Leaving group effects in thiolester alkaline hydrolysis. Part 1. A keten-mediated (E1 cB) pathway for basic hydrolysis of S-acetoacetylcoenzyme A and analogues

Abstract

The basic hydrolysis of a series of leaving-group substituted acetothiolacetates (CH₃COCH₂COSR) has been studied in aqueous media. Hydrolysis of N-acetyl-S-acetoacetylcysteamine follows a kinetic ionisation curve with an inflexion corresponding to the pK of this ester as determined by spectrophotometric and electrometric titrations. The rate constant at high pH was shown to follow a Brønsted relationship with β_L.G.–1.13, where β_L.G. is the slope of a plot of the logarithm of the rate constant versus the pK_a of the conjugate acid of the leaving group. This, and other evidence from rate comparisons, activation parameters, and kinetic solvent isotope effects, indicated an E1 cB hydrolytic mechanism involving unimolecular collapse of the ester enolate ions via a ketenoid transition-state. S-Acetoacetylcoenzyme A was also hydrolysed in base by this mechanism. Direct comparison of rates of leaving group expulsion for ArS and ArO was possible by means of this unimolecular process. For a leaving group with pK_L.G. 10, the oxyanion departs ca. 1 or 2 orders of magnitude faster than the thiolate anion; for pK_L.G. 6.0, the advantage of oxygen over sulphur is 10³–10⁴ fold. In a direct structural comparison, PhS departs 32 times as rapidly as PhO. The contribution of steric release in the E1 cB transition-state for S-t-butyl acetothiolacetate hydrolysis is discussed. The pK_a values of some acetothiolacetates were measured.