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Knoevenagel condensation

Organic chemical reaction

Knoevenagel condensation
Summary

Organic chemical reaction

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.{{cite journal |trans-title= Condensation of malonic acid with aromatic aldehydes via ammonia and amines

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).

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. [[Acrolein]] and [[malonic acid]] react in [[pyridine]] to give trans-2,4-pentadienoic acid with the loss of [[carbon dioxide]].]]{{clear}}

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.{{cite journal

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.

center|400px|A knoevenagel condensation

The Knoevenagel condensation is a key step in the commercial production of the antimalarial drug lumefantrine (a component of Coartem):

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:

Knoevenagel tandem application

Weiss–Cook reaction

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:[[File:Weiss–Cook reaction.png|center|650px]]

References

References

  1. {{March6th
  2. G. Jones. (2004). "Organic Reactions".
  3. (1979). "1-''N''-Acylamino-1,3-dienes from 2,4-Pentadienoic Acids by the Curtius Rearrangement: benzyl ''trans''-1,3-butadiene-1-carbamate".
  4. (1944). "Sorbic Acid". Organic Syntheses.
  5. ''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 [http://www.mdpi.net/molbank/molbank2004/m0359.htm] {{Webarchive. link. (9 July 2011 publication.)
  6. ''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
  7. ''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 [https://content.arkat-usa.org/ARKIVOC/JOURNAL_CONTENT/manuscripts/2006/06-2251BP%20as%20published%20mainmanuscript.pdf Link]
  8. (1968). "A one-step synthesis of ketonic compounds of the pentalane, [3,3,3]- and [4,3,3]-propellane series". Tetrahedron Letters.
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