Kumar Devesh, de Visser Samuël P, Sharma Pankaz K, Cohen Shimrit, Shaik Sason
Department of Organic Chemistry and the Lise-Meitner-Minerva Center for Computational Quantum Chemistry, The Hebrew University of Jerusalem, 91904 Jerusalem, Israel.
J Am Chem Soc. 2004 Feb 18;126(6):1907-20. doi: 10.1021/ja039439s.
There is an ongoing and tantalizing controversy regarding the mechanism of a key process in nature, C-H hydroxylation, by the enzyme cytochrome P450 (Auclaire, K.; Hu, Z.; Little, D. M.; Ortiz de Montellano, P. R.; Groves, J. T. J. Am. Chem. Soc. 2002, 124, 6020-6027. Newcomb, M.; Aebisher, D.; Shen, R.; Esala, R.; Chandrasena, P.; Hollenberg, P. F.; Coon, M. J. J. Am. Chem. Soc. 2003, 125, 6064-6065). To definitely resolve this controversy, theory must first address the actual systems that have been used by experiment, and that generated the controversy. This is done in the present paper, which constitutes the first extensive theoretical study of such two experimental systems, trans-2-phenylmethyl-cyclopropane (1) and trans-2-phenyl-iso-propylcyclopropane (4). The theoretical study of these substrates reveals that the only low energy pathway for C-H hydroxylation is the two-state rebound mechanism described originally for methane hydroxylation (Ogliaro, F.; Harris, N.; Cohen, S.; Filatov, M.; de Visser, S. P.; Shaik, S. J. Am. Chem. Soc. 2000, 122, 8977-8989). The paper shows that the scenario of a two-state rebound mechanism accommodates much of the experimental data. The computational results provide a good match to experimental results concerning the very different extents of rearrangement for 1 (20-30%) vs 4 (virtually none), lead to product isotope effect for the reaction of 1, in the direction of the experimental result, and predict as well the observed metabolic switching from methyl to phenyl hydroxylation, which occurs upon deuteration of the methyl group. Furthermore, the study reveals that an intimate ion pair species involving an alkyl carbocation derived from 4 gives no rearranged products, again in accord with experiment. This coherent match between theory and experiment cannot be merely accidental; it comes close to being aproof that the actual mechanism of C-H hydroxylation involves the two-state reactivity revealed by theory. Analysis of the rearrangement modes of the carbocations derived from 1 and 4 excludes the participation of free carbocations during the hydroxylation of these substrates. Finally, the mechanistic significance of product isotope effect (different isotope effects for the rearranged and unrearranged alcohol products) is analyzed. It is shown to be a sensitive probe of two-state reactivity; the size of the intrinsic product isotope effect and its direction reveal the structural differences of the hydrogen abstraction transition states in the low-spin vs high-spin reaction manifolds.
关于自然界中一个关键过程——细胞色素P450酶催化的C-H羟基化反应的机制，一直存在着激烈且引人入胜的争议（奥克莱尔，K.；胡，Z.；利特尔，D. M.；奥尔蒂斯·德·蒙特利亚诺，P. R.；格罗夫斯，J. T. 《美国化学会志》2002年，124卷，6020 - 6027页。纽科姆，M.；埃比舍尔，D.；沈，R.；埃萨拉，R.；钱德拉塞纳，P.；霍伦贝格，P. F.；库恩，M. J. 《美国化学会志》2003年，125卷，6064 - 6065页）。为了彻底解决这一争议，理论首先必须针对实验中使用的实际体系展开研究，正是这些体系引发了争议。本文即为此而作，它是对反式 - 2 - 苯甲基环丙烷（1）和反式 - 2 - 苯基异丙基环丙烷（4）这两个实验体系进行的首次全面理论研究。对这些底物的理论研究表明，C-H羟基化的唯一低能途径是最初为甲烷羟基化所描述的双态反弹机制（奥利亚罗，F.；哈里斯，N.；科恩，S.；菲拉托夫，M.；德·维瑟，S. P.；谢克，S. 《美国化学会志》2000年，122卷，8977 - 8989页）。本文表明，双态反弹机制的设想与许多实验数据相符。计算结果与关于1（20 - 30%）和4（几乎没有）重排程度差异极大的实验结果匹配良好，得出了1反应的产物同位素效应，且方向与实验结果一致，同时还预测了甲基氘代后观察到的从甲基羟基化到苯基羟基化的代谢转换。此外，研究表明涉及由4衍生的烷基碳正离子的紧密离子对物种不会产生重排产物，这同样与实验结果相符。理论与实验之间的这种连贯匹配并非偶然；它几乎可以证明C-H羟基化的实际机制涉及理论所揭示的双态反应性。对由1和4衍生的碳正离子重排模式的分析排除了这些底物羟基化过程中自由碳正离子的参与。最后，分析了产物同位素效应（重排和未重排醇产物的不同同位素效应）的机制意义。结果表明它是双态反应性的灵敏探针；固有产物同位素效应的大小及其方向揭示了低自旋与高自旋反应流形中氢提取过渡态的结构差异。
