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Z. Fu and J. Chen
pound I, Compound 0, and FeOO
2− , were previously evaluated for their reactivity
toward S-oxidation. A cluster model study by Li et al. [32] concluded Compound I
as the preponderant oxidant in S-oxidation of dimethyl sulfide. The same reaction
was revisited [33] by QM/MM simulations, which also indicated that Compound 0
is a sluggish oxidant and less competent than Compound I for sulfoxidation.
17.3.1.3 Mechanisms for Phenyl Hydroxylation
Phenyl groups are prevalent in molecules of environmental contaminants, e.g.,
polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs),
polybrominated diphenyl ethers (PBDEs), and polychlorodibenzo-p-dioxins/furans
(PCDD/Fs). When subjected to metabolism by P450 enzymes, the phenyl group
would likely be transformed into epoxides that are reactive electrophilic agents
toward bio-macromolecules, or yield hydroxylated products which are suspected
endocrine disruptors. As a consequence, mechanisms for phenyl hydroxylation by
P450 enzymes have attracted much attention. Owing to the strong electronic πconjugation, phenyl C–H bonds possess BDE values larger than those of alkyl C–H
bonds, which renders the disobedience of the phenyl oxidation mechanisms from
alkane C–H hydroxylation.
Using DFT calculations, Shaik et al. first explained the mechanism for benzene
hydroxylation [19] and clarified that the SET (as in N-hydroxylation) and HAT (as
in alkyl hydroxylation) schemes are less viable and the reaction proceeds primarily
on the low-spin doublet state. Three feasible mechanisms are illustrated in Fig. 17.8.
According to previous studies, these mechanisms share a preceding rate-determining
electrophilic π-addition of Compound I to the phenyl carbon, leading to a radical- or
cation-like tetrahedral adduct. The radical-type intermediate is prone to subsequent
epoxidation via addition of the O atom to the adjacent C atom, while the cation tetrahedral intermediate is liable to arrange via a National Institute of Health (NIH) shift
that delivers the ipso-H atom to the neighboring C atoms, giving a cyclohexanone
product. Moreover, if the tetrahedral intermediate takes on a “side-on” conformation
wherein the phenyl is perpendicular to the porphyrin macrocycle, a proton shuttle
mechanism can be viable that shifts the H atom first to porphyrin N, followed by H
bounce back to the carbonyl O or neighboring atoms, resulting in phenol or cyclohexanone, respectively. QM/MM calculations [34] have revealed that epoxides and
ketones are the two products most likely to be formed from “face-on” transition state
conformations wherein the phenyl is parallel to the porphyrin, whereas epoxide and
phenol products are favorable for “side-on” conformations.
For halogenated phenyl groups, the π-addition of Compound I to the halogensubstituted phenyl carbons requires increased activation barriers due to steric hindrance. In this case, the π-addition would initiate a NIH shift of the halogen atom,
yielding a cyclohexanone product. Furthermore, when the phenyl is perhalogenated
or the halogen NIH shift is hampered by steric hindrance, the oxidative reaction
would lead to dehalogenated products. For substituted benzenes, DFT studies [35]
have revealed lower activation barriers for π-addition of Compound I to phenyl car-
Z. Fu and J. Chen
pound I, Compound 0, and FeOO
2− , were previously evaluated for their reactivity
toward S-oxidation. A cluster model study by Li et al. [32] concluded Compound I
as the preponderant oxidant in S-oxidation of dimethyl sulfide. The same reaction
was revisited [33] by QM/MM simulations, which also indicated that Compound 0
is a sluggish oxidant and less competent than Compound I for sulfoxidation.
17.3.1.3 Mechanisms for Phenyl Hydroxylation
Phenyl groups are prevalent in molecules of environmental contaminants, e.g.,
polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs),
polybrominated diphenyl ethers (PBDEs), and polychlorodibenzo-p-dioxins/furans
(PCDD/Fs). When subjected to metabolism by P450 enzymes, the phenyl group
would likely be transformed into epoxides that are reactive electrophilic agents
toward bio-macromolecules, or yield hydroxylated products which are suspected
endocrine disruptors. As a consequence, mechanisms for phenyl hydroxylation by
P450 enzymes have attracted much attention. Owing to the strong electronic πconjugation, phenyl C–H bonds possess BDE values larger than those of alkyl C–H
bonds, which renders the disobedience of the phenyl oxidation mechanisms from
alkane C–H hydroxylation.
Using DFT calculations, Shaik et al. first explained the mechanism for benzene
hydroxylation [19] and clarified that the SET (as in N-hydroxylation) and HAT (as
in alkyl hydroxylation) schemes are less viable and the reaction proceeds primarily
on the low-spin doublet state. Three feasible mechanisms are illustrated in Fig. 17.8.
According to previous studies, these mechanisms share a preceding rate-determining
electrophilic π-addition of Compound I to the phenyl carbon, leading to a radical- or
cation-like tetrahedral adduct. The radical-type intermediate is prone to subsequent
epoxidation via addition of the O atom to the adjacent C atom, while the cation tetrahedral intermediate is liable to arrange via a National Institute of Health (NIH) shift
that delivers the ipso-H atom to the neighboring C atoms, giving a cyclohexanone
product. Moreover, if the tetrahedral intermediate takes on a “side-on” conformation
wherein the phenyl is perpendicular to the porphyrin macrocycle, a proton shuttle
mechanism can be viable that shifts the H atom first to porphyrin N, followed by H
bounce back to the carbonyl O or neighboring atoms, resulting in phenol or cyclohexanone, respectively. QM/MM calculations [34] have revealed that epoxides and
ketones are the two products most likely to be formed from “face-on” transition state
conformations wherein the phenyl is parallel to the porphyrin, whereas epoxide and
phenol products are favorable for “side-on” conformations.
For halogenated phenyl groups, the π-addition of Compound I to the halogensubstituted phenyl carbons requires increased activation barriers due to steric hindrance. In this case, the π-addition would initiate a NIH shift of the halogen atom,
yielding a cyclohexanone product. Furthermore, when the phenyl is perhalogenated
or the halogen NIH shift is hampered by steric hindrance, the oxidative reaction
would lead to dehalogenated products. For substituted benzenes, DFT studies [35]
have revealed lower activation barriers for π-addition of Compound I to phenyl car-