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.
15.25:
Aldol Condensation with β-Diesters: Knoevenagel Condensation
The Knoevenagel condensation is an aldol-type reaction involving the condensation of aldehydes or ketones with active methylene compounds such as β-diesters to produce substituted olefins.
The reaction is catalyzed by amine base, which abstracts the acidic α hydrogen of the activated methylene to generate a resonance stabilized enolate ion. The basic strength of the amine is insufficient to form the enolate of aldehydes or ketones. However, it acts as a nucleophile that attacks the carbonyl compound to form an iminium ion intermediate. The nucleophilic enolate attacks the iminium ion to generate an addition product. Further protonation of the amino group in the adduct makes it a better leaving group. The base abstracts a second proton from the resulting molecule. It leads to a rearrangement step yielding the substituted olefinic product, thereby regenerating the amine catalyst.