Microwave Dielectric heating in Synthetic Organic Chemistry Synthetic Organic Chemistry           Bunyarat Rungtaweevorani...
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3
Microwave                                                                                   • 1 cm – 1 m                  ...
Electric component                                                                                       • Dipolar polariz...
1. Dipolar polarization mechanism (electric component)C. Oliver Kappe, D. D., and S. Shaun Murphee Practical Microwave Syn...
1. Dipolar polarization mechanism (electric component)C. Oliver Kappe, D. D., and S. Shaun Murphee Practical Microwave Syn...
2. Conduction mechanism (electric component)C. Oliver Kappe, D. D., and S. Shaun Murphee Practical Microwave Synthesis for...
2. Conduction mechanism (electric component)C. Oliver Kappe, D. D., and S. Shaun Murphee Practical Microwave Synthesis for...
3. Ohmic heating mechanism (magnetic component)                                                                           ...
       Solvent                        tan δ (2.45 GHz)*       Ethylene glycol                       1.350       Ethanol ...
1. Magnetron   2. Waveguide                              12
1. Multimode                   waveguide                                                            used in domestic micr...
2. Single-mode          used in dedicated microwave reactor for chemical synthesisC. Oliver Kappe, D. D., and S. Shaun Mu...
Conventional heating- Vessel gets heated first- Both gas and solution phase get heated- T high pressure -> E l i !  Too hi...
Solvent                                                                            Temperature (°C)                       ...
17
Intramolecular Diels-Alder cycloaddition                            Intramolecular Diels-Alder                            ...
Negishi couplings                                                    Temperature         Reaction time                Conv...
Relationship between temperature and time for a typical 1st order reaction                                                ...
Synthesis of quinoxalines                                       Temperature (°C)                Reaction time      Yield (...
The temperature profile after 60 sec of heating                           Microwave irradiation   Oil-bath heatingSchanche...
Multi-component reactions                                              O                                  Ph       Ph   O ...
Thermodynamic and kinetic control in brominationGlasnov, T. N.; Stadlbauer, W.; Kappe, C. O. J. Org. Chem. 2005, 70, 3864....
25
Entry       Nucleophile               Electrophile   Product            Yield (%)         1                               ...
Leadbeater, N. E.; Torenius, H. M. J. Org. Chem. 2002, 67, 3145.   27
Ring-closure metathesis with concurrent removal of ethylene                      Et3SiO           Me                      ...
Ring-closure metathesis with concurrent removal of ethylene                   Et3SiO        Me                            ...
Entry             Aryl bromide       Yield (%)                                1                                     79    ...
F       pyrrolidine, K2CO3, H2O             N         CH2(CN)2, H2O                  N                                    ...
Temperature            Reaction time              Yield (%)   ee (%)            Conventional                 60 °C        ...
• Microwave can be used in a reaction that requires heat.• At least one of components in reaction mixtures must be respons...
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Microwave assisted organic synthesis

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Microwave assisted organic synthesis

  1. 1. Microwave Dielectric heating in Synthetic Organic Chemistry Synthetic Organic Chemistry Bunyarat Rungtaweevoranit 7 January 2011Kappe, C. O. Chem. Soc. Rev. 2008, 37, 1127-1139.
  2. 2. 2
  3. 3. 3
  4. 4. Microwave • 1 cm – 1 m Commercial MW • 2.45 GHz • 0.154 kJ mol-1 Brownian motion Hydrogen bonds Covalent bonds Ionic bonds 435 (C-H) Energy (kJ mol-1) 1.64 3.8 - 42 730 368 (C-C)Loupy, A. Microwaves in Organic Synthesis; Wiley-VCH, 2002. 4
  5. 5. Electric component • Dipolar polarization • Conduction Magnetic component • Ohmic heatingC. Oliver Kappe, D. D., and S. Shaun Murphee Practical Microwave Synthesis for Organic Chemists: 5Strategies, Instruments, and Protocals; Wiley-VCH, Weinheim, 2008.
  6. 6. 1. Dipolar polarization mechanism (electric component)C. Oliver Kappe, D. D., and S. Shaun Murphee Practical Microwave Synthesis for Organic Chemists: 6Strategies, Instruments, and Protocals; Wiley-VCH, Weinheim, 2008.
  7. 7. 1. Dipolar polarization mechanism (electric component)C. Oliver Kappe, D. D., and S. Shaun Murphee Practical Microwave Synthesis for Organic Chemists: 7Strategies, Instruments, and Protocals; Wiley-VCH, Weinheim, 2008.
  8. 8. 2. Conduction mechanism (electric component)C. Oliver Kappe, D. D., and S. Shaun Murphee Practical Microwave Synthesis for Organic Chemists: 8Strategies, Instruments, and Protocals; Wiley-VCH, Weinheim, 2008.
  9. 9. 2. Conduction mechanism (electric component)C. Oliver Kappe, D. D., and S. Shaun Murphee Practical Microwave Synthesis for Organic Chemists: 9Strategies, Instruments, and Protocals; Wiley-VCH, Weinheim, 2008.
  10. 10. 3. Ohmic heating mechanism (magnetic component) Induced current Thin metalC. Oliver Kappe, D. D., and S. Shaun Murphee Practical Microwave Synthesis for Organic Chemists: 10Strategies, Instruments, and Protocals; Wiley-VCH, Weinheim, 2008.
  11. 11.  Solvent tan δ (2.45 GHz)* Ethylene glycol 1.350 Ethanol Eh l 0.941 0 941   Dimethylsulfoxide 0.825 tan   1,2-dichlorobenzene , 0.280  1,2-dichloroethane 0.127 the loss factor, quantifies the Water 0.123   efficiency by which the absorbed y y Chlorobenzene 0.101 energy is converted into heat Chloroform 0.091 Dielectric constant or relative permittivity, permittivity the ability of the  Acetonitrile 0.062 0 062 material to store electrical Acetone 0.054 potential energy under the Dichloromethane 0.042 influence of an electric field Toluene 0.040 Hexane 0.020 *Loss tangents of different solvents (2.45 GHz, 20 °C)Gabriel, C.; Gabriel, S.; H. Grant, E.; S. J. Halstead, B.; Michael P. Mingos, D. Chem. Soc. Rev. 1998, 27, 213. 11Hayes, B. L. Microwave Synthesis: Chemistry at the Speed of Light; CEM Publishing: Matthews, NC, 2002.
  12. 12. 1. Magnetron 2. Waveguide 12
  13. 13. 1. Multimode waveguide  used in domestic microwave oven  used in MW batch reactorC. Oliver Kappe, D. D., and S. Shaun Murphee Practical Microwave Synthesis for Organic Chemists: 13Strategies, Instruments, and Protocals; Wiley-VCH, Weinheim, 2008.
  14. 14. 2. Single-mode  used in dedicated microwave reactor for chemical synthesisC. Oliver Kappe, D. D., and S. Shaun Murphee Practical Microwave Synthesis for Organic Chemists: 14Strategies, Instruments, and Protocals; Wiley-VCH, Weinheim, 2008.
  15. 15. Conventional heating- Vessel gets heated first- Both gas and solution phase get heated- T high pressure -> E l i ! Too hi h Explosion!MW heating- Only solution gets heated 15
  16. 16. Solvent Temperature (°C) bpName 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 barTetrahydrofuran 65                                                 Methanol 65                                                 Acetone 56                                         > 20 barDichloromethane 40                                         hazard! C. Oliver Kappe, D. D., and S. Shaun Murphee Practical Microwave Synthesis for Organic Chemists: 16 Strategies, Instruments, and Protocals; Wiley-VCH, Weinheim, 2008.
  17. 17. 17
  18. 18. Intramolecular Diels-Alder cycloaddition Intramolecular Diels-Alder Hydrolysis Mode Solvent Temperature Reaction time Solvent Temperature Reaction timeConventional Chlorobenzene reflux (132 °C) 1 day CHCl3 RT 18 h Microwave 1,2-DCE 190 °C 8 min added H2O 130 °C 5 min De Borggraeve, W M.; R b t F J. R.; V bi t B M P V d E k D B W. M Rombouts, F. J R Verbist, B. M. P.; Van der Eycken, E V.; H E. V Hoornaert, G J. t G. J Tetrahedron Lett. 2002, 43, 447. Van der Eycken, E.; Appukkuttan, P.; De Borggraeve, W.; Dehaen, W.; Dallinger, D.; Kappe, C. O. 18 J. Org. Chem. 2002, 67, 7904.
  19. 19. Negishi couplings Temperature Reaction time Conventional 100 °C in sealed vessel 24 h Microwave 175 °C in sealed vessel 10 minDai, C.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 2719. 19Walla, P.; Kappe, C. O. Chem. Commun. 2004, 564.
  20. 20. Relationship between temperature and time for a typical 1st order reaction  Ea k  Ae RT 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-1Mingos, D. M. P.; Baghurst, D. R. Chem. Soc. Rev. 1991, 20, 1. 20
  21. 21. Synthesis of quinoxalines Temperature (°C) Reaction time Yield (%) Conventional 100 2-12 h 32-85 Microwave 165 5 min 99Zhao, Z.; Wisnoski, D. D.; Wolkenberg, S. E.; Leister, W. H.; Wang, Y.; Lindsley, C. W. 21Tetrahedron Lett. 2004, 45, 4873.
  22. 22. The temperature profile after 60 sec of heating Microwave irradiation Oil-bath heatingSchanche, J. S. Mol. Diversity 2003, 7, 291. 22
  23. 23. Multi-component reactions O Ph Ph O Ph Ph NaOEt, EtOH N + + Me N Me N NH2 O heat N O N H Me H H OH Me 10 11 12 13 MW reflux 150 °C, 20 min 80 °C, 2 h Ph Ph Ph Ph O N OH N Me N N N N H Me H H Me O Me 15 14Chebanov, V. A.; Saraev, V. E.; Desenko, S. M.; Chernenko, V. N.; Shishkina, S. V.; Shishkin, O. V.; Kobzar, 23K. M.; Kappe, C. O. Org. Lett. 2007, 9, 1691.
  24. 24. Thermodynamic and kinetic control in brominationGlasnov, T. N.; Stadlbauer, W.; Kappe, C. O. J. Org. Chem. 2005, 70, 3864. 24
  25. 25. 25
  26. 26. Entry Nucleophile Electrophile Product Yield (%) 1 83 O 2 76 Ph Ph O 3 Ph 95 N H 4 70Zhan, Z. P.; Lang, K. Synlett 2005, 1551. 26
  27. 27. Leadbeater, N. E.; Torenius, H. M. J. Org. Chem. 2002, 67, 3145. 27
  28. 28. Ring-closure metathesis with concurrent removal of ethylene Et3SiO Me HO H 1. Grubbs II catalyst H toluene O H O H Me + H2C CH2 O oil bath, 80 °C O H H 2. TBAF 25 26 27 Entry Conditions Time Yield (%) 1 10 mol % catalyst, N2 atmosphere 1d 35 2 10 mol % catalyst, N2 sparging 1d 66 3 15 mol % catalyst, N2 sparging 1d 80Nosse, B.; Schall, A.; Jeong, W. B.; Reiser, O. Adv. Synth. Catal. 2005, 347, 1869. 28
  29. 29. Ring-closure metathesis with concurrent removal of ethylene Et3SiO Me HO H 1. 15 mol % Grubbs II catalyst H toluene O H O H Me + H2C CH2 O heat, Ar sparging O H H 2. TBAF 25 26 27 Temperature Reaction time Yield (%) reflux (110 °C) 120 min 60 Conventional reflux (110 °C) 250 min 82 Microwave reflux (110 °C) 90 min 98Nosse, B.; Schall, A.; Jeong, W. B.; Reiser, O. Adv. Synth. Catal. 2005, 347, 1869. 29
  30. 30. Entry Aryl bromide Yield (%) 1 79 2 73 COMe 3 91 Br 4 86Leadbeater, N. E.; Marco, M. J. Org. Chem. 2002, 68, 888. 30
  31. 31. F pyrrolidine, K2CO3, H2O N CH2(CN)2, H2O N CN H MW, 130 °C, 3 min H MW, 100 °C, 10 min CN O O 31 32 33 1 drop of TFA MW, 200 °C, 3 min , 00 C, N CN CN 34 (50% o erall yield) overall ield)Kaval, N.; Dehaen, W.; Matyus, P.; Van der Eycken, E. Green Chem. 2004, 6, 125. 31
  32. 32. Temperature Reaction time Yield (%) ee (%) Conventional 60 °C 10 min 91 >99 Microwave 60 °C 10 min 90 >99Hosseini, M.; Stiasni, N.; Barbieri, V.; Kappe, C. O. J. Org. Chem. 2007, 72, 1417. 32
  33. 33. • 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
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