NCH2 CH2C C
O O
R1 R2
C C COORH
R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5
Y=H NO2 OCH3 CH3 Cl BrX=Br Cl
bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998
bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001
bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004
bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new substituted pyridinium-indolizines
Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate
COO NO2CHC
N NH3C
OR
I IN NH3C
OR
IN NH3C
OR
I
H
KFNMP
-HI
NMP
95oC 30 min
N NH3CO
RN NH3C
O
R
O OO
NO2
O
NO2
-2[H]-2[H]
II
I II
N NH3CO
R
O O
NO2
IN NH3C
O
R
O O
NO2
I
(9a-d)(10a-d)
(15a-d)
(A) (B)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
12
34
56
78 9
10
11
12 3
4
56
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Carbon-Carbon Bond Formation
Toda Tanada Iwata J Org Chem 1989 54 3007
Solventless Photo Coupling and Photo Rearangements
Y Ito S Endo J Am Chem Soc 1997 119 5974
Shin Keating Maribay J Am Chem Soc 1996 118 7626
Solvent - Free Condensation
Z Gross et al Org Letters 1999 1 599
Solid-State Preparationof Dumb-bell-shaped C120
Wang Komatsu Murata Shiro Nature 1997 387 583
Advantages of Solid Mineral Supports(Alumina Silica and Clay)
Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area
The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity
Solids are generally easier and safer to handle than liquids or gaseous reagents
Inexpensive recyclable and environmentally benign nature
Solid-supported Solventless Reactions
bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation
R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43
Supported ReactionsUsing Microwaves
E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945
Microwave-Assisted Deacetylationon Alumina
Varma et al J Chem Soc Perkin Trans 1 999 (1993)
Deprotection of Benzyl Esters viaMicrowave Thermolysis
A practical alternative to traditional catalytic hydrogenation
Varma et al Tetrahedron Lett 34 4603 (1993)
Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of
Carbonyl Compounds Using Microwaves
Varma Meshram Tetrahedron Lett 38 5427 (1997)
Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm
PersulfatendashClay using Microwave and Ultrasonic Irradiation
Varma Meshram Tetrahedron Lett 38 7973 (1997)
Solid Supported Solvent-freeOxidation under MW
Varma et al Tetrahedron Lett 1997 38 2043 and 7823
Solvent-free Reduction Using MW
Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction
Varma et al Tetrahedron Lett 1997 38 4337
Hydrodechlorination under continuous MW
Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)
Synthesis of Heterocyclic Compounds
Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)
Synthesis of Heterocyclic Compounds
Organometallic Reactions
Rearrangements
Rearrangements
INDOLIZINES
Heterocyclic systems 10- electronics
Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine
Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds
N
1
2
34567
8R2
R3
R1
Why interest for indolizinic products
Strong fluorescent properties luminiscent products luminiscent products
Potentially fluorescents marker Potentially laserldquoscintillatersrdquo
bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999
Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )
Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2
ldquoCalcium-entryrdquo blockers
Indolizines by irradiation with microwaves in MCR
RBr
O+
N
R1 R2+N
R2
R1
COR
AcOAl2O3 Mw
R=Ph p-Tolil Stiril
R1= H COOMeR2= COOEt COOMe
Asymmetric indolizines by irradiation with microwaves in MCR
R1
O
Cl+ R2
N NEtOOC
OOMe
Br BrN N
EtOOC
COR1
R2COR1
R2
OOMe
2 [Pd(PPh3)2Cl24 CuI
20 echiv Et3N THF tc 2h
R1=Ph 4-OMe-C6H4R2= Ph
U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003
A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new indolizines
[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical
II
IHH
COORCOOR
N C C
O
R2NCC
O
R1
(B)
(A)
R1
O
C C N R2
O
CCN
H H
ROOC COOR
R1
O
C C N R2
O
CCN
COOR COOR
ROOC COOR
2
2 ROOC C C COOR
R1
O
C CH N R2
O
CCHN
H H
N NCH CHC C
O O
R1 R2
- 2 HX TEAanhydrous solvents
X-
X-
N NCH2 CH2C C
O O
R1 R2
C C COORH
R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5
Y=H NO2 OCH3 CH3 Cl BrX=Br Cl
bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998
bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001
bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004
bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new substituted pyridinium-indolizines
Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate
COO NO2CHC
N NH3C
OR
I IN NH3C
OR
IN NH3C
OR
I
H
KFNMP
-HI
NMP
95oC 30 min
N NH3CO
RN NH3C
O
R
O OO
NO2
O
NO2
-2[H]-2[H]
II
I II
N NH3CO
R
O O
NO2
IN NH3C
O
R
O O
NO2
I
(9a-d)(10a-d)
(15a-d)
(A) (B)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
12
34
56
78 9
10
11
12 3
4
56
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Solventless Photo Coupling and Photo Rearangements
Y Ito S Endo J Am Chem Soc 1997 119 5974
Shin Keating Maribay J Am Chem Soc 1996 118 7626
Solvent - Free Condensation
Z Gross et al Org Letters 1999 1 599
Solid-State Preparationof Dumb-bell-shaped C120
Wang Komatsu Murata Shiro Nature 1997 387 583
Advantages of Solid Mineral Supports(Alumina Silica and Clay)
Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area
The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity
Solids are generally easier and safer to handle than liquids or gaseous reagents
Inexpensive recyclable and environmentally benign nature
Solid-supported Solventless Reactions
bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation
R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43
Supported ReactionsUsing Microwaves
E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945
Microwave-Assisted Deacetylationon Alumina
Varma et al J Chem Soc Perkin Trans 1 999 (1993)
Deprotection of Benzyl Esters viaMicrowave Thermolysis
A practical alternative to traditional catalytic hydrogenation
Varma et al Tetrahedron Lett 34 4603 (1993)
Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of
Carbonyl Compounds Using Microwaves
Varma Meshram Tetrahedron Lett 38 5427 (1997)
Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm
PersulfatendashClay using Microwave and Ultrasonic Irradiation
Varma Meshram Tetrahedron Lett 38 7973 (1997)
Solid Supported Solvent-freeOxidation under MW
Varma et al Tetrahedron Lett 1997 38 2043 and 7823
Solvent-free Reduction Using MW
Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction
Varma et al Tetrahedron Lett 1997 38 4337
Hydrodechlorination under continuous MW
Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)
Synthesis of Heterocyclic Compounds
Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)
Synthesis of Heterocyclic Compounds
Organometallic Reactions
Rearrangements
Rearrangements
INDOLIZINES
Heterocyclic systems 10- electronics
Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine
Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds
N
1
2
34567
8R2
R3
R1
Why interest for indolizinic products
Strong fluorescent properties luminiscent products luminiscent products
Potentially fluorescents marker Potentially laserldquoscintillatersrdquo
bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999
Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )
Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2
ldquoCalcium-entryrdquo blockers
Indolizines by irradiation with microwaves in MCR
RBr
O+
N
R1 R2+N
R2
R1
COR
AcOAl2O3 Mw
R=Ph p-Tolil Stiril
R1= H COOMeR2= COOEt COOMe
Asymmetric indolizines by irradiation with microwaves in MCR
R1
O
Cl+ R2
N NEtOOC
OOMe
Br BrN N
EtOOC
COR1
R2COR1
R2
OOMe
2 [Pd(PPh3)2Cl24 CuI
20 echiv Et3N THF tc 2h
R1=Ph 4-OMe-C6H4R2= Ph
U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003
A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new indolizines
[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical
II
IHH
COORCOOR
N C C
O
R2NCC
O
R1
(B)
(A)
R1
O
C C N R2
O
CCN
H H
ROOC COOR
R1
O
C C N R2
O
CCN
COOR COOR
ROOC COOR
2
2 ROOC C C COOR
R1
O
C CH N R2
O
CCHN
H H
N NCH CHC C
O O
R1 R2
- 2 HX TEAanhydrous solvents
X-
X-
N NCH2 CH2C C
O O
R1 R2
C C COORH
R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5
Y=H NO2 OCH3 CH3 Cl BrX=Br Cl
bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998
bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001
bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004
bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new substituted pyridinium-indolizines
Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate
COO NO2CHC
N NH3C
OR
I IN NH3C
OR
IN NH3C
OR
I
H
KFNMP
-HI
NMP
95oC 30 min
N NH3CO
RN NH3C
O
R
O OO
NO2
O
NO2
-2[H]-2[H]
II
I II
N NH3CO
R
O O
NO2
IN NH3C
O
R
O O
NO2
I
(9a-d)(10a-d)
(15a-d)
(A) (B)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
12
34
56
78 9
10
11
12 3
4
56
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Solvent - Free Condensation
Z Gross et al Org Letters 1999 1 599
Solid-State Preparationof Dumb-bell-shaped C120
Wang Komatsu Murata Shiro Nature 1997 387 583
Advantages of Solid Mineral Supports(Alumina Silica and Clay)
Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area
The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity
Solids are generally easier and safer to handle than liquids or gaseous reagents
Inexpensive recyclable and environmentally benign nature
Solid-supported Solventless Reactions
bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation
R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43
Supported ReactionsUsing Microwaves
E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945
Microwave-Assisted Deacetylationon Alumina
Varma et al J Chem Soc Perkin Trans 1 999 (1993)
Deprotection of Benzyl Esters viaMicrowave Thermolysis
A practical alternative to traditional catalytic hydrogenation
Varma et al Tetrahedron Lett 34 4603 (1993)
Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of
Carbonyl Compounds Using Microwaves
Varma Meshram Tetrahedron Lett 38 5427 (1997)
Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm
PersulfatendashClay using Microwave and Ultrasonic Irradiation
Varma Meshram Tetrahedron Lett 38 7973 (1997)
Solid Supported Solvent-freeOxidation under MW
Varma et al Tetrahedron Lett 1997 38 2043 and 7823
Solvent-free Reduction Using MW
Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction
Varma et al Tetrahedron Lett 1997 38 4337
Hydrodechlorination under continuous MW
Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)
Synthesis of Heterocyclic Compounds
Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)
Synthesis of Heterocyclic Compounds
Organometallic Reactions
Rearrangements
Rearrangements
INDOLIZINES
Heterocyclic systems 10- electronics
Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine
Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds
N
1
2
34567
8R2
R3
R1
Why interest for indolizinic products
Strong fluorescent properties luminiscent products luminiscent products
Potentially fluorescents marker Potentially laserldquoscintillatersrdquo
bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999
Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )
Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2
ldquoCalcium-entryrdquo blockers
Indolizines by irradiation with microwaves in MCR
RBr
O+
N
R1 R2+N
R2
R1
COR
AcOAl2O3 Mw
R=Ph p-Tolil Stiril
R1= H COOMeR2= COOEt COOMe
Asymmetric indolizines by irradiation with microwaves in MCR
R1
O
Cl+ R2
N NEtOOC
OOMe
Br BrN N
EtOOC
COR1
R2COR1
R2
OOMe
2 [Pd(PPh3)2Cl24 CuI
20 echiv Et3N THF tc 2h
R1=Ph 4-OMe-C6H4R2= Ph
U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003
A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new indolizines
[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical
II
IHH
COORCOOR
N C C
O
R2NCC
O
R1
(B)
(A)
R1
O
C C N R2
O
CCN
H H
ROOC COOR
R1
O
C C N R2
O
CCN
COOR COOR
ROOC COOR
2
2 ROOC C C COOR
R1
O
C CH N R2
O
CCHN
H H
N NCH CHC C
O O
R1 R2
- 2 HX TEAanhydrous solvents
X-
X-
N NCH2 CH2C C
O O
R1 R2
C C COORH
R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5
Y=H NO2 OCH3 CH3 Cl BrX=Br Cl
bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998
bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001
bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004
bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new substituted pyridinium-indolizines
Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate
COO NO2CHC
N NH3C
OR
I IN NH3C
OR
IN NH3C
OR
I
H
KFNMP
-HI
NMP
95oC 30 min
N NH3CO
RN NH3C
O
R
O OO
NO2
O
NO2
-2[H]-2[H]
II
I II
N NH3CO
R
O O
NO2
IN NH3C
O
R
O O
NO2
I
(9a-d)(10a-d)
(15a-d)
(A) (B)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
12
34
56
78 9
10
11
12 3
4
56
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Solid-State Preparationof Dumb-bell-shaped C120
Wang Komatsu Murata Shiro Nature 1997 387 583
Advantages of Solid Mineral Supports(Alumina Silica and Clay)
Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area
The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity
Solids are generally easier and safer to handle than liquids or gaseous reagents
Inexpensive recyclable and environmentally benign nature
Solid-supported Solventless Reactions
bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation
R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43
Supported ReactionsUsing Microwaves
E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945
Microwave-Assisted Deacetylationon Alumina
Varma et al J Chem Soc Perkin Trans 1 999 (1993)
Deprotection of Benzyl Esters viaMicrowave Thermolysis
A practical alternative to traditional catalytic hydrogenation
Varma et al Tetrahedron Lett 34 4603 (1993)
Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of
Carbonyl Compounds Using Microwaves
Varma Meshram Tetrahedron Lett 38 5427 (1997)
Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm
PersulfatendashClay using Microwave and Ultrasonic Irradiation
Varma Meshram Tetrahedron Lett 38 7973 (1997)
Solid Supported Solvent-freeOxidation under MW
Varma et al Tetrahedron Lett 1997 38 2043 and 7823
Solvent-free Reduction Using MW
Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction
Varma et al Tetrahedron Lett 1997 38 4337
Hydrodechlorination under continuous MW
Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)
Synthesis of Heterocyclic Compounds
Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)
Synthesis of Heterocyclic Compounds
Organometallic Reactions
Rearrangements
Rearrangements
INDOLIZINES
Heterocyclic systems 10- electronics
Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine
Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds
N
1
2
34567
8R2
R3
R1
Why interest for indolizinic products
Strong fluorescent properties luminiscent products luminiscent products
Potentially fluorescents marker Potentially laserldquoscintillatersrdquo
bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999
Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )
Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2
ldquoCalcium-entryrdquo blockers
Indolizines by irradiation with microwaves in MCR
RBr
O+
N
R1 R2+N
R2
R1
COR
AcOAl2O3 Mw
R=Ph p-Tolil Stiril
R1= H COOMeR2= COOEt COOMe
Asymmetric indolizines by irradiation with microwaves in MCR
R1
O
Cl+ R2
N NEtOOC
OOMe
Br BrN N
EtOOC
COR1
R2COR1
R2
OOMe
2 [Pd(PPh3)2Cl24 CuI
20 echiv Et3N THF tc 2h
R1=Ph 4-OMe-C6H4R2= Ph
U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003
A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new indolizines
[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical
II
IHH
COORCOOR
N C C
O
R2NCC
O
R1
(B)
(A)
R1
O
C C N R2
O
CCN
H H
ROOC COOR
R1
O
C C N R2
O
CCN
COOR COOR
ROOC COOR
2
2 ROOC C C COOR
R1
O
C CH N R2
O
CCHN
H H
N NCH CHC C
O O
R1 R2
- 2 HX TEAanhydrous solvents
X-
X-
N NCH2 CH2C C
O O
R1 R2
C C COORH
R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5
Y=H NO2 OCH3 CH3 Cl BrX=Br Cl
bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998
bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001
bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004
bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new substituted pyridinium-indolizines
Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate
COO NO2CHC
N NH3C
OR
I IN NH3C
OR
IN NH3C
OR
I
H
KFNMP
-HI
NMP
95oC 30 min
N NH3CO
RN NH3C
O
R
O OO
NO2
O
NO2
-2[H]-2[H]
II
I II
N NH3CO
R
O O
NO2
IN NH3C
O
R
O O
NO2
I
(9a-d)(10a-d)
(15a-d)
(A) (B)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
12
34
56
78 9
10
11
12 3
4
56
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Advantages of Solid Mineral Supports(Alumina Silica and Clay)
Good dispersion of active (reagent) site can lead to significant improvement of reactivityndashlarge surface area
The constraints of the (molecular dimensions) pores and the characteristics of the surface adsorption can lead to useful improvement in reaction selectivity
Solids are generally easier and safer to handle than liquids or gaseous reagents
Inexpensive recyclable and environmentally benign nature
Solid-supported Solventless Reactions
bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation
R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43
Supported ReactionsUsing Microwaves
E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945
Microwave-Assisted Deacetylationon Alumina
Varma et al J Chem Soc Perkin Trans 1 999 (1993)
Deprotection of Benzyl Esters viaMicrowave Thermolysis
A practical alternative to traditional catalytic hydrogenation
Varma et al Tetrahedron Lett 34 4603 (1993)
Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of
Carbonyl Compounds Using Microwaves
Varma Meshram Tetrahedron Lett 38 5427 (1997)
Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm
PersulfatendashClay using Microwave and Ultrasonic Irradiation
Varma Meshram Tetrahedron Lett 38 7973 (1997)
Solid Supported Solvent-freeOxidation under MW
Varma et al Tetrahedron Lett 1997 38 2043 and 7823
Solvent-free Reduction Using MW
Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction
Varma et al Tetrahedron Lett 1997 38 4337
Hydrodechlorination under continuous MW
Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)
Synthesis of Heterocyclic Compounds
Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)
Synthesis of Heterocyclic Compounds
Organometallic Reactions
Rearrangements
Rearrangements
INDOLIZINES
Heterocyclic systems 10- electronics
Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine
Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds
N
1
2
34567
8R2
R3
R1
Why interest for indolizinic products
Strong fluorescent properties luminiscent products luminiscent products
Potentially fluorescents marker Potentially laserldquoscintillatersrdquo
bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999
Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )
Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2
ldquoCalcium-entryrdquo blockers
Indolizines by irradiation with microwaves in MCR
RBr
O+
N
R1 R2+N
R2
R1
COR
AcOAl2O3 Mw
R=Ph p-Tolil Stiril
R1= H COOMeR2= COOEt COOMe
Asymmetric indolizines by irradiation with microwaves in MCR
R1
O
Cl+ R2
N NEtOOC
OOMe
Br BrN N
EtOOC
COR1
R2COR1
R2
OOMe
2 [Pd(PPh3)2Cl24 CuI
20 echiv Et3N THF tc 2h
R1=Ph 4-OMe-C6H4R2= Ph
U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003
A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new indolizines
[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical
II
IHH
COORCOOR
N C C
O
R2NCC
O
R1
(B)
(A)
R1
O
C C N R2
O
CCN
H H
ROOC COOR
R1
O
C C N R2
O
CCN
COOR COOR
ROOC COOR
2
2 ROOC C C COOR
R1
O
C CH N R2
O
CCHN
H H
N NCH CHC C
O O
R1 R2
- 2 HX TEAanhydrous solvents
X-
X-
N NCH2 CH2C C
O O
R1 R2
C C COORH
R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5
Y=H NO2 OCH3 CH3 Cl BrX=Br Cl
bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998
bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001
bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004
bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new substituted pyridinium-indolizines
Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate
COO NO2CHC
N NH3C
OR
I IN NH3C
OR
IN NH3C
OR
I
H
KFNMP
-HI
NMP
95oC 30 min
N NH3CO
RN NH3C
O
R
O OO
NO2
O
NO2
-2[H]-2[H]
II
I II
N NH3CO
R
O O
NO2
IN NH3C
O
R
O O
NO2
I
(9a-d)(10a-d)
(15a-d)
(A) (B)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
12
34
56
78 9
10
11
12 3
4
56
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Solid-supported Solventless Reactions
bull Microwave irradiation of solventless reactions with inorganic mineral supports such as alumina silica or clays have resulted in faster reactions with higher yields with simplified separation
R S Varma Tetrahedron 2002 58 1235R S Varma Green Chem 1999 1 43
Supported ReactionsUsing Microwaves
E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945
Microwave-Assisted Deacetylationon Alumina
Varma et al J Chem Soc Perkin Trans 1 999 (1993)
Deprotection of Benzyl Esters viaMicrowave Thermolysis
A practical alternative to traditional catalytic hydrogenation
Varma et al Tetrahedron Lett 34 4603 (1993)
Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of
Carbonyl Compounds Using Microwaves
Varma Meshram Tetrahedron Lett 38 5427 (1997)
Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm
PersulfatendashClay using Microwave and Ultrasonic Irradiation
Varma Meshram Tetrahedron Lett 38 7973 (1997)
Solid Supported Solvent-freeOxidation under MW
Varma et al Tetrahedron Lett 1997 38 2043 and 7823
Solvent-free Reduction Using MW
Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction
Varma et al Tetrahedron Lett 1997 38 4337
Hydrodechlorination under continuous MW
Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)
Synthesis of Heterocyclic Compounds
Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)
Synthesis of Heterocyclic Compounds
Organometallic Reactions
Rearrangements
Rearrangements
INDOLIZINES
Heterocyclic systems 10- electronics
Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine
Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds
N
1
2
34567
8R2
R3
R1
Why interest for indolizinic products
Strong fluorescent properties luminiscent products luminiscent products
Potentially fluorescents marker Potentially laserldquoscintillatersrdquo
bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999
Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )
Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2
ldquoCalcium-entryrdquo blockers
Indolizines by irradiation with microwaves in MCR
RBr
O+
N
R1 R2+N
R2
R1
COR
AcOAl2O3 Mw
R=Ph p-Tolil Stiril
R1= H COOMeR2= COOEt COOMe
Asymmetric indolizines by irradiation with microwaves in MCR
R1
O
Cl+ R2
N NEtOOC
OOMe
Br BrN N
EtOOC
COR1
R2COR1
R2
OOMe
2 [Pd(PPh3)2Cl24 CuI
20 echiv Et3N THF tc 2h
R1=Ph 4-OMe-C6H4R2= Ph
U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003
A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new indolizines
[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical
II
IHH
COORCOOR
N C C
O
R2NCC
O
R1
(B)
(A)
R1
O
C C N R2
O
CCN
H H
ROOC COOR
R1
O
C C N R2
O
CCN
COOR COOR
ROOC COOR
2
2 ROOC C C COOR
R1
O
C CH N R2
O
CCHN
H H
N NCH CHC C
O O
R1 R2
- 2 HX TEAanhydrous solvents
X-
X-
N NCH2 CH2C C
O O
R1 R2
C C COORH
R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5
Y=H NO2 OCH3 CH3 Cl BrX=Br Cl
bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998
bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001
bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004
bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new substituted pyridinium-indolizines
Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate
COO NO2CHC
N NH3C
OR
I IN NH3C
OR
IN NH3C
OR
I
H
KFNMP
-HI
NMP
95oC 30 min
N NH3CO
RN NH3C
O
R
O OO
NO2
O
NO2
-2[H]-2[H]
II
I II
N NH3CO
R
O O
NO2
IN NH3C
O
R
O O
NO2
I
(9a-d)(10a-d)
(15a-d)
(A) (B)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
12
34
56
78 9
10
11
12 3
4
56
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Supported ReactionsUsing Microwaves
E Gutterrez A Loupy G Bram E Ruiz-Hitzky Tetrahedron Lett 1989 30 945
Microwave-Assisted Deacetylationon Alumina
Varma et al J Chem Soc Perkin Trans 1 999 (1993)
Deprotection of Benzyl Esters viaMicrowave Thermolysis
A practical alternative to traditional catalytic hydrogenation
Varma et al Tetrahedron Lett 34 4603 (1993)
Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of
Carbonyl Compounds Using Microwaves
Varma Meshram Tetrahedron Lett 38 5427 (1997)
Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm
PersulfatendashClay using Microwave and Ultrasonic Irradiation
Varma Meshram Tetrahedron Lett 38 7973 (1997)
Solid Supported Solvent-freeOxidation under MW
Varma et al Tetrahedron Lett 1997 38 2043 and 7823
Solvent-free Reduction Using MW
Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction
Varma et al Tetrahedron Lett 1997 38 4337
Hydrodechlorination under continuous MW
Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)
Synthesis of Heterocyclic Compounds
Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)
Synthesis of Heterocyclic Compounds
Organometallic Reactions
Rearrangements
Rearrangements
INDOLIZINES
Heterocyclic systems 10- electronics
Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine
Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds
N
1
2
34567
8R2
R3
R1
Why interest for indolizinic products
Strong fluorescent properties luminiscent products luminiscent products
Potentially fluorescents marker Potentially laserldquoscintillatersrdquo
bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999
Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )
Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2
ldquoCalcium-entryrdquo blockers
Indolizines by irradiation with microwaves in MCR
RBr
O+
N
R1 R2+N
R2
R1
COR
AcOAl2O3 Mw
R=Ph p-Tolil Stiril
R1= H COOMeR2= COOEt COOMe
Asymmetric indolizines by irradiation with microwaves in MCR
R1
O
Cl+ R2
N NEtOOC
OOMe
Br BrN N
EtOOC
COR1
R2COR1
R2
OOMe
2 [Pd(PPh3)2Cl24 CuI
20 echiv Et3N THF tc 2h
R1=Ph 4-OMe-C6H4R2= Ph
U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003
A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new indolizines
[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical
II
IHH
COORCOOR
N C C
O
R2NCC
O
R1
(B)
(A)
R1
O
C C N R2
O
CCN
H H
ROOC COOR
R1
O
C C N R2
O
CCN
COOR COOR
ROOC COOR
2
2 ROOC C C COOR
R1
O
C CH N R2
O
CCHN
H H
N NCH CHC C
O O
R1 R2
- 2 HX TEAanhydrous solvents
X-
X-
N NCH2 CH2C C
O O
R1 R2
C C COORH
R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5
Y=H NO2 OCH3 CH3 Cl BrX=Br Cl
bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998
bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001
bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004
bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new substituted pyridinium-indolizines
Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate
COO NO2CHC
N NH3C
OR
I IN NH3C
OR
IN NH3C
OR
I
H
KFNMP
-HI
NMP
95oC 30 min
N NH3CO
RN NH3C
O
R
O OO
NO2
O
NO2
-2[H]-2[H]
II
I II
N NH3CO
R
O O
NO2
IN NH3C
O
R
O O
NO2
I
(9a-d)(10a-d)
(15a-d)
(A) (B)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
12
34
56
78 9
10
11
12 3
4
56
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Microwave-Assisted Deacetylationon Alumina
Varma et al J Chem Soc Perkin Trans 1 999 (1993)
Deprotection of Benzyl Esters viaMicrowave Thermolysis
A practical alternative to traditional catalytic hydrogenation
Varma et al Tetrahedron Lett 34 4603 (1993)
Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of
Carbonyl Compounds Using Microwaves
Varma Meshram Tetrahedron Lett 38 5427 (1997)
Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm
PersulfatendashClay using Microwave and Ultrasonic Irradiation
Varma Meshram Tetrahedron Lett 38 7973 (1997)
Solid Supported Solvent-freeOxidation under MW
Varma et al Tetrahedron Lett 1997 38 2043 and 7823
Solvent-free Reduction Using MW
Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction
Varma et al Tetrahedron Lett 1997 38 4337
Hydrodechlorination under continuous MW
Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)
Synthesis of Heterocyclic Compounds
Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)
Synthesis of Heterocyclic Compounds
Organometallic Reactions
Rearrangements
Rearrangements
INDOLIZINES
Heterocyclic systems 10- electronics
Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine
Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds
N
1
2
34567
8R2
R3
R1
Why interest for indolizinic products
Strong fluorescent properties luminiscent products luminiscent products
Potentially fluorescents marker Potentially laserldquoscintillatersrdquo
bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999
Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )
Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2
ldquoCalcium-entryrdquo blockers
Indolizines by irradiation with microwaves in MCR
RBr
O+
N
R1 R2+N
R2
R1
COR
AcOAl2O3 Mw
R=Ph p-Tolil Stiril
R1= H COOMeR2= COOEt COOMe
Asymmetric indolizines by irradiation with microwaves in MCR
R1
O
Cl+ R2
N NEtOOC
OOMe
Br BrN N
EtOOC
COR1
R2COR1
R2
OOMe
2 [Pd(PPh3)2Cl24 CuI
20 echiv Et3N THF tc 2h
R1=Ph 4-OMe-C6H4R2= Ph
U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003
A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new indolizines
[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical
II
IHH
COORCOOR
N C C
O
R2NCC
O
R1
(B)
(A)
R1
O
C C N R2
O
CCN
H H
ROOC COOR
R1
O
C C N R2
O
CCN
COOR COOR
ROOC COOR
2
2 ROOC C C COOR
R1
O
C CH N R2
O
CCHN
H H
N NCH CHC C
O O
R1 R2
- 2 HX TEAanhydrous solvents
X-
X-
N NCH2 CH2C C
O O
R1 R2
C C COORH
R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5
Y=H NO2 OCH3 CH3 Cl BrX=Br Cl
bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998
bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001
bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004
bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new substituted pyridinium-indolizines
Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate
COO NO2CHC
N NH3C
OR
I IN NH3C
OR
IN NH3C
OR
I
H
KFNMP
-HI
NMP
95oC 30 min
N NH3CO
RN NH3C
O
R
O OO
NO2
O
NO2
-2[H]-2[H]
II
I II
N NH3CO
R
O O
NO2
IN NH3C
O
R
O O
NO2
I
(9a-d)(10a-d)
(15a-d)
(A) (B)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
12
34
56
78 9
10
11
12 3
4
56
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Deprotection of Benzyl Esters viaMicrowave Thermolysis
A practical alternative to traditional catalytic hydrogenation
Varma et al Tetrahedron Lett 34 4603 (1993)
Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of
Carbonyl Compounds Using Microwaves
Varma Meshram Tetrahedron Lett 38 5427 (1997)
Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm
PersulfatendashClay using Microwave and Ultrasonic Irradiation
Varma Meshram Tetrahedron Lett 38 7973 (1997)
Solid Supported Solvent-freeOxidation under MW
Varma et al Tetrahedron Lett 1997 38 2043 and 7823
Solvent-free Reduction Using MW
Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction
Varma et al Tetrahedron Lett 1997 38 4337
Hydrodechlorination under continuous MW
Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)
Synthesis of Heterocyclic Compounds
Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)
Synthesis of Heterocyclic Compounds
Organometallic Reactions
Rearrangements
Rearrangements
INDOLIZINES
Heterocyclic systems 10- electronics
Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine
Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds
N
1
2
34567
8R2
R3
R1
Why interest for indolizinic products
Strong fluorescent properties luminiscent products luminiscent products
Potentially fluorescents marker Potentially laserldquoscintillatersrdquo
bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999
Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )
Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2
ldquoCalcium-entryrdquo blockers
Indolizines by irradiation with microwaves in MCR
RBr
O+
N
R1 R2+N
R2
R1
COR
AcOAl2O3 Mw
R=Ph p-Tolil Stiril
R1= H COOMeR2= COOEt COOMe
Asymmetric indolizines by irradiation with microwaves in MCR
R1
O
Cl+ R2
N NEtOOC
OOMe
Br BrN N
EtOOC
COR1
R2COR1
R2
OOMe
2 [Pd(PPh3)2Cl24 CuI
20 echiv Et3N THF tc 2h
R1=Ph 4-OMe-C6H4R2= Ph
U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003
A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new indolizines
[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical
II
IHH
COORCOOR
N C C
O
R2NCC
O
R1
(B)
(A)
R1
O
C C N R2
O
CCN
H H
ROOC COOR
R1
O
C C N R2
O
CCN
COOR COOR
ROOC COOR
2
2 ROOC C C COOR
R1
O
C CH N R2
O
CCHN
H H
N NCH CHC C
O O
R1 R2
- 2 HX TEAanhydrous solvents
X-
X-
N NCH2 CH2C C
O O
R1 R2
C C COORH
R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5
Y=H NO2 OCH3 CH3 Cl BrX=Br Cl
bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998
bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001
bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004
bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new substituted pyridinium-indolizines
Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate
COO NO2CHC
N NH3C
OR
I IN NH3C
OR
IN NH3C
OR
I
H
KFNMP
-HI
NMP
95oC 30 min
N NH3CO
RN NH3C
O
R
O OO
NO2
O
NO2
-2[H]-2[H]
II
I II
N NH3CO
R
O O
NO2
IN NH3C
O
R
O O
NO2
I
(9a-d)(10a-d)
(15a-d)
(A) (B)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
12
34
56
78 9
10
11
12 3
4
56
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Solid State Deoximation with Ammonium Persulfate-Silica gel Regeneration of
Carbonyl Compounds Using Microwaves
Varma Meshram Tetrahedron Lett 38 5427 (1997)
Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm
PersulfatendashClay using Microwave and Ultrasonic Irradiation
Varma Meshram Tetrahedron Lett 38 7973 (1997)
Solid Supported Solvent-freeOxidation under MW
Varma et al Tetrahedron Lett 1997 38 2043 and 7823
Solvent-free Reduction Using MW
Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction
Varma et al Tetrahedron Lett 1997 38 4337
Hydrodechlorination under continuous MW
Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)
Synthesis of Heterocyclic Compounds
Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)
Synthesis of Heterocyclic Compounds
Organometallic Reactions
Rearrangements
Rearrangements
INDOLIZINES
Heterocyclic systems 10- electronics
Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine
Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds
N
1
2
34567
8R2
R3
R1
Why interest for indolizinic products
Strong fluorescent properties luminiscent products luminiscent products
Potentially fluorescents marker Potentially laserldquoscintillatersrdquo
bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999
Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )
Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2
ldquoCalcium-entryrdquo blockers
Indolizines by irradiation with microwaves in MCR
RBr
O+
N
R1 R2+N
R2
R1
COR
AcOAl2O3 Mw
R=Ph p-Tolil Stiril
R1= H COOMeR2= COOEt COOMe
Asymmetric indolizines by irradiation with microwaves in MCR
R1
O
Cl+ R2
N NEtOOC
OOMe
Br BrN N
EtOOC
COR1
R2COR1
R2
OOMe
2 [Pd(PPh3)2Cl24 CuI
20 echiv Et3N THF tc 2h
R1=Ph 4-OMe-C6H4R2= Ph
U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003
A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new indolizines
[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical
II
IHH
COORCOOR
N C C
O
R2NCC
O
R1
(B)
(A)
R1
O
C C N R2
O
CCN
H H
ROOC COOR
R1
O
C C N R2
O
CCN
COOR COOR
ROOC COOR
2
2 ROOC C C COOR
R1
O
C CH N R2
O
CCHN
H H
N NCH CHC C
O O
R1 R2
- 2 HX TEAanhydrous solvents
X-
X-
N NCH2 CH2C C
O O
R1 R2
C C COORH
R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5
Y=H NO2 OCH3 CH3 Cl BrX=Br Cl
bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998
bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001
bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004
bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new substituted pyridinium-indolizines
Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate
COO NO2CHC
N NH3C
OR
I IN NH3C
OR
IN NH3C
OR
I
H
KFNMP
-HI
NMP
95oC 30 min
N NH3CO
RN NH3C
O
R
O OO
NO2
O
NO2
-2[H]-2[H]
II
I II
N NH3CO
R
O O
NO2
IN NH3C
O
R
O O
NO2
I
(9a-d)(10a-d)
(15a-d)
(A) (B)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
12
34
56
78 9
10
11
12 3
4
56
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Solid State Cleavage of SemicarbazonesPhenylhydrazones with Amm
PersulfatendashClay using Microwave and Ultrasonic Irradiation
Varma Meshram Tetrahedron Lett 38 7973 (1997)
Solid Supported Solvent-freeOxidation under MW
Varma et al Tetrahedron Lett 1997 38 2043 and 7823
Solvent-free Reduction Using MW
Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction
Varma et al Tetrahedron Lett 1997 38 4337
Hydrodechlorination under continuous MW
Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)
Synthesis of Heterocyclic Compounds
Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)
Synthesis of Heterocyclic Compounds
Organometallic Reactions
Rearrangements
Rearrangements
INDOLIZINES
Heterocyclic systems 10- electronics
Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine
Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds
N
1
2
34567
8R2
R3
R1
Why interest for indolizinic products
Strong fluorescent properties luminiscent products luminiscent products
Potentially fluorescents marker Potentially laserldquoscintillatersrdquo
bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999
Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )
Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2
ldquoCalcium-entryrdquo blockers
Indolizines by irradiation with microwaves in MCR
RBr
O+
N
R1 R2+N
R2
R1
COR
AcOAl2O3 Mw
R=Ph p-Tolil Stiril
R1= H COOMeR2= COOEt COOMe
Asymmetric indolizines by irradiation with microwaves in MCR
R1
O
Cl+ R2
N NEtOOC
OOMe
Br BrN N
EtOOC
COR1
R2COR1
R2
OOMe
2 [Pd(PPh3)2Cl24 CuI
20 echiv Et3N THF tc 2h
R1=Ph 4-OMe-C6H4R2= Ph
U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003
A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new indolizines
[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical
II
IHH
COORCOOR
N C C
O
R2NCC
O
R1
(B)
(A)
R1
O
C C N R2
O
CCN
H H
ROOC COOR
R1
O
C C N R2
O
CCN
COOR COOR
ROOC COOR
2
2 ROOC C C COOR
R1
O
C CH N R2
O
CCHN
H H
N NCH CHC C
O O
R1 R2
- 2 HX TEAanhydrous solvents
X-
X-
N NCH2 CH2C C
O O
R1 R2
C C COORH
R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5
Y=H NO2 OCH3 CH3 Cl BrX=Br Cl
bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998
bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001
bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004
bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new substituted pyridinium-indolizines
Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate
COO NO2CHC
N NH3C
OR
I IN NH3C
OR
IN NH3C
OR
I
H
KFNMP
-HI
NMP
95oC 30 min
N NH3CO
RN NH3C
O
R
O OO
NO2
O
NO2
-2[H]-2[H]
II
I II
N NH3CO
R
O O
NO2
IN NH3C
O
R
O O
NO2
I
(9a-d)(10a-d)
(15a-d)
(A) (B)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
12
34
56
78 9
10
11
12 3
4
56
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Solid Supported Solvent-freeOxidation under MW
Varma et al Tetrahedron Lett 1997 38 2043 and 7823
Solvent-free Reduction Using MW
Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction
Varma et al Tetrahedron Lett 1997 38 4337
Hydrodechlorination under continuous MW
Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)
Synthesis of Heterocyclic Compounds
Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)
Synthesis of Heterocyclic Compounds
Organometallic Reactions
Rearrangements
Rearrangements
INDOLIZINES
Heterocyclic systems 10- electronics
Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine
Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds
N
1
2
34567
8R2
R3
R1
Why interest for indolizinic products
Strong fluorescent properties luminiscent products luminiscent products
Potentially fluorescents marker Potentially laserldquoscintillatersrdquo
bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999
Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )
Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2
ldquoCalcium-entryrdquo blockers
Indolizines by irradiation with microwaves in MCR
RBr
O+
N
R1 R2+N
R2
R1
COR
AcOAl2O3 Mw
R=Ph p-Tolil Stiril
R1= H COOMeR2= COOEt COOMe
Asymmetric indolizines by irradiation with microwaves in MCR
R1
O
Cl+ R2
N NEtOOC
OOMe
Br BrN N
EtOOC
COR1
R2COR1
R2
OOMe
2 [Pd(PPh3)2Cl24 CuI
20 echiv Et3N THF tc 2h
R1=Ph 4-OMe-C6H4R2= Ph
U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003
A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new indolizines
[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical
II
IHH
COORCOOR
N C C
O
R2NCC
O
R1
(B)
(A)
R1
O
C C N R2
O
CCN
H H
ROOC COOR
R1
O
C C N R2
O
CCN
COOR COOR
ROOC COOR
2
2 ROOC C C COOR
R1
O
C CH N R2
O
CCHN
H H
N NCH CHC C
O O
R1 R2
- 2 HX TEAanhydrous solvents
X-
X-
N NCH2 CH2C C
O O
R1 R2
C C COORH
R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5
Y=H NO2 OCH3 CH3 Cl BrX=Br Cl
bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998
bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001
bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004
bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new substituted pyridinium-indolizines
Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate
COO NO2CHC
N NH3C
OR
I IN NH3C
OR
IN NH3C
OR
I
H
KFNMP
-HI
NMP
95oC 30 min
N NH3CO
RN NH3C
O
R
O OO
NO2
O
NO2
-2[H]-2[H]
II
I II
N NH3CO
R
O O
NO2
IN NH3C
O
R
O O
NO2
I
(9a-d)(10a-d)
(15a-d)
(A) (B)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
12
34
56
78 9
10
11
12 3
4
56
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Solvent-free Reduction Using MW
Chemoselective reduction of trans-cinnamaldehyde olefinic moiety remains intact and the aldehyde functionality is reduced in a facile reaction
Varma et al Tetrahedron Lett 1997 38 4337
Hydrodechlorination under continuous MW
Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)
Synthesis of Heterocyclic Compounds
Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)
Synthesis of Heterocyclic Compounds
Organometallic Reactions
Rearrangements
Rearrangements
INDOLIZINES
Heterocyclic systems 10- electronics
Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine
Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds
N
1
2
34567
8R2
R3
R1
Why interest for indolizinic products
Strong fluorescent properties luminiscent products luminiscent products
Potentially fluorescents marker Potentially laserldquoscintillatersrdquo
bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999
Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )
Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2
ldquoCalcium-entryrdquo blockers
Indolizines by irradiation with microwaves in MCR
RBr
O+
N
R1 R2+N
R2
R1
COR
AcOAl2O3 Mw
R=Ph p-Tolil Stiril
R1= H COOMeR2= COOEt COOMe
Asymmetric indolizines by irradiation with microwaves in MCR
R1
O
Cl+ R2
N NEtOOC
OOMe
Br BrN N
EtOOC
COR1
R2COR1
R2
OOMe
2 [Pd(PPh3)2Cl24 CuI
20 echiv Et3N THF tc 2h
R1=Ph 4-OMe-C6H4R2= Ph
U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003
A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new indolizines
[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical
II
IHH
COORCOOR
N C C
O
R2NCC
O
R1
(B)
(A)
R1
O
C C N R2
O
CCN
H H
ROOC COOR
R1
O
C C N R2
O
CCN
COOR COOR
ROOC COOR
2
2 ROOC C C COOR
R1
O
C CH N R2
O
CCHN
H H
N NCH CHC C
O O
R1 R2
- 2 HX TEAanhydrous solvents
X-
X-
N NCH2 CH2C C
O O
R1 R2
C C COORH
R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5
Y=H NO2 OCH3 CH3 Cl BrX=Br Cl
bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998
bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001
bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004
bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new substituted pyridinium-indolizines
Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate
COO NO2CHC
N NH3C
OR
I IN NH3C
OR
IN NH3C
OR
I
H
KFNMP
-HI
NMP
95oC 30 min
N NH3CO
RN NH3C
O
R
O OO
NO2
O
NO2
-2[H]-2[H]
II
I II
N NH3CO
R
O O
NO2
IN NH3C
O
R
O O
NO2
I
(9a-d)(10a-d)
(15a-d)
(A) (B)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
12
34
56
78 9
10
11
12 3
4
56
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Hydrodechlorination under continuous MW
Pillai Sahle-Demessie Varma Green Chemistry 6 295 (2004)
Synthesis of Heterocyclic Compounds
Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)
Synthesis of Heterocyclic Compounds
Organometallic Reactions
Rearrangements
Rearrangements
INDOLIZINES
Heterocyclic systems 10- electronics
Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine
Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds
N
1
2
34567
8R2
R3
R1
Why interest for indolizinic products
Strong fluorescent properties luminiscent products luminiscent products
Potentially fluorescents marker Potentially laserldquoscintillatersrdquo
bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999
Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )
Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2
ldquoCalcium-entryrdquo blockers
Indolizines by irradiation with microwaves in MCR
RBr
O+
N
R1 R2+N
R2
R1
COR
AcOAl2O3 Mw
R=Ph p-Tolil Stiril
R1= H COOMeR2= COOEt COOMe
Asymmetric indolizines by irradiation with microwaves in MCR
R1
O
Cl+ R2
N NEtOOC
OOMe
Br BrN N
EtOOC
COR1
R2COR1
R2
OOMe
2 [Pd(PPh3)2Cl24 CuI
20 echiv Et3N THF tc 2h
R1=Ph 4-OMe-C6H4R2= Ph
U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003
A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new indolizines
[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical
II
IHH
COORCOOR
N C C
O
R2NCC
O
R1
(B)
(A)
R1
O
C C N R2
O
CCN
H H
ROOC COOR
R1
O
C C N R2
O
CCN
COOR COOR
ROOC COOR
2
2 ROOC C C COOR
R1
O
C CH N R2
O
CCHN
H H
N NCH CHC C
O O
R1 R2
- 2 HX TEAanhydrous solvents
X-
X-
N NCH2 CH2C C
O O
R1 R2
C C COORH
R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5
Y=H NO2 OCH3 CH3 Cl BrX=Br Cl
bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998
bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001
bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004
bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new substituted pyridinium-indolizines
Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate
COO NO2CHC
N NH3C
OR
I IN NH3C
OR
IN NH3C
OR
I
H
KFNMP
-HI
NMP
95oC 30 min
N NH3CO
RN NH3C
O
R
O OO
NO2
O
NO2
-2[H]-2[H]
II
I II
N NH3CO
R
O O
NO2
IN NH3C
O
R
O O
NO2
I
(9a-d)(10a-d)
(15a-d)
(A) (B)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
12
34
56
78 9
10
11
12 3
4
56
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Synthesis of Heterocyclic Compounds
Varma et al J Chem Soc Perkin Trans 1 4093 (1998)Varma J Heterocycl Chem 36 1565 (1999)
Synthesis of Heterocyclic Compounds
Organometallic Reactions
Rearrangements
Rearrangements
INDOLIZINES
Heterocyclic systems 10- electronics
Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine
Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds
N
1
2
34567
8R2
R3
R1
Why interest for indolizinic products
Strong fluorescent properties luminiscent products luminiscent products
Potentially fluorescents marker Potentially laserldquoscintillatersrdquo
bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999
Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )
Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2
ldquoCalcium-entryrdquo blockers
Indolizines by irradiation with microwaves in MCR
RBr
O+
N
R1 R2+N
R2
R1
COR
AcOAl2O3 Mw
R=Ph p-Tolil Stiril
R1= H COOMeR2= COOEt COOMe
Asymmetric indolizines by irradiation with microwaves in MCR
R1
O
Cl+ R2
N NEtOOC
OOMe
Br BrN N
EtOOC
COR1
R2COR1
R2
OOMe
2 [Pd(PPh3)2Cl24 CuI
20 echiv Et3N THF tc 2h
R1=Ph 4-OMe-C6H4R2= Ph
U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003
A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new indolizines
[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical
II
IHH
COORCOOR
N C C
O
R2NCC
O
R1
(B)
(A)
R1
O
C C N R2
O
CCN
H H
ROOC COOR
R1
O
C C N R2
O
CCN
COOR COOR
ROOC COOR
2
2 ROOC C C COOR
R1
O
C CH N R2
O
CCHN
H H
N NCH CHC C
O O
R1 R2
- 2 HX TEAanhydrous solvents
X-
X-
N NCH2 CH2C C
O O
R1 R2
C C COORH
R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5
Y=H NO2 OCH3 CH3 Cl BrX=Br Cl
bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998
bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001
bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004
bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new substituted pyridinium-indolizines
Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate
COO NO2CHC
N NH3C
OR
I IN NH3C
OR
IN NH3C
OR
I
H
KFNMP
-HI
NMP
95oC 30 min
N NH3CO
RN NH3C
O
R
O OO
NO2
O
NO2
-2[H]-2[H]
II
I II
N NH3CO
R
O O
NO2
IN NH3C
O
R
O O
NO2
I
(9a-d)(10a-d)
(15a-d)
(A) (B)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
12
34
56
78 9
10
11
12 3
4
56
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Synthesis of Heterocyclic Compounds
Organometallic Reactions
Rearrangements
Rearrangements
INDOLIZINES
Heterocyclic systems 10- electronics
Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine
Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds
N
1
2
34567
8R2
R3
R1
Why interest for indolizinic products
Strong fluorescent properties luminiscent products luminiscent products
Potentially fluorescents marker Potentially laserldquoscintillatersrdquo
bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999
Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )
Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2
ldquoCalcium-entryrdquo blockers
Indolizines by irradiation with microwaves in MCR
RBr
O+
N
R1 R2+N
R2
R1
COR
AcOAl2O3 Mw
R=Ph p-Tolil Stiril
R1= H COOMeR2= COOEt COOMe
Asymmetric indolizines by irradiation with microwaves in MCR
R1
O
Cl+ R2
N NEtOOC
OOMe
Br BrN N
EtOOC
COR1
R2COR1
R2
OOMe
2 [Pd(PPh3)2Cl24 CuI
20 echiv Et3N THF tc 2h
R1=Ph 4-OMe-C6H4R2= Ph
U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003
A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new indolizines
[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical
II
IHH
COORCOOR
N C C
O
R2NCC
O
R1
(B)
(A)
R1
O
C C N R2
O
CCN
H H
ROOC COOR
R1
O
C C N R2
O
CCN
COOR COOR
ROOC COOR
2
2 ROOC C C COOR
R1
O
C CH N R2
O
CCHN
H H
N NCH CHC C
O O
R1 R2
- 2 HX TEAanhydrous solvents
X-
X-
N NCH2 CH2C C
O O
R1 R2
C C COORH
R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5
Y=H NO2 OCH3 CH3 Cl BrX=Br Cl
bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998
bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001
bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004
bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new substituted pyridinium-indolizines
Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate
COO NO2CHC
N NH3C
OR
I IN NH3C
OR
IN NH3C
OR
I
H
KFNMP
-HI
NMP
95oC 30 min
N NH3CO
RN NH3C
O
R
O OO
NO2
O
NO2
-2[H]-2[H]
II
I II
N NH3CO
R
O O
NO2
IN NH3C
O
R
O O
NO2
I
(9a-d)(10a-d)
(15a-d)
(A) (B)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
12
34
56
78 9
10
11
12 3
4
56
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Organometallic Reactions
Rearrangements
Rearrangements
INDOLIZINES
Heterocyclic systems 10- electronics
Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine
Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds
N
1
2
34567
8R2
R3
R1
Why interest for indolizinic products
Strong fluorescent properties luminiscent products luminiscent products
Potentially fluorescents marker Potentially laserldquoscintillatersrdquo
bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999
Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )
Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2
ldquoCalcium-entryrdquo blockers
Indolizines by irradiation with microwaves in MCR
RBr
O+
N
R1 R2+N
R2
R1
COR
AcOAl2O3 Mw
R=Ph p-Tolil Stiril
R1= H COOMeR2= COOEt COOMe
Asymmetric indolizines by irradiation with microwaves in MCR
R1
O
Cl+ R2
N NEtOOC
OOMe
Br BrN N
EtOOC
COR1
R2COR1
R2
OOMe
2 [Pd(PPh3)2Cl24 CuI
20 echiv Et3N THF tc 2h
R1=Ph 4-OMe-C6H4R2= Ph
U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003
A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new indolizines
[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical
II
IHH
COORCOOR
N C C
O
R2NCC
O
R1
(B)
(A)
R1
O
C C N R2
O
CCN
H H
ROOC COOR
R1
O
C C N R2
O
CCN
COOR COOR
ROOC COOR
2
2 ROOC C C COOR
R1
O
C CH N R2
O
CCHN
H H
N NCH CHC C
O O
R1 R2
- 2 HX TEAanhydrous solvents
X-
X-
N NCH2 CH2C C
O O
R1 R2
C C COORH
R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5
Y=H NO2 OCH3 CH3 Cl BrX=Br Cl
bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998
bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001
bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004
bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new substituted pyridinium-indolizines
Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate
COO NO2CHC
N NH3C
OR
I IN NH3C
OR
IN NH3C
OR
I
H
KFNMP
-HI
NMP
95oC 30 min
N NH3CO
RN NH3C
O
R
O OO
NO2
O
NO2
-2[H]-2[H]
II
I II
N NH3CO
R
O O
NO2
IN NH3C
O
R
O O
NO2
I
(9a-d)(10a-d)
(15a-d)
(A) (B)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
12
34
56
78 9
10
11
12 3
4
56
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Rearrangements
Rearrangements
INDOLIZINES
Heterocyclic systems 10- electronics
Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine
Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds
N
1
2
34567
8R2
R3
R1
Why interest for indolizinic products
Strong fluorescent properties luminiscent products luminiscent products
Potentially fluorescents marker Potentially laserldquoscintillatersrdquo
bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999
Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )
Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2
ldquoCalcium-entryrdquo blockers
Indolizines by irradiation with microwaves in MCR
RBr
O+
N
R1 R2+N
R2
R1
COR
AcOAl2O3 Mw
R=Ph p-Tolil Stiril
R1= H COOMeR2= COOEt COOMe
Asymmetric indolizines by irradiation with microwaves in MCR
R1
O
Cl+ R2
N NEtOOC
OOMe
Br BrN N
EtOOC
COR1
R2COR1
R2
OOMe
2 [Pd(PPh3)2Cl24 CuI
20 echiv Et3N THF tc 2h
R1=Ph 4-OMe-C6H4R2= Ph
U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003
A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new indolizines
[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical
II
IHH
COORCOOR
N C C
O
R2NCC
O
R1
(B)
(A)
R1
O
C C N R2
O
CCN
H H
ROOC COOR
R1
O
C C N R2
O
CCN
COOR COOR
ROOC COOR
2
2 ROOC C C COOR
R1
O
C CH N R2
O
CCHN
H H
N NCH CHC C
O O
R1 R2
- 2 HX TEAanhydrous solvents
X-
X-
N NCH2 CH2C C
O O
R1 R2
C C COORH
R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5
Y=H NO2 OCH3 CH3 Cl BrX=Br Cl
bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998
bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001
bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004
bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new substituted pyridinium-indolizines
Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate
COO NO2CHC
N NH3C
OR
I IN NH3C
OR
IN NH3C
OR
I
H
KFNMP
-HI
NMP
95oC 30 min
N NH3CO
RN NH3C
O
R
O OO
NO2
O
NO2
-2[H]-2[H]
II
I II
N NH3CO
R
O O
NO2
IN NH3C
O
R
O O
NO2
I
(9a-d)(10a-d)
(15a-d)
(A) (B)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
12
34
56
78 9
10
11
12 3
4
56
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Rearrangements
INDOLIZINES
Heterocyclic systems 10- electronics
Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine
Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds
N
1
2
34567
8R2
R3
R1
Why interest for indolizinic products
Strong fluorescent properties luminiscent products luminiscent products
Potentially fluorescents marker Potentially laserldquoscintillatersrdquo
bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999
Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )
Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2
ldquoCalcium-entryrdquo blockers
Indolizines by irradiation with microwaves in MCR
RBr
O+
N
R1 R2+N
R2
R1
COR
AcOAl2O3 Mw
R=Ph p-Tolil Stiril
R1= H COOMeR2= COOEt COOMe
Asymmetric indolizines by irradiation with microwaves in MCR
R1
O
Cl+ R2
N NEtOOC
OOMe
Br BrN N
EtOOC
COR1
R2COR1
R2
OOMe
2 [Pd(PPh3)2Cl24 CuI
20 echiv Et3N THF tc 2h
R1=Ph 4-OMe-C6H4R2= Ph
U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003
A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new indolizines
[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical
II
IHH
COORCOOR
N C C
O
R2NCC
O
R1
(B)
(A)
R1
O
C C N R2
O
CCN
H H
ROOC COOR
R1
O
C C N R2
O
CCN
COOR COOR
ROOC COOR
2
2 ROOC C C COOR
R1
O
C CH N R2
O
CCHN
H H
N NCH CHC C
O O
R1 R2
- 2 HX TEAanhydrous solvents
X-
X-
N NCH2 CH2C C
O O
R1 R2
C C COORH
R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5
Y=H NO2 OCH3 CH3 Cl BrX=Br Cl
bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998
bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001
bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004
bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new substituted pyridinium-indolizines
Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate
COO NO2CHC
N NH3C
OR
I IN NH3C
OR
IN NH3C
OR
I
H
KFNMP
-HI
NMP
95oC 30 min
N NH3CO
RN NH3C
O
R
O OO
NO2
O
NO2
-2[H]-2[H]
II
I II
N NH3CO
R
O O
NO2
IN NH3C
O
R
O O
NO2
I
(9a-d)(10a-d)
(15a-d)
(A) (B)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
12
34
56
78 9
10
11
12 3
4
56
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
INDOLIZINES
Heterocyclic systems 10- electronics
Structure of many naturals alkaloids (-) slaframine (-) dendroprimine indalozine coniceine
Key intermediates in indolizidines bisindolizines ciclofans ciclazines synthesis- biologic actives compounds
N
1
2
34567
8R2
R3
R1
Why interest for indolizinic products
Strong fluorescent properties luminiscent products luminiscent products
Potentially fluorescents marker Potentially laserldquoscintillatersrdquo
bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999
Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )
Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2
ldquoCalcium-entryrdquo blockers
Indolizines by irradiation with microwaves in MCR
RBr
O+
N
R1 R2+N
R2
R1
COR
AcOAl2O3 Mw
R=Ph p-Tolil Stiril
R1= H COOMeR2= COOEt COOMe
Asymmetric indolizines by irradiation with microwaves in MCR
R1
O
Cl+ R2
N NEtOOC
OOMe
Br BrN N
EtOOC
COR1
R2COR1
R2
OOMe
2 [Pd(PPh3)2Cl24 CuI
20 echiv Et3N THF tc 2h
R1=Ph 4-OMe-C6H4R2= Ph
U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003
A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new indolizines
[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical
II
IHH
COORCOOR
N C C
O
R2NCC
O
R1
(B)
(A)
R1
O
C C N R2
O
CCN
H H
ROOC COOR
R1
O
C C N R2
O
CCN
COOR COOR
ROOC COOR
2
2 ROOC C C COOR
R1
O
C CH N R2
O
CCHN
H H
N NCH CHC C
O O
R1 R2
- 2 HX TEAanhydrous solvents
X-
X-
N NCH2 CH2C C
O O
R1 R2
C C COORH
R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5
Y=H NO2 OCH3 CH3 Cl BrX=Br Cl
bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998
bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001
bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004
bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new substituted pyridinium-indolizines
Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate
COO NO2CHC
N NH3C
OR
I IN NH3C
OR
IN NH3C
OR
I
H
KFNMP
-HI
NMP
95oC 30 min
N NH3CO
RN NH3C
O
R
O OO
NO2
O
NO2
-2[H]-2[H]
II
I II
N NH3CO
R
O O
NO2
IN NH3C
O
R
O O
NO2
I
(9a-d)(10a-d)
(15a-d)
(A) (B)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
12
34
56
78 9
10
11
12 3
4
56
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Why interest for indolizinic products
Strong fluorescent properties luminiscent products luminiscent products
Potentially fluorescents marker Potentially laserldquoscintillatersrdquo
bull Bioorg amp Med Chem Lett 16 59 2006bullTetrahedron 61 4643 2005bull Bioorg amp Med Chem 10 2905 2002bull J Org Chem 69 2332 2004bull Dyes and Pigments 46 23 2000bullJ of Luminiscence 82 155 1999
Strong inhibitors for lipid peroxydation (15-lipooxygenase inhibitors )
Biologic actives productsLigands for estrogen receptors Possible inhibitory activity for phospholipase A2
ldquoCalcium-entryrdquo blockers
Indolizines by irradiation with microwaves in MCR
RBr
O+
N
R1 R2+N
R2
R1
COR
AcOAl2O3 Mw
R=Ph p-Tolil Stiril
R1= H COOMeR2= COOEt COOMe
Asymmetric indolizines by irradiation with microwaves in MCR
R1
O
Cl+ R2
N NEtOOC
OOMe
Br BrN N
EtOOC
COR1
R2COR1
R2
OOMe
2 [Pd(PPh3)2Cl24 CuI
20 echiv Et3N THF tc 2h
R1=Ph 4-OMe-C6H4R2= Ph
U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003
A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new indolizines
[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical
II
IHH
COORCOOR
N C C
O
R2NCC
O
R1
(B)
(A)
R1
O
C C N R2
O
CCN
H H
ROOC COOR
R1
O
C C N R2
O
CCN
COOR COOR
ROOC COOR
2
2 ROOC C C COOR
R1
O
C CH N R2
O
CCHN
H H
N NCH CHC C
O O
R1 R2
- 2 HX TEAanhydrous solvents
X-
X-
N NCH2 CH2C C
O O
R1 R2
C C COORH
R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5
Y=H NO2 OCH3 CH3 Cl BrX=Br Cl
bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998
bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001
bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004
bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new substituted pyridinium-indolizines
Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate
COO NO2CHC
N NH3C
OR
I IN NH3C
OR
IN NH3C
OR
I
H
KFNMP
-HI
NMP
95oC 30 min
N NH3CO
RN NH3C
O
R
O OO
NO2
O
NO2
-2[H]-2[H]
II
I II
N NH3CO
R
O O
NO2
IN NH3C
O
R
O O
NO2
I
(9a-d)(10a-d)
(15a-d)
(A) (B)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
12
34
56
78 9
10
11
12 3
4
56
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Indolizines by irradiation with microwaves in MCR
RBr
O+
N
R1 R2+N
R2
R1
COR
AcOAl2O3 Mw
R=Ph p-Tolil Stiril
R1= H COOMeR2= COOEt COOMe
Asymmetric indolizines by irradiation with microwaves in MCR
R1
O
Cl+ R2
N NEtOOC
OOMe
Br BrN N
EtOOC
COR1
R2COR1
R2
OOMe
2 [Pd(PPh3)2Cl24 CuI
20 echiv Et3N THF tc 2h
R1=Ph 4-OMe-C6H4R2= Ph
U Bora A Saikia R C Boruah ndash Organic Lett 5 (4) 435 2003
A Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new indolizines
[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical
II
IHH
COORCOOR
N C C
O
R2NCC
O
R1
(B)
(A)
R1
O
C C N R2
O
CCN
H H
ROOC COOR
R1
O
C C N R2
O
CCN
COOR COOR
ROOC COOR
2
2 ROOC C C COOR
R1
O
C CH N R2
O
CCHN
H H
N NCH CHC C
O O
R1 R2
- 2 HX TEAanhydrous solvents
X-
X-
N NCH2 CH2C C
O O
R1 R2
C C COORH
R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5
Y=H NO2 OCH3 CH3 Cl BrX=Br Cl
bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998
bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001
bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004
bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new substituted pyridinium-indolizines
Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate
COO NO2CHC
N NH3C
OR
I IN NH3C
OR
IN NH3C
OR
I
H
KFNMP
-HI
NMP
95oC 30 min
N NH3CO
RN NH3C
O
R
O OO
NO2
O
NO2
-2[H]-2[H]
II
I II
N NH3CO
R
O O
NO2
IN NH3C
O
R
O O
NO2
I
(9a-d)(10a-d)
(15a-d)
(A) (B)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
12
34
56
78 9
10
11
12 3
4
56
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Synthesis of new indolizines
[3+2] dipolar cycloaddition of symmetrical or non-symmetrical 44rsquo-bipyridinium-methyne-ylids with actives alkynes symmetrical or non-symmetrical
II
IHH
COORCOOR
N C C
O
R2NCC
O
R1
(B)
(A)
R1
O
C C N R2
O
CCN
H H
ROOC COOR
R1
O
C C N R2
O
CCN
COOR COOR
ROOC COOR
2
2 ROOC C C COOR
R1
O
C CH N R2
O
CCHN
H H
N NCH CHC C
O O
R1 R2
- 2 HX TEAanhydrous solvents
X-
X-
N NCH2 CH2C C
O O
R1 R2
C C COORH
R1= COOR C6H4YR2=COOR C6H4YR=CH3 C2H5
Y=H NO2 OCH3 CH3 Cl BrX=Br Cl
bullI Druţă R Dinică E Bacirccu I Humelnicu ndash Tetrahedron 54 10811 1998
bullR Dinică C Pettinari ndash Heterocycl Comm 07(4) 381 2001
bullA V Rotaru R P Dănac I Druţă ndash J Heterocyclic Chem 41 893 2004
bullA Rotaru I Druţă T Oeser T Muller ndash Helv Chim Acta 88 1798 2005
Synthesis of new substituted pyridinium-indolizines
Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate
COO NO2CHC
N NH3C
OR
I IN NH3C
OR
IN NH3C
OR
I
H
KFNMP
-HI
NMP
95oC 30 min
N NH3CO
RN NH3C
O
R
O OO
NO2
O
NO2
-2[H]-2[H]
II
I II
N NH3CO
R
O O
NO2
IN NH3C
O
R
O O
NO2
I
(9a-d)(10a-d)
(15a-d)
(A) (B)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
12
34
56
78 9
10
11
12 3
4
56
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Synthesis of new substituted pyridinium-indolizines
Indolizinic cycloadducts using like dipolarophile 4-nitro-phenyl propiolate
COO NO2CHC
N NH3C
OR
I IN NH3C
OR
IN NH3C
OR
I
H
KFNMP
-HI
NMP
95oC 30 min
N NH3CO
RN NH3C
O
R
O OO
NO2
O
NO2
-2[H]-2[H]
II
I II
N NH3CO
R
O O
NO2
IN NH3C
O
R
O O
NO2
I
(9a-d)(10a-d)
(15a-d)
(A) (B)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
12
34
56
78 9
10
11
12 3
4
56
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
C N
R1
CN
R1
R2
R2R1R2 CC
microunde KF alumina
2
R R
N NR X
+2
CH2
N X
CH2
NX
C
NR1
C
N
R1
R2
R2
R1
R2
C
C+
a) (C2H5)3N in C6H6sau N-metilpirolidona
b) microunde KF alumina
2
R
R
R
R
Indolizine synthesis in solid phase under microwaves
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Monoindolizine synthesis in solid phase under microwaves
N
N
CH3
OR
I
I
b)Et3NNMP
50-60oC 6-9h
(9a-d)
+ HC C COOC2H5
a) KFAl2O3
MW
10 min 95oC
c)KFAl2O3
95oC 10 min
N
N
CH3
O
R
I
O
OC2H5
(12a-d)
a R= OCH3b R= C6H5c R= p-C6H4-OCH3d R= p-C6H4-NO2
Reaction conditions and the yelds for synthesized compounds (12a-d)
Comp
Solution Solid phase Microwaves
Time
(min)
T
(degC)
Time
(min)
T
(degC)
Time
(min)
T
(degC)
12a 480 50 63 10 95 57 10 95 84
12b 480 50 61 10 95 50 10 95 77
12c 480 55 71 10 95 52 10 95 85
12d 480 60 53 10 95 47 10 95 71
bull B Furdui R Dinică I Druţă M Demeunynck ndashSynthesis 16 2640 2006
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Benefits of MW-Assisted Reactions
bull Higher temperatures (superheating sealed vessels)
bull 1048707 Faster reactions higher yields any solvent (bp)
bull 1048707 Absolute control over reaction parametersbull 1048707 Selective heatingactivation of catalysts
specific effectsbull 1048707 Energy efficient rapid energy transferbull 1048707 Can do things that you can not do
conventionallybull 1048707 Automation parallel synthesis ndash combichem
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
MW-Assisted Solvent-free Three Component Coupling
Formation of Propargylamines
Ju Li and Varma QSAR amp Combinatorial Science 2004 23 891
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Solvent-free Synthesis of Ionic Liquids
Varma Namboodiri Chem Commun 2001 643Varma Namboodiri Pure Appl Chem 2001 73 1307Namboodiri Varma Chem Commun 2002 342
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
MW Synthesis ofTetrahalideindate(III)-based IL
Kim and Varma J Org Chem 2005 70 7882
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
PEG a Biodegradable ldquoSolventrdquobull 1048707 PEG has been applied in bioseparationsbull 1048707 PEG is on the FDArsquos GRAS list (compounds Generallybull Recognized as Safe) and has been approved by the FDA forbull Internal consumptionbull 1048707 PEG is weakly immunogenic a factor which has enabledbull the development of PEGndashprotein conjugates as drugsbull 1048707 Aqueous solutions of PEG are biocompatible and arebull utilized in tissue culture media and for organ preservationbull 1048707 PEGs are nonvolatilebull 1048707 PEG has low flammabilitybull 1048707 PEG is biodegradable
J Chen S K Spear J G Huddleston RD Rogers Green Chem 2005 7 64
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Suzuki Cross-Coupling Reactionin PEG Accelerated by Microwaves
V Namboodiri R S Varma Green Chemistry 2001 3 146
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Advantages of Present Approach
PEG offers a convenient recyclable reaction medium
Good substitute for volatile organic solvents The microwave heating offers a rapid and clean
alternative at high solid concentration and reduces the reaction times from hours to minutes
The recyclability of the catalyst makes the reaction economically and potentially viable for commercial applications
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Water as a ldquocleanerrdquo solvent
bull Water is not a popular choice of solventbull reactivity in heterogeneous aqueous media isbull not very well understoodbull But It brings biochemistry and organicbull chemistry closer together in the beneficial usebull of water as the reaction medium it is abundantbull inexpensive and clean
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Cu (I) Catalyzed Click Chemistry
P Appukkuttan W Dehaen V V Fokin E Van der EyckenOrg Lett 2004 6 4223
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
N-alkylation of Aminesusing Alkyl Halides
Ju Y Varma R S Green Chem 2004 6 219-221
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Aqueous N-alkylation of Aminesusing Microwave Irradiation
Ju Y Varma R S Green Chem 2004 6 219-221
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Why Amines and Heterocycles
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
MW Synthesis of N-Aryl Azacycloalkanes
Ju Varma Tetrahedron Lett 2005 46 6011Ju Varma J Org Chem 2006 71 135
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Choice of Reaction Media
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
MW -assisted one-pot synthesis of triazoles
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Designing a ldquogreenerrdquo synthesisbull Planbull Maximize convergencebull Consider using renewable starting materialsbull Avoid super toxic reagentsbull Strive for high atom economy
ndash Use catalytic over stoichiometricndash Avoid auxiliaries and protecting groups
bull Consider greener solventsbull Minimize number of purifications
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Take Awaysbull ldquoGreen chemistryrdquo is not so far away from
what we do everydayndash High yieldsndash Minimal number of stepsndash Minimize number of purifications
bull Green principles to keep in mindndash Strive for atom economyndash Consider the toxicity and necessity of
reagents and solvents
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Green Chemistry OpportunitiesConferences
ndash Annual ACS Green Chemistry and Engineering Conference
ndash Annual Gordon Conferenece Green Chemistry
bull Fundingndash PRF green chemistry grantsndash NSF green chemistry grantsndash EPA funding
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Conclusion
Green chemistry Not a solution
to all environmental problems But the most fundamental approach to preventing pollution
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
bull Today a large body of work on microwave-assisted synthesis exists in the published and patent literature
bull Many review articles several books and information on the world-wide-web already provide extensive coverage of the subject
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Lead References
bull Lidstroumlm P Tierney JP Wathey B Westman J Tetrahedron 2001 57 9225
bull Hayes Brittany L Microwave Synthesis Chemistry at the Speed of Light North Carolina CEM Publishing 2002
bull Tierney JP and P Lidstroumlm ed Microwave Assisted Organic Synthesis Oxford Blackwell Publishing Ltd 2005
bull de la Hoz A Diaz-Ortiz A Moreno A Chem Soc Rev 2005 34 164
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
Lead Referencesreviews
A Loupy A Petit J Hamelin F Texier- Boullet P Jacquault D Math_
Synthesis1998 1213ndash1234 R S Varma Green Chem 1999 43ndash55 M
Kidawi Pure Appl Chem 2001 73 147ndash151 R S Varma Pure Appl
Chem 2001 73 193ndash198 R S Varma Tetrahedron 2002 58 1235ndash1255
R S Varma Advances in Green Chemistry Chemical Syntheses Using
Microwave Irradiation Kavitha Printers Bangalore 2002 A K Bose B K
Banik N Lavlinskaia M Jayaraman M S Manhas Chemtech 1997 27
18ndash24 A K Bose M S Manhas S N Ganguly A H Sharma B K
Banik Synthesis 2002 1578ndash1591 C R Strauss R W Trainor Aust J
Chem 1995 48 1665ndash1692 C R Strauss Aust J Chem 1999 52 83ndash
96 C R Strauss
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
References books
Microwaves in Combinatorial and High-Throughput Synthesis (Ed C O Kappe)
Kluwer Dordrecht 2003 (a special issue of Mol Diversity 2003 7 pp 95ndash307)
Stadler C O Kappe Microwave-Assisted Organic Synthesis (Eds P Lidstr_m J P
Tierney) Blackwell Publishing Oxford 2005 (Chapter 7)
A Loupy (Ed) Microwaves in Organic Synthesis Wiley-VCH Weinheim 2002
B L Hayes Microwave Synthesis Chemistry at the Speed of Light CEM Publishing
Matthews NC 2002
P Lidstrom J P Tierney (Eds) Microwave- Assisted Organic Synthesis Blackwell
Publishing Oxford 2005
For online resources on microwave-assisted organic synthesis (MAOS) see
wwwmaosnet
118
THANK YOU
FOR YOUR ATTENTION
118
THANK YOU
FOR YOUR ATTENTION
Top Related