Knoevenagel reaction

1. Knoevenagel reaction

2. 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-CH 2- Z or Z-CHR-Z where Z is an electron withdrawing group. Introduction

3. Active hydrogen compound Eg : Diethyl malonate , Malonic acid and ethyl acetoacetate H 5 C 2 OOC-CH 2 -COOC 2 H 5 Diethyl malonate HOOC-CH 2 -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 .

4. The carbonyl group is an aldehyde or a ketone. Eg : Acetaldehyde (CH 3 CHO), Acetone (CH 3 CO CH 3) The  catalyst is usually a weakly basic amine. Eg : Pyridine (C 5 H 5 N)

5. 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 .

6. 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

7. Step:1 : An enol intermediate is formed initially. Mechanism of Knoevenagal condensation

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

9. With malonic compounds the reaction product can lose a molecule of carbon dioxide in a subsequent step. T he 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 Acrolein Malonic acid trans-2,4-Pentadienoic acid

10. 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