D. A. Evans Claisen Condensation Related Processes Chem 206 Claisen Condensation: Condensation of 2 esters I Analysis of the two processes i Conventional Carbomethoxylation: Equilibrium achieved between all species oR+ COmE Intramolecular Variant: Dieckmann Condensation CO,Me RO Keg -10 MeoH COmE Me2CO3 ly speaking, the Claisen and Dieckmann condensations are defined as condensations discussion, we choose to liberalize the classifcation to include ketone enolates as well. I a Reaction Thermodynamics: Overall Keq -1 with aromatic ring disrupting the required planarity of the delo by peri-interaction Critical issue: Product enolate a is significantly destabi eater stability of B dictates the product. RO I Final enolization Step: Keq -10 COmE L This type of control is general rOH 2Et pKa 12 pKa 16 HCO2Et Me Me Reaction Control Elements: These reactions can be manipulated to give Meyers, JOC 1976, 41, 1976 either kinetic or thermodynamic control HCO2Et kinetic product Piers. Tet. Let 1968. 583 HCODEt hermodynamic MeO OM H23-02-Claisen Condensation 11/5/00 8: 17 PMLDA D. A. Evans Claisen Condensation & Related Processes Chem 206 ■ Claisen Condensation: Condensation of 2 esters + RO– H3O+ ■ Intramolecular Variant: Dieckmann Condensation H3O+ RO– Strictly speaking, the Claisen and Dieckmann condensations are defined as condensations between ester enolates & ester electrophiles. In this discussion, we choose to liberalize the classifcation to include ketone enolates as well. ■ Reaction Thermodynamics: Overall Keq ~ 1 RO– + 2 + RO + – + ROH ■ Final enolization Step: Keq ~ 10+4 Contrary to popular belief, final enolization step does not render the process irreversible pKa 12 pKa 16 Reaction Control Elements: NaH kinetic product Thermodynamic product -78 °C 0 °C ■ Analysis of the two processes: Conventional Carbomethoxylation: Equilibrium achieved between all species Me2CO3 + MeO– + MeOH Keq ~ 10-2 Keq ~ 10+4 Me2CO3 Keq > 10+4 Critical issue: Product enolate A is significantly destabilized by peri-interaction with aromatic ring disrupting the required planarity of the delocalized enolate. Hence, the greater stability of B dictates the product. A B Keq >> 1 A B ■ This type of control is general: HCO2Et KOtBu Meyers, JOC 1976, 41, 1976 Piers, Tet. Let 1968, 583 MeO– HCO2Et benzene benzene HCO2Et MeO– JACS 1965, 87, 5728 These reactions can be manipulated to give either kinetic or thermodynamic control: CO2Me R Me CO2Me OR O O OR R O OR O R R O Me CO2Me R R O OR O R R O OR R O OR O O OR O– R R O NC OMe O O CO2Me O MeO OMe CO2Me O Me CO2Et O OH Me Me OH O CO2Et Me O– O CO2Me CO2Me O– O– CO2Me O O– CO2Me O– MeO O H CO2Me O– O Me O Me Me O Me O Me Me OH RO– H23-02-Claisen Condensation 11/5/00 8:17 PM