Microwave in Organic Chemistry

Stoltz Group Literature PresentationStoltz Conference RoomThursday 23, 12.00 pm

Yeeman K. Ramtohul

N

Cl Pd(Ph3P)2Cl2, CuI

Ph3P, Et2NH, DMF

TMS

N

TMS

Isolated Yield

Classic: 12 h, 120 °C 80%MIcrwave: 25 min, 120 °C 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

1

• 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

History

NH2

O

OH

O20% H2SO4

conventional heating: 1h 90%MW heating: 10m min 99%

• 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 2

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• 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

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

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

Perreux, L.; Loupy, A Tetrahedron 2001, 57, 9199

E = O E ! O

Dipolar Polarization• For MW heating to occur the matrix should be dipolar or ionic

Polar solvents e.g. water, DMF, CH2Cl2 with a dipole moment, i.e. high dielectric constant are MW-active whereas non-polar solvents like toluene, diethyl ether, benzene are MW-inactive

• 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

• MW heating occurs via dipolar polarization or conduction mechanism

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

3

-------------------------------------------------------------------------------------------------------------------------------------- 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

tan ! = ""/ "'

"" = 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

• 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 "' tan ! (2.45 GHz)

dichloromethane tetrahydrofuran acetone ethyl acetate acetonitrile chloroform water dimethylformamide acetic acid methanol dimethyl sulfoxide ethanol ethylene glycol

9.1 0.0420.0470.054

7.6216.0384.880

376.133472438

0.160.170.660.820.941.17

0.0590.0620.0910.12

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

4

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 oC• 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 --------------------------------------------------------------------------------------------------------------------------------------

O2S

O

HO

O

NH

NMP N

O

O

O2S

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 = !H - T!S

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

!G, free energy of activation 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

Calculations showed that the increase in rate might be explained by an increase in the factor A also.

!G (KJ/mol) log A

MW

Classical heating

57 ± 5

105 ± 14

13 ± 1

24 ± 4

5

NH2

NH2BuO

CF3

OR

CO2Et

CO2Et

NH2

NH2

CF3

O

OBu

R

A B A B

CO2Et

CO2Et

N

NH

R

CF3

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

Effects According to Reaction Mechanism

• 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

+Xylene

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

Productshv

+ MW

Xylene,15 min, 77%

‡

! +

! "

• 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

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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 C70 fullerene under MW can be altered

Langa et al. J. Org. Chem. 2000, 65, 2499

Classical heating

MW

ODCB, 120 min, 32% yield

ODCB, 120W, 30 min, 39% yield

• Theoretical studies suggest that under kinetic control, 1a and 1b have a more polar TS

ODCB - o-dichlorobenzene

46%

50%

46%

50%

8%

0%

6

O

O

O

OH

HOO

OH

OH

O

OH

HOO

O

O

R

Ph

Me

N

H

O

O

O

N

H

O

O

Ph

Me

Application of MW in Organic Chemistry

Green chemistry

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

• 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"

0.05% NaOH, H2O,

200 oC, 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

Clay, RCHO

MW, 10 min, 66%

+KMnO4/Al2O3

15 min

!, 140 oC <2%

MW, 300W, 140 oC 83%

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OH

Ph NPh

O

PhO

N

Ph

Ph

Ph

OH O R

O

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

Enzymatic Catalysis in "Dry Media"

• Enzyme immobilized on solid support - optimal activty 80 - 100 oC

Candida antartica lipase on acrylic resin, (novozym)

+ CH3-(CH2)6-CO2H

Novozyme

10 min, 78 oC

+

!, 140 oC

MW, 60-20W

48%52%

62%93%

ee ee

944

E

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

!, 34 h 80%MW, 6 min 76%

+

7

O

N2

H

Ph

O

N2

H

Ph

O

PhHN

Bn

O

H

N

N

Ph

O

N

H

NPh

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

Wolf Rearangement

Z - Dipole moment - 3.69D E - Dipole moment - 1.89D

• 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

BnNH2, 15 min

170 oC

! 56% MW, 300W 92%

Microwave Specific effect?

H

OH

O

H

NH

O

Ph

O

N2

O

MW (300W),

H2O, 70%

or

", 180 oC,

PhCH2NH2, 43%

MW (300, 600W),PhCH2NH2, 73%

hv, dioxane/H2O, 70%

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

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O

O

O

O O

OEtR

O

R

HO

O

OH

MW and Solid Phase Synthesis

Lew, A. et al J. Combi. Chem. 2002, 4, 95

• Solid phase synthesis - prolong heating may cause degradation of the resin- Claisen Rearrangement

i) DMF/K2CO3, MW (600W), 4-6 min

ii) TFA, DCM

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 Bu4NBr (TBAB)

R = Et, Bu, Hex

Classical Method: DMSO, CaCl2 (5 eq.)PTC, oil bathPTC, MW

LiBr/H2O (2 eq.)

TBAB (10%), 160 oC

3h, 20%3h, 60%15 min, 94%

Calssical heating - 10-16h, 140 oC

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MW- Accelerated Homogeneous CatalysisHomogeneous palladium-catalyzed reactions

• Heck coupling • Sonogashira Coupling

• Suzuki Cross Coupling

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

• Stille Coupling

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TsN

EtO2C CO2Et

OCOOEt

TSN

EtO2C CO2Et

N

O

O

MW

% conversion (NMR)

NH HN

O O

PPh2 Ph2P

N N

BF4

• 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.

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

• Ionic liquids - "green solvent", liquid at room temperature, reasonably polar,

dissolve organic compounds, high bp (>200 oC), can be recycled

• Interact very efficiently with MW1-butyl-3-methylimidazolium tetrafluoroborate (bmim)

3% Ru - 2o

3% Ru - 2o

Thermal

bmim, 15sDCM, 120 s

bmim, 15sDCM, 120s

100%100%

100%91%

3%21%

0%45%

MW- Accelerated Ru-Catalyzed Olefin Metathesis

Asymmetric Catalysis

Phalimide, L,

[(all)PdCl]2, CH3CN

Classic, 10 min, 140 oC

MW, 1.5 min, 100 W

Yield ee

51%

87%

95%

96%

9

F NH

N

O

NCO2Et

11CH3I

F N

N

O

NCO2Et

11CH3

NaOH

F N

N

O

NCO2H

11CH3

MW-Enhanced Radiochemistry

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

• 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

N (t1/2 = 10 min), 18

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

In Acetone

5 min, 70 oC, 45%

0.5 min, 100W, 65%

In DMF

0.5 min, 50W, 80%

In Acetone

2 min, 70 oC, 40%

0.5 min, 100W, 60%

In DMF

0.5 min, 50W, >95%

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• 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.

Conclusion

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