Knoevenagel Reaction

Introduction

The Knoevenagel¹ Reaction is where aldehyde or ketones, which don't normally contain an a hydrogen, perform a condensation reaction with compounds of the form Z-CH₂-Z' or Z-CHR-Z'. The Z groups are electron withdrawing groups, such as CHO, COR, COOH, COOR, CN, NO₂, SOR, SO₂R, SO₂OR or similar groups. The Knoevenagel Reaction is a modified version of the aldol reaction. The reaction serves particularly for the chain extension of more aromatic aldehydes. However, if a strong enough base is used then the reaction can be performed on compounds possessing only one Z group, i.e. CH₃Z. Plus, other active hydrocarbons can be used, such as CHCl₃, cyclopentadienes, to name a couple. In reality, any compound that contains a C-H bond that can be removed by a base can be used.

A few examples are listed below:-

Examples of the Knoevenagel reactions

However, there is a simpler pattern than these. There is a basic formula of reactants, and this is shown below, bearing in mind that R is any hydrocarbon group and Z is the list of groups above.

The basics of the Knoevenagel reaction

Using this method many important compounds can be made from existing chemicals.

Mechanism

The mechanism is complex, but will explained as clearly as possible. In this example, I will use benzaldehyde and a 1,3-diketone, ethyl-3-oxobutanoate, with 2,6-diethylpiperidine as the base. The first step is that the base will attack a benzaldehyde molecule at the carbonyl positon, and this is helped by the product being a stable iminium salt, stabilised by the weak acid.

First Step: Formation of the Iminium Salt From The Benzaldehyde

Also, the ethyl-3-oxobutanoate also undergoes enolisation, and therefore will be able to attack the iminium salt, and so complete the reaction. As a side point, without this iminium salt it would be very doutbful if the reaction would proceed. This is beacuse the two reaction species would both be neutral. It would be very unlikely for a neutral enol to react with a neutral aldehyde. Therefore a positive charge is needed on one of the species, and the easiest thing would be to protonate the aldehyde. However, since the Knoevenagel Reaction is performed in base coniditons, then it will not be possible to protonate the aldehyde. Turning it into an iminium salt means that the positive charge is allowed and that the aldehyde is now reactive enough for the reaction to proceed.

First Step: Formation of the Enol of the 1,3-diketone

As you can see, the intermediate has two forms of enol. However, both reaction paths will go through the same carbon atom, and so there will be only one product.

Mechanism of the Knovenagel Reaction

As I said above, the two enol forms will both give the same product, and this picture below will prove why.

Click here for an animated file of the Knoevenagel Reaction, using the above example

Knoevenagel Product in 3D

Self-Assesment Questions

Here are a few self-assessment questions to show the different types of reactions and the way that the mechanism will be the same for all types of reactions. It is also to show the different uses for the Knoevenagel Reaction

Question 1

Here is an example of a Knoevenagel Reaction. Write down the product(s) and the reaction mechanism.

Question 1

Answer to question 1

Question 2

Using these materials, how would you make the following product? What type of base would be good suitable for the reaction to proceed?

Question 2

Answer to question 2

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¹Emil Knoevenagel (1865 - 1921), born in Hanover. Thesis in Goettingen, worked at the University of Heidelberg (Ruperto Carola)

© 2001 Ian Kerrigan