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


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


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


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


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


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


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


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



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


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


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.


EtOH



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

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


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


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.



38




39



Temp

(°C)

Rxn Time

(min)

CH Yield

(%)

MW Yield

(%)

140 15 11 8

140 90 43 37

200 30 73 77






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.


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



+

Ph42

43

Bp= 142-144°C

30

40

50

60

Asymmetric Diels-Alder

Diels-Alder at 140°C



0

10

20

30

0 100 200 300

% Yield

Time (min)

MW

CH

45






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


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


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


Heating with SiC

CCl4Hexane

Toluene

Dioxane

THF


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)


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


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






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


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


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.






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

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