Arene oxides, formation

As with an isolated double bond, epoxide formation in an aromatic ring, i.e., arene oxide formation, can occur mechanistically either by a concerted addition of oxene to form the arene oxide in a single step, pathway 1, or by a stepwise process, pathway 2 (Fig. 4.78). The stepwise process, pathway 2, would involve the initial addition of enzyme-bound Fe03+ to a specific carbon to form a tetrahedral intermediate, electron transfer from the aryl group to heme to form a carbonium ion adjacent to the oxygen adduct followed by... 

Phenacetin Analgesic NH-COCH3 9 O-CHsCHg 0-Dealkylation, N-hydro-xylation and arene oxide formation Glutathione conjugates 0-Dealkylation (Cunninghamella elegans) [97]... 

Fig. 31.15 Addition-rearrangement mechanism for arene oxide formation and proton-catalysed rearrangement of an arena oxide to a phenol (After Silverman ).

The isolation of a stable arene oxide metabolite of naphthalene in liver microsomal incubations provided evidence for the CYP- catalyzed epoxidation on the sp carbons on a simple phenyl ring (Scheme 13). Carcinogenesis following exposure to polycyclic aromatic hydrocarbons (PAHs) such as benzo[a]pyrene is thought to arise from arene oxide formation. Arene oxides... 

Obtained by isomerization of photoxide of 1,3-diphenyl- y isobenzofuran, via an arene oxide formation, in acetic... 

Numerous reactions have been described in which the oxygen of the oxepin system is removed to give benzene derivatives. The formation of the aromatic products can be rationalized by an arene oxide as intermediate. A suitable reagent for the elimination of an oxygen atom from this heterocycle is triphenylphosphane, e.g. formation of l,24 2a,12 and 2b.1,9... 

Arene oxides can be intermediates in the bacterial transformation of aromatic compounds and initiate rearrangements (NIH shifts) (Dalton et al. 1981 Cerniglia et al. 1984 Adriaens 1994). The formation of arene oxides may plausibly provide one mechanism for the formation of nitro-substituted products during degradation of aromatic compounds when nitrate is present in the medium. This is discussed in Chapter 2. 

A rearrangement (NIH shift) occurred during the transformation of 2-chlorobiphenyl to 2-hydroxy-3-chlorobiphenyl by a methanotroph, and is consistent with the formation of an intermediate arene oxide (Adriaens 1994). The occurrence of such intermediates also offers plausible mechanisms for the formation of nitro-containing metabolites that have been observed in the degradation of 4-chlo-robiphenyl in the presence of nitrate (Sylvestre et al. 1982). 

The first step in any of the degradation pathways is the formation of 2-quinolinone/2-hydroxyquinoline/2-oxo-l, 2-dihydroquinoline and quinoline2-oxidoreductase has been shown to be responsible for this initial metabolic reaction [318], When the oxidation is carried out by a dioxygenase, it resulted in the formation of ds-hydrodiol derivatives and when oxidation is carried out by a monooxygenase monohydroxilated derivatives are formed, via the arene oxide intermediates [323],... 

These are the same quinones that are formed when 6-hydroxy-BP is oxidized by air or microsomes (19). However, there is no definitive evidence that 6-hydroxy-BP is an intermediate in their formation by PGH synthase. Among all of the stable metabolites of BP, the quinones are distinctive because, unlike phenols and dihydrodiols, they are not derived from arene oxides. Thus, arene oxides do not appear to be products of BP oxidation by PGH synthase (19,20). 

FIGURE 4.78 Mechanistic pathways for aromatic hydroxylation by concerted addition of oxene, pathway 1, or by stepwise addition of oxene, pathway 2. Pathways 2, 3, and 4 describe the formation of phenol that bypasses the arene oxide intermediate. 

It is sometimes assumed that every phenol metabolite indicates the formation of an arene oxide intermediate however, as discussed above, arene oxides are not obligate intermediates in the formation of phenols. This is an important distinction because arene oxides and other epoxides are reactive intermediates that 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 and has implications for toxicity as discussed in Chapter 8. 

The observation of a dihydrodiol has been taken as proof that an epoxide (arene oxide) is the precursor metabolite. Many epoxides, such as the 10,11-epoxide of carbamazepine shown above and even the arene oxide of benzene, which is quite reactive, have been directly observed. Others such as the epoxide of phenytoin are only inferred. It is conceivable that some dihydrodiols are formed by reaction of an intermediate with water in the active site of P450 without the formation of an epoxide. One clue to the origin of the dihydrodiol is the stereochemistry an exclusively tram-dihydrodiol suggests that it was formed via the EH-mediated hydrolysis of an epoxide or arene oxide. 

Detailed kinetic studies comparing the chemical reactivity ofK-region vs. non-K-region arene oxides have yielded important information. In aqueous solution, the non-K-region epoxides of phenanthrene (the 1,2-oxide and 3,4-oxides) yielded exclusively phenols (the 1-phenol and 4-phenol, respectively, as major products) in an acid-catalyzed reaction, as do epoxides of lower arenes (Fig. 10.1). In contrast, the K-region epoxide (i.e., phenanthrene 9,10-oxide 10.29) gave at pH < 7 the 9-phenol and the 9,10-dihydro-9,10-diol (predominantly trans) in a ratio of ca. 3 1. Under these conditions, the formation of this dihydrodiol was found to result from trapping of the carbonium ion by H20 (Fig. 10.11, Pathway a). At pH > 9, the product formed was nearly ex-... 

The mechanism of 1,4-dichlorobenzene oxidation to 2,5-dichlorophenol has not yet been thoroughly investigated. The metabolism of 1,4-dichlorobenzene could involve the formation of an arene oxide... 

The metabolism of 1,4-dichlorobenzene could involve the formation of an arene oxide intermediate, as has been proposed to occur in the oxidative metabolism of many halogenated aromatic hydrocarbons (Jerina and Daly 1974). 1,4-Dichlorobenzene has not been shown to be mutagenic in microbial or mammalian systems, a result that may be viewed as further suggestive evidence that an arene oxide intermediate is not involved in its metabolism. 

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