The nucleophilic acyl substitution reaction

The fact that the atom adjacent to the carbonyl carbon in carboxylic acid derivatives is an electronegative heteroatom – rather than a carbon like in ketones or a hydrogen like in aldehydes - is critical to understanding the reactivity of these functional groups. Just like in aldehydes and ketones, carboxylic acid derivatives are attacked from one side of their trigonal planar carbonyl carbon by a nucleophile, converting this carbon to tetrahedral (sp³) geometry. In carboxylic acid derivatives, the acyl X group is a potential leaving group. What this means is that the tetrahedral product formed from attack of the nucleophile on the carbonyl carbon is not the product: it is a reactive intermediate. The tetrahedral intermediate rapidly collapses: the carbon-oxygen double bond re-forms, and the acyl X group is expelled.

Notice that in the product, the nucleophile becomes the new acyl X group. This is why this reaction type is called a nucleophilic acyl substitution: one acyl X group is substituted for another. For example, in the reaction below, one alcohol X group (3-methyl-1-butanol) is replaced by another alcohol X group (methanol), as one ester is converted to another.

Another way of looking at this reaction is to picture the acyl group being transferred from one acyl X group to another: in the example above, the acetyl group is being transferred from 3-methyl-1-butanol to methanol. For this reason, nucleophilic acyl substitutions are also commonly referred to as acyl transfer reactions.

When the incoming nucleophile in an acyl substitution is a water molecule, the reaction is also referred to as an acyl hydrolysis. For example, the following reaction can be described as the hydrolysis of an ester (to form a carboxylic acid and an alcohol).

We could also describe this reaction as the transfer of an acyl group from an alcohol to a water molecule.

In a similar vein, the hydrolysis of an amide to form a carboxylic acid could be described as the transfer of an acyl group from ammonia (NH₃) to water.

As we will see in later sections of this chapter the hydrolysis of esters and amides are particularly important reaction types in biochemical pathways. When your body digests the fat in a hamburger, for example, enzymes in your pancreas called lipases first catalyze ester hydrolysis reactions to free the fatty acids.