Knoevenagel condensation

In organic chemistry, the Knoevenagel condensation reaction is a type of chemical reaction named after German chemist 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 a dehydration reaction in which a molecule of water is eliminated. The product is often an α,β-unsaturated ketone.
Image:KnoevenagelGeneral.png|center|400px|General Knoevenagel layout
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:

or for instance diethyl malonate, Meldrum's acid, ethyl acetoacetate or malonic acid, or cyanoacetic acid.
, 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.

Examples and applications

A Knoevenagel condensation is demonstrated in the reaction of 2-methoxybenzaldehyde 1 with the thiobarbituric acid 2 in ethanol using piperidine as a base. The resulting enone 3 is a charge transfer complex molecule.
image:Knoevenagelreaction.svg|center|400px|A knoevenagel condensation
The Knoevenagel condensation is a key step in the commercial production of the antimalarial drug lumefantrine :
Image:Lumefantrine.png|center|400px|Final step in Lumefantrine synthesis
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:
Image:KnoevenagelApplic.png|center|600px|Knoevenagel tandem application

Weiss–Cook reaction

The Weiss–Cook reaction consists in the synthesis of cis-bicyclooctane-3,7-dione employing an acetonedicarboxylic acid ester and a diacyl. The mechanism operates in the same way as the Knoevenagel condensation: