Knoevenagel Reaction

The Knoevenagel reaction is a variant of the aldol condensation historically performed with malonic acid (or malonate ethyl), although it can theoretically be performed with any 1 - 3 dicarbonyl compound (β- dicarbonyl). To generate the enolate of malonic acid pyridine or piperidine are usually used. In this article we will see a particular variant of the reaction, the one conducted in acid environment.

Knoevenagel condensation

The reaction product is an α, β unsaturated carboxylic acid .

Mechanism of reaction

Suppose we perform the following reaction:

complessive knoevenagel reaction

Let's see step by step how this happens. (Theoretically, the reaction can also be performed with ketones, but it works particularly well with aldehydes)


Knoevenagel step 1Initially, the secondary amine is added to the carbonyl. In dehydrating conditions we could get an enammine. But one of the advantages of the Knoevenagel reaction are the mild conditions that requires. It can in fact be performed in an aqueous environment. The result is then an iminium salt, for which we can write a resonance formula with the positive charge on the carbon.


Knoevenagel step 2

Observing the product of this second step it appears that the α carbon acts as a carbanion. But we are in an acid environment, and the reaction can't proceed through the formation of a carbanion (in general the acid environment stabilizes the positive charges while the basic stabilizes the negative charges). The proposed mechanism is then concerted, made possible by the very strong electrophilic character of the carbon adjacent to the nitrogen. Nitrogen rips a proton from the carbon in α (between the two carbonyls) and simultaneously the two bonding electrons move on the same carbon.


Step 3 Knoevenagel

Once formed the abductee, since we have a compound 1-3 dicarbonyl substituted in α and we are in an acid environment, it has spontaneous decarboxylation ( - CO 2 ).


Step 4 Knoevenagel

It is given that the amine is protonated and is therefore a good leaving group (it would leave as a neutral amine, conjugated base of the ammonium ion), a basic molecule (piperidine in this case) can tear a proton to the carbon in α with consequent formation of a double bond and output of piperidine. The result is a carboxylic acid α, β unsaturated.

In summary ... 

Substantially the reaction allows us to add two carbons to our organic molecule. Both are derived from malonic acid. The double bond can be easily hydrogenated: