Arene oxides structure

Thermolysis of 3-oxaquadricyclanes in which the bond between Cl and C2 is part of a cyclohexane structure gives a,/J-annulated oxepins 11 in good yield.133 The enlargement of the an-nulated ring favors the arene oxide structure.134... 

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. 

For clarity, the term arene oxide has been used in the following discussion (and arene-oxide structural formulas have been used in Tables 1 and 2), although a... 

The proposed reaction pathway leading to these products is depicted in figure 5. The electron-rich pyrrole ring system is oxidized to the reactive arene oxide (structure 32) which rearranges to the zwitterionic species... 

Diol epoxides. Structural considerations. Because enzymatic hydration of arene oxides produces trans dihydrodiols in mammalian cells, there are two diastereomeric series of diol epoxides. In... 

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 data in Table 10.1 suggest that the reactivity of epoxide hydrolase toward alkene oxides is highly variable and appears to depend, among other things, on the size of the substrate (compare epoxybutane to epoxyoctane), steric features (compare epoxyoctane to cycloalkene oxides), and electronic factors (see the chlorinated epoxides). In fact, comprehensive structure-metabolism relationships have not been reported for substrates of EH, in contrast to some narrow relationships that are valid for closely related series of substrates. A group of arene oxides, along with two alkene oxides to be discussed below (epoxyoctane and styrene oxide), are compared as substrates of human liver EH in Table 10.2 [119]. Clearly, the two alkene oxides are among the better substrates for the human enzyme, as they are for the rat enzyme (Table 10.1). 

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 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). 

Scheme 2 Resonance structures for monosubstituted oxepins-arene oxides...

Oxepin (25) was not observed since this structure would incorporate the antiaromatic cyclobutadiene ring system, i.e. the arene oxide tautomer appeared to be formed exclusively <74AG(E)277>. 

Substituted l,2,4-triazoline-3,5-diones are excellent dienophiles which react rapidly at room temperature with oxepins, but particularly with the arene oxide valence tautomer. A similar [4+2] cycloaddition reaction between the episulfide tautomer of thiepin (44) and 4-phenyl-l,2,4-triazoline-3,5-dione has been reported (74AG(E)736>. Benzene episulfide (the valence tautomer of thiepin 44) was generated in situ by thermal decomposition of the diepisulfide (151) at 20 °C and trapped as a cycloadduct at the same temperature (equation 34). A 1,3-dipolar cycloaddition reaction between thiepin (152) and diazomethane has been reported (56CB2608). Two possible cycloadduct products are shown since the final structure has not been unequivocally established (equation 35). 

PBBs and PBDEs may also cause toxicity by other mechanisms of action. For example, some PBB congeners can be metabolized to reactive arene oxides (Kohli and Safe 1976 Kohli et al. 1978) that may alkylate critical cellular macromolecules and result in injury. PBDEs may disrupt thyroid hormones by induction of hepatic microsomal UDPGT, which increases the rate of T4 conjugation and excretion, or by mimicking T4 or T3 PBDEs and their hydroxy metabolites are structurally similar to these thyroid hormones which are also hydroxy-halogenated diphenyl ethers (see Section 3.5.2). Clinical interventions designed to interfere with this mechanism or the metabolism of PBBs have yet to be developed. 

One of the important features of the structure and reactivity of arene oxides is the possibility of their involvement in valence tautomerism with the oxepin system. In benzene oxide (86) the two n bonds and the C—C a bond undergo facile disrotatory electrocyclic reaction to give a 6rc-oxepin system (96). 

On the other hand, certain arene oxides do not undergo this valence tautomerism. Thus the arene oxide formulation can fully represent the structure and reactivity of a compound, but in other cases the oxepin form alone fits the structure and reactivity. 

All four arene oxides derivable from naphthalene have been prepared, and their structures are sufficiently well defined. None of them shows valence tautomerism. They exist exclusively either in the oxepin or arene oxide forms. 

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... 

The configurational data of some arene oxides are collected in Table III. The molecular structures of 30 and 1 have been determined by X-ray crystallography.87 Compound 1 is approximately planar, excluding the... 

Detailed studies by Bruice, Jerina, and co-workers, referred to earlier, showed that three factors determine whether nucleophilic reaction of tissue materials with arene oxides occur directly. They are (a) the structure of the... 

Z1220 (351) is shown to have a benzene dioxide structure.194 Likewise, metabolites 352195 and 353196 from Verongia sponges were postulated to have been biosynthesized through arene oxides. 

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... 

Structural information in the crystalline state can be obtained directly by x-ray diffraction studies, but this method has not been used extensively in the arene oxide-oxepin series since the majority of the monocyclic arene oxide-oxepins synthesized to date have been liquids and since chemical instability at ambient temperature is a common feature of many mono- and polycyclic arene oxides. X-ray crystal structure analysis has been carried out on the relatively stable K-region arene oxides 2-4. ° Similarly, an x-ray analysis of 5, a crystalline annelated benzene oxide (which, however, exists in both arene oxide and oxepin form in solution), has been reported and indicates that the six-membered ring is almost planar. The oxepin ring in compound 6 has been shown to exist in the boat conformation both in solution and in the crystalline state. The structural information thus obtained in the crystalline state is totally consistent with the spectroscopic data and the chemical reactivity of the arene oxides in solution and has been used in theoretical studies of the arene oxide-oxepin system. ... 

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. 

A further factor that has a marked influence upon the arene oxide-oxepin distribution is the effect of substituents. With the numbering system shown below, arene oxides, monosubstituted arene 1,2-, or 3,4-, and 1,2 disubstituted 1,2-oxides prefer their oxepin forms whereas arene 2,3-oxides prefer their oxide tautomers. These observations concur with MINDO/3 calculations and may be rationalized in terms of the maximum number of low-energy valence-bond structures for tt-electron-donating or withdrawing substituents (Figure 1). 

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