Arene oxide-oxepin equilibrium

The metabolism of polycyclic aromatic hydrocarbons by enzymes present in animal livers involves epoxidation as the initial step. As indicated in Section 5.17.1.2, evidence is available to suggest that oxepins (29)-(34) are present as minor contributors to the arene oxide-oxepin equilibrium and thus may legitimately be considered as metabolic intermediates. 

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... 

The bulk of the polycyclic arene oxides do not show a dynamic equilibrium with the oxepin valence tautomer. This is particularly true for the K-region arene oxides, which exist exclusively in the arene oxide forms. A number of oxepins exist only as such and do not show physical, spectroscopic, or chemical reactivities corresponding to the arene oxide form, e.g., 70,170,171, etc. Tautomeric behavior of some representative arene oxide-oxepin pairs is summarized in Table I.8... 

Structural identification of arene oxides-oxepins by such chemical transformations to stable products does not, however, provide any information on the relative proportions of the contributing valence tautomers where the barriers to tautomerization are low and a state of dynamic equilibrium exists. Ultraviolet spectroscopy was used initially to establish that a rapid equilibration of la and lb occurred at ambient temperature and that the distribution of tautomers was markedly temperature and solvent-dependent. Thus, the less conjugated arene oxide form la was favored at low temperature or in polar solvents and was a colorless liquid. In contrast, the more conjugated bright yellow oxepin lb formed... 

A completely novel preparation of alkylidene oxepines has been provided by Bourelle-Wargrier et who studied the gas- and liquid-phase thermolyses of the ethynyl vinyl oxiranes (403). Ethynyl cyclopropyl ketones such as (404) were the sole product in the gas phase, but these rearranged further in the liquid phase to the isomeric dihydro-oxepins (405) and (406). A trace of phenolic products was thought to have arisen from arene-oxides in equilibrium with the oxepines. 

Fig. 5. Left oxepine (87) in equilibrium with arene oxide (88). Right general structures (89 and 90) that have been referred to as oxepines.

The nature and position of substitution has a profound influence upon the oxepin-arene oxide equilibrium position. The effect of substituents on the relative energies of each valence tautomer has been calculated (80JA1255) and these theoretical results are in accord with the limited experimental data which are available. In general terms, oxepins substituted at the 3-position are less favored than the corresponding arene oxides, while the reverse obtained for 2- and 4-substituted oxepins. This substituent effect has been rationalized in terms of a preference for the maximum number of alternative resonance contributors. The influence of both 7r donating and v withdrawing substituents oh the oxepin contribution is summarized in Scheme 2. This latter effect may be considered as an electronic substituent effect. 

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... 

Oxepins having annelated aromatic rings may in principle equilibrate with the valence tautomeric arene oxide forms. In practice, the equilibrium distribution will be dominated by a resonance effect, i.e. the preference for the isomer having the maximum degree of aromaticity. 

In the aromatic-ring-annelated oxepin series the resonance effect is clearly the major influence dominating other factors (e.g. temperature, solvent, etc.) which affect the oxepin-arene oxide equilibrium. It is however very difficult to exclude the presence of a minor (spectroscopically undetectable) contribution from either tautomer at equilibrium. This problem has been investigated by the synthesis of chiral arene oxides from polycyclic aromatic hydrocarbons (PAHs). The presence of oxepin (26) in equilibrium with naphthalene 1,2-oxide has been excluded by the synthesis of the optically active arene oxide which showed no evidence of racemization in solution at ambient temperature via the achiral oxepin (26) <79JCS(Pl)2437>. 

Factors which affect the oxepin-benzene oxide equilibrium positions are similarly expected to influence the thiepin-benzene episulfide distribution at equilibrium. Since however the thianorcaradiene tautomer has not to date been detected, the main evidence for this form is based upon the thermal instability and reactions of the thiepin system. Thus it is assumed that where the thianorcaradiene isomer is present, a spontaneous thermal decomposition involving extrusion of a sulfur atom will occur. Substitution at the 2,7-positions in the oxepin-arene oxide system leads to a preference for the seven-membered ring form and this effect was further enhanced by bulky substituents (e.g. Bu ). A similar effect was observed in thiepins and thus the remarkable thermal stability of (49) (2,7-r-butyl groups) and (51) (2,7-hydroxyisopropyl groups) contrasts with the behavior of thiepin (55)(2,7-isopropyl groups), which was thermally unstable even at -70 °C (78CL723). The stability of thiepin (49) results from the 2,7-steric (eclipsed) interactions which obtain in the thianorcaradiene form but which are diminished in the thiepin tautomeric form (relative to the episulfide tautomer). 

As in the oxepin-arene oxide system, the resonance effect will also influence the position of equilibrium in the analogous organosulfur series. Compounds (46) and (53) thus appear to exist exclusively in the thiepin form. Since the resonance factor would favor the 1,2-episulfide of naphthalene over the thiepin tautomer (54) it is highly improbable that this thiepin will be detectable at ambient temperature. Both thiepins (46) and (55) have been isolated as thermolabile compounds (78JOC3379, 81MI51700). 

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... 

For oxirane rings an IR absorption around 890 cm-1 is characteristic. This is also observed in the case of K-region epoxides and can be used for diagnostic purposes, but it is not sensitive enough to provide detailed structural information. The oxepins ordinarily do not show this band. Ultraviolet spectroscopy has been invaluable in studying the dynamic equilibrium between the arene oxides and oxepins. The solvent variation of UV spectra has also been exploited very effectively.8... 

Many arene oxides are in dynamic equilibrium with their oxepin forms. The parent molecules, benzene oxide la and oxepin lb, are related as valence tautomers that interconvert by an allowed disrotatory electrocyclic reaction. Structural identification of la and lb was based initially upon spectroscopic evidence and chemical transformation to stable products of known structure. Thus the arene-oxide structure was inferred from its typical dienoid (4 + 27t cycloaddition) and epoxide (ring-opening, aromatization) reactions, while the oxepin structure was deduced by catalytic hydrogenation of the triene oxepin to form oxepane. 

Preferred geometry of the benzene oxide-oxepin system can be predicted by molecular orbital methods. Thus benzene oxide la is predicted to be markedly non-planar (with the epoxide ring at an angle of 73° to the benzene ring), while the oxepin lb has been predicted to prefer a shallow boat structure (MINDO/3) or a planar structure ab initio) As previously mentioned, the proportion of each tautomer present at equilibrium is both temperature and solvent-dependent. Molecular orbital calculations have been used to rationalize the solvent effects, both in terms of the more polar character of the arene oxide that is favored in polar solvents and the strengthening of the oxirane C-C bond upon coordination of the oxygen atom lone pair in polar solvents. Thus values in the range 1.5-2.0 D and 0.76-1.36 D for the dipole moments of arene oxide la and oxepin lb have been calculated. 

The survey of reactivity of oxepines given in CHEC-I <84CHEC-I(7)547> is still noteworthy. The survey in CHEC-I covers such topics as (i) thermal and photochemical reactions, (ii) electrophilic attack on the ring oxygen atom, (iii) nucleophilic attack on carbon atoms, and (iv) reactions involving cyclic transition states. Considering other reactions of oxepines, the existence of oxepin-arene oxide equilibrium should be taken into account since some of the reactions can involve the latter form. Specific properties of the arene oxide system make it possible to interpret why electrophilic attack at carbon, and nucleophilic attack at the hydrogen atom, are not characteristic of oxepines. There is a lack of information devoted to reactions of oxepines with, for example, radicals and carbenes. 

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