Epoxides of phenanthrene

Synthesis of the anti and syn isomers of the 1,2-diol-3,4-epoxide of phenanthrene by epoxidation of the 1,2-dihydrodiol has been reported by Whalen et al. (57). 

Detailed kinetic studies comparing the chemical reactivity ofK-region vs. non-K-region arene oxides have yielded important information. In aqueous solution, the non-K-region epoxides of phenanthrene (the 1,2-oxide and 3,4-oxides) yielded exclusively phenols (the 1-phenol and 4-phenol, respectively, as major products) in an acid-catalyzed reaction, as do epoxides of lower arenes (Fig. 10.1). In contrast, the K-region epoxide (i.e., phenanthrene 9,10-oxide 10.29) gave at pH < 7 the 9-phenol and the 9,10-dihydro-9,10-diol (predominantly trans) in a ratio of ca. 3 1. Under these conditions, the formation of this dihydrodiol was found to result from trapping of the carbonium ion by H20 (Fig. 10.11, Pathway a). At pH > 9, the product formed was nearly ex-... 

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.,... 

Epoxidation. In the presence of catalytic amounts of 18-crown-6 and an acyl chloride, KO, can effect epoxidation of alkenes and of some polycyclic arenes derived from phenanthrene. The most effective acyl chlorides are phosgene and benzoyl chloride. The highest yields of epoxides are formed from fran,v-stilbene (89%) and cyclohexene (80%). The 9,10-epoxide of phenanthrene is obtained in 38% yield. 

Benzo(c)phenanthrene (BcP) is exceptionally weak or inactive as a carcinogen in experimental animals (51). On the other hand, the bay region anti diol epoxide of BcP (14) exhibits high tumor initiating activity on mouse skin (65). 

Phenanthrene (10.28, Fig. 10.10) is the positional isomer of anthracene, yet the differences in reactivity and metabolism between the two compounds are marked. Whereas epoxidation of anthracene in mammals occurs only at the 1,2-position (Fig. 10.9), phenanthrene is epoxidized at the 9,10- (major), 1,2- (minor), and 3,4-positions (trace). The reason for preferential oxygenation at the 9,10-position is due at least in part to its higher reactivity. This position within a phenanthrene-like topography, known as the K region, is found in a number of PAHs with four or more cycles. Phenanthrene is also representative of higher PAHs since it contains a so-called bay region (Fig. 

The EH-catalyzed hydration of the enantiomers of the K-region epoxides of BaA, CR, and BcPh allows informative comparisons to be made [92 - 94], With four among the six substrates, nucleophilic attack is selective for the oxirane C-atom with (5)-configuration (Fig. 10.12). This is, for example, true for the two enantiomers of chrysene 5,6-oxide. Looking at the data in another way, it is also apparent that, irrespective of the enantiomer, nucleophilic attack occurs preferentially at C(5) for benz[a]anthracene 5,6-oxide, but at C(6) for benzo[c]phenanthrene 5,6-oxide. In other words, the regio- and... 

L. Lewis-Bevan, S. B. Little, J. R. Rabinowitz, Quantum Mechanical Studies of the Structure and Reactivities of the Diol Epoxides of Benzo[c]phenanthrene , Chem. Res. Toxicol. 1995, 8, 499 - 505. 

A parallel was drawn between stable ion and AMI studies of methylphenanthrenes and solvolytic studies of K-region and non-K-region phenanthrene oxides. The carbocation formed by opening of the 1,2-epoxide closely resembled the 2-methylphenanthrene cation (and 7H ), and the regiochemistry of phenol formation (1-phenanthrol) could be understood. Similarly, phenanthrenium cations derived from the 3-methyl and dimethylated compounds served as models for carbo-cations formed by solvolysis of phenanthrene-3,4-epoxide (formation of 4-phenanthrol following hydride shift). 

Epoxidation of aromatic hydrocarbons is an important method for the preparation of arene oxides. m-Chloroperbenzoic acid (MCPBA) is used in a two-phase system that involves treating the hydrocarbon with a large excess ( 10-fold) of MCPBA in methylene chloride-aqueous sodium bicarbonate at room temperature. The yields are moderate (10-60%). Because the arene oxides are sensitive to acids, the presence of sodium bicarbonate buffer is necessary. A number of K-region (see Section VII for a definition) epoxides like phenanthrene 9,10-oxide (1, 59%), 9,10-dimethylphenanthrene 9,10-oxide (2,40%), 9-phenylphenanthrene 9,10-epoxide (3,50%), pyrene 4,5-oxide (4, 14%), and chrysene 4,5-oxide (5,9%) have been prepared by this method.9... 

The first arene oxides to be synthesized (1964) were obtained by the cyclization of appropriate seco derivatives. 0,0-Diformylbiphenyl derivatives, when treated with Mark s reagent [tris(dimethylamino)phosphine], gave arene oxides [Eq. (3)]. Thus K-region epoxides from phenanthrene and its analogs, benz[a]anthracene and its 7,12-dimethyl analog, have been prepared.34... 

Naphthalene 1,2-oxide (136), a non-K-region epoxide, shows low thermal stability. Anthracene 1,2-oxide, on the other hand, is stable at ambient temperatures for several weeks. Preparation of (+ )-(lR,2S)-anthracene 1,2-oxide (137), using the above method, constitutes the first example of preparation of an optically pure arene oxide. However, the non-K-region oxides of phenanthrene, namely, its 1,2- and 3,4-oxides (47 and 48), obtained from chiral precursors, racemize fast.66 Perturbational molecular orbital calculations indicate that epoxide-oxepin valence tautomerism is possible. However, the oxepin could not be detected by NMR. 

The diol epoxides are generally formed by epoxidation of the trans-diols formed by the opening of the arene oxide by epoxide hydrase. A mechanism for phenanthrene is illustrated in Scheme 6 absolute stereochemistry is not implied.208... 

Phenanthrene is transformed to trans-9,10- (major), trans-1,2- (minor), and trans-3,4-dihydrodiol (minor) metabolites via monooxygenase-catalyzed formation of arene oxides, followed by epoxide hydrolase-catalyzed hydration in mammalian liver systems.219-221 In bacterial cultures, phenanthrene is converted to cis-3,4- (major) and cis-1,2- dihydrodiols (minor) through the action of dioxygenase enzymes and molecular oxygen.221,222 Recently, Boyd et al.10 have prepared trons-3,4-dihydroxy-1,2,3,4-tetrahydrophenanthrene (359) and cis-3,4-dihydroxy-1,2,3,4-tetrahydrophenanthrene (360) in optically pure forms. These compounds have made possible the determination of the configurations of the trans- and cis-3,4-dihydrodiol metabolites of phenanthrene (361 and 362) as (-)-(3R,4R) and ( + )-(3S,4R), respectively. 

Analytical Properties Resolution of several enantiomers of polycyclic aromatic hydrocarbons, for example, chrysene 5,6-epoxide, dibenz[a,h]anthracene 5,6-epoxide, 7-methyl benz[a]anthracene 5,6-epoxide resolution of barbiturates, mephenytoin, benzodiazepinones, and succinimides direct separation of some mono-ol and diol enantiomers of phenanthrene, benz[a]anthrene, and chrysene ionically bonded to silica gel, this phase provides resolution of enantiomers of c/s-dihydroidiols of unsubstituted and methyl- and bromo-substituted benz[a]anthracene derivatives having hydroxyl groups that adopt quasiequatorial-quasiaxial and quasiaxial-quasiequatorial conformation Reference 31-35... 

In general, K-region arene oxides behave rather like aliphatic epoxides and thus readily undergo hydration reactions, whereas benzene oxides and non-K-region arene oxides form dihydrodiols much more reluctantly. Kinetic studies of the mechanism of solvolysis of phenanthrene 9,10-oxide 2 have been carried out in several laboratories.Below pH 7 the hydrolysis reaction was acid-catalyzed and the products included the trans- and c/s-9,10-dihydrodiols along with a preponderance of 9-phenanthrol, while above pH 7 the reaction proceeded via the spontaneous mechanism ( o) mainly the frans-dihydrodiol. 

Since it is the smallest aromatic hydrocarbon to have a bay-region and a K-region , phenanthrene is often used as a model substrate for studies on metabolism of carcinogenic PAHs. Phenanthrene is absorbed following oral and dermal exposure. Data from structurally related PAHs suggest that phenanthrene would be absorbed from the lungs. Metabolites of phenanthrene identified in in vivo and in vitro studies indicate that metabolism proceeds by epoxidation at the 1-2, 3-4, and 9-10 carbons, with dihydrodiols as the primary metabolites. 

Wood AW, Chang RL, Levin W, et al. 1979a. Mutagenicity and tumorigenicity of phenanthrene and chrysene epoxides and diol epoxides. Cancer Res 39 4069-4077. 

Lewis-Bevan, L., Little, S. B., and Rabinowitz, J. R. (1995). Quanmm mechanical studies of the structure and reactivities of the diol epoxides of benzo[c]phenanthrene. Chem Res Toxicol 8, 499—505. Lodovici, M., Akpan, V., Giovannini, L., Migliani, E., and Dolara, P. (1998). Benzo[a]pyrene diol-epoxide DNA adducts and levels of polycyclic aromatic hydrocarbons in autoptic samples from human... 

Amin, S., Krzeminski, J., Rivenson, A., Kurtzke, C., Hecht, S.S., and El-Bay-oumy, K. (1995) Mammary cardno-genidty in female CD rats of fjord region diol epoxides of benzo[c] phenanthrene, benzo[g]chrysene and dibenzo[a,l]pyrene. Carcinogenesis, 16, 1971-1974. 

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