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Microwave Chemistry: Magic or a Bunch of Hot Air · Microwave Chemistry: Magic or a Bunch of Hot...
Transcript of Microwave Chemistry: Magic or a Bunch of Hot Air · Microwave Chemistry: Magic or a Bunch of Hot...
Microwave Chemistry:
Magic or a Bunch of Hot AirMagic or a Bunch of Hot Air
Steven DuLaney
Michigan State University
January 20, 2010
History of Microwaves
• 1937 Chain Home
• Spencer’s chocolate
• 1947 “Radarange”
– Hamburgers 35 seconds
– Hotdogs 10 seconds
• Alien technology
2
Image courtesy of http://www.southgatearc.org/news/august2006/great_baddow_radar_tower.htm
David, L. Mechanix Illustrated January, 1947, 52-55.
Stuerga, D. Microwave-Material Interactions. Loupy, A.; Editor, Microwaves in Organic Synthesis Volume 1. 2006; p 523 pp
Electromagnetic Spectrum
3
Image adapted from http://mivim.gel.ulaval.ca/imgs/figs/Figure_001big.gif
What are microwaves?
• 1 m – 1 cm wavelength
• Wide ranging uses
• 2.45 GHz
Image courtesy of http://www.geo.mtu.edu/rs/back/spectrum/
Image courtesy of http://www.raytheon.com/capabilities/products/silent_guardian/4
Dielectric Heating
5
Gabriel, C.; Gabriel, S.; Grant, E. H.; Grant, E. H.; Halstead, B. S. J.; Mingos, D. M. P., Chem. Soc. Rev. 1998, 27, (3), 213-224.
Loupy, A.; Editor, Microwaves in Organic Synthesis: Second, Completely Revised and Enlarged Edition, Volume 1. 2006; p 523 pp.
Dielectric Heating
6
Gabriel, C.; Gabriel, S.; Grant, E. H.; Grant, E. H.; Halstead, B. S. J.; Mingos, D. M. P., Chem. Soc. Rev. 1998, 27, (3), 213-224.
Loupy, A.; Editor, Microwaves in Organic Synthesis: Second, Completely Revised and Enlarged Edition, Volume 1. 2006; p 523 pp.
Dielectric and Dielectric Loss
Dielectric
H2O
7
Loss Factor
2.45 GHz
Gabriel, C.; Gabriel, S.; Grant, E. H.; Grant, E. H.; Halstead, B. S. J.; Mingos, D. M. P., Chem. Soc. Rev. 1998, 27, (3), 213-224.
Microwave Assisted Organic Synthesis
• Gedye in 1986
• Temperature and
NH2
O
H2O, H2SO4 OH
O
MW, 10 min.
6x faster
O
MeOH
O
orReflux 1 hr.1 2
• Temperature and
Pressure
• Explosions
Gedye, R.; Smith, F.; Westaway, K.; Ali, H.; Baldisera, L.; Laberge, L.; Rousell, J., Tetrahedron Lett. 1986, 27, (3), 279-82.
8
OHMeOH
OMe
O
NC
Na BnCl OBn
NC
240x Faster
MW, 5 min.or
Reflux 8 hr.
96x faster
MW, 3 min.or
Reflux 12 hr.
3 4
5 6
200
250
300
350
Microwave Assisted Organic Synthesis
• Gedye in 1986
• Temperature and
0
50
100
150
200
0 0.5 1 1.5 2 2.5 3 3.5
Volume (mL)
Time (min)
• Temperature and
Pressure
• Explosions
Gedye, R.; Smith, F.; Westaway, K.; Ali, H.; Baldisera, L.; Laberge, L.; Rousell, J., Tetrahedron Lett. 1986, 27, (3), 279-82.
9
The Magic of Microwaves
Ben Alloum, A.; Labiad, B.; Villemin, D., J. Chem. Soc., Chem. Commun. 1989, (7), 386-7.
Kiddle, J. J., Tetrahedron Lett. 2000, 41, (9), 1339-1341.10
N
BrPh3P +
MW, 3min
Xylene99%
NPh3P
Br
N
BrPh3P +
336 hours
Reflux PhHN
Ph3P
Br
10
10
11
11
12
12
The Magic of Microwaves
IPh3P +
MW, 4min
neat92%
Ph3P
I
10 13 14
IPh3P +
48 hours
Reflux PhH Ph3P
I
10 13 14
Kiddle, J. J., Tetrahedron Lett. 2000, 41, (9), 1339-1341.
11
ATP Cleavage
12
Sun, W. C.; Guy, P. M.; Jahngen, J. H.; Rossomando, E. F.; Jahngen, E. G. E., J. Org. Chem. 1988, 53, (18), 4414-16.
ATP Cleavage
ATP CH
15
10
13
Sun, W. C.; Guy, P. M.; Jahngen, J. H.; Rossomando, E. F.; Jahngen, E. G. E., J. Org. Chem. 1988, 53, (18), 4414-16.
1 2 3 4 15
Minutes
ATP MW
ADP MW
AMP MWnMol
0
2
6
Non-thermal Microwave Effects
Ph3P + MW, 10min
neat, 100 C
99%
Br PPh3
Br
Cl10 18 19
14
Ph3P +MW, 10min
neat, 100 C
78%
Cl
Ph3P + MW, 10min
neat, 150 C
70%
NMe3
PPh3
PPh3
Cl
ClCl
10
10
20 21
22 21
Cvengros, J.; Toma, S.; Marque, S.; Loupy, A., Can. J. Chem. 2004, 82, (9), 1365-1371.
Ph3P + CH, 10min
neat, 100 C
99%
Br PPh3
Br
Cl10 18 19
Non-thermal Microwave Effects
MW = 99%
Ph3P +CH, 10min
neat, 100 C
24%
Cl
Ph3P + CH, 10min
neat, 150 C
0%
NMe3
PPh3
PPh3
Cl
ClCl
10
10
20 21
22 21
Cvengros, J.; Toma, S.; Marque, S.; Loupy, A., Can. J. Chem. 2004, 82, (9), 1365-1371.
MW = 78%
MW = 70%
15
Theory of Non-Thermal Effects
16Perreux, L.; Loupy, A., Tetrahedron 2001, 57, (45), 9199-9223.
Energy
Transition State
Theory of Non-Thermal Effects
Reactant
Product
Ph3P +X PPh3
X
Ph3P X
+ -
17Perreux, L.; Loupy, A., Tetrahedron 2001, 57, (45), 9199-9223.
X
CH
Yield (%)
MW Yield
(%)
Br 99 99
Cl 24 78
NMe3 0 70
Evaluating Non-Thermal Effects
• Proper temperature monitoring
• Reaction with polar transition structure
• Non-polar solvent, or no solvent
• Vary density of microwaves
18
Problems Evaluating Claims
• Multimode vs.
Monomode
• Monitoring
temperature
19
Nuechter, M.; Mueller, U.; Ondruschka, B.; Tied, A.; Lautenschlaeger, W., Chem. Eng. Technol. 2003, 26, (12), 1207-1216.
Lentz, R. R., J. Microwave Power 1980, 15, (2), 107-11.
.Hosseini, M.; Stiasni, N.; Barbieri, V.; Kappe, C. O., J. Org. Chem. 2007, 72, (4), 1417-1424.
Problems Evaluating Claims
• Multimode vs.
Monomode H2O 1% Wt NaCl
• Monitoring
temperature
20
Nuechter, M.; Mueller, U.; Ondruschka, B.; Tied, A.; Lautenschlaeger, W., Chem. Eng. Technol. 2003, 26, (12), 1207-1216.
Lentz, R. R., J. Microwave Power 1980, 15, (2), 107-11.
.Hosseini, M.; Stiasni, N.; Barbieri, V.; Kappe, C. O., J. Org. Chem. 2007, 72, (4), 1417-1424.
Crude Temperature Monitoring
21Barnier, J. P.; Loupy, A.; Pigeon, P.; Ramdani, M.; Jacquault, P., J. Chem. Soc., Perkin Trans. 1 1993, (4), 397-8.
R Time (min) Temp (°C)
Yield
MW
Yield
CH
H 8 138 96 2
Et 15 160 94 2
n-Bu 20 167 89 2
n-Hex 20 186 87 2
Chemistry at Atmospheric Pressure
• MORE Chemistry
– Microwave-induced
Organic Reaction
Enhancement
HN O
NMW 10 min90%
POCl3,
1,2,4 trichlorobenzene
26 27
• Traditional glassware
– Multigram scale
• Higher boiling solvents
Bose, A. K.; Manhas, M. S.; Ghosh, M.; Shah, M.; Raju, V. S.; Bari, S. S.; Newaz, S. N.; Banik, B. K.; Chaudhary, A. G.;
Barakat, K. J., J. Org. Chem. 1991, 56, (25), 6968-70.22
Evaluation of ATP Cleavage
23
Sun, W. C.; Guy, P. M.; Jahngen, J. H.; Rossomando, E. F.; Jahngen, E. G. E., J. Org. Chem. 1988, 53, (18), 4414-16.
Kinetics of ATP Cleavage
24
Jahngen, E. G. E.; Lentz, R. R.; Pesheck, P. S.; Sackett, P. H., J. Org. Chem. 1990, 55, (10), 3406-9.
Microwave Heating
• Prediction off by 3%
after 5 minutes
• Deviates 8% after 15
minutes
25
Sun, W. C.; Guy, P. M.; Jahngen, J. H.; Rossomando, E. F.; Jahngen, E. G. E., J. Org. Chem. 1988, 53, (18), 4414-16.
Jahngen, E. G. E.; Lentz, R. R.; Pesheck, P. S.; Sackett, P. H., J. Org. Chem. 1990, 55, (10), 3406-9.
Apparent Microwave Effects
26Goncalo, P.; Roussel, C.; Melot, J. M.; Vebrel, J., J. Chem. Soc., Perkin Trans. 2. 1999, (10), 2111-2115.
Temp
(°C)
Rxn Time
(min)
CH Yield
(%)
MW Yield
(%)
210 1.5 7 9
210 3 17 43
210 4.5 39 72
210 6 63 85
Apparent Microwave Effects
27Goncalo, P.; Roussel, C.; Melot, J. M.; Vebrel, J., J. Chem. Soc., Perkin Trans. 2. 1999, (10), 2111-2115.
x/mm y/mm
Temp
(°C)
0 0 259
0 1.5 256
0 3 262
3 0 245
3 3 265
6 0 275
6 3 290
Apparent Microwave Effects
Temp
(°C)
Rxn Time
(min)
CH Yield
(%)
MW Yield
(%)
210 1.5 7 9
210 3 17 43
210 4.5 39 72
210 6 63 85
245 6 85 85
28Goncalo, P.; Roussel, C.; Melot, J. M.; Vebrel, J., J. Chem. Soc., Perkin Trans. 2. 1999, (10), 2111-2115.
Temp
(°C)
Rxn Time
(min)
CH Yield
(%)
MW Yield
(%)
210 1.5 7 9
210 3 17 43
210 4.5 39 72
210 6 63 85
x/mm y/mm
Temp
(°C)
0 0 259
0 1.5 256
0 3 262
3 0 245
3 3 265
6 0 275
6 3 290
IR Temperature Monitoring
CCl4
29Moseley, J. D.; Lenden, P.; Thomson, A. D.; Gilday, J. P., Tetrahedron Lett. 2007, 48, (35), 6084-6087.
Kremsner, J. M.; Kappe, C. O., J. Org. Chem. 2006, 71, (12), 4651-4658.
IR Temperature Monitoring
EtOH
30Moseley, J. D.; Lenden, P.; Thomson, A. D.; Gilday, J. P., Tetrahedron Lett. 2007, 48, (35), 6084-6087.
Kremsner, J. M.; Kappe, C. O., J. Org. Chem. 2006, 71, (12), 4651-4658.
IR Temperature Monitoring
31Moseley, J. D.; Lenden, P.; Thomson, A. D.; Gilday, J. P., Tetrahedron Lett. 2007, 48, (35), 6084-6087.
Kremsner, J. M.; Kappe, C. O., J. Org. Chem. 2006, 71, (12), 4651-4658.
Microwave Synthesizer
Fiber Optic Probe
Favretto, L., Mol. Diversity 2003, 7, (2-4), 287-290.32
MW
Magnetic Stirrer
IR Window
Location, Location, Location
Instrument
Temp
(°C)
Solvent
(mL)
Stirred
Conversion (%)
Unstirred
Conversion (%)
Discover 160 0.2 65 100
Discover 160 2 65 100
Discover 160 5 65 100
Initiator 160 2 58 48
Initiator 160 3 60 65
Initiator 160 4 58 73
Initiator 160 5 58 80
Initiator
Discover
®
®
Moseley, J. D.; Lenden, P.; Thomson, A. D.; Gilday, J. P., Tetrahedron Lett. 2007, 48, (35), 6084-6087. 33
IR vs Fiber Optic
NMPNMP
34Herrero, M. A.; Kremsner, J. M.; Kappe, C. O., J. Org. Chem. 2008, 73, (1), 36-47.
Microwave Effects with IR
Ph3P + MW, 10min
neat, 100 C
99%
Br PPh3
Br
Cl10 18 19
35
Cvengros, J.; Toma, S.; Marque, S.; Loupy, A., Can. J. Chem. 2004, 82, (9), 1365-1371.
Ph3P +
99%
MW, 10min
neat, 100 C
78%
Cl
Ph3P + MW, 10min
neat, 150 C
70%
NMe3
PPh3
PPh3
Cl
ClCl
10
10
20 21
22 21
Microwave Effects with IR
Ph3P + CH, 10min
neat, 100 C
99%
Br PPh3
Br
Cl10 18 19
36
Cvengros, J.; Toma, S.; Marque, S.; Loupy, A., Can. J. Chem. 2004, 82, (9), 1365-1371.
Ph3P +
99%
CH, 10min
neat, 100 C
24%
Cl
Ph3P + CH, 10min
neat, 150 C
0%
NMe3
PPh3
PPh3
Cl
ClCl
10
10
10
18 19
20 21
22 21
Problems With Heterogeneity
37
Herrero, M. A.; Kremsner, J. M.; Kappe, C. O., J. Org. Chem. 2008, 73, (1), 36-47.
Cvengros, J.; Toma, S.; Marque, S.; Loupy, A., Can. J. Chem. 2004, 82, (9), 1365-1371.
Problems With Heterogeneity
38
Herrero, M. A.; Kremsner, J. M.; Kappe, C. O., J. Org. Chem. 2008, 73, (1), 36-47.
Cvengros, J.; Toma, S.; Marque, S.; Loupy, A., Can. J. Chem. 2004, 82, (9), 1365-1371.
Problems With Heterogeneity
39
Herrero, M. A.; Kremsner, J. M.; Kappe, C. O., J. Org. Chem. 2008, 73, (1), 36-47.
Cvengros, J.; Toma, S.; Marque, S.; Loupy, A., Can. J. Chem. 2004, 82, (9), 1365-1371.
Temp
(°C)
Rxn Time
(min)
CH Yield
(%)
MW Yield
(%)
140 15 11 8
140 90 43 37
200 30 73 77
Evaluating Non-Thermal Effects
• Proper temperature monitoring
• Reaction with polar transition structure
• Non-polar solvent, or no solvent
• Vary density of microwaves
40
Polar vs Isopolar
41Loupy, A.; Petit, A.; Ramdani, M.; Yvanaeff, C.; Majboub, M.; Labiad, B.; Villemin, D., Can. J. Chem. 1993, 71, (1), 90-5.
Giguere, R. J.; Bray, T. L.; Duncan, S. M.; Majetich, G., Tetrahedron Lett. 1986, 27, (41), 4945-8.
Polar vs Isopolar
42Loupy, A.; Petit, A.; Ramdani, M.; Yvanaeff, C.; Majboub, M.; Labiad, B.; Villemin, D., Can. J. Chem. 1993, 71, (1), 90-5.
Giguere, R. J.; Bray, T. L.; Duncan, S. M.; Majetich, G., Tetrahedron Lett. 1986, 27, (41), 4945-8.
Non-thermal Microwave Effects
43
Substrate Heating Temperature Time (hr) Yield a Yield b
45 CH 120°C 24 8% 11%
45 MW 120°C 2 25% 55%
43 CH 150°C 24 44% 0%
43 MW 150°C 3 64% 0%
Loupy, A.; Maurel, F.; Sabatie-Gogova, A., Tetrahedron 2004, 60, (7), 1683-1691.
Asymmetric Diels-Alder
O
CO2Me
O+
150 C
3 hr
O
O
CO2Me+
O
O
CO2MePh
44
Herrero, M. A.; Kremsner, J. M.; Kappe, C. O., J. Org. Chem. 2008, 73, (1), 36-47.
Loupy, A.; Maurel, F.; Sabatie-Gogova, A., Tetrahedron 2004, 60, (7), 1683-1691.
+
Ph42
43
Bp= 142-144°C
30
40
50
60
Asymmetric Diels-Alder
Diels-Alder at 140°C
Herrero, M. A.; Kremsner, J. M.; Kappe, C. O., J. Org. Chem. 2008, 73, (1), 36-47.
Loupy, A.; Maurel, F.; Sabatie-Gogova, A., Tetrahedron 2004, 60, (7), 1683-1691.
0
10
20
30
0 100 200 300
% Yield
Time (min)
MW
CH
45
Evaluating Non-Thermal Effects
• Proper temperature monitoring
• Reaction with polar transition structure
• Non-polar solvent, or no solvent
• Vary density of microwaves
46
Reactions on Dry Media
47
Loupy, A.; Petit, A.; Ramdani, M.; Yvanaeff, C.; Majboub, M.; Labiad, B.; Villemin, D., Can. J. Chem. 1993, 71, (1), 90-5.
Gutierrez, E.; Loupy, A.; Bram, G.; Ruiz-Hitzky, E., Tetrahedron Lett. 1989, 30, (8), 945-8.
Reactions on Dry Media
Heating Dry Support
Perreux, L.; Loupy, A., Tetrahedron 2001, 57, (45), 9199-9223.
48
Condensation on Solid Support
OH
H
O
OEt
O
Cl+TBAB, K2CO3,
85 C
O
H
O
OEt
O
O
OEt
O
49 5047 48
Volume
EtOH (mL)
Heating
Method
Rxn
Time
(min)
Yield 49
(%)
Yield 50
(%)
0 CH 20 90 10
0 MW 20 15 85
1.5 CH 30 47 53
1.5 MW 30 0 100
Bogdal, D.; Bednarz, S.; Lukasiewicz, M., Tetrahedron 2006, 62, (40), 9440-9445.
49
Dry Media
Area
Temp
(°C)
Yield 49
(%)
Yield 50
(%)
P1 70 100 0
50
Bogdal, D.; Bednarz, S.; Lukasiewicz, M., Tetrahedron 2006, 62, (40), 9440-9445.
P1 70 100 0
P2 125 55 45
P3 200 0 100
Dry Media
Area
Temp
(°C)
Yield 49
(%)
Yield 50
(%)
P1 70 100 0
51
Bogdal, D.; Bednarz, S.; Lukasiewicz, M., Tetrahedron 2006, 62, (40), 9440-9445.
P1 70 100 0
P2 125 55 45
P3 200 0 100
Solvent Choice
40
50
60
70
Temp
Ethyl Acetate
1-Propanol
Acetic Acid
0
10
20
30
40
0 5 10 15 20
Temp
Increase
°C (15s)
Dielectric Constant
Gedye, R. N.; Smith, F. E.; Westaway, K. C., Can. J. Chem. 1988, 66, (1), 17-26.
52
1,4 Dioxane
Ionic Liquids
53Leadbeater, N. E.; Torenius, H. M., J. Org. Chem. 2002, 67, (9), 3145-3148.
Solvent
Ionic
Liquid
Time
(s)
Temp
(°C)
Temp Without
Ionic Liquid (°C)
Boiling
Point (°C)
hexane 52 10 217 46 69
53 15 228
toluene 52 150 195 109 111
53 130 234
THF 52 70 268 112 66
53 60 242
dioxane 52 90 264 76 101
53 90 246
Ionic Liquids
• Use of non-polar
solvent
• Decant or extract
N N
I-
N N
Br-
160 CH3C I N N
N NH3C Br160 C
52
53
54 55
56 57
• Decant or extract
• Problems with
Decomposition
54
Leadbeater, N. E.; Torenius, H. M., J. Org. Chem. 2002, 67, (9), 3145-3148.
N NH + R Br
MW, NEt3,Toluene,
Ionic Liquid
60
Passive Heating Elements
• Weflon, Carboflon
• Ease of Use
55Kremsner, J. M.; Kappe, C. O., J. Org. Chem. 2006, 71, (12), 4651-4658.
Image courtesy of www.milestonesci.com/images/weflon_button.jpg
• Recyclable
• Problems above 200°C
• Silicon Carbide
• Melting Point 2700°C
Passive Heating Elements
• Sintered at 1600°C
56Kremsner, J. M.; Kappe, C. O., J. Org. Chem. 2006, 71, (12), 4651-4658.
Heating with SiC
CCl4Hexane
Toluene
Dioxane
THF
57Kremsner, J. M.; Kappe, C. O., J. Org. Chem. 2006, 71, (12), 4651-4658.
RCM Utilizing Ionic Liquids
58Mayo, K. G.; Nearhoof, E. H.; Kiddle, J. J., Org. Lett. 2002, 4, (9), 1567-1570.
Using a Less Polar Solvent
DCM Heating
Temp (°C)
59Mayo, K. G.; Nearhoof, E. H.; Kiddle, J. J., Org. Lett. 2002, 4, (9), 1567-1570.
Time (s)
EtO2C CO2Et
Ts
2 min, DCM
2-3 mol% cat
CO2EtEtO2C
Ts
MW= 100% CH= 21%
61 62
RCM Utilizing Ionic Liquids
N
Ts
OTBS
N
OTBS
MW= 91% CH= 45%
MW= 64% CH= 7%
2 min, DCM
2-3 mol% cat
2 min, DCM
2-3 mol% cat
63
65
64
66
60Mayo, K. G.; Nearhoof, E. H.; Kiddle, J. J., Org. Lett. 2002, 4, (9), 1567-1570.
Standardized RCM
Rxn Time Temp CH MW
61
Garbacia, S.; Desai, B.; Lavastre, O.; Kappe, C. O., J. Org. Chem. 2003, 68, (23), 9136-9139.
Mayo, K. G.; Nearhoof, E. H.; Kiddle, J. J., Org. Lett. 2002, 4, (9), 1567-1570.
Rxn Time
(min)
Temp
(°C)
CH
Yield (%)
MW
Yield (%)
2 60 99 99
5 40 65 70
10 40 92 99
Guides to Authors
• Organic Letters
– Domestic oven at atmospheric pressure
– Temperature monitoring method
Organic Letters 2010 Guideline for Authors. http://pubs.acs.org/paragonplus/submission/orlef7/orlef7_authguide.pdf
(accessed 1/8/10)Journal of Organic Chemistry 2010 Guideline for Authors http://pubs.acs.org/paragonplus/submission/joceah/joceah_authguide.pdf
(accessed 1/8/10)
• Journal of Organic Chemistry
– Compare conventional heating with domestic
62
Evaluating Non-Thermal Effects
• Proper temperature monitoring
• Reaction with polar transition structure
• Non-polar solvent, or no solvent
• Vary density of microwaves
63
Simultaneous Heating and Cooling
64Hosseini, M.; Stiasni, N.; Barbieri, V.; Kappe, C. O., J. Org. Chem. 2007, 72, (4), 1417-1424.
Simultaneous Heating and Cooling
O+
O
CO2Et
CO2Et
CO2Et
CO2Et
MW, 15min
47 CMW w/ Cooling = 27%
MW = 1%
39 40 41
65
Leadbeater, N. E.; Pillsbury, S. J.; Shanahan, E.; Williams, V. A., Tetrahedron 2005, 61, (14), 3565-3585.
CEM . The Facts About Simultaneous Cooling. http://www.cem.de/documents/pdf/publikation/synthese/
Facts%20about%20cooling.pdf. (accessed 12/31/09).
MW Power
(W)
Temp
(°C) Cooling
Yield
(%)
Total MW
power (W)
10 97 No 43 11,997
70 101 Yes 44 83,856
Asymmetric Evaluation
66Hosseini, M.; Stiasni, N.; Barbieri, V.; Kappe, C. O., J. Org. Chem. 2007, 72, (4), 1417-1424.
N
CO2Et
HN
OMeHO2C
MW Power Temp Yield
Asymmetric Evaluation
Solvent
MW Power
(W)
Temp
(°C) Cooling
Yield
(%) ee (%)
DMSO - 60 - 91 99
DMSO 49 60 No 90 99
DMSO 207 60 Yes 92 99
DMSO - 40 - 55 99
DMSO 1 40 No 57 99
DMSO 203 40 Yes 54 99
Dioxane - 60 - 48 99
Dioxane 20 60 No 51 99
67Hosseini, M.; Stiasni, N.; Barbieri, V.; Kappe, C. O., J. Org. Chem. 2007, 72, (4), 1417-1424.
Microwave Heating without
Microwaves
68Obermayer, D.; Gutmann, B.; Kappe, C. O., Angew. Chem., Int. Ed. 2009, 48, (44), 8321-8324,.
Microwave Heating without
Microwaves
SiC Pyrex
69Obermayer, D.; Gutmann, B.; Kappe, C. O., Angew. Chem., Int. Ed. 2009, 48, (44), 8321-8324,.
Sample Reactions
70Obermayer, D.; Gutmann, B.; Kappe, C. O., Angew. Chem., Int. Ed. 2009, 48, (44), 8321-8324.
Temperature Profile
Heating of Heck Reaction
71Obermayer, D.; Gutmann, B.; Kappe, C. O., Angew. Chem., Int. Ed. 2009, 48, (44), 8321-8324.
Evaluating Non-Thermal Effects
• Proper temperature monitoring
• Reaction with polar transition structure
• Non-polar solvent, or no solvent
• Vary density of microwaves
72
Summary of MAOS
Cons
• Not magic
• Specialized equipment
Pros
• Rapid and even heating
• Non-contact heating• Specialized equipment
• Difficult to optimize
conditions
• Non-contact heating
• Easier access to higher
temperatures and pressures
73
Scale up of MAOS
• Batch Reactors
– 20ml – 300ml
• Limitations
74
• Limitations
– 6mm at 3°C
– 40mm at 60°C
Kremsner, J. M.; Stadler, A.; Kappe, C. O., Top. Curr. Chem. 2006, 266, (Microwave Methods in Organic Synthesis), 233-278.
Roberts, B. Strauss, C. Scale up of microwave-assisted organic synthesis. Microwave Assisted Organic Synthesis;
Lidstrom, P. Tierney, J. Blackwell Pubslishing: 2006, 237-271.
Scale up of MAOS
• Batch Reactors
– 20ml – 300ml
• Limitations
75
• Limitations
– 6mm at 3°C
– 40mm at 60°C
Kremsner, J. M.; Stadler, A.; Kappe, C. O., Top. Curr. Chem. 2006, 266, (Microwave Methods in Organic Synthesis), 233-278.
Roberts, B. Strauss, C. Scale up of microwave-assisted organic synthesis. Microwave Assisted Organic Synthesis;
Lidstrom, P. Tierney, J. Blackwell Pubslishing: 2006, 237-271.
Batch Pilot Plant
Wave Guide
30 KWMW Generator
50 L Batch Reactor
image courtesy of Sairem www.sairem.com (accessed 12/31/09). Pilot scale chemistry equipment.76
Continuous Flow Systems
• No need to scale up
• Automation• Automation
77
Kremsner, J. M.; Stadler, A.; Kappe, C. O., Top. Curr. Chem. 2006, 266, (Microwave Methods in Organic Synthesis), 233-278.Wilson, N. S.; Sarko, C. R.; Roth, G. P., Org. Process Res. Dev. 2004, 8, (3), 535-538.
Comer, E.; Organ, M. G., J. Am. Chem. Soc. 2005, 127, (22), 8160-8167.
Continuous Flow Systems
• No need to scale up
• Automation• Automation
78
Kremsner, J. M.; Stadler, A.; Kappe, C. O., Top. Curr. Chem. 2006, 266, (Microwave Methods in Organic Synthesis), 233-278.Wilson, N. S.; Sarko, C. R.; Roth, G. P., Org. Process Res. Dev. 2004, 8, (3), 535-538.
Comer, E.; Organ, M. G., J. Am. Chem. Soc. 2005, 127, (22), 8160-8167.
Examples of Flow Reactions
+MW, 5hr, (2eq) Et3N
20 mol% PdCl2(PPh3)2
EtOH, 140 C
OCHO
O
B(OH)2 84%1.3g
Br
CHO
75 76 77
79
Wilson, N. S.; Sarko, C. R.; Roth, G. P., Org. Process Res. Dev. 2004, 8, (3), 535-538.
NO2
F
+
NH2MW, 5hr
(2eq) iPr2NEt,
EtOH, 120 C2eq
H2N NO2
NH
81%9.3g
H2N
78 79 80
Continuous Flow Pilot Plant
80image courtesy of Sairem www.sairem.com (accessed 12/31/09). Pilot scale chemistry equipment.
Acknowledgments
• Dr. Xuefei Huang
• Dr. Babak Borhan
• Medha, Dino, Hovig, Vivian, Gilbert, Bo, Mo,
Gopi, Phil, HerbertGopi, Phil, Herbert
• Nicole, Micah, Dennis
• Emily
81
82