Intramolecular catalysis of organic reactions. III. Hydrolysis of 5-Nitro-2-(trifluoroacetylamino)benzoic acid

Abstract

The hydrolysis of 5-nitro-2-(trifluoroacetylamino)benzoic acid (2) has been studied over the pH range 0-12. In acidic solution (pH 0-3.5), the hydrolysis occurs with intramolecular general acid catalysis by the adjacent CO₂H group. Between pH 3.5 and 8, a plateau is observed in the pH-rate profile, and this is interpreted as acid catalysis by a water molecule of the breakdown of the tetrahedral intermediate formed between (2) and another water molecule. In alkaline solution (pH > 8), hydrolysis occurs with general acid-catalysed C-N bond breaking.

Catalysis by phosphate and borate buffers was observed in the pH range 6-10. Phthalate buffers did not catalyse the reaction. For phosphate and borate buffers, plots of buffer concentration against rate showed a saturation phenomenon which was interpreted as indicating a change from rate-limiting decomposition of the tetrahedral intermediate to rate-limiting formation of the tetrahedral intermediate as the buffer concentration was increased.

The pK_a of the acid group was found to be about 2.5 as expected, but the pK_a of the NH group is 10.4, higher than expected. The reduced acidity of the NH group is attributed to electrostatic effects of the adjacent ionized carboxy group.

Unlike for aspirin, intramolecular catalysis by the ionized carboxy group was not observed, a result, perhaps, of intramolecular hydrogen bonding between the carboxylate ion and the adjacent NH group. Such an interaction would be geometrically unfavourable for either intramolecular general base or nucleophilic participation by the carboxylate ion.