Knoevenagel condensation

The Knoevenagel condensation reaction is an organic reaction named after Emil Knoevenagel. It is a modification of the Aldol condensation.

A Knoevenagel condensation is a nucleophilic addition of an active hydrogen compound to a carbonyl group followed by an dehydration reaction in which a molecule of water is eliminated (hence condensation). The product is often an alpha, beta 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 form


 * Z-CH2-Z or Z-CHR-Z  for instance diethyl malonate, Meldrum's acid, ethyl acetoacetate or malonic acid.
 * Z-CHR1R2 for instance nitromethane.

where Z is an electron withdrawing functional group. Z must be powerful enough to facilitate hydrogen abstraction 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


With malonic compounds the reaction product can lose a molecule of carbon dioxide in a subsequent step. In the so-called Doebner modification the base required is pyridine. For example the reaction product of acrolein and malonic acid in pyridine is trans-2,4-Pentadienoic acid with one carboxylic acid group and not two

Scope
A Knoevenagel condensation is demonstrated in the reaction of 2-methoxybenzaldehyde 1 with the barbituric acid 2 in ethanol using piperidine as a base. The resulting enone 3 is a charge transfer complex molecule.



The Knoevelagel condensation is a key step in the commercial production of the antimalarial drug lumefantrine (a component of Coartem) :



The initial reaction product is a 50:50 mixture of E and Z isomers but because both isomers equilibrate rapidly around their common hydroxyl precursor, the more stable Z-isomer can eventually be obtained.

A multicomponent reaction featuring a Knoevenagel condensation is demonstrated in this MORE synthesis with cyclohexanone, malononitrile and 3-amino-1,2,4-triazole :