Kinetics and Isotope Effects of the Aldol−Tishchenko Reaction between Lithium Enolates and Aldehydes

The lithium enolate of isobutyrophenone reacts with two molecules of benzaldehyde at room temperature in THF to yield after protonation a 1,3-diol monoester. The kinetics of this process was studied for the reaction of the lithium enolate of p-(phenylsulfonyl)isobutyrophenone (LiSIBP) and benzaldehyde in THF by monitoring the disappearance of LiSIBP. The observed rates obey the rate law −d[{LiSIBP}]/dt = k_ob[{LiSIBP}]^0.83[benzaldehyde]^2.0 (braces denote initial formal concentration of LiSIBP) and exhibit a kinetic isotope effect k_H/k_D = 2.0 (determined from independent experiments using benzaldehyde-d). These results and competitive isotope effect experiments are consistent with formation of an initial lithium aldolate (P1), followed by reaction with a second aldehyde to form a ketal (P2), and finally a rate-limiting intramolecular hydride transfer (Tishchenko reaction). These reactions are modeled with ab initio molecular orbital calculations. Corresponding theoretical kinetic and equilibrium isotope effects match the experimentally observed isotope effects and support the proposed reaction scheme.