Which species is least reactive toward nucleophilic acyl substitution?

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

Answer: (A)

In nucleophilic acyl substitution, the reaction rate is governed by how electrophilic the carbonyl carbon is and how favorable the leaving group is for the elimination step. Amides are least reactive because the nitrogen donates electron density into the carbonyl by resonance, giving the C=O a partial C–N character that heavily reduces electrophilicity. This resonance also makes the potential leaving group (an amide) very poor at stabilizing negative charge, so the loss step is unfavorable. In contrast, acid chlorides have a highly electrophilic carbonyl and a very good leaving group (chloride), so substitution proceeds rapidly. Anhydrides are more reactive than esters because the leaving carboxylate is resonance-stabilized and the adjacent acyl groups withdraw electron density, increasing the carbonyl’s susceptibility to attack. Esters are more reactive than amides since alkoxide is a better leaving group than an amide and resonance with nitrogen is weaker. Thus the species least reactive toward nucleophilic acyl substitution is the amide.