R

Figure 4 Mechanism for aromatic hydroxylation.

specific carbon atom, to form a tetrahedral intermediate; (2) electron transfer from the aryl group to heme, to form a carbonium ion adjacent to the oxygen adduct; followed by (3) ring closure, to form the epoxide (pathway 2, Figure 4). From this point on to the formation of the final product phenol, both mechanisms are identical: the ring opens, generating an adjacent carbonium ion, and the hydride moiety shifts to satisfy the adjacent carbonium ion, as a pair of electrons from the oxygen atom moves in to satisfy the positive charge being developed as the hydride leaves; this overall process leads to the formation of a ketone, which then tautomerizes to generate the phenol. The stepwise mechanism does not necessarily have to close to epoxide. At step 2 it can bypass epoxide formation, to form the ketone directly, then the phenol (pathway 3, Figure 4), or it can form the phenol directly by proton transfer to a pyrrole nitrogen atom (pathway 4, Figure 4).

A concerted mechanism would require obligatory epoxide formation on the path to phenol, whereas a stepwise mechanism would not necessarily have to pass through the epoxide. Since epoxides can be toxic or even carcinogenic (e.g., epoxides of some polycyclic aromatic hydrocarbons), the question of whether their formation is obligatory is significant for drug design and development.

A theoretical study101 and several experimental studies102-105 have provided strong evidence for the stepwise mechanism, and, most recently, de Visser and Shaik106 examined the problem using density functional calculations, and came to the same basic conclusion.

5.05.2.1.3.3 Carbonyl carbon atoms

The conversion of acetaldehyde to acetic acid by cytochrome P450 has been clearly established.107 But of the aldehydes that have been shown to be metabolized by cytochrome P450, allylic or aryl aldehydes appear to be the best substrates.108 For example, retinal (68)109 and the 11-oxo metabolite of tetrahydrocannabinol (70)110 are oxidized to carboxylic acids (eqns [24] and [25]).

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