Isotope TrackingEasier way to use isotopes in mechanistic analysis is to simply track location of isotope in products.Classic Example: Eschenmoser’s experiment.Tenud, L.; Farouq, S.; Seible, J.; Eschenmoser, A. Helv. Chim. Acta 1970, 53, 2054.RSOO OCH3RSOO OCH3HRSOO OCH3HHHbaseExpected that reaction was intramolecular.Isotope TrackingEasier way to use isotopes in mechanistic analysis is to simply track location of isotope in products.Classic Example: Eschenmoser’s experiment.Tenud, L.; Farouq, S.; Seible, J.; Eschenmoser, A. Helv. Chim. Acta 1970, 53, 2054.RSOO OCH3HHD3CRSOO OCD3HHH3C+RSOO OCH3HbaseD3CRSOO OCD3HH3C+(expected)RSOO OCH3HHD3CRSOO OCD3HHH3C+RSOO OCH3HbaseD3CRSOO OCD3HH3CRSOO OCD3HD3CRSOO OCH3HH3CIsotope TrackingEasier way to use isotopes in mechanistic analysis is to simply track location of isotope in products.Classic Example: Eschenmoser’s experiment.Tenud, L.; Farouq, S.; Seible, J.; Eschenmoser, A. Helv. Chim. Acta 1970, 53, 2054.25% 25%25%25%Isotope scrambling indicated intermolecularmechanism.RSOO OCH3HRSOOOCH3HH(observed)allows forco-linearC--CH3-ODiverting Intermediates andMechanistic Clocks• Sometimes is possible to test hypotheses about mechanisms, intermediates by intentionally diverting them.• For more info, read MPOC Chapter 8.8.Understanding Rate-Determining Transition StatesWhy?• Optimize reaction conditions. Knowing about rate-determining step may lead to improvements.• Design catalysts. Catalysts only work if they lower the energy of the rate-determining transition state.• Design therapeutic inhibitors. Pharmaceuticals that bind enzyme active site better than the natural transition state can stop catalytic activity.Principles of CatalysisReview:E + PE + SESk1k-1ESkcat,]S[]S[]E[]P[Mtotcat+=∂∂KktSet of reactions regenerates E.PSUsed [E]tot= [E] + [ES]to derive11kkkK−+=catM(Michealis-Menton equation)Principles of CatalysisReview:EPE + SESk1k-1ESkcatPSEPE + PfastWe’ll assume catalyst actually binds product complex as well.Principles of CatalysisEPE + SESk1k-1ESkcatPSfastEP E + PESPreaction coordinateΔG‡uncatPrinciples of CatalysisEPE + SESk1k-1ESkcatPSfastEP E + PESPCatalysts stabilize (bind) the transition state.reaction coordinateΔGa(TS)Principles of CatalysisESPPauling’s Hypothesis: By definition, catalysts must bind the transition state more strongly than starting materials.reaction coordinateEPE + SESk1k-1ESkcatPSfastEP E + PΔGa(TS)Principles of CatalysisΔGa(TS)ESPPauling’s Hypothesis: By definition, catalysts must bind the transition state more strongly than starting materials.reaction coordinateEPE + SESk1k-1ESkcatPSfastEP E + PESEPΔGa(S)If ΔGa(S) ≤ ΔGa(TS),then ΔG‡overallisnot improved.This is not a catalyst.ΔG‡overallPrinciples of CatalysisΔGa(TS)ESPPauling’s Hypothesis: By definition, catalysts must bind the transition state more strongly than starting materials.reaction coordinateEPE + SESk1k-1ESkcatPSfastEP E + PESEPΔGa(S)(doesn’t have tobe negative!)If ΔGa(S) > ΔGa(TS),then reaction is catalyzed.ΔG‡cat< ΔG‡uncatPrinciples of CatalysisPauling’s Hypothesis: By definition, catalysts must bind the transition state more strongly than starting materials.E + SE·SKa(S)kcatE + [TS]‡[E·TS]‡Ka(TS)kuncatAnother way of looking at it:ΔGa(TS)Sreaction coordinateESΔGa(S)ΔG‡catEΔG‡uncatΔG‡uncat- ΔG‡cat= ΔGa(S) - ΔGa(TS)orkcatkuncat=Ka(TS)Ka(S)(rel. effectiveness of catalyst =rel. effectiveness of binding TS)Principles of CatalysisAnslyn & Dougherty draw:Figure 9.17, p.528Warning:This notation conflicts with mine.E + S E·SKa(S)kcatE + [TS]‡[E·TS]‡Ka(TS)kuncatFor me,ΔG‡catcomes from this