Mechanism of the Piperidine-Catalyzed Knoevenagel Condensation Reaction in Methanol: The Role of Iminium and Enolate Ions

Abstract

The free energy profile of the piperidine catalyzed Knoevenagel condensation reaction of acetylacetone with benzaldehyde has been obtained by theoretical calculations. The carbinolamine formation step involves catalysis by methanol solvent, and its decomposition takes place via hydroxide ion elimination without a classical transition state, leading to the iminium ion. Hydroxide ion deprotonates the acetylacetone, forming an enolate that attacks the iminium ion and leads to an addition intermediate. The final step involves elimination of piperidine catalyst. Our analysis suggests the iminium ion formation has the highest barrier and the catalytic effect of piperidine is facilitating the elimination step rather than activation of the benzaldehyde electrophile. Experimental measures of the kinetics lead to an observed free energy barrier of 20.0 kcal mol, in good agreement with the theoretical value of 21.8 kcal mol based on the free energy profile.

Unprecedented Nucleophilic Attack of Piperidine on the Electron Acceptor during the Synthesis of Push‐Pull Dyes by a Knoevenagel Reaction

“…As a result, the expected products can be generally recovered in pure form by a simple filtration on a glass filtrate. Among amines, piperidine is the most widely used . In this field, the first condensation of benzaldehyde with ethyl acetoacetate in the presence of piperidine was reported as soon as 1896 by Knoevenagel providing the product in 95 % yield …”

“…Among amines, piperidine is the most widely used. [18,19] In this field, the first condensation of benzaldehyde with ethyl acetoacetate in the presence of piperidine was reported as soon as 1896 by Knoevenagel providing the product in 95 % yield. [20] In this work, an unprecedented nucleophilic attack of piperidine during a Knoevenagel reaction with 2-(3oxo-2,3-dihydro-1H-cyclopenta [b] naphthalen-1-ylidene)malononitrile Napht-EA was evidenced (see Figure 1).…”

Greener and practical synthesis of 4,4′‐(arylmethylene)bis(3‐methyl‐1‐phenyl‐1H‐pyrazol‐5‐ol)s through a conventional heating and a mechanochemical procedure

“…A schematic plausible reaction mechanism was proposed, as shown in Scheme 2 35 . The TMDP can act simultaneously as a hydrogen bond donor and a Lewis base through the nitrogen atom of second piperidine moiety to promote the condensation of phenylhydrazine and ethyl acetoacetate which gives 3‐methyl‐l‐phenyl‐5‐pyrazolone.…”

Exploration of the Role of Double Schiff Bases as Catalytic Intermediates in the Knoevenagel Reaction of Furanic Aldehydes: Mechanistic Considerations

“…This is because the carboxylic acids of malonic acid also have catalytic activity in the condensation reaction. 27 In order to block the effect of the carboxylic acid groups of malonic acid and to obtain an accurate picture of the catalytic activ-…”