15.25 : Aldol Condensation with β-Diesters: Knoevenagel Condensation

The Knoevenagel reaction involves the condensation of aldehydes or ketones with active methylene compounds to produce substituted olefins.

Activated methylenes such as β-diesters comprise α hydrogens flanked by electron-withdrawing substituents, which makes these hydrogens highly acidic.

The Knoevenagel condensation is catalyzed by a weak secondary amine base.

In general, the secondary base abstracts the acidic hydrogen from the β-diester, forming an enolate ion that is stabilized by resonance.

The question that arises is—will the base also abstract the α hydrogen of the other carbonyl substrate to form the corresponding enolate?

Amine bases are incompetent for such reactions; however, they do tend to behave as nucleophiles and react with the carbonyl compound to form a hemiaminal, followed by an iminium ion intermediate.

The charged intermediate is then attacked by the enolate to produce the addition product.

The adduct undergoes further protonation of the amine part, making it a good leaving group.

A second proton abstraction by the base initiates a rearrangement step, which eliminates the amine—the regenerated catalyst—while also producing the desired substituted olefin.