Knoevenagel condensation
Template:Short description Template:Use dmy dates Template:Reactionbox
In organic chemistry, the Knoevenagel condensation (Script error: No such module "IPA".) reaction is a type of chemical reaction named after German chemist Emil Knoevenagel. It is a modification of the aldol condensation.[1][2]
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 forms:[3]
- Template:Chem2 or Template:Chem2 for instance diethyl malonate, Meldrum's acid, ethyl acetoacetate or malonic acid, or cyanoacetic acid.[1]
- Template:Chem2, 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 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.[4] For example, the reaction of acrolein and malonic acid in pyridine gives trans-2,4-entadienoic acid with one carboxylic acid group and not two.[5] Sorbic acid can be prepared similarly by replacing acrolein with crotonaldehyde.[6]
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.[7] 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):[8]
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:[9]
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:[10]
See also
References
<templatestyles src="Reflist/styles.css" />
- ↑ a b Script error: No such module "citation/CS1".
- ↑ Script error: No such module "Citation/CS1".
- ↑ Template:March6th
- ↑ Script error: No such module "Citation/CS1".
- ↑ Script error: No such module "Citation/CS1"..
- ↑ Script error: No such module "Citation/CS1".
- ↑ 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] Template:Webarchive 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) Script error: No such module "CS1 identifiers".
- ↑ 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
- ↑ Script error: No such module "Citation/CS1".
Script error: No such module "Check for unknown parameters".