The "Rebound Controversy": An Overview and Theoretical Modeling of the Rebound Step in C-H Hydroxylation by Cytochrome P450

C-H hydroxylation by the enzyme cytochrome P450 is one of Nature's important and most ubiquitous processes. There is strong evidence that the mechanism proceeds by initial hydrogen abstraction, from the alkane, by the high-valent iron-oxo species of the enzyme, followed by a rebound of the alkyl radical to form the ferric-alcohol product complex (the Groves "rebound" mechanism). Nevertheless, the "rebound" mechanism is still controversial due to the ultrashort radical lifetimes deduced from radical-clock experiments. This review describes the main elements of the controversy and its updated resolution by theory, with an emphasis on the controversial rebound step. The theoretically derived model for alkane hydroxylation is found to involve two-state reactivity (TSR). In TSR, radicals are produced on two different spin-state surfaces, and thereafter they react differently; on the low-spin surface, the rebound proceeds with no product rearrangement and the lifetime of the radicals is ultrashort (or zero), while on the high-spin surface the barrier for rebound is substantial and the lifetime of the radical is sufficiently long that rearrangement may compete with product formation by rebound, A new valence-bond model is developed to model the rebound barrier on the high-spin surface and conceptualize its dependence on the nature of the alkyl radical. The possible intermediacy of carbocationic intermediates alongside radicals is discussed. It is shown that the TSR scenario provides a satisfactory rationale for the controversial findings in the field, and makes verifiable predictions. One of the predictions of TSR is that the ratio of unrearranged to rearranged products, [U/R], will be subject to an intrinsic isotope effect that is substrate-dependent. This prediction and its possible verification by experiment are discussed.