Bernasconi Claude F, Brown Shoshana D, Ali Mahammad, Rappoport Zvi, Yamataka Hiroshi, Salim Hatim
Department of Chemistry and Biochemistry of the University of California, Santa Cruz, California 95064, USA.
J Org Chem. 2006 Jun 23;71(13):4795-802. doi: 10.1021/jo060254o.
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.
在20℃下，于50%二甲基亚砜-50%水（v/v）的碱性和酸性溶液中测定了α-R-α-（甲硫基）亚甲基丙二酸亚异丙酯（8-R，R = H、Me、Et、s-Bu和t-Bu）的水解速率。在碱性溶液（KOH）中，亲核进攻形成四面体中间体（T(OH)-）对所有底物来说都是限速步骤（k1(OH)）。在酸性溶液（HCl）和中间pH值（醋酸盐缓冲液）中，对于8-Me、8-Et和8-s-Bu，水进攻（k1(H2O)）是限速步骤；对于8-t-Bu推测也是如此，但在低pH下速率太慢以至于无法进行准确测量。对于8-H，在中间pH值时水进攻是限速步骤，但在pH < 4.5时，甲硫基（MeS-）从四面体中间体离去成为限速步骤。我们对这些结果的解释基于一个反应方案，该方案涉及将T(OH)-转化为产物的三条途径，其中两条是水解反应特有的，利用了T(OH)-中OH基团的酸性。该方案解释了为什么即使在高[KOH]时，T(OH)-也不会积累到可检测水平，尽管预期OH-加成到8-R的平衡有利于T(OH)-，以及为什么在低pH下，对于R = Me、Et、s-Bu和t-Bu水进攻是限速步骤，但对于空间位阻小的R = H离去基团离去成为限速步骤。k1(OH)和k1(H2O)的趋势表明，随着R尺寸的增加，过渡态的空间拥挤程度增加，但这种效应被8-R中C=C双键的空间诱导扭曲部分抵消，这导致其伸长，使底物稳定性降低，因此反应性更高。我们的计算结果表明，这种效应对于R = t-Bu尤为明显，这解释了为什么8-t-Bu的k1(OH)比空间位阻较小的8-s-Bu略高。
