Arene oxides NIH shift

Cerniglia CE, JP Ereeman, EE Evans (1984) Evidence for an arene oxide-NIH shift pathway in the transformation of naphthalene to 1-naphthol hy Bacillus cereus. Arch Microbiol. 138 283-286. 

Cerniglia CE, JR Althus, EE Evans, JP Freeman, RK Mitchum, SK Yang (1983) Stereochemistry and evidence for an arene oxide-NIH shift pathway in the fungal metabolism of naphthalene. Chem-Biol Interactions 44 119-132. 

The early functional models for this oxidation chemistry were rather simple Udenfriend used iron(II), EDTA, ascorbic acid (as the reducing agent) and O2 to hydroxylate arenes, while Hamilton showed that the same system hydroxylates unactivated C—H bonds (e.g. androsten-3-ol-17-one is converted to androsten-3,7-diol-17-one). Mimoun developed the use of an iron(II)/PhNHNHPh/ H1CO2H/O2 system which is also active for alkane hydroxylation. Curiously, other metals [copperfll), manganese(II), vanadium(II), cobalt(II)] are also active. In the hydroxylation of arenes, an arene oxide is believed to be the intermediate in P-450 dependent systems, because a 1,2-shift of a proton in the arene, the NIH shift is often observed. Neither the Udenfriend nor Mimoun models show such a shift, however. 

Transition-metal complexes such as [Rh(CO)2Cl]2,204 Rh(butadiene)2Cl,205 or Cr(CO)3(NH3)312 have also been used for the deoxygenation of oxepins to give 312,204 205 and benzoxepins to give 4.12,204 Occasionally, substantial amounts of phenolic compounds have been isolated due to the competing NIH shift of the arene oxide.204 1-Benzoxepin and 3-benzoxepin resist oxygen extrusion under these conditions probably due to their inability to form arene oxi-des.133,204... 

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. 

Daly JW, DM Jerina, B Witkop (1972) Arene oxides and the NIH shift the metabolism, toxicity and carcinogenicity of aromatic compounds. Experientia 28 1129-1149. 

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 NIH shift has been found to occur during aromatic hydroxylations catalyzed by enzymes present in plants, animals, fungi and bacteria. It is thus evident that the acid catalyzed (or spontaneous) isomerization of oxepins-arene oxides is a very important type of in vivo reaction. It should be emphasized that the NIH shift may occur under either acid-catalyzed or neutral (spontaneous) conditions (76ACR378). The direct chemical oxidation of aromatic rings has also yielded both phenols (obtained via the NIH shift) and arene oxides (80JCS(P1)1693>. 

This hydroxylation-induced intramolecular migration, known as the NIH shift, was explained by the involvement of arene oxides formed by the attack of electrophilic oxoiron(V) porphyrin on the aromatic ring.753 Intermediate 98 was also suggested to be formed in hydroxylation by the Fenton and related reagents in aprotic media after initial oxidation with an oxoiron(V) complex followed by electron transfer.744 754... 

Some of the reagents used in olefin epoxidation can be applied in the direct oxidation of arenes to arene oxides. Benzene oxide, however, like other arene oxides, exists in equilibrium with oxepin, its valence tautomer, and has not been isolated. Existence of benzene oxides as intermediates can be concluded from observations like the NIH shift discussed above.752,753... 

Recently, the PCB-biodegradative capabilities of methanotrophs have been demonstrated (Adriaens, 1994). In this study, 2-CB was oxidized by a methanotrophic culture (CSC1) to a hydroxylated chlorobiphenyl intermediate identified as 2-hydroxy-3-chlorobiphenyl. This intermediate indicated that the metabolite was formed via a concerted oxidation involving an arene oxide which rearranges spontaneously via an NIH shift. No studies have shown, however, that methanotrophs can degrade more highly chlorinated PCBs, and their utility for bioremediation processes does not seem promising. 

NADH-dependent reductase, thus allowing the biopterin cofactor to function catalytically (72JBC(247)6082). That the conversion of phenylalanine to tyrosine involves an arene oxide intermediate is suggested by the observation of the so-called NIH shift phenomenon (i.e. migration and retention of the para substituents such as deuterium, tritium, methyl and bromine when these para-substituted phenylalanines are enzymatically hydroxylated) <66BBR(24)720, 67MI11000). 

Such an attack could lead in step a either to an epoxide (arene oxide) or directly to a carbocation as shown in Eq. 18-47. Arene oxides can be converted, via the carbocation step b, to end products in which the NIH shift has occurred.438 The fact that phenylalanine hydroxylase also catalyzes the conversion of the special substrate shown in Eq. 18-48 to a stable epoxide, which cannot readily undergo ring opening, also supports this mechanism. 

In mammalian liver microsomes, cytochrome P-450 is not specific and catalyzes a wide variety of oxidative transformations, such as (i) aliphatic C—H hydroxylation occurring at the most nucleophilic C—H bonds (tertiary > secondary > primary) (ii) aromatic hydroxylation at the most nucleophilic positions with a characteristic intramolecular migration and retention of substituents of the aromatic ring, called an NIH shift,74 which indicates the intermediate formation of arene oxides (iii) epoxidation of alkenes and (iv) dealkylation (O, N, S) or oxidation (N, S) of heteroatoms. In mammalian liver these processes are of considerable importance in the elimination of xenobiotics and the metabolism of drugs, and also in the transformation of innocuous molecules into toxic or carcinogenic substances.75 77... 

Aromatic hydrocarbons are mainly hydroxylated to phenolic products. Complex (12) hydroxylated benzene in MeCN at 20 °C into phenol in ca. 55% yield, and no isotope effect was found for this reaction. Hydroxylation of toluene mainly occurs at the ring positions, with minor amounts of benzylic oxidation products. Hydroxylation of 4-deuterotoluene by (12) occurred with 70% retention and migration of deuterium in the formation of p-cresol. This high NIH shift value is in the same range as that found for liver microsome cytochrome P-450 hydroxylase, and suggests the transient formation of arene oxide intermediates. 

Polynuclear aromatic compounds such as naphthalene or anthracene are oxidized by chromyl reagents mainly into quinones, with a significant NIH shift, providing evidence for the intermediacy of arene oxide intermediates.306,54... 

Institute of Health) shift.80,110,111 Originally, the term NIH shift was used as a phenomenological description of the consequence of hydroxylation of aromatic compounds by mixed-function oxygenases. These enzymes catalyze the oxidation of aromatic substrates by deriving oxygen from molecular oxygen and not from water.80,110,111 Later studies narrowed the term to include arene oxide involvement.80... 

On the basis of these observations, the NIH shift was attributed to a chemical sequence involving oxidation of the aromatic ring to an arene oxide, opening of the oxide to an ionic intermediate, and finally rearrangement to a phenol with migration of a substituent. When appropriately labeled arene oxides were prepared, shifts to the extent of about 95% were observed. 

The NIH shift has been recognized to be so general that whenever a 1,2-shift occurs in aromatic hydroxylation reactions, it is assumed that arene oxides are involved. This need not be so. That the 1,2-shift could take place without the... 

Hydroxylation of aromatic rings is a very common and an important step in the biosynthesis of natural products.181,182 Arene oxides were suggested as intermediates in the biosynthesis of natural products as early as in 1967.183 However, not all hydroxylations proceed through arene oxides. A number of instances have been documented,184 as in the case of cinnamic and benzoic acids, where ortho and para hydroxylations take place by the involvement of an NIH shift (arene oxides). 

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