The Complete Mechanism of an Aldol Condensation

Abstract

Although aldol condensation is one of the most important organic reactions, capable of forming new C–C bonds, its mechanism has never been fully established. We now conclude that the rate-limiting step in the base-catalyzed aldol condensation of benzaldehydes with acetophenones, to produce chalcones, is the final loss of hydroxide and formation of the CC bond. This conclusion is based on a study of the partitioning ratios of the intermediate ketols and on the solvent kinetic isotope effects, whereby the condensations are faster in D2O than in H2O, regardless of substitution.

DFT investigations of the unusual reactivity of 2‐pyridinecarboxaldehyde in base‐catalyzed aldol reactions with acetophenone

“…Indeed, one would expect the anti conformer to predominate since torsional strain is minimized. Recently, Perrin and Chang repeated earlier kinetic investigations of the aldol condensation that supports an E1cB R pathway for chalcone formation from ketol intermediate 3 in Scheme . Under basic conditions in aqueous solutions, enolization of 3 is rapid and reversible, and loss of hydroxide from intermediate 7 is rate determining.…”

“…Under basic conditions in aqueous solutions, enolization of 3 is rapid and reversible, and loss of hydroxide from intermediate 7 is rate determining. In their paper, they further point out that “the rate‐limiting step for the reverse reaction must be … Michael addition of HO − to the C═C bond” . It comes as no surprise, then, that Michael addition by the enolate of acetophenone to the α,β‐unsaturated ketone formed by condensation with benzaldehyde is not significant since the product isolated in this reaction is trans ‐chalcone.…”

“…To probe the conformational preferences of the intermediates in the reaction, our computational investigations focused on the reactions of the sodium enolate of acetophenone with benzaldehyde and with 2‐pyridinecarboxaldehyde. In protic solvents, base‐promoted elimination from β‐hydroxy carbonyl compounds proceed via an E1cB pathway; reversible enolate formation (intermediates 3 and 7 in Scheme ) precedes the departure of the hydroxyl group . Therefore, three intermediates are considered in the transformation of the β‐hydroxyketone to an α,β‐unsaturated ketone: A , metal‐ion coordinated keto alkoxide intermediate 6 (Figure ); B , the ketol intermediate 3 (Figure ); and C , the β‐hydroxyenolate 7 (Figure ).…”

“…Recently, Perrin and Chang repeated earlier kinetic investigations of the aldol condensation that supports an E1cB R pathway [26,27] for chalcone formation from ketol intermediate 3 in Scheme 3. [28] Under basic conditions in aqueous solutions, enolization of 3 is rapid and reversible, and loss of hydroxide from intermediate 7 is rate determining. In their paper, they further point out that "the rate-limiting step for the reverse reaction must be … Michael addition of HO − to the C═C bond".…”

On the asymmetric autocatalysis of aldol reactions: The case of 4‐nitrobenzaldehyde and acetone. A critical appraisal with a focus on theory

“…53 Because the transformation creates new chiral centers, stereoselectivity is usually controlled with preformed enol derivatives. 56 For the sake of brevity, this semantic distinction is no longer held hereafter as the reaction of both substrates occurs under neutral conditions ending up in single bonds. Surprisingly and despite its huge versatility, the rate-limiting step of the base-catalyzed aldol condensation has remained uncertain.…”