The C–H bond activation of alkane by compound I of cytochrome P450 is studied with density functional theory calculations, particularly with respect to the kinetic isotope effects (KIEs). The transition state for the C–H bond dissociation involves a linear array of C–H–O(Fe), which leads to an Fe–OH intermediate and an alkyl radical species. The “oxene insertion” mechanism is unlikely to occur in P450-mediated hydroxylation. The KIE values calculated with transition state theory for the H/D abstraction in C2H6/CH2DCH3, C2H6/CD3CH3, and C2H6/C2D6 are 7, 11, and 14, respectively, at 300 K. Thus, molecular parts that have no direct relevance to the abstraction reaction significantly affect the KIEs.
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