Arene oxide isomerization

It must be stressed that arene hydroxylation is often achieved in nature via multistep pathways, particularly via arene oxides. In contrast to the dehydration required to access phenols 166 fiom arene ds-diols 2, the transformation of an arene oxide into a phenol is simply an isomerization. Several mechanisms may be proposed by which such an isomerization may occur, and extensive studies with isotopicaUy labeled substrates have elucidated a process known as the NIH shift that is common to many arene oxide isomerizations [101]. As shown in Scheme 32.22, if apara-deuterated arene 179 is oxidized by an arene monooxygenase to the corresponding arene oxide 180,... 

Dihydro-9,10-epoxyphenanthrene and related arene oxides are of considerable interest as carcinogens formed by polycyclic aromatic hydrocarbons in vivo.45 Phenanthrene oxide does not isomerize to the corresponding dibenzoxepin under thermal conditions. Photolysis of... 

Vol. E19b, p 1866f).190 191 Bulky substituents in the 2- and 7-positions, sueh as /erf-butyl groups, prevent the isomerization to arene oxides.191... 

In rearrangement reactions that lead to isomerization, an important discrimination must be made between epoxides of aromatic compounds, e.g., benzene oxide (10.1, Fig. 10.1), and epoxides of alkenes. As a class, epoxides of aromatic compounds (also known as arene oxides) are markedly un-... 

Fig. 10.1. Simplified mechanisms of the spontaneous and acid-catalyzed isomerization of arene oxides to phenols via a carbonium ion intermediate (benzene oxide (10.1) as the... 

Another isomerization reaction of arene oxides is equilibrium with oxe-pins [5], Here, the fused six-membered carbocycle and three-membered oxirane merge to form a seven-membered heterocycle, as shown in Fig. 10.2. An extensive computational and experimental study involving 75 epoxides of monocyclic, bicyclic, and polycyclic aromatic hydrocarbons has revealed much information on the structural factors that influence the reaction rate and position of equilibrium [11], Thus, some compounds were stable as oxepins (e.g., naphthalene 2,3-oxide), while others exhibited a balanced equilibrium... 

Fig. 10.2. The arene oxide-oxepin isomerization, which may lead to racemization in certain...

In other words, the non-K-region epoxides of phenanthrene react like epoxides of lower arenes (Fig. 10.1). In contrast, the K-region epoxide of phenanthrene, under alkaline conditions, hydrolyzes as does an olefin epoxide (i.e., as in Fig. 10.4), but seemingly faster. Under acidic conditions, however, it exhibits dual behavior, isomerizing mainly like an arene oxide (i.e.,... 

The oxepin ring structure (8) appeared to be formed in preference to the arene oxide tautomer according to the NMR spectrum, and the oxepin form was unequivocally established by X-ray structure analysis (78AG(E)12l). Unfortunately the molecular dimensions of the oxepin ring in structure (8) were not included in the original report. In contrast, the valence isomeric arene oxide form of oxepin (9) was found to predominate and detailed information about the arene oxide molecular geometry was provided by the X-ray diffraction method (Table 3) (80LA1889). 

The preference of 2,7-disubstituted oxepins for this tautomeric form at equilibrium may be rationalized in terms of a steric substituent effect. The eclipsing interactions of the 2,7-substituents in the arene oxide form will be diminished by isomerization to the oxepin. When the 2,7-substituents form part of an annelated ring system, e.g. (22)-(24), the tautomeric preference will be determined by the size of the methylene bridge (67AG(E)385). Thus when n = 5 the annelated oxepin (24) was present in approximately equal proportions with the arene oxide form. However with n =4. (23) tetralin 9,10-oxide was dominant. The... 

Kinetic data on the oxepin-benzene oxide equilibration have been obtained from the temperature-dependent NMR studies. Low values were observed for the enthalpy of isomerization of oxepin (7.1 kJ mol-1) and 2-methyloxepin (1.7 kJ mol-1) to the corresponding benzene oxides (67AG(E)385). The relatively small increase in entropy associated with oxepin formation (5-11 J K 1 mol-1) is as anticipated for a boat conformation in a rapid state of ring inversion. Thermal racemization studies of chrysene 1,2- and 3,4-oxides have allowed accurate thermodynamic parameters for the oxepin-arene oxide equilibration process in the PAH series to be obtained (81CC838). The results obtained from racemization of the 1,2- (Ea 103.7 kJ mol-1, AS 3.7 JK-1 mol-1 and 3,4- (Ea 105.3 kJmoF1, AS 0.7 J K"1 mol ) arene oxides of chrysene are as anticipated for the intermediacy of the oxepins (31) and (32) respectively. 

The protonation of oxepins-arene oxides at the ring oxygen atom and subsequent acid-catalyzed isomerization are very dependent upon the nature of substituents on the ring. This is exemplified by a comparison of the relative stabilities of oxepin (7) and oxepin-2,7-dicarboxylic acid (18) under acid conditions. Thus oxepin (7) spontaneously decomposed on clean glassware at ambient temperature (unless prewashed with base) while (18) showed no change over a period of 10 days in trifluoroacetic acid (79JA2470). 

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>. 

A similar solvent trapping mechanism has been proposed to account for formation of 5-indanol from acid-catalyzed isomerization of the arene oxide tautomer of oxepin (22) (73JA60641). 

As stated in Section 5.17.1.4, simple thiepins (e.g. 44) are generally too reactive to be isolable under ambient conditions. Thiepins (49), (50) and (51) are among the relatively few stable monocyclic thiepins to have been reported and the majority of reactivity studies on thiepins have been carried out on polycyclic thiepins. The chemical reactivity of thiepins can be considered separately from the reactivity of the valence tautomeric thianorcaradienes more readily than was the case for oxepins-arene oxides. A spontaneous thermal extrusion of sulfur appears to occur from the episulfide tautomer of thiepins and the stable thiepins (49)-(51) would thus appear to exist exclusively in this valence isomeric form. 

The oxepins (7 equation 54) and (92 equation 55) resulted from the spontaneous isomerization of their valence tautomeric arene oxide forms which were produced by photorearrangement of 2,3-epoxybicyclo[2.2.0]hex-5-ene (67JA3922) and phenanthrene 9,10-oxide (91) (73CC37) respectively. A rather specific synthetic route to the relatively stable oxepins (180)-(182) was based upon the acid-catalyzed dehydration and ring expansion of 2,6-di-r-butylcyclohexadiene-l,4-diols (Scheme 34) <71AG(E)425,71TL1257). 

As has been stated before, oxirane derivatives are formed as intermediates during metabolic oxidations at carbon-carbon double bonds. These epoxides (arene oxides) undergo spontaneous isomerization to phenols, or enzymic hydration via epoxide hydrase to trans- dihydrodiols, or reaction with reduced glutathione (GSH) via specific GSH-transferases to the corresponding conjugates (Scheme 11), which eventually appear in urine... 

Hexahydroanthracene (120) on treatment with perbenzoic acid produces the isomeric diepoxides 121 and 122. The syn-diepoxide 121 with bromine, followed by potassium t-butoxide treatment, produces the annulene 123, whereas similar reactions with the anfi-diepoxide 122 give the arene oxide 124,8... 

Isomerization of 181 has been shown to lead to 2,5- and 2,4-dimethyl-phenols (189 and 190), respectively. At low acidity, 13% of 189 and 87% of 190 are formed. The rate of decomposition of arene oxide is the same as the rate of formation of these products. Under stronger acidic conditions the product ratio changes to 54% of 189 and 46% of 190. These discrepancies have been shown to arise from the accumulation of intermediate 182.91,92... 

Relatively stable arene oxides are the expected intermediates in the metabolism of halobenzenes to a variety of products.214 Oxide 107 isomerizes exclusively to 2-chlorophenol, whereas 109 rearranges exclusively to 4-chlorophenol. Both 107 and 109 react with glutathione and are converted to trans-dihydrodiols. 

A number of drugs having aromatic rings are metabolized by hydroxylation in the liver,225-227 e.g., in the metabolism of mepivacaine (368), isomeric 3-hydroxy (370) and 4-hydroxy compounds have been isolated, out of which 370 has been shown to be formed through the involvement of arene oxide 369.228... 

The inwitro metabolites of chlorobenzene are o-chlorophenol, m- chlorophenol, and p-chlorophenol the proportions differ according to the source of the mono-oxygenase system and its state of purity (Selander et al. 1975). The o- and p-chlorophenols result from isomerization of the intermediate 3-and 4-chlorobenzene oxides, respectively. The formation of m-chlorophenol appears to occur via a direct oxidative pathway (Oesch et al. 1973). In vitro conjugation of the arene oxide with glutathione or hydration is not a significant pathway (Selander et al. 1975). 

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