The Knoevenagel condensation (pronounced [ˈknøːvənaːɡl̩]) 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 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 form
where Z is an electron withdrawing functional 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.
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 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.
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.
The Knoevenagel 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:
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 same way as the Knoevenagel condensation:
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- ^ Emil Knoevenagel (1898). "Condensation von Malonsäure mit aromatischen Aldehyden durch Ammoniak und Amine" [Condensation of malonic acid with aromatic aldehydes via ammonia and amines]. Berichte der deutschen chemischen Gesellschaft. 31 (3): 2596–2619. doi:10.1002/cber.18980310308.
- ^ March, Jerry (1985), Advanced Organic Chemistry: Reactions, Mechanisms, and Structure (3rd ed.), New York: Wiley, ISBN 0-471-85472-7
- ^ G. Jones (2004). "The Knoevenagel Condensation". Organic Reactions. doi:10.1002/0471264180.or015.02.
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- ^ Peter J. Jessup, C. Bruce Petty, Jan Roos, and Larry E. Overman (1988). "1-N-Acylamino-1,3-dienes from 2,4-pentadienoic acids by the curtius rearrangement: benzyl trans-1,3-butadiene-1-carbamate". Organic Syntheses. ; Collective Volume, 6, p. 95
- ^ 1,3-Diethyl-5-(2-methoxybenzylidene)-2-thioxodihydropyrimidine-4,6(1H,5H)-dione Abdullah Mohamed Asiria, Khaled Ahmed Alamrya Abraham F. Jalboutb, Suhong Zhang Molbank 2004, M359  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 medium Arkivoc 2007 (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.