Ferryl species electrophilicity

Fig. 14. Manifold of reactive species produced from the reaction of a heme group with oxygen and two reducing equivalents. The rate of conversion of A to B limits the lifetime (and therefore reactivity) of the Fe peroxo anion. The rate of formation of the ferryl species C via the Fe -OOH complex B competes with the intramolecular hydroxylation reaction to give hydroxyheme. Reactions of the Fe -hydroperoxy complex B with exogenous electrophilic substrates must compete with conversion of the intermediate to both C and meso-hydroxyheme. The Fe -OOH complex B can also be formed directly with H2O,.

A less common reactive species is the Fe peroxo anion expected from two-electron reduction of O2 at a hemoprotein iron atom (Fig. 14, structure A). Protonation of this intermediate would yield the Fe —OOH precursor (Fig. 14, structure B) of the ferryl species. However, it is now clear that the Fe peroxo anion can directly react as a nucleophile with highly electrophilic substrates such as aldehydes. Addition of the peroxo anion to the aldehyde, followed by homolytic scission of the dioxygen bond, is now accepted as the mechanism for the carbon-carbon bond cleavage reactions catalyzed by several cytochrome P450 enzymes, including aromatase, lanosterol 14-demethylase, and sterol 17-lyase (133). A similar nucleophilic addition of the Fe peroxo anion to a carbon-nitrogen double bond has been invoked in the mechanism of the nitric oxide synthases (133). 

Two additional intermediates, the ferric peroxy anion and ferric hydroperoxo complex, have been proposed to substitute for the ferryl as the actual oxidizing species in at least some P450 reactions. The role of the ferric peroxy anion in some reactions is supported by good evidence and is discussed in the section on carbon-carbon bond cleavage reactions (see Section 8), but the proposed role of the ferric hydroperoxide in electrophilic double bond and heteroatom oxidations is discussed here. 

Scheme 5. An alternative mechanism. Radical addition (instead of base-catalyzed abstraction) leading to species X is followed by formation of a ferryl heme species (Compound II) and a proposed epoxide species (55). Formation of an epoxide has also been suggested from computational work (51) (it was also considered in an earlier study, but initially considered energetically unfavorable in the gas phase (50)). Electrophilic addition (Scheme 4) could also involve epoxide formation through a similar (two-electron) mechanism. Possible ring opening of the epoxide is also indicated (third step).

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