Hydrolysis of alpha-alkyl-alpha-(methylthio)methylene Meldrum's acids. A kinetic and computational investigation of steric effects.
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 degrees C. In basic solution (KOH), nucleophilic attack to form a tetrahedral intermediate (T(OH)-) 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 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 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 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 k1(OH) for 8-t-Bu is somewhat higher than for the less crowded 8-s-Bu.
Bernasconi
Claude F
CF
Department of Chemistry and Biochemistry of the University of California, Santa Cruz, California 95064, USA. bernasconi@chemistry.ucsc.edu
Brown
Shoshana D
SD
Ali
Mahammad
M
Rappoport
Zvi
Z
Yamataka
Hiroshi
H
Salim
Hatim
H
D003198:Computer Simulation; D004121:Dimethyl Sulfoxide / Q000737:chemistry; D004146:Dioxanes / Q000737:chemistry*; D006868:Hydrolysis; D007700:Kinetics; D008956:Models, Chemical; D015394:Molecular Structure; D013237:Stereoisomerism; D014867:Water / Q000737:chemistry
D004146:Dioxanes; D014867:Water; C076489:Meldrum's acid; D004121:Dimethyl Sulfoxide