Knoevenagel condensation
From Wikipedia, the free encyclopedia
The Knoevenagel condensation reaction is an organic reaction named after Emil Knoevenagel. It is a modification of the Aldol condensation [1].
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 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 [2]
- 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.
Contents |
[edit] 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 [3] 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 [4]
[edit] 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 [5]. 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) [6]:
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 [7]:
[edit] See also
[edit] References
- ^ Emil Knoevenagel (1898). "Condensation von Malonsäure mit Aromatiachen Aldehyden durch Ammoniak und Amine". Berichte der deutschen chemischen Gesellschaft 31: 2596-2619. doi:.
- ^ March, Jerry (1985). Advanced Organic Chemistry, Reactions, Mechanisms and Structure, third Edition, John Wiley & Sons. ISBN 0-471-85472-7.
- ^ O. Doebner (1902). "Ueber die der Sorbinsäure homologen, ungesättigten Säuren mit zwei Doppelbindungen". Berichte der deutschen chemischen Gesellschaft 35: 1136 - 1136. doi:.
- ^ 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". Org. Synth.; Coll. Vol. 6: 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 [1] 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 - 345; (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
