14.8 : Relative Reactivity of Carboxylic Acid Derivatives

Carboxylic acid derivatives such as acid halides, anhydrides, esters, and amides undergo nucleophilic acyl substitution reactions with varying degrees of reactivity.

A key factor in assessing the reactivity of the acid derivatives is the basicity of the substituent or the leaving group. The lower the basicity of the leaving group, the higher the reactivity of the derivative. The basicity of the leaving group follows this order:

Halide ions < Acyloxy ions < Alkoxy ions < Amine ions

Consequently, acid halides are the most reactive, while amides are the least reactive.

Another factor that determines the relative reactivity arises from a combination of resonance and inductive effects. In acid derivatives, the electronegativity of the substituent influences the electrophilicity of the carbonyl carbon. A highly electronegative substituent will exhibit a stronger electron-withdrawing inductive effect, making the carbonyl carbon more electrophilic and more susceptible to a nucleophilic attack. The electron-withdrawing ability of the substituents follows this order:

Halide ions > Acyloxy ions > Alkoxy ions > Amine ions

Accordingly, the reactivity trend from the most reactive to the least reactive acid derivative is:

Acid halides > Acid anhydrides > Esters > Amides