Stoltz Group Literature Presentation Stoltz Conference Room Thursday 23, 12.

00 pm

Microwave in Organic Chemistry

Yeeman K. Ramtohul

TMS

Cl N

TMS

Pd(Ph3P)2Cl2, CuI Ph3P, Et2NH, DMF N

Isolated Yield Classic: 12 h, 120 C MIcrwave: 25 min, 120 C 80% 97%

Microwave in Organic Chemistry

Yeeman K. Ramtohul History General principles of MW radiation Theory of MW heating Specific MW effect Application of MW in organic chemistry Reviews
- Lared, M.; Moberg, C.; Hallberg, A Acc. Chem. Res. 2002, 35, 717 - Lew, A. et al J. Combi. Chem. 2002, 4, 95 - Lidstrom, p.; Tierney, J.; wathey, B.; Westman, J. Tetrahedron 2001, 57, 9225 - Perreux, L.; Loupy, A Tetrahedron 2001, 57, 9199

Books
- Microwave in Organic Chemistry, Andre Loupy (Ed.), 2002 - Microwave-Enhanced Chemistry, Kingston, H. M., Haswell S. J. (Ed.) 1997

History
1864 - J. Maxwell theorized that, if combined, electrical and magnetic energy would be able to travel through space in a wave 1888 - H. Hertz first succeeded in showing experimental evidence of radio waves 1940's - First generator of microwave power for radar, called magnetron at the University of Birmingham 1946 - Percy Spencer engineer at Raytheon Corp., US observed melting of a chocolate bar in his pocket while working with a new MW vacuum tube, magnetron 1947 - first commercial MW oven "Radarange", 5 1/2 feet tall, 750 pounds, over $5,000 bake biscuit in 29s, cook hamburgers in 35s. Myths and fear of possible risk of radiation poisoning, going blind and sterile 1975 - Widespread domestic use due to technological advances and cheaper prices 1986 - First report of MW reaction in organic chemistry, "The use of microwave ovens for rapid organic synthesis" - Hydrolysis of benzamide under acidic condition, Gedye et al, TL 1986, 27, 279
O NH2 20% H2 SO4 conventional heating: 1h 90% MW heating: 10m min 99% O OH

Applied to a variety of organic transforamtions Slow uptake of the technology - lack of controllability and reproducibility, safety aspects and low understanding of the MW dipolar heating Since the mid 90's significant amount of publication

General Principles

Electromagnetic Spectrum MW have wavelengths 1mm - 1m , frequencies of 0.3 - 300 GHz To avoid interfernce with telecommunication, cellular phones and radar, by International convention most domestic and commercial MW heating operate at wavelength of 12.2 cm, 2.45 GHz MW can be divided in an electric field and a magnetic field component and the former is responsible for heating

Hoz, A.; Diaz-Ortis, A.; Moreno, A.; Langa, F Eur. J. Org. Chem. 2000, 3659

------------------------------------------------------------------------------------------------------------------------------------- MW is generated by vacuum tubes, magnetron, multimode or mono-mode Commercial ovens - multimode, distribution of electric field is not homogeneous

More sophisticated and expensive mono-mode reactor - Focus electromagnetic waves with a waveguide, homogeneous distribution of energy - Allow temperature control using optical fibre or IR detection

Hoz, A.; Diaz-Ortis, A.; Moreno, A.; Langa, F Eur. J. Org. Chem. 2000, 3659

Theory of Microwave Heating

MW heating occurs via dipolar polarization or conduction mechanism

Dipolar Polarization
For MW heating to occur the matrix should be dipolar or ionic Polar solvents e.g. water, DMF, CH2 Cl2 with a dipole moment, i.e. high dielectric constant are MW-active whereas non-polar solvents like toluene, diethyl ether, benzene are MW-inactive

E= O

E!O

In the presence of an electric field - dipole moment tend to align parallel to the applied field by rotation If the electric field oscillates, the dipole realigns and rotate in respond to the alternate electric field The molecules are extremely agitated, the molecular friction and collisions give rise to dipolar heating, ~10 oC per second Note - gases are not microwave active because the rotating molecules are far apart

Conduction Mechanism
This applies for ions in solutions The ions will move through the solution under the influence of an electric field, the increased collision rate generates heat Heat generated is stronger than the dipolar mechanism, e.g. tap water will have higher temperature than distiled water at the same MW radiation power Problem - non polar solvents are MW-inactive
Perreux, L.; Loupy, A Tetrahedron 2001, 57, 9199

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Loss Angle, !
Choosing a good solvent for reaction under MW condition The capabilities to absorb the MW energy and to convert the absorbed energy into heat must also be taken into consideration. These factors may be considered using the loss angle, !, which is expressed in the form of tangent "" = The loss factor, quantifies the efficiency with which the absorbed energy is converted into heat "' = dielectric constant or realative permitivity, the ability of the material to store electrical potential energy under the influence of an electric field

tan ! = ""/ "'

Higher the tan ! value, the better is the solvent at absorbing MW and generating heat Loss Angle Tangent Data for Common Pure Solvents at Room Temperature solvent dichloromethane tetrahydrofuran acetone ethyl acetate acetonitrile chloroform water dimethylformamide acetic acid methanol dimethyl sulfoxide ethanol ethylene glycol "' 9.1 7.6 21 6.0 38 4.8 80 37 6.1 33 47 24 38 tan ! (2.45 GHz) 0.042 0.047 0.054 0.059 0.062 0.091 0.12 0.16 0.17 0.66 0.82 0.94 1.17

Lared, M.; Moberg, C.; Hallberg, A Acc. Chem. Res. 2002, 35, 717

Superheating effect
The combination of temperature and frequency of the MW causes the the loss tangent to increase. This causes the heating rate to increase during MW heating by limiting the formation of "boiling nuclei". Superheating may result in a raised of boiling point by up to 26 o C This phenomenon is believed to be responsible for the rate increases in solution phase MW reaction

MW produces eficient internal energy transter (in situ heating) compared to the wall heat transfer in the conventional thermal heating. As a result the tendency for seed formation (the initiation of boiling) is reduced and superheating is possible.

Temperature profiles of MW flash-heated palladium-

catalyzed alkylation in acetonitrile (bp, 81- 82oC). The reaction was performed in Septum-sealed Pyrex vessels

Lared, M.; Moberg, C.; Hallberg, A Acc. Chem. Res. 2002, 35, 717

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Is There A Specific MW effect ?

Since the introduction of MW in organic chemistry in 1986, the main debate still reamains, waht alter the outcome of the synthesis. Is it merely a thermal or a specific MW effect. Rate of the reaction, Arrhenius equation

K = A e -!G/RT
!G, free energy of activation

!G = !H - T!S

A, pre-exponential factor

Change in temperature would have an effect on !G, which in turn would affect the rate The pre-exponential factor, A, describes the molecular mobility and depends on the frequency of vibrations of the molecules. Since, MW induces an increase in molecular vibrations, it's been proposed that this factor, A, can also be affected. Imidization of Polyamic acid
O 2S N H HO O MW Classical heating !G (KJ/mol) 57 5 105 14 log A 13 1 24 4 O NMP O 2S O N O

Calculations showed that the increase in rate might be explained by an increase in the factor A also.
Lidstrom, p.; Tierney, J.; wathey, B.; Westman, J. Tetrahedron 2001, 57, 9225

Effects According to Reaction Mechanism

MW causes dipolar polarization by interacting with polar molecule The greater the polarity of the molecule the more efficient is the energy transfer. Specific MW effect can be expected for a polar mechanism, when the polarity is increased during the reaction from GS towards the TS. e.g. Synthesis of diazepine - Conventional heating gave a complex mixture of products In non polar solvents only the reactants absorb the MW
CF3 NH2 + NH2 O BuO CF3 R MW Xylene, 15 min, 77% !" O ! + NH
2

N N H

CF3 R

OBu

NH2

Concerted reaction - e.g. DA, Cope rearrangement and ene reaction, no charges are developed during the reaction path. No specific MW effect would be expected for these reactions e.g. No MW effect for the DA reaction of anthracene in non polar solvent, Xylene
CO2 Et + CO2 Et CO2 Et CO2 Et

Xylene

Photochemical coupled with MW effect Homogeneous bond breaking leads to radical ions - interact with MW
hv

A B

Products

Lidstrom, p.; Tierney, J.; wathey, B.; Westman, J. Tetrahedron 2001, 57, 9225

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MW effect on selectivity of reactions

Since MW can interact with a polar TS. The product formed via a more polar TS will be favored Regioselectivity in Cycloaditions of C 70 fullerene under MW can be altered

Classical heating MW

ODCB, 120 min, 32% yield ODCB, 120W, 30 min, 39% yield

46% 50%

46% 50%

8% 0%

Theoretical studies suggest that under kinetic control, 1a and 1b have a more polar TS
ODCB - o-dichlorobenzene Langa et al. J. Org. Chem. 2000, 65, 2499

Application of MW in Organic Chemistry

Green chemistry
Some reactions can be performed in water as solvent. In a high-pressure reactor, water temperatures of 200-300 oC can be reached. Under these high pressures, the dielectric constant of water changes considerably and water behaves as a "pseudoorganic solvent"
O O 0.05% NaOH, H2O, O 200 o C, MW, 81%

Solvent-free organic synthesis Advantages cf organic solvent - Clean, efficient and economical process, safety is largely increased, workup is simplified, increased amounts of reactants can be used in the same equipment and sometimes reactivities are enhanced. MW interact directly with the reagents General procedure, impregnate a solid support capable of absorbing MW (i.e., silica, clay or alumina) or catalyst with a solution of the reactant in a volatile solvent. Evaporate the solvent and irradiate the dry mixture with MW Alumina can act as base for acids, KF on alumina acts as strong base (pKa ~ 35), montmorillonites (clays) - acidity close to sulfuric acid
OH OH O HO OH O MW, 10 min, 66% Clay, RCHO R O O O HO O H Me !, 140 o C MW, 300W, 140 o C O KMnO4 /Al2 O3 N Ph 15 min N O H <2% 83% O Ph + Me O

OH Kuhnert, N. Angew. Chem. Int. Ed. 2002, 41, 1863 Loupy et al Synthesis 1998, 8, 1213

-------------------------------------------------------------------------------------------------------------------------------------Enzymatic Catalysis in "Dry Media"

Enzyme immobilized on solid support - optimal activty 80 - 100 oC Candida antartica lipase on acrylic resin, (novozym)
OH Novozyme + CH3 -(CH2 )6 -CO2 H 10 min, 78 oC + O

O R

OH

!, 140 o C MW, 60-20W

ee 48% 52%

ee 62% 93%

E 9 44

E - enantioselectivity coefficients Possible explanation under MW condition - Efficient removal of low molecularr weight alcohols or water - entropic effect due to dipolar polarization

Solvent- Free 1,3-dipolar Cycloaddition

Ph Ph N O Ph + Ph N O Ph Ph

!, 34 h MW, 6 min

80% 76%

Loupy et al Synthesis 1998, 8, 1213 Baruah, J. A et al Synth. Commun, 1997, 27, 2888

Wolf Rearangement
Diazocarbonyl groups are dipolar and possess high permanent dipole moment - MW active 2 possible configuration for !-diazoketone, Z - type is the preferred configuration for orientation to align with the magnetic field of MW
O Ph H N2 Ph N N Z - Dipole moment - 3.69D N2 H BnNH2 , 15 min 170 oC ! MW, 300W 56% 92% Ph O H N O H Ph H O N N

E - Dipole moment - 1.89D

O Ph

Bn

Microwave Specific effect?

O N H Ph MW (300, 600W), PhCH2NH2 , 73% O O N2 OH H hv, dioxane/ H2 O, 70% MW (300W), H2 O, 70% or

", 180 oC, PhCH2 NH2 , 43%

Ab initio calculations - difference in dipole between E and Z conformers

Sudrik, S. et al J. Org. Chem. 2002, 67, 1574

-------------------------------------------------------------------------------------------------------------------------------------MW and Solid Phase Synthesis

Solid phase synthesis - prolong heating may cause degradation of the resin - Claisen Rearrangement
O O O i) DMF/K2 CO3 , MW (600W), 4-6 min ii) TFA, DCM OH Calssical heating - 10-16h, 140 C
o

O HO

84-92%

Solvent-Free Solid-Liquid PTC

PTC solid-liquid, in the absence of solvent, its difficult to achieve a homogeneous heating under conventional heating. Ion pairs Q+Nu - , highly polar species, prone to MW interaction Krapcho reaction - dealkoxycarbonylation of activated esters. DMSO and alkaline salts are used at high temperatures. Decomposition and tedious workup. Modification - LiBr and Bu4 NBr (TBAB)
O O R OEt LiBr/H2 O (2 eq.) TBAB (10%), 160 o C Classical Method: DMSO, CaCl 2 (5 eq.) PTC, oil bath PTC, MW Lew, A. et al J. Combi. Chem. 2002, 4, 95 3h, 20% 3h, 60% 15 min, 94% O R R = Et, Bu, Hex

MW- Accelerated Homogeneous Catalysis

Homogeneous palladium-catalyzed reactions Heck coupling Sonogashira Coupling

Suzuki Cross Coupling

Stille Coupling

Lared, M.; Moberg, C.; Hallberg, A Acc. Chem. Res. 2002, 35, 717

-------------------------------------------------------------------------------------------------------------------------------------Asymmetric Catalysis
Higher ee are generally obtained at lower temperature, but reaction also slows down. Heating over long period of time may causse degradation of the catalyst system. MW heating occasionally prevents degradation due to rapid heating.
O OCOOEt Phalimide, L, [(all)PdCl]2 , CH3 CN Yield Classic, 10 min, 140 C MW, 1.5 min, 100 W
o

N O ee 95% 96%

O NH HN PPh2 Ph2P

51% 87%

MW- Accelerated Ru-Catalyzed Olefin Metathesis

Ionic liquids - "green solvent", liquid at room temperature, reasonably polar, dissolve organic compounds, high bp (>200 oC), can be recycled Interact very efficiently with MW
EtO2 C CO2 Et 3% Ru - 2o EtO 2 C CO2 Et bmim, 15s DCM, 120 s Ts N 3% Ru - 2o TS N N N

BF 4

1-butyl-3-methylimidazolium tetrafluoroborate (bmim)

% conversion (NMR) Thermal MW 100% 3% 100% 21%

bmim, 15s DCM, 120s

100% 91%

0% 45%

Lared, M.; Moberg, C.; Hallberg, A Acc. Chem. Res. 2002, 35, 717 Kiddle, J. et al Org. Lett. 2002, 4, 1567

MW-Enhanced Radiochemistry
Pharmaceutical industry - radiolabeled compounds are used for screening new targets, binding experiments, identification of metabolites, distribution and excretion studies and qunatifying concentrations in target organs Positron emission toppgraphy (PET) for human studies, positron emitters e.g. 11 C (t1/2 = 20.4 min), 13 18 N (t1/2 = 10 min), F (t1/2 = 110 min) Need an efficient synthesis with short reaction time in order to achieve a good radiochemical yield Using MW, the reaction time reduced 25-50% e.g. Synthesis of [N-methyl-11 C]Flumazenil

N CO 2 Et N NH O In Acetone 5 min, 70 o C, 45% 0.5 min, 100W, 65% In DMF 0.5 min, 50W, 80%
11

N CO 2 Et CH3I F O N N
11

N CO 2 H NaOH F CH3 In Acetone 2 min, 70 o C, 40% 0.5 min, 100W, 60% In DMF 0.5 min, 50W, >95% O N N
11

CH3

Wathey, B. et al Drug. Disc. Today 2002, 7, 373

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Conclusion
MW provides an interesting alternative for heating chemical reactions. The drastic rate enhancement observed confims the usefulness of the MW technique. Solvent-free reactions under MW - promising future The availability of commercial MW instrument for organic chemistry make this technique a routine use in the laboratory. The existence of a specific MW effect is still a debate.

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