Hydrolysis of α-alkyl-α-(methylthio)methylene Meldrum's acids.: A kinetic and computational investigation of steric effects

[GRAPHICS] The rates of hydrolysis of alpha-R-alpha-( 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 ( T-OH(-)) is rate limiting for all substrates ( k(1)(OH)). In acidic solution ( HCl) and at intermediate pH values ( acetate buffers), water attack ( k(1)(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 T-OH- to products, two of which being unique to hydrolysis reactions and taking advantage of the acidic nature of the OH group in T-OH(-). This scheme provides an explanation why even at high [ KOH] T-OH(-) does not accumulate to detectable levels even though the equilibrium for OH- addition to 8-R is expected to favor T-OH(-), 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 k(1)(OH) and k(1)(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 C=C 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 k(1)(OH) for 8-t-Bu is somewhat higher than for the less crowded 8-s-Bu.