Microwave AssistedOrganic Synthesis

Danielle L. JacobsCrimmins Group Meeting

10/11/06

So how did those TVdinners become sopopular?

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 wasperceived heating phenomenon aroseexclusively 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 ittakes for a collection of molecules torandomize after electric field is switchedoff• Debye Equationτ = 4Πr3η/kT

• r ~ molecular size• η ~ viscosity (intermolecular forces)

Dipolar Polarization

• Loss Tangent (Energy Dissipation Factor) –a measure of the ability to absorbmicrowave energy and convert it intothermal energy (heat)• Derived from Maxwell’s eqn

tanδ = ε”/ε’• ε” = loss factor• ε’ = dielectric constant

Conduction

• Due to translational motion of electriccharges when an electric field is applied

• Ions cause increased collision rate andconvert kinetic energy to heat

• Tap water vs. distilled water

Rate Enhancement

• Arrhenius Equationk = 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 formicrowave energytransfer

Thermodynamics vs. Kinetics

resonance-stabilizedintermediates oftenhave longer lifetimes

Thermal Effects

• More efficient energetic coupling of solventwith microwaves promotes higher rate oftemperature 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

MCROrganocatalysisOlefinationRadical rxnsMetathesisReductionRearrangementOxidationOrganometallic rxnsHeterocycles(Trans)esterification(De)protectionCycloadditionCondensationNucleophilic substitutionAlkyl/aryl couplingAlkylationN-acylation

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 occurswithout 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, 9225Hayes, Brittany, L. Microwave Synthesis. Chemistry at theSpeed of Light. North Carolina: CEM Publishing, 2002.Tierney, J.P., and P. Lidström, ed. Microwave AssistedOrganic Synthesis. Oxford: Blackwell Publishing Ltd, 2005.de la Hoz, A.; Diaz-Ortiz, A.; Moreno, A. Chem. Soc. Rev.2005, 34, 164.