Hydrolysis of r-Alkyl-r-(methylthio)methylene Meldrum’s Acids. A Kinetic and Computational Investigation of Steric Effects

Abstract

The rates of hydrolysis of R-R-R-(methylthio)methylene Meldrum’s acids (8-R with R ) H, Me, Et, s-Bu, and t-Bu) were determined in basic and acidic solution in 50% DMSO-50% water (v/v) at 20 °C. In basic solution (KOH), nucleophilic attack to form a tetrahedral intermediate (TOH - ) is rate limiting for all substrates (k1 OH). In acidic solution (HCl) and at intermediate pH values (acetate buffers), water attack (k1 H2O) is rate limiting for 8-Me, 8-Et, and 8-s-Bu; the same is presumably the case for 8-t-Bu, but rates were too slow for accurate measurements at low pH. For 8-H, water attack is rate limiting at intermediate pH but at pH < 4.5 MeS- departure from the tetrahedral intermediate becomes rate limiting. Our interpretation of these results is based on a reaction scheme that involves three pathways for the conversion of TOH - to products, two of which being unique to hydrolysis reactions and taking advantage of the acidic nature of the OH group in TOH - . This scheme provides an explanation why even at high [KOH] TOH - does not accumulate to detectable levels even though the equilibrium for OH- addition to 8-R is expected to favor TOH - , and why at low pH water attack is rate limiting for R ) Me, Et, s-Bu, and t-Bu but leaving group departure becomes rate limiting with the sterically small R ) H. The trend in the k1 OH and k1 H2O indicates increasing steric crowding at the transition state with increasing size of R, but this effect is partially offset by a sterically induced twisting of the CdC double bond in 8-R which leads to its elongation and makes the substrate less stable and hence more reactive. Our computational results suggest that this effect becomes particularly pronounced for R ) t-Bu and explains why k1 OH for 8-t-Bu is somewhat higher than for the less crowded 8-s-Bu.