Which species is most reactive toward nucleophilic acyl substitution?

• A. Acid chloride
• B. Anhydride
• C. Ester
• D. Amide

Answer: (A)

Reactivity toward nucleophilic acyl substitution depends on two main factors: how electrophilic the carbonyl carbon is and how good the leaving group will be when the substitution occurs. Acid chlorides have a highly polarized carbonyl because chlorine withdraws electron density, making the carbonyl carbon very susceptible to attack. Chloride is an excellent leaving group (Cl− is a stable conjugate base), so after the nucleophile adds, chloride can depart readily and re-form the carbonyl. This combination—high electrophilicity and a superb leaving group—drives acid chlorides to react fastest.

Anhydrides are next because the leaving group is a carboxylate, which is a decent leaving group, and the carbonyl is activated by adjacent carbonyls, but not as strongly as in the acid chloride. Esters have alkoxide as the leaving group, which is a much poorer leaving group than chloride or carboxylate, so these react more slowly. Amides are the least reactive since the nitrogen donates electron density into the carbonyl via resonance, greatly reducing electrophilicity, and the leaving group would be an amide anion, a poor leaving group.

So, the acid chloride is most reactive for nucleophilic acyl substitution.