microwave assisted organic synthesis

Microwave Dielectric heating inSynthetic Organic ChemistrySynthetic Organic Chemistry

Bunyarat RungtaweevoranitBunyarat Rungtaweevoranit7 January 2011

Kappe, C. O. Chem. Soc. Rev. 2008, 37, 1127-1139.

Microwave-assisted organic synthesis

Theoretical background

Applications

2

Microwave-assisted organic synthesis

Microwave basic theory

Theoretical background

Applications

3

Where is microwave?

Microwave• 1 cm – 1 m1 cm 1 m

Commercial MW• 2.45 GHz2.45 GHz• 0.154 kJ mol-1

Brownian motion Hydrogen bonds Covalent bonds Ionic bonds

Energy (kJ mol-1) 1.64 3.8 - 42435 (C-H)

730

4Loupy, A. Microwaves in Organic Synthesis; Wiley-VCH, 2002.

Energy (kJ mol ) 1.64 3.8 42 730368 (C-C)

Heating mechanism

Electric component• Dipolar polarization• Conduction

Magnetic component• Ohmic heating

5C. Oliver Kappe, D. D., and S. Shaun Murphee Practical Microwave Synthesis for Organic Chemists:Strategies, Instruments, and Protocals; Wiley-VCH, Weinheim, 2008.

Heating mechanism

1. Dipolar polarization mechanism (electric component)

6C. Oliver Kappe, D. D., and S. Shaun Murphee Practical Microwave Synthesis for Organic Chemists:Strategies, Instruments, and Protocals; Wiley-VCH, Weinheim, 2008.

Heating mechanism

1. Dipolar polarization mechanism (electric component)

7C. Oliver Kappe, D. D., and S. Shaun Murphee Practical Microwave Synthesis for Organic Chemists:Strategies, Instruments, and Protocals; Wiley-VCH, Weinheim, 2008.

Heating mechanism

2. Conduction mechanism (electric component)

8C. Oliver Kappe, D. D., and S. Shaun Murphee Practical Microwave Synthesis for Organic Chemists:Strategies, Instruments, and Protocals; Wiley-VCH, Weinheim, 2008.

Heating mechanism

2. Conduction mechanism (electric component)

9C. Oliver Kappe, D. D., and S. Shaun Murphee Practical Microwave Synthesis for Organic Chemists:Strategies, Instruments, and Protocals; Wiley-VCH, Weinheim, 2008.

Heating mechanism

3. Ohmic heating mechanism (magnetic component)

Induced current

Thin metal

10C. Oliver Kappe, D. D., and S. Shaun Murphee Practical Microwave Synthesis for Organic Chemists:Strategies, Instruments, and Protocals; Wiley-VCH, Weinheim, 2008.

Loss tangent (tan )

Solvent tan δ (2.45 GHz)*

Ethylene glycol 1.350

E h l 0 941Ethanol 0.941

Dimethylsulfoxide 0.825

1,2-dichlorobenzene 0.280

tan

,

1,2-dichloroethane 0.127

Water 0.123 the loss factor, quantifies the efficiency by which the absorbed

Chlorobenzene 0.101

Chloroform 0.091

Acetonitrile 0 062

y yenergy is converted into heat

Dielectric constant or relative permittivity the ability of theAcetonitrile 0.062

Acetone 0.054

Dichloromethane 0.042

permittivity, the ability of the material to store electrical potential energy under the influence of an electric field

Toluene 0.040

Hexane 0.020

11Gabriel, C.; Gabriel, S.; H. Grant, E.; S. J. Halstead, B.; Michael P. Mingos, D. Chem. Soc. Rev. 1998, 27, 213.Hayes, B. L. Microwave Synthesis: Chemistry at the Speed of Light; CEM Publishing: Matthews, NC, 2002.

*Loss tangents of different solvents (2.45 GHz, 20 °C)

Instrumentation

1. Magnetron 2. Waveguide

12

Instrumentation

1. Multimode

waveguide

used in domestic microwave oven used in MW batch reactorused in MW batch reactor

13C. Oliver Kappe, D. D., and S. Shaun Murphee Practical Microwave Synthesis for Organic Chemists:Strategies, Instruments, and Protocals; Wiley-VCH, Weinheim, 2008.

Instrumentation

2. Single-mode

used in dedicated microwave reactor for chemical synthesisused in dedicated microwave reactor for chemical synthesis

14C. Oliver Kappe, D. D., and S. Shaun Murphee Practical Microwave Synthesis for Organic Chemists:Strategies, Instruments, and Protocals; Wiley-VCH, Weinheim, 2008.

Sealed tube

Conventional heating- Vessel gets heated first- Both gas and solution phase get heated

T hi h E l i !- Too high pressure -> Explosion!

MW heating- Only solution gets heated

15

Sealed tube

Solvent Temperature (°C)

Name bp(°C) 50 60 70 80 90 100 110  120 130 140 150 160 170 180 190 200 (°C)

N,N-dimethylformamide 153                                                 

Toluene 110                                                 

Water 100   

1,2-dichloroethane 83                                                 

Acetonitrile 81     < 1 bar                                       

Ethanol 78                 1-5 bar                           

Ethyl acetate 77                             5-10 bar 

Hexane 69 > 10 barHexane 69    > 10 bar

Tetrahydrofuran 65                                                 

Methanol 65                                                 

Acetone 56                                         > 20 bar

Dichloromethane 40                                         hazard!

16C. Oliver Kappe, D. D., and S. Shaun Murphee Practical Microwave Synthesis for Organic Chemists:Strategies, Instruments, and Protocals; Wiley-VCH, Weinheim, 2008.

Microwave-assisted organic synthesis

Basic concepts in microwave synthesis

Theoretical background

Applications

17

Reducing reaction times

Intramolecular Diels-Alder cycloaddition

ModeIntramolecular Diels-Alder Hydrolysis

ModeSolvent Temperature Reaction time Solvent Temperature Reaction time

Conventional Chlorobenzene reflux (132 °C) 1 day CHCl3 RT 18 h

D B W M R b t F J R V bi t B M P V d E k E V H t G J

Microwave 1,2-DCE 190 °C 8 min added H2O 130 °C 5 min

18

De Borggraeve, W. M.; Rombouts, F. J. R.; Verbist, B. M. P.; Van der Eycken, E. V.; Hoornaert, G. J. Tetrahedron Lett. 2002, 43, 447.Van der Eycken, E.; Appukkuttan, P.; De Borggraeve, W.; Dehaen, W.; Dallinger, D.; Kappe, C. O. J. Org. Chem. 2002, 67, 7904.

Reducing reaction times

Negishi couplings

Temperature Reaction time

Conventional 100 °C in sealed vessel 24 h

Microwave 175 °C in sealed vessel 10 min

19Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 2719.Walla, P.; Kappe, C. O. Chem. Commun. 2004, 564.

Reducing reaction times

Relationship between temperature and time for a typical 1st order reaction

aERTk Ae

Temperature (°C) Rate constant*, k (s-1) Time (90% conversion)

27 1.55×10-7 68 d

77 4.76×10-5 13.4 h

127 3.49×10-3 11.4 min

177 9.86×10-2 23.4 s

227 1.43 1.61 s

*A = 4×1010 mol-1 s-1, Ea = 100 kJ mol-1

20Mingos, D. M. P.; Baghurst, D. R. Chem. Soc. Rev. 1991, 20, 1.

Improving yields

Synthesis of quinoxalines

Temperature (°C) Reaction time Yield (%)

Conventional 100 2-12 h 32-85

Microwave 165 5 min 99

21Zhao, Z.; Wisnoski, D. D.; Wolkenberg, S. E.; Leister, W. H.; Wang, Y.; Lindsley, C. W. Tetrahedron Lett. 2004, 45, 4873.

Homogeneous heating provided by MW heating

The temperature profile after 60 sec of heating

Microwave irradiation Oil-bath heating

22Schanche, J. S. Mol. Diversity 2003, 7, 291.

Influencing selectivity

Multi-component reactions

NN NH2

PhPh

O

O

Me+NaOEt, EtOH

heatN

NMe

OPhPh

+NH

NH2 OO

Meheat N

HNH MeOH

MW reflux

1310 11 12

PhPh OPhPh

MW150 °C, 20 min

reflux80 °C, 2 h

NN

NH

OMe

OHNH

NNH

Me

Me

15OMe

14

15

23Chebanov, V. A.; Saraev, V. E.; Desenko, S. M.; Chernenko, V. N.; Shishkina, S. V.; Shishkin, O. V.; Kobzar,K. M.; Kappe, C. O. Org. Lett. 2007, 9, 1691.

Influencing selectivity

Thermodynamic and kinetic control in bromination

24Glasnov, T. N.; Stadlbauer, W.; Kappe, C. O. J. Org. Chem. 2005, 70, 3864.

Microwave-assisted organic synthesis

Theoretical background

Applications

25

SmI3 catalyzed Michael addition reaction

Entry Nucleophile Electrophile Product Yield (%)

1 83

2 76Ph

O

3 95Ph

Ph O

4 70

NH

26Zhan, Z. P.; Lang, K. Synlett 2005, 1551.

Diels-Alder reaction

27Leadbeater, N. E.; Torenius, H. M. J. Org. Chem. 2002, 67, 3145.

Ring closure metathesis

Ring-closure metathesis with concurrent removal of ethylene

MeEt3SiOH

H Me

HO

O

H

H + H C CH

1. Grubbs II catalysttoluene

OO

H

H MeO

O

H

H + H2C CH2oil bath, 80 °C

2. TBAF

25 26 27

Entry Conditions Time Yield (%)

1 10 mol % catalyst, N2 atmosphere 1 d 35

2 10 mol % catalyst, N2 sparging 1 d 66

3 15 mol % catalyst, N2 sparging 1 d 80

28Nosse, B.; Schall, A.; Jeong, W. B.; Reiser, O. Adv. Synth. Catal. 2005, 347, 1869.

Ring closure metathesis

Ring-closure metathesis with concurrent removal of ethylene

MeEt3SiOH

O H Me

HO

O

H

H + H2C CH2

1. 15 mol % Grubbs II catalysttoluene

OO

HO

Hheat, Ar sparging

2. TBAF

25 26 27

Temperature Reaction time Yield (%)

Conventionalreflux (110 °C) 120 min 60

reflux (110 °C) 250 min 82

Microwave reflux (110 °C) 90 min 98

29Nosse, B.; Schall, A.; Jeong, W. B.; Reiser, O. Adv. Synth. Catal. 2005, 347, 1869.

Suzuki coupling

Entry Aryl bromide Yield (%)

1 79

2 73

3 91COMe

Br

4 86

30Leadbeater, N. E.; Marco, M. J. Org. Chem. 2002, 68, 888.

Synthesis of pyrrolo-fused ring systems

F

H

O

N

H

O

pyrrolidine, K2CO3, H2O

MW, 130 °C, 3 min

CH2(CN)2, H2O

MW, 100 °C, 10 min

N

CN

CN

MW, 200 °C, 3 min

31 32 33

1 drop of TFA

N

, 00 C, 3

CNCN

34(50% o erall ield)(50% overall yield)

31Kaval, N.; Dehaen, W.; Matyus, P.; Van der Eycken, E. Green Chem. 2004, 6, 125.

MW assisted asymmetric Mannich reaction

Temperature Reaction time Yield (%) ee (%)

Conventional 60 °C 10 min 91 >99

Microwave 60 °C 10 min 90 >99

32Hosseini, M.; Stiasni, N.; Barbieri, V.; Kappe, C. O. J. Org. Chem. 2007, 72, 1417.

Conclusion

• Microwave can be used in a reaction that requires heat.

• At least one of components in reaction mixtures must be responsive to microwave.

• In several cases, microwave can reduce reaction time and increase yield.

33