Oxidative dehalogenation of perhalogenated benzenes by cytochrome P450 Compound I
Oxidative dehalogenation of perhalogenated benzenes by cytochrome P450 Compound I
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DOI：
10.1021/bi700365x
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发表时间：
2007-05-22
期刊：
影响因子：
2.9
通讯作者：
Hadad, Christopher M.
中科院分区：
文献类型：
--
作者：
Hackett, John C.;Sanan, Toby T.;Hadad, Christopher M.
分辨PBE（RI-PBE）和B3 LYP密度泛函理论计算用于理解细胞色素P450催化的、化合物I介导的全氯苯、全氟苯、它们的酚和混合氯氟苯氧化形成苯醌的过程。将化合物I加成到全氯苯和全氯苯酚的含氯碳上导致氯原子明显无势垒的1，2-位移，分别形成六氯环己二烯酮和羟基五氯环己二烯酮。六氯环己二烯酮具有很强的电子亲和性，其自由基阴离子可以轻易地排斥氯离子，生成五氯苯氧基自由基。羟基五氯环己二烯酮的去质子化导致氯化物的排出，并提供了生产四氯醌的直接途径。化合物I添加到六氟苯和五氟苯酚的含氟碳的势垒高度与通过类似反应路径计算的苯氧化的势垒高度相当。与氯化情况相反，氟迁移到环己二烯酮的势垒中等。此外，从六氟环己二烯酮自由基阴离子和去质子化的羟基五氟环己二烯酮气相消除氟化物并不容易。相反，需要考虑隐式和显式溶剂，以实现有利的热化学消除氟化物和生成实验观察到的产品。最后，本文所述的理论方法预测了实验观察到的从氯五氟苯和1，3，5-三氯-2，4，6-三氟苯中优先消除氟。这些研究说明了P450化合物I作为卤代芳烃（其是持久性环境污染物）的氧化剂的有效性，以及这种计算方法用于预测P450代谢的潜在效用。
Resolution of the identity PBE (RI-PBE) and B3LYP density functional theory calculations are used to understand the cytochrome P450-catalyzed, Compound I-mediated oxidation of perchlorobenzenes, perfluorobenzenes, their phenols, and mixed chlorofluorobenzenes to form benzoquinones. Addition of Compound I to the chlorine-bearing carbon of perchlorobenzenes and perchlorophenols results in an apparently barrierless 1,2-shift of the chlorine atom to form hexachlorocyclohexadienones and hydroxypentachlorocyclohexadienones, respectively. Hexachlorocyclohexadienone has a significant electron affinity, and its radical anion expels chloride in a facile manner to give the pentachlorophenoxyl radical. Deprotonation of hydroxypentachlorocyclohexadienones results in the expulsion of chloride and provides a direct route to the production of tetrachloroquinones. Barrier heights for Compound I addition to fluorine-bearing carbons of hexafluorobenzene and pentafluorophenol are comparable to those computed for oxidation of benzene via an analogous reaction path. In contrast to the chlorinated cases, fluorine migration to cyclohexadienones occurs with a moderate barrier. Additionally, gas-phase elimination of fluoride from the hexafluorocyclohexadienone radical anion and deprotonated hydroxypentafluorocyclohexadienone are not facile. Rather, consideration of implicit and explicit solvent is required to achieve favorable thermochemistry for fluoride elimination and generation of the experimentally observed products. Finally, the theoretical approach described herein is predictive of the experimentally observed preferential elimination of fluorine from chloropentafluorobenzene and 1,3,5-trichloro-2,4,6-trifluorobenzene. These studies illustrate the effectiveness of P450 Compound I as an oxidant of halogenated aromatic hydrocarbons, which are persistent environmental contaminants, and the potential utility of such computational methods for predicting P450 metabolism.