Microwave Assisted Organic Synthesis

Danielle L. Jacobs Crimmins Group Meeting 10/11/06

So how did those TV dinners become so popular?

History
Randall & Booth (WWII) Formed basis of radar transmitters Raytheon Company (1946) Commercially available in 1954 for $5,000 Industrial/domestic wavelength regulated at 2.45 GHz Initially used in industry for irradiating coal, drying, ceramic processing, etc

History
Other applications limited as it was perceived heating phenomenon arose exclusively from w intrxns with water Used since late 1970s for inorganic rxns Organic rxns in mid-1980s, but only recently exploded Lack of controllability, reproducibility, safety aspects

Electromagnetic Spectrum
Electric field component Responsible for dielectric heating Dipolar polarization Conduction Magnetic field component

Dipolar Polarization
Average Relaxation Time average time it takes for a collection of molecules to randomize after electric field is switched off Debye Equation = 4r3/kT r ~ molecular size ~ viscosity (intermolecular forces)

Dipolar Polarization
Loss Tangent (Energy Dissipation Factor) a measure of the ability to absorb microwave energy and convert it into thermal energy (heat) Derived from Maxwells eqn tan = / = loss factor = dielectric constant

Conduction
Due to translational motion of electric charges when an electric field is applied Ions cause increased collision rate and convert kinetic energy to heat Tap water vs. distilled water

Rate Enhancement
Arrhenius Equation k = Ae-Ea/RT Does not decrease rxn Ea Increases pre-exponential factor A Thermodynamic rxns more affected than kinetic rxns

Thermodynamics vs. Kinetics

polar transition state: excellent for microwave energy transfer

Thermodynamics vs. Kinetics

resonance-stabilized intermediates often have longer lifetimes

Thermal Effects
More efficient energetic coupling of solvent with microwaves promotes higher rate of temperature increase Inverted heat transfer, volumetric Hot spots in monomode microwaves Selective on properties of material (solvents, catalysts, reagents, intermediates, products, susceptors)

Selective Solvent Effects

Biphasic systems Ionic solvents High BP, low VP, high thermal stability, environmentally friendly Nucleation Limited Boiling Point (NLBP)

Method Development
Open vessel vs. pressurized system Solvent selection Polar/ionic rapid rise in T, above BP Non-polar behaves as heat sink Solventless rxn mixture is absorbing Time, temperature, power settings Reflux, simultaneous cooling, or continuous flow options

Microwaves in Industry
Pharmaceuticals Combichem Med chem Process chemistry Green chemistry Solvent-free rxns Solid-support MORE

The Contest

Recent Applications of MAOS

N-acylation Alkyl/aryl coupling Condensation (De)protection Heterocycles Oxidation Reduction Radical rxns Organocatalysis Alkylation Nucleophilic substitution Cycloaddition (Trans)esterification Organometallic rxns Rearrangement Metathesis Olefination MCR

Heterocycles

Fresneda, P.M.; Molina, P.; Sanz, M.A.; Synlett 2001, 218. Coleman, C.M.; MacElroy, J.M.D.; Gallagher, J.F.; OShea, D.F. J. Combinatorial Chem. 2002, 4, 87. Nolt, M.B., et. al. Tetrahedron 2006, 62, 4698.

Organometallic Reactions

Skoda, Foldes, R., et. al. Steroids, 2002, 67, 709. Trost, B.M.; Andersen, N.G.; J. Am. Chem. Soc. 2002, 124, 14320. Trost, B.M>; MeEachern, E.J.; Toste, F.D.; J. Am. Chem. Soc. 1998, 120, 12702.

Rearrangements

Pelc, M.J.; Zakarian, A. Tetrahedron Lett. 2006, 47, 7519. Pelc, M.J.; Zakarian, A. Org. Lett. 2005, 7, 1629. Pelc, M.J. Thesis, Florida State University.

Rearrangements

Craig, D.; Henry, G.D. Eur. J. Org. Chem. 2006, 3558.

Cross Metathesis

Bargiggia, F.C.; Murray, W.V. J. Org. Chem. 2005, 70, 9636.

What the Hell is Sparging?

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

Radical Initiation
Homolytic cleavage of weak bonds occurs without initiators

Jessop, C.M.; Parsons, A.F.; Routledge, A.; Irvine, D.J. Eur. J. Org. Chem. 2006, 1547. Hartung, J.; Daniel, K.; Gottwald, T.; Grob, A.; Schneiders, N. Org. Biomol. Chem. 2006, 4, 2313.

Lead References
Lidstrm, P.; Tierney, J.P.; Wathey, B.; Westman, J. Tetrahedron 2001, 57, 9225 Hayes, Brittany, L. Microwave Synthesis. Chemistry at the Speed of Light. North Carolina: CEM Publishing, 2002. Tierney, J.P., and P. Lidstrm, ed. Microwave Assisted Organic Synthesis. Oxford: Blackwell Publishing Ltd, 2005. de la Hoz, A.; Diaz-Ortiz, A.; Moreno, A. Chem. Soc. Rev. 2005, 34, 164.