Knoevenagel reaction

Knoevenagel condensation is 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.

Knoevenagel reaction is a modification of Aldol condensation reaction.

The active hydrogen compound used should be of the form Z-CH2-Z or Z-CHR-Z where Z is an electron withdrawing group.

Introduction

Active hydrogen compound Eg: Diethyl malonate, Malonic acid and ethyl acetoacetate

H5C2OOC-CH2-COOC2H5

Diethyl malonate

HOOC-CH2-COOH

Malonic acid

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 carbonyl group is an aldehyde or a ketone.

Eg: Acetaldehyde (CH3CHO), Acetone (CH3CO CH3)

The catalyst is usually a weakly basic amine.

Eg: Pyridine (C5H 5N)

Knoevenagel reaction

Knoevenagel condensation is 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.

Knoevenagal reaction and its modification

The condensation of carbon acid compounds with aldehydes to afford α,β-unsaturated compounds.The Doebner Modification, which is possible in the presence of carboxylic acid groups, includes a pyridine-induced decarboxylation

Step:1: An enol intermediate is formed initially.

Mechanism of Knoevenagal condensation

Step:2: The enol formed reacts with aldehyde, and the resulting aldol undergoes based induced elimination.

Mechanism continued…

With malonic compounds the reaction product can lose a molecule of carbon dioxide in a subsequent step. The base is pyridine. For example, the reaction product of acrolein (allyl aldehyde) and malonic acid in pyridine is trans-2,4-Pentadienoic acid with one carboxylic acid group and not two.

Doebner modification

AcroleinMalonic acid

trans-2,4-Pentadienoic acid

The Knoevenagel condensation is a key step in the commercial production of the antimalarial drug lumefantrine.

Knoevenagal reaction is used in the synthesis of conjugated enones which serve as key intermediates in various reactions.

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.

Scope of Knoevenagal reaction