microwave assisted organic synthesis - the university of ... · electromagnetic spectrum...
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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
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
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.
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.