Unit 3: Aromatic and Heterocyclic Chemistry Cytotoxin- Inhibits DNA-topoisomerase enzymes Happy Tree...
-
Upload
waylon-craner -
Category
Documents
-
view
220 -
download
1
Transcript of Unit 3: Aromatic and Heterocyclic Chemistry Cytotoxin- Inhibits DNA-topoisomerase enzymes Happy Tree...
Unit 3: Aromatic and Heterocyclic Chemistry
Cytotoxin- Inhibits DNA-topoisomerase enzymes
Happy Tree(China)
Aromatic Compounds
• Many aromatic substances have rather simple structures and contain a six-carbon unit (C6H5)
• Arenes = aromatic hydrocarbon• Aromatic: refers to the level of stability for
an arene
• Benzene: is the parent hydrocarbon of the class or aromatic compounds
When Is A Molecule Aromatic?• For a molecule to be aromatic it must:
• Be cyclic• Have a p-orbital on every atom in ring• Be planar• Posses 4n+2 p electrons (n = any integer)
benzene naphthalene
+
cyclopropenyl cation[14]-Annulene
Erich Hückel
Discovery of Benzene
• Isolated in 1825 by Michael Faraday who determined C:H ratio to be 1:1.
• Synthesized in 1834 by Eilhard Mitscherlich who determined molecular formula to be C6H6.
• Other related compounds with low C:H ratios had a pleasant smell, so they were classified as aromatic. =>
Benzene properties
• The carbon to hydrogen ration in benzene suggest a highly unsaturated structure, however it behaves as if it were saturated.
• Does not decolorize bromine solution the way alkenes and alkynes do
• It is not easily oxidized by potassium permanganate
• Does not undergo addition reactions the same as alkenes or alkynes
Benzene
• Benzene is one of the most important commercial organic chemicals with approximately 17 billion pounds produced annually the United States alone.
8
Two Lewis structures for the benzene ring.
• Friedrich Kekule (1865) proposed the tetracovalence of carbon in the structure of benzene (alternating double single bonds)
Kekulé Structure
• Proposed in 1866 by Friedrich Kekulé, shortly after multiple bonds were suggested.
• Thus benzene is often written as a circle to remind us of the delocalize nature of the electrons
• Failed to explain existence of only one isomer of 1,2-dichlorobenzene.
CC
CC
C
C
H
H
HH
H
H
12
Some common mono-substituted benzene molecules
Toluene, sometimes you see this on marker pens ”contains no toluene”
Has the condensed structural
formula C6H5CH3
Common Names of Benzene Derivatives
OH OCH3NH2CH3
phenol toluene aniline anisole
CH
CH2 C
O
CH3C
O
HC
O
OH
styrene acetophenone benzaldehyde benzoic acid=>
Disubstituted Benzenes
The prefixes ortho-, meta-, and para- arecommonly used for the 1,2-, 1,3-, and 1,4-positions, respectively.
Br
Bro-dibromobenzene or1,2-dibromobenzene
HO
NO2
p-nitrophenol or4-nitrophenol
=>
3 or More Substituents Use the smallest possible numbers, butthe carbon with a functional group is #1.
NO2
NO2
O2N
1,3,5-trinitrobenzene
NO2
NO2
O2N
OH
2,4,6-trinitrophenol
=>
Phenyl and Benzyl
• Aromatic hydrocarbons are classified as arenes.
• The symbol Ar is used for an aryl group ( just as R symbolizes alkyl group)
• Two groups with special names occur frequently in aromatic compounds: phenyl group and benzyl group
Phenyl and Benzyl
Br
phenyl bromide
CH2Br
benzyl bromide
Phenyl indicates the benzene ringattachment. The benzyl group hasan additional carbon.
=>
Common Names forDisubstituted Benzenes
CH3
CH3
CH3
CH3H3C
CH3
CO OH
OH
H3Cm-xylene mesitylene o-toluic acid p-cresol
=>
Reactivity of Polynuclear Hydrocarbons
As the number of aromatic rings increases, the resonance energy per ring decreases, so larger PAH’s will add Br2.
H Br
H BrH Br
Br
H
(mixture of cis and trans isomers) =>
Physical Properties
• Melting points: More symmetrical than corresponding alkane, pack better into crystals, so higher melting points.
• Boiling points: Dependent on dipole moment, so ortho > meta > para, for disubstituted benzenes.
• Density: More dense than nonaromatics, less dense than water.
• Solubility: Generally insoluble in water. =>
Electrophilic Aromatic substitution
• The most common reaction of aromatic compounds involves substitution of other atoms or groups for a ring hydrogen
• Chlorination
• C6H6 + Cl2 ----- C6H5Cl + HCl FeCl3 is catalyst
Friedel-Crafts reaction
• Refers to Alkylation of aromatics
• The Friedel-Craft alkylation reaction has some limitations…it cannot be applied to an aromatic ring that already has one it a nitro or sulfonic acid group
Ortho, Para-directing and Meta-directing groups
• Substituents already present on an aromatic ring determine the position taken by a new substituent.
• Certain groups are ortho, para directing, and others are meta directing
Directing and activation effects of common functional groups (groups are
listed in decreasing order of activation)
• Substituent group• -NH2, -NHR, -NR2
• -OH, -OHCH3, -OOR
• O• -NHC—R
• -CH3, -CH2,CH3, -R
• ________________________• -F, -Cl, -Br, -I• ________________________
• Name of group • Amino• Hydroxyl, alkoxy
• acylamino• Alkyl• ________________________• Halo
• ________________________
Directing and activation effects of common functional groups (groups are
listed in decreasing order of activation)Substituent group O O-C-R, -C-OH acyl, carboxy O O-C-NH2, -C-OR carboxamindo, carboalkoxy O-S-OH sulfonic acid O-C=N cyano O-N nitro O
• Name of group
Heterocyclic Chemistry
The largest class of organic compounds.
Most drugs contain herocyclic rings
Cytotoxin- Inhibits DNA-topoisomerase enzymes
Happy Tree(China)
Definition: Heterocyclic compounds are organic compounds that contain a ring structure containing atoms in addition to carbon, such as sulfur, oxygen or nitrogen, as the heteroatom. The ring may be aromatic or non-aromatic
Significance – Two thirds of all organic compounds are aromatic
heterocycles. Most pharmaceuticals are heterocycles.
Examples
Quinine
Pfizer: Viagra
Treatment of malaria for 400 years (Peru)Erectile dysfunction
N
N
Me
N NHMe
NNC
H
H
Ovarian & lung cancer
GSK - TopotecanPfizer - Irinotecan
Camptothecin Analogues
Treating stomach & intestinal ulcers
More soluble & less side-effects
Heteroatoms
• Are atoms other than carbon or hydrogen that may be present in an organic compound.
• The most common heteroatoms are oxygen, nitrogen and sulfur
Six Membered Heterocycles: Pyridine
N N
Hpyridine piperidine
Pyridine replaces the CH of benzene by a N atom (and a pair of electrons)
Hybridization = sp2 with similar resonance stabilization energy
Lone pair of electrons not involved in aromaticity
N
H
HH
H H
pyridine
8.5
7.1
7.5
1H NMR: Pyridinium ion: pKa = 5.5
Piperidine: pKa = 11.29
diethylamine : pKa = 10.28
Pyridine is a weak basePyridine is -electron deficientElectrophilic aromatic substitution is difficultNucleophilic aromatic substitution is easy
Chemistry of pyridine
Electrophilic substitution in pyridine
N CH3H3C
H N O 3
H 2 S O 4 N CH3H3C
NO2
81%
Pyridine is less active, than benzene toward electrophilic agents, because nitrogen ismore electronegative, than carbon and acts like an electron withdrawing substituent,including the meta-directing effect.
It undergoes this reaction only under drastic conditions, ex nitration or bromination and requires high temperatures and strong acid catalyst
Example:
DMAP (DimethylAminoPyridine)
N
NCH3CH3
NN
H
N
NO2
+
ii
i, HNO3, H2SO4
Whereas acylations “catalyzed” by pyridine are normally carried out in pyridine as the reaction solvent. Only small amounts of DMAP are required to do acylations
Attempted Electrophilic Aromatic Substitution
NN
AlCl3
N
R
O
+
iiii
ii, AlCl3, RCOCl_
Unreactive, Stable
Nucleophilic aromatic substitution
• The reaction of pyridines
• A nucleophile displaces a hydride or halide ion from the aromatic ring
N
Me I
N
Me+ I
_
O
O
O OH O
O
O
R X
O
R OR
+ Pyr
+Pyr
R1-OH 1
X = OAc, Cl, Br
Pyridine as a nucleophile
Use Pyridine as a solvent to make esters
N
O R
+
Acyl pyridinium ionReactive intermediate
E.g.
Nucleophilic Substitution at 2- and 4-positions of pyridine is most favoured
N Cl N Cl
Nu
N Nu_
_Nu
N Cl N SPh
PhSH, NEt3
93%
E.g.
N
Br
Br
N
NH2
BrNH3 (aq)
65%
Heterocycles
• The pyridine ring can be fused with benze rings t produce polycyclic aromatic heterocycles.
• Examples of 6-membered heterocycles include quinoline and isoquinoline
Five Membered Heterocycles: Pyrrole
N
H
H
H
H
H
Pyrrole
6.5
6.2
1H NMR: Aromatic: Thus, 6 electrons
Sp2 hybridised and planar
Lone pair tied up in aromatic ring
Pyrrole is -electron excessive
Thus, Electrophilic Aromatic Substitution is Easy
Nucleophilic Substitution is Difficult
N
HN
H O
H
O
H NMe2
N
SO2Ph
N
SO2Ph
Me
O
N
H
Me
O
N
H
N
H
NO2N
H
NO2
+
1. POCl32. Na2CO3, H2O
59%
Ac2O, AlCl3
rt
NaOH (aq)
82%
AcONO2, AcOH/ -10 C+
51% 13%
Electrophilic Aromatic Substitution preferred at the 2-position
Normal acidic nitration causes polymerization
Vilsmeier Reaction
Electron-withdrawing group allows substitution at the 3-position
N
H
N
H
H
H N
H
N
H
H
H N
H
H++
+
reaction continues to give polymer
Organic Synthesis with Pyrrole should avoid strong acids
N
H
N
H
Cl
N
H
N
H
ClCl
ClCl
80%
80%
i; 1 X SO2Cl2, Et2O
ii; 4 X SO2Cl2, Et2O
i
ii
Indole
Lysergic acid (LSD) Strychnine
Indole Alkaloids
N
H
Indole
N
HN
H
CHOVilsmeier
55%
Aromatic due to 10 -electrons
Benzene part is non-reactive
Electrophilic aromatic substitution
occurs at the 3-position
OCONH2
N
OMe
NH
NH2
Me
O
O
Mitomycin C
Other Five Membered Heterocycles
N
HS O
Pyrrole
Thiophene Furan
The least aromatic:The O atom is too electronegative
Can give addition, as well as substitution products when reacted with E+
Less reactive than pyrrole, but substitution always at 2-position
More aromatic than Furan
Electrophilic Substitution, not addition
Least reactive
Thiophene has similar reactivity to benzene
Avoid concentrated mineral acids or strong Lewis acids, e.g. AlCl3
Electrophilic Aromatic Substitution of Thiophene
SS
O
H
O
H NMe2
S S NO2
S S ClS Cl
Cl
+
1. POCl32. Na2CO3, H2O
68%
HNO3, AcOH, Ac2O / -10 C
85%
43%
SO2Cl2, heat
10%
S SO
O
O
O
O OO
O
O
O
+ZnCl2, 100 C
+ZnCl2, 0 C
83%
95%
Some Reactions of Furan
OO
Br
Br
Br
Br O
OMeMeO
H H
CHOOHC
OPh3P
OHC
CHO
CHOOHC
Br2, CCl4 Br2, MeOH
H+, H2O
+_
not a clean reaction
Furan is more reactive than thiophene
Addition product
Hydrolysis of acetal
Wittig reaction
Furan is easily cleaved to dicarbonyls
Furan is a source of 1,4-dicarbonyls in Organic Synthesis
O
OMeMeO
H H
O OH H
O
R H
O RH
O RHR H
O O RR
OR R O OR R
cis-butenediol(too unstable to isolate)
H+, H2O
acetal acetal
+1
1 11 - H2O
acetalaldehyde + 2 x alcohol
H+, H2O
acid-catalysed
Diels–Alder reaction
• is an organic chemical reaction (specifically, a cycloaddition) between a conjugated diene( chemical with 2 double bonds) and a substituted alkene, commonly termed the dienophile, to form a substituted cyclohexene system
The Diels-Alder Reaction
Otto Diels
Kurt Alder
Noble Prize in 1950
O
O
O
O
O
O
+100 C
benzene
100%Diene
4 systemdienophile2 system 4+2 cycloaddition
Electron rich
Electron poor
O
H
O
H+
30 C
100%
H
H
O
O
OMe
OMe
H
H
CO2Me
CO2Me
H
H
O
OMe
O
MeO
H
H
CO2Me
CO2Me
+
+
The configuration of the dienophile is retained
Always reacts via the cis-diene
O
O
O
O
O
O
H
H
HH
OO
O
+25 C
100%
endo product(100%)
Under kinetic control
OO
O
O
Thermodynamicexo-product forms as the
temperature is raised
endo-product
Furan readily undergoes the Diels-Alder reaction with maleic anhydride
More stable due to less steric reasons
Aromaticity prevents thiophene from taking part in the Diels-Alder reaction
S
O
OX
S OO
X
X
+- SO2
This sulfone is not aromatic & very reactive
Five-membered Rings with Two or More Nitrogens
Diazoles
N
N
H
NN
H
ImidazolePyrazole
Imidazole is more basic than pyridine, but more acidic than pyrrole
N
N
H
H
N
NH
H
N
N
N
N
+
_
_
Imidazole + H+
Imidazole - H+NaOH
Properties: Very stable cation and anion of imidazole is formed
pKa = 14.5
(imidazole)
pKa = 16.5
(pyrrole)
- H2O
Histidine
Is one of the essential amino acids.A relatively small change in cellular pH can result in a change in its charge
Some Natural Imidazole Compounds
Important ligand to many metalloproteins
histidine carboxylase
histamine
Carnosine
Dipeptide in high concentrations in the brain & muscles- Improves social interactions & treatment of autism
Body neurotransmitter & local immune response
N
O
OMe
O
Cl
H
N
OMe
O
Cl
NN
NNH
Indomethacin
Tetrazole derivative
Tetrazoles are used in drugs as replacements for CO2H
Anti-arthritis drug- Non steroidal anti-inflammatory drug – reduces fever, pain, stiffness, delays premature labour & other uses
Indomethacin
Bioreductive Anti-Tumour AgentsOCONH2
N
OMe
NH
NH2
Me
O
O
N
N
O
OR
O
O
N
Me
N
N
O
O
N
N N Tr
O
O
( )n
IC50 ≈ 1.0 µM
IC50 ≈ 0.001 µM
Mitomycin C
E. B. Skibo et al., J. Med. Chem., 2002, 45, 1211
K. Fahey, F. Aldabbagh, Tetrahedron Lett., 2008, 49, 5235
Pyrrolo[1,2-a]benzimidazole (PBI)
M. Lynch, S. Hehir, M. P. Carty, F. Aldabbagh, Chem. Eur. J. 2007, 13, 3218
S. Hehir, L. O’Donovan, M. P. Carty, F. Aldabbagh, Tetrahedron 2008, 64, 4196
1
10
L. O’Donovan, F. Aldabbagh, Chem. Commun., 2008, 5592.
Hypersensitive to Fanconi AnemiaMore selective to hypoxia
Mitomycin C (MMC)
SET - activation
O
O
N
NH2
Me
OCONH2
OMe
NH
O
O
N
NH2
Me
OCONH2
NH
OMe
O
O
N
NH2
MeNH2
DNA
O
O
N
NH2
Me
OCONH2
OMe
NH N
NH2
Me
OCONH2
OMe
OH
OH
NH N
NH2
Me
OH
OH NH2
DNA+ 2 e-
+ 2 H+
CY P450 reductase
Two electron activation
DT-diaphorase
.
+ 1 e-
- 1 e-
- 1 e-
1
10
DNA alkylation
S. E. Wolkenberg and D. L. Boger, Chem Rev., 2002, 102, 2477
steps
DNA alkylation
Measuring the Effect of FANCD2 Expression on Cell Viability
N NH
OMe
OCONH2O
O
NH2
Me
N
N
OMe
OMe
N Tr
●, ● PD20i cells (lack FANCD2)▲, ▲ PD20:RV (express FANCD2)
K. Fahey, L O’Donovan, M. Carr, M. P. Carty, F. Aldabbagh, Eur. J. Med Chem. 2010, 45, 1873-1879
0
20
40
60
80
100
0 2 4 6 8 10
Concentration (x 10-3µ M)
Ce
ll V
iab
ility
%
N
H
N-
RMgBr
pKa = 23
Pyrrole is a stronger acid, than secondary amines, due to the aromatic stabilization of the conjugate base
N
H
pKa = 44
3. Chemistry of pyrrole, furan, and thiophene
>
= 1.7 D
All three heterocycles have an atom with at least one lone electron pair, involved to the aromatic conjugation. It is evidenced both by physical and chemical properties.
N
H
O S
O O
pyrrole furan thiophene
>
Reactivity in electrophilic substitution:
= 0.7 D
b.p. = 31.4 oC b.p. = 67 oC
>
X
X E
H
X E
H
X E
H
X
HH
X
H
H
preferred substitution1
2
3
E+
E+
+
++
++
Electrophilic substitution in pyrrole, furan and thiophene
X = O, NH, or S
N
H
N
H
NO2 N
H
NO2
+50%
15%
O O
O
50%
S S NO2 S
NO2
+
70% 5%
a c e t ic a n h yd r id e ,B F 3 ,
C H 3 C O O H
2 0 oC
a c e t ic a n h yd r id e
H N O 3 , 2 0 oC
a c e t ic a n h yd r id e
H N O 3 , 2 0 oC
Examples:
O
+O OO
O
O
O
O
HH90%
Furan is able to act as a diene in the reactions of cycloaddition
The Fisher synthesis of indoles
N
HIndoleNH NH2
+ CH3
O
N
H 2-Phenylindole
P o lyp h o sp h o r ic a c id+ NH3
Nucleophilic substitution in pyridine
N NNH270%
+ +H2 NaOH 1 . N a N H 2 , h e a t
2 . H 2 O
NH2-
N-
NH2 H
CH-
NNH2 HN
CH-
HNH2
The most contributing structure
NNH
H
+ H-
NNH-
OH2
The presence of nitrogen enables pyridine to react with nucleophilic agents, like an electron withdrawing substituents enables benzene to participate in such reactions,including the ortho-directing effect.
These reactions require very strong nucleophiles and heat, because H- is a very weakleaving group. In ortho- or para-substituted pyridines nucleophilic substitution proceeds much easier.
Another example:
N N
50%
P h L i
h e a t+ LiH
N Cl N OCH395%
N a O C H 3
C H 3 O H+ NaCl
Have practical uses for example: solvents, insecticides, herbicides, fire
retardants, cleaning fluids, refrigerants, polymers ex teflon
Aryl Halides Ar-X
Organic compounds with a halogen atom attached to an aromatic carbon are very different from those compounds where the halogen is attached to an aliphatic compound(alkanes, alkenes, alkynes).
While the aliphatic compounds readily undergo nucleophilic substitution and elimination reactions, the aromatic compounds resist nucleophilic substitution, only reacting under severe conditions or when strongly electron withdrawing groups are present ortho/para to the halogen.
Nucleophilic substition
• Nucleophile: electron rich reactants sharing electrons with electrophiles ex SN1 and SN2 and nuclephilic acyl substitution rxn
• Electrophile: electron poor reactant . They seek electrons and form bonds with nucleophiles.
• Nucleophilic substitution reaction: a reaction in which a nucleophile displaces a leaving group from a substrate.
Nucleophilic substition
• OH + CH3CH2—Br H2O CH2CH3—OH + Br
• Hydroxide ion is the nucleophile• It reacts with the substrate ethyl bromide• It displaces bromide ion which is the leaving
group
Examples of Nucleophilic
• The most common nucleophiles are :
• Oxygen
• Nitrogen
• Sulfur
• Halogens
• carbon nucleopiles
In aryl halides, the carbon to which the halogen is attached is sp2 hybrizided. The bond is stronger and shorter than the carbon-halogen bond in aliphatic compounds where the carbon is sp3 hybridized. Hence it is more difficult to break this bond and aryl halides resist the typical nucleophilic substitution reactions of alkyl halides.
The same is true of vinyl halides where the carbon is also sp2 hybridized and not prone to nucleophilic substitution.
Substitution reactions in Table 6:1 have some limitations with respect to the
structure of the R group in the alkyl halide
Nucleophilic substitution mechanisms
• There are two main nucleophilic substitution mechanisms:
• SN1
• SN2
• The SN part of each symbol stands for substitution nucleophilic
• The numbers will be explained later
SN2 mechanism
• Is a one-step process in which the bond to the leaving group begins t break as the bond to the nucleophile begins to form.
• The nucleophile attacks from the back side of the C—L bond.
• At some stage the nucleophile and the leaving group are both partly bonded to the carbon at which the substitution occurs.
• As the leaving group departs with its electron pair, the nucleophile supplies another electron pair to the carbon atom.
SN2 mechanism
• The number 2 to show that two molecules – the nucleophile and the substrate are involved
SN2 mechanism
• SN2 mechanism is a one-step process favored for methyl and primary halides.
• It occurs more slowly with secondary halides and usually not at all with tertiary halides.
• It occurs with inversion of configuration and its rate depends on the concentration of both the nucleophile and the substrate
SN1 mechanism
• A two step process where the bond between the carbon and the leaving group breaks first and then the resulting carbocation combines with the nucleophile
• The number 1 designates the mechanism because the slow or rate determing step involves only one of the two reactants
SN1 mechanism
• SN1 mechanism is a two step process and is favored when the alkyl halide is tertiary. The SN1 process occurs with racemization and its rate is independent of the nucleophile’s concentration.
• Racemization: a 50:50 mixture of enantiomers
Dehydrohalogenation, an elimination reaction: the E2 and E1 mechanisms
When an alky halide with a hydrogen attached to the carbon adjacent to the halogen-bearing carbon reacts with a nucleophile, 2 competing reaction paths are possible: substitution or elimination
. Substitution
elimination
elimination reactions of alkyl halides
• In an elimination ( dehydrohalogenation) reactions of alkyl halides, a hydrogen atom and a halogen atom from adjacent carbons are eliminated and a carbon-carbon double bond is formed.
Elimination reactions
• E2 mechanism: reactions of alkyl halides : a one step process in which HX is eliminated and a C=C bond is formed .
• B is the nucleophile, acting as a base, removes the proton (hydrogen on a carbon adjacent to the one that bears the leaving group designated X
• At the same time the leaving group departs a double bond forms
Elimination reactions
• E1 mechanism: is a two step process with the same first step as an SN1 reaction (slow and rate-determining ionization of the substrate to give a carbocation)
Polyhalogenated aliphatic compounds
•Polyhalogenated compounds are industrially created compounds substituted with multiple halogens.
• Many of them are very toxic and bioaccumulate in humans, and have a very wide application range.
•They include the much maligned PCBs, PBDEs, and PFCs as well as numerous other compounds.
PCB and PBDE
• Polychlorinated biphenyl: (PCB) is any of the 209 configurations of organochlorides with 1 to 10 chlorine atoms attached to biphenyl, which is a molecule composed of two benzene rings and is used as dielectric and coolant fluids, for example in transformers, capacitors, and electric motors
• Polybrominated diphenyl ethers or PBDEs, are organobromine compounds that are used as flame retardant
PFC and CFC
• perfluorinated compound (PFC) 1s an organofluorine compound with all hydrogens replaced by fluorine on a carbon chain
• used to make fluoropolymers such as Teflon, among other applications
• Chlorofluorocarbons (CFC) also known as freon are polyhalogenated compounds containing chlorine and fluorine