Intramolecular Catalysis of Carbonyl Substitution Reactions

The TS for the rapid hydrolysis of the monoanion is depicted as involving an intramolecular general acid catalysis by the carboxylic acid group, with participation by the anionic carboxylate group, which becomes bound at the developing electrophilic center. The un-ionized carboxylic acid group acts as a general acid catalyst and the 

The case of intramolecular carboxylate participation in ester hydrolysis has been extensively studied using acetylsalicylic acid (aspirin) and its derivatives. The kinetic data show that the anion is hydrolyzed more rapidly than the neutral species, indicating 

Mechanism II. General Base Catalysis of Water Attack 

Mechanism III. General Acid Catalysis of Hydroxide Ion Attack 

Mechanism I was ruled out by an isotopic-labeling experiment. The mixed anhydride of salicylic acid and acetic acid is an intermediate if nucleophilic catalysis occurs by Mechanism I. This molecule, which can be prepared independently, hydrolyzes in water with about 25% incorporation of solvent water into the salicylic acid. 

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