The reactivity order for nucleophilic acyl substitution is acid chloride > anhydride > ester > amide. True or false?

• A. False
• B. Not enough information
• C. True
• D. Depends on nucleophile

Answer: (C)

In nucleophilic acyl substitution, how fast a derivative reacts mainly depends on two factors: how electrophilic the carbonyl carbon is and how good the leaving group will be after substitution. Acid chlorides have the most electrophilic carbonyl and chloride is an excellent leaving group, so nucleophiles attack them the fastest. Anhydrides come next: they have a decently good leaving group (carboxylate) and their carbonyls are still highly activated, but not as much as acid chlorides. Esters are slower because the leaving group is an alkoxide, which is a poorer leaving group, and the carbonyl is less activated due to resonance with the OR group. Amides are the slowest since the nitrogen lone pair strongly donates into the carbonyl, greatly stabilizing it and reducing electrophilicity, and the potential leaving group (amide) is very poor. For common nucleophiles and typical conditions, this qualitative order—acid chloride > anhydride > ester > amide—holds true. The exact rates can vary with the nucleophile and conditions, but the trend is consistent.