Mechanistic imperatives for catalysis of aldol addition reactions: Partitioning of the enolate intermediate between reaction with Bronsted acids and the carbonyl group

The lyoxide ion catalyzed intramolecular aldol addition reaction of 2-(2-ox opropyl)benzaldehyde (1) to give the aldol adduct 3 proceeds via essentiall y irreversible formation of the acetone-like enolate intermediate 2, becaus e 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 S-substituted quinuclidine buffers proceeds via reversible deprotonation of 1 to give the enolate 2, and rate-determining addition of the enolate to t he 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 c arbonyl group and protonation by solvent water. The corresponding ratios k( BH)/k(c) (M-1) for the protonation of 2 by Bronsted buffer acids and intram olecular 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 electr ophilic reactivity of the benzaldehyde carbonyl group toward intramolecular addition of the enolate 2 is the same as that of a hypothetical tertiary a mmonium cation of pK(BH) = 13.3. The Marcus intrinsic barrier for addition of the enolate 2 to the carbonyl group is unexpectedly small, which suggest s that the transition state for this reaction is stabilized by interactions between the soft-soft acid-base pair. The relevance of this work to chemic al and enzymatic catalysis of aldol condensation reactions is discussed.