Knoevenagel condensation

A Knoevenagel condensation is a nucleophilic addition of an active hydrogen compound to a carbonyl group followed by a dehydration reaction in which a molecule of water is eliminated (hence condensation). The product is often an α,β-unsaturated ketone (a conjugated enone).

In this reaction the carbonyl group is an aldehyde or a ketone. The catalyst is usually a weakly basic amine. The active hydrogen component has the forms:

• Z−CH₂−Z or Z−CHR−Z for instance diethyl malonate, Meldrum's acid, ethyl acetoacetate or malonic acid, or cyanoacetic acid.
• Z−CHRR', for instance nitromethane.

where Z is an electron withdrawing group. Z must be powerful enough to facilitate deprotonation to the enolate ion even with a mild base. Using a strong base in this reaction would induce self-condensation of the aldehyde or ketone.

The Hantzsch pyridine synthesis, the Gewald reaction and the Feist–Benary furan synthesis all contain a Knoevenagel reaction step. The reaction also led to the discovery of CS gas.

Doebner modification

The Doebner modification of the Knoevenagel condensation entails the use of pyridine as a solvent with at least one of the withdrawing groups on the nucleophile is a carboxylic acid, for example, with malonic acid. Under these conditions the condensation is accompanied by decarboxylation. For example, the reaction of acrolein and malonic acid in pyridine gives trans-2,4-entadienoic acid with one carboxylic acid group and not two. Sorbic acid can be prepared similarly by replacing acrolein with crotonaldehyde.