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 µw 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 τ = 4Πr3η/kT • r ~ molecular size • η ~ 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 Maxwell’s eqn tanδ = ε”/ε’ • ε” = loss factor • ε’ = 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.; O’Shea, 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
Lidström, 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. Lidström, 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.

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