Radical Clock Substrates, Their C-H Hydroxylation Mechanism by Cytochrome P450, and Other Reactivity Patterns: What Does Theory Reveal about the Clocks' Behavior?

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• 作者：Devesh Kumar ; Samuë ; l P. de Visser ; Pankaz K. Sharma ; Shimrit Cohen ; and Sason Shaik
• 刊名：Journal of the American Chemical Society
• 出版年：2004
• 出版时间：February 18, 2004
• 年：2004
• 卷：126
• 期：6
• 页码：1907 - 1920
• 全文大小：289K
• 年卷期：v.126,no.6(February 18, 2004)
• ISSN：1520-5126

文摘

There is an ongoing and tantalizing controversy regarding the mechanism of a key process innature, C-H hydroxylation, by the enzyme cytochrome P450 (Auclaire, K.; Hu, Z.; Little, D. M.; Ortiz deMontellano, 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 beenused by experiment, and that generated the controversy. This is done in the present paper, which constitutesthe 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 thatthe only low energy pathway for C-H hydroxylation is the two-state rebound mechanism described originallyfor 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 mechanismaccommodates much of the experimental data. The computational results provide a good match toexperimental results concerning the very different extents of rearrangement for 1 (20-30%) vs 4 (virtuallynone), lead to product isotope effect for the reaction of 1, in the direction of the experimental result, andpredict as well the observed metabolic switching from methyl to phenyl hydroxylation, which occurs upondeuteration of the methyl group. Furthermore, the study reveals that an intimate ion pair species involvingan alkyl carbocation derived from 4 gives no rearranged products, again in accord with experiment. Thiscoherent 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 participationof free carbocations during the hydroxylation of these substrates. Finally, the mechanistic significance ofproduct isotope effect (different isotope effects for the rearranged and unrearranged alcohol products) isanalyzed. It is shown to be a sensitive probe of two-state reactivity; the size of the intrinsic product isotopeeffect and its direction reveal the structural differences of the hydrogen abstraction transition states in thelow-spin vs high-spin reaction manifolds.