Although most cytochrome P450-metabolism of benzene proceeds via 1,2-benzene oxide and its isomerization to phenol, roughly ten percent of benzene is metabolized to muconaldehyde isomers that are among the most toxic metabolites. In the 1970s, Davies and Whitham postulated 2,3-epoxyoxepin as an intermediate derived from oxepin, the valence isomer of 1,2-benzene oxide. They employed m-cpba to oxidize oxepins, obtained strong indirect evidence, but due to acidic conditions could not isolate or observe the putative intermediates. Development of dioxiranes in the 1980s led to strong, neutral oxidizing reagents. Thus, DMDO reaction with 2,7-dimethyloxepin at low-temperature gave a trace of the corresponding 2,3-epoxyoxepin derivative which ring-opened at about -20 oC. Reaction of DMDO with 4,5-benzoxepin at -60 oC provided a high yield of the 2,3-epoxyoxepin which rearranged to 2H-pyran-2-carboxaldehyde at ca -15 oC. Following work published by Golding's group, we found that reaction of cerium(IV) ammonium nitrate (CAN) with 4,5-benzoxepin yielded completely different products (two dimeric molecules). Incubation of 4,5-benzoxepin with three different P450 isoforms as well as human liver microsomal extract yielded 2H-pyran-2-carboxaldehyde as the major product with the dimeric molecules as minor products. These observations support the hypothesis that 2,3-epoxyoxepin is the critical intermediate en route to metabolic ring opening of benzene to muconaldehyde. Included in this talk will be brief discussion of why monooxygenase metabolism of benzene differs from metabolism of toluene, xylenes, naphthalene and polycyclic aromatic hydrocarbons (PAH).

Monooxygenase-catalyzed ring opening of benzene to muconaldehyde likely involves 2,3-epoxyoxepin

ACS Spring Meeting 2021

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