Naphthalene, arene oxide formation

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... 

The epoxidation of aldrin to dieldrin is an example of the metabolic formation of a stable epoxide (Figure 10.1A), while the oxidation of naphthalene was one of the earliest understood examples of an epoxide (arene oxide) as an intermediate in aromatic hydroxylation (Figure 10.1B). The arene oxide can rearrange nonenzy-matically to yield predominantly 1-naphthol, can interact with the enzyme epoxide hydrolase to yield the dihydrodiol, or can interact with glutathione -transferase to yield the glutathione conjugate that ultimately is metabolized to a mercapturic acid. This reaction is also of importance in the metabolism of the insecticide carbaryl, which contains the naphthalene nucleus. 

To date, the only natural product containing a benzene dioxide moiety is the antibiotic 149. In addition to this cis dioxide, there is evidence that trans naphthalene dioxide 152 may be an intermediate in the hepatic metabolism of naphthalene. The reactivity of the cis (153) and trans (152) naphthalene dioxides with nucleophiles and the relative stereochemistry of the adducts has been determined. The possibility that arene dioxide intermediates form during metabolism of PAHs has been discussed frequently. Indeed, the detection of a rrans-diol epoxide such as that derived from arene oxide 25, or the isolation of a rra s-diol oxepin (e.g., 165) is mechanistically consistent with the formation of two epoxides on either the same or different rings. However, presently available evidence would suggest that it is most unlikely that either diol metabolite was derived from an arene dioxide intermediate. Involvement of dioxide intermediates in the metabolism of PAHs will require further experimental verification. 

The epoxidation reaction of arene oxide-oxepins has been encountered in the formation of the arene dioxides of naphthalene and anthracene rings A similar approach to the synthesis of epoxides of benzene oxide-oxepin using a peroxyacid oxidant, however, was unsuccessful (Z,Z)-muconaldehyde was isolated presumably via an oxepin-epoxide intermediate. The disubstituted benzene... 

DM Jerina, JW Daly, B Witkop, P Zaltzaman-Nirenberg, S Udenffiend. The role of arene oxide-oxepin systems in the metabolism of aromatic substrates. III. Formation of 1,2-naphthalene oxide from naphthalene in microsomes. J Am Chem Soc 90 6525-6527, 1968. 

Isomerization of appropriately deuterated arene oxides to phenols is accompanied by migration and retention of the deuterium in an adjacent position, as in the isomerization of 1-deutero-naphthalene 1,2-oxide to 2-deutero-l-naphthol.53 similar migrations of ring substituents occur during aromatic "hydroxylations" and have been called the "NIH Shift." Because of its widespread and characteristic nature, the "NIH Shift" is now used as a criterion for monoxygenase-catalyzed phenol formation.55 The only apparent exceptions are during "hydroxylations" of phenols and aniline in which retentions are very low probably due to the reactive nature of the ring. The proposed mechanism for the "NIH Shift" is as shown. The substrate 6 is converted to the arene oxide 7, which then... 

Jerina, D. M., j. W. Daly, B. Witkop, P. Zaltzman-Niremberg, and S. Uden-FRIEND The Role of Arene Oxide-Oxepin System in the Metabolism of Aromatic Substrates. Formation of 1,2-Naphthalene Oxide from Naphthalene by Liver Micro-somes. J. Amer. Chem. Soc. 90, 6525-6527 (1968). 

A second class of oxidation in which these systems have been applied is conversion of electron-rich arenes to quinones.50 Oxidation of 2-methyl-naphthalene showed a significant selectivity for formation of 2-methylnaph-thoquinone over the 6-methyl isomer. This was later proposed33 to proceed via epoxidation of the electron-rich arene ring, followed by ring opening and further oxidation of the hydroquinone. 

However, the substitution pattern on the arene is crucial for the success of the Heck reaction. When a second Heck coupling takes place in an ortho position of another alkenyl unit, cyclization of the intermediately formed palladium complex may occur. Hence, formation of alkylideneindanes and alkylindenes, especially under classical Heck conditions with phosphines in the catalyst cocktail, was observed (Scheme 5-22). Alternatively, 6ji-electrocyclization/oxidation might occur to yield naphthalenes or related compounds. ... 

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