nucleophilic acyl substitution

Meaning: A nucleophile replaces the leaving group on a carboxylic acid derivative (acyl chloride, anhydride, ester, amide) or a carboxylic acid in two steps. The nucleophile adds to the electrophilic carbonyl carbon, forming a tetrahedral intermediate; the C=O then reforms and the leaving group departs. The acyl group stays and its partner is swapped.

Reactivity tracks leaving-group ability (weaker bases leave more easily): acyl chloride > anhydride > ester ≈ carboxylic acid > amide. A reactive derivative can generally be converted into a less reactive one, but the reverse is not easy without activation.

On the MCAT: Predict products: acyl chloride + alcohol gives an ester, acyl chloride + amine gives an amide, ester hydrolysis gives the acid and alcohol. Fischer esterification and peptide bond formation or hydrolysis are common settings. Acid catalysis protonates the carbonyl oxygen, making the carbon more electrophilic.

Common confusion: It is not SN2. The attack is on an sp2 carbonyl carbon and passes through a tetrahedral intermediate, not a single backside-attack step. It also differs from nucleophilic addition to aldehydes and ketones, which lack a good leaving group, so their intermediate is typically protonated to an alcohol instead.