Mechanistically, the reaction is bounded by two extremes. At one extreme, FeO3 + adds to the double bond in a single step, while at the other a two-step reaction involving the generation of an intermediate is operative. Evidence exists for both pathways, but again the two-state reactivity paradigm of Shaik and co-workers appears to resolve the dilemma.96'97
The frequency of aromatic hydroxylation as a metabolic event is undoubtedly a reflection of the commonality of an aromatic ring as a structural component of many drugs. While a phenol is usually not the major metabolite of such a drug, it often is found as a significant contributor to the metabolism of that drug. In general, phenol formation follows the rules of electrophilic aromatic hydroxylation established by the linear free energy relationships of physical organic chemistry (i.e., para > ortho > meta). This order prevails unless the system is deactivated by a substituent that on balance withdraws electron density from the ring (e.g., nitro group). In such a case, meta substitution dominates, since it is the site that is the least deactivated toward electrophilic attack. In the case of cytochrome P450 catalysis, an exception would occur if the stearic demands of the active site architecture of the enzyme for a specific substrate favored meta hydroxylation.
These general observations suggest that if the enzyme has a sterically permissive active site that is not overly restrictive to substrate motion, the electronic properties of the substrate should determine regioselectivity of hydroxylation. Thus, the development of computational models for predicting aliphatic hydroxylation, aromatic hydroxylation, or a combination of the two, pioneered by Jones, Korzekwa, and colleagues,10'45'98'99 is not only promising but has already met with considerable success.
Establishing the exact mechanism for aromatic hydroxylation has proved to be difficult. If deuterium is present in the substrate at the site of hydroxylation, a fractional amount of deuterium will almost always be retained in the product owing to migration to the adjacent carbon atom during the process of phenol formation. This is the well-known NIH shift.100 It was believed to occur upon ring opening of an initially formed epoxide (arene oxide) (pathway 1 in Figure 4). Mechanistically, epoxide formation can occur either by a concerted addition of oxygen to form the epoxide in a single step or by a stepwise process. The stepwise process would involve: (1) the initial addition of oxygen to a
Was this article helpful?