In this reaction the carbonyl group is an aldehyde or a ketone. The catalyst is usually a weakly basicamine. The active hydrogen component has the form[3]
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 Doebner modification of the Knoevenagel condensation. Acrolein and malonic acid react in pyridine to give trans-2,4-pentadienoic acid with the loss of carbon dioxide.
When one of the withdrawing groups on the nucleophile is a carboxylic acid, for example, with malonic acid, the condensation product can undergo a decarboxylation process in a subsequent step. In the so-called Doebner modification[5] the base is pyridine. For example, the reaction product of acrolein and malonic acid in pyridineistrans-2,4-Pentadienoic acid with one carboxylic acid group and not two.[6]
The Knoevenagel condensation is a key step in the commercial production of the antimalarial drug lumefantrine (a component of Coartem):[8]
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.
The Weiss–Cook reaction consists in the synthesis of cis-bicyclo[3.3.0]octane-3,7-dione employing an acetonedicarboxylic acid ester and a diacyl (1,2 ketone). The mechanism operates in the same way as the Knoevenagel condensation:[10]
^1,3-Diethyl-5-(2-methoxybenzylidene)-2-thioxodihydropyrimidine-4,6(1H,5H)-dione Abdullah Mohamed Asiria, Khaled Ahmed Alamrya Abraham F. Jalboutb, Suhong Zhang Molbank2004, M359 [1]Archived 9 July 2011 at the Wayback Machine publication.
^An Improved Manufacturing Process for the Antimalaria Drug Coartem. Part II Ulrich Beutler, Peter C. Fuenfschilling, and Andreas Steinkemper Org. Process Res. Dev.; 2007; 11(3) pp. 341–45; (Article) doi:10.1021/op060244p
^Mild and ecofriendly tandem synthesis of 1,2,4-triazolo[4,3-a]pyrimidines in aqueous mediumArkivoc2007 (06-2251BP) Anshu Dandia, Pritima Sarawgi, Kapil Arya, and Sarita Khaturia Link
^Weiss, U.; Edwards, J. M. (1968). "A one-step synthesis of ketonic compounds of the pentalane, [3,3,3]- and [4,3,3]-propellane series". Tetrahedron Letters. 9 (47): 4885. doi:10.1016/S0040-4039(00)72784-5.