Knoevenagel condensation

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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 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

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

File:Doebner modification.png
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.


With malonic compounds the reaction product can lose a molecule of carbon dioxide in a subsequent step. In the so-called Doebner modification [2] 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 [3]

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 [4]. 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) [5]:

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 [6]:

References

  1. E. Knoevenagel (1898). "Condensation von Malondiure mit Aromatiachen Aldehyden durch Ammoniak und Amine". Berichte der deutschen chemischen Gesellschaft. 31: 2596–2619. doi:10.1002/cber.18980310308.
  2. O. Doebner (1902). "Ueber die der Sorbinsäure homologen, ungesättigten Säuren mit zwei Doppelbindungen". Berichte der deutschen chemischen Gesellschaft. 35: 1136–1136. doi:10.1002/cber.190203501187.
  3. 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. 
  4. 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.
  5. 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
  6. 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

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