Mechanistic Imperatives for Catalysis of Aldol Addition Reactions:  Partitioning of the Enolate Intermediate between Reaction with Brønsted Acids and the Carbonyl Group

The lyoxide ion catalyzed intramolecular aldol addition reaction of 2-(2-oxopropyl)benzaldehyde (1) to give the aldol adduct 3 proceeds via essentially irreversible formation of the acetone-like enolate intermediate 2, because reprotonation of 2 by a solvent of H2O or D2O (k HOH or k DOD) is much slower than intramolecular addition of the enolate to the carbonyl group (k c). The aldol addition reaction of 1 catalyzed by high concentrations of 3-substituted quinuclidine buffers proceeds via reversible deprotonation of 1 to give the enolate 2, and rate-determining addition of the enolate to the carbonyl group. A rate constant ratio of k c/k HOH = 35 was determined for partitioning of the enolate 2 between intramolecular addition to the carbonyl group and protonation by solvent water. The corresponding ratios k BH/k c (M-1) for the protonation of 2 by Brønsted buffer acids and intramolecular aldol addition increase from 7 to 450 as the acidity of the buffer acid is increased from pK BH = 11.5 to 7.5. The data show that the electrophilic reactivity of the benzaldehyde carbonyl group toward intramolecular addition of the enolate 2 is the same as that of a hypothetical tertiary ammonium cation of pK BH = 13.3. The Marcus intrinsic barrier for addition of the enolate 2 to the carbonyl group is unexpectedly small, which suggests that the transition state for this reaction is stabilized by interactions between the soft−soft acid−base pair. The relevance of this work to chemical and enzymatic catalysis of aldol condensation reactions is discussed.