Carboxylic Acid Derivatives - Reactivity Order

Question

Carboxylic acid derivatives differ widely in how fast they undergo nucleophilic acyl substitution, so which derivative is the most reactive toward such substitution?

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Nucleophilic acyl substitution proceeds through a tetrahedral intermediate that collapses by expelling a leaving group, so reactivity is controlled by two factors: how good the leaving group is and how much the attached atom donates electron density into the carbonyl to deactivate it. Acid chlorides have chloride, an excellent leaving group, and chlorine donates little electron density, so acetyl chloride is the most reactive derivative and is the correct answer. Anhydrides are next because a carboxylate is a reasonable leaving group but less stabilising than chloride, so acetic anhydride is slower than the acid chloride. Esters have an alkoxy group whose oxygen lone pair donates into the carbonyl, raising electron density and making ethyl acetate considerably less reactive. Amides are least reactive because nitrogen donates its lone pair strongly into the carbonyl and amide ion is a very poor leaving group, so acetamide reacts slowest. This reactivity order acid chloride > anhydride > ester > amide is core NCERT and a classic JEE Advanced question. As a check, the order tracks both leaving-group ability and decreasing carbonyl electrophilicity, confirming acetyl chloride.

Carboxylic Acid Derivatives - Reactivity Order

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