Download - 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
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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
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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
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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.
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