A mechanism for efficient proton-transfer catalysis. Intramolecular general acid catalysis of the hydrolysis of 1-arylethyl ethers of salicylic acid

Abstract

The tert-butyl (1) and 1-arylethyl ethers (2) of salicylic acid are hydrolyzed with efficient general acid catalysis by the ortho-COOH group. The half-life of the neutral COOH form of the tert-butyl ether is 15.2 min at 39°, and the estimated acceleration by the COOH group of 2, X = Me, Y = H is 2.13 × 105. The salicylate leaving group from 2 (X = Me, Y = H) has an effective pKa of 2.9, compared with a nominal pKa of 8.52. Analysis of substituent effects in both arylethyl and leaving groups provides the most detailed available mechanistic insight into a reaction involving efficient intramolecular proton-transfer catalysis. The mechanism is very different from classical general acid-base catalysis. Proton transfer takes place very rapidly within a developing strong hydrogen bond, and though an integral part of the C—O cleavage process is practically uncoupled from it. "Strategic delay" of the proton-transfer step, relative to C—O cleavage, makes a significant contribution to efficiency by setting up the conditions for the formation of the strong, intramolecular hydrogen bond.Key words: catalysis, carboxyl, hydrogen bond, proton transfer, enzyme mechanism.