Chem. Res. Toxicol. 1994, 7, 534-543
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An Ab Initio Computational Molecular Orbital Study of the Conformers of Muconaldehyde, and the Possible Role of 2-Formyl-2H-pyranin Bringing about the Conversion of a (2,Z)-MuconaldehydeStructure into an (E,Z)-Muconaldehyde Structure' Charles W. Bock,? Philip George,$Arthur Greenberg,$ and Jenny P. Glusker'J Department of Chemistry, Philadelphia College of Textiles and Science, Philadelphia, Pennsylvania 19144,The Institute for Cancer Research, The Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, and Department of Environmental Sciences, Cook College, Rutgers University, New Brunswick, New Jersey 08903 Received January 10,1994"
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To determine whether conformers of 2-formyl-2H-pyran (2F2HP) can serve as intermediates (E,Z)-muconaldehyde-an essential step in the in the isomerization (2,Z)-muconaldehyde metabolic oxidation of benzene in which (E&-muconic acid is formed-we have carried out ab initio molecular orbital calculations a t the MP2/6-31G* (frozen core, valence orbitals active) level with full geometry optimization at the RHF/6-31G* level. Taking account of the configuration about the carbon-carbon single bonds as well as that about the double bonds, the six conformers of (Z,Z)-muconaldehydehave been characterized, as well as the eight conformers of (E,Z)-muconaldehyde. Axial and equatorial conformers of 2F2HP have been identified, which exist in stable syn or anti forms depending on the relative position of the pyran and carbonyl O-atoms. Each step in the metabolic pathway is stereospecific. The initial ring opening in 2,3-epoxyoxepin gives (eZz2z)-muconaldehyde, which then undergoes ring closure to give anti-axial-2F2HP (step a). Inversion of the ring gives anti-equatorial-2F2HP, which upon ring opening gives (zEz2z)-muconaldehyde (step b). An alternative pathway links (zZzZz)muconaldehyde with syn-axia2-2F2HP (step a'), and syn-equatorial with (eEzZz)-muconaldehyde (step b'). Half-reaction times, taking into account the fractional representation of each reacting conformer in rapidly established equilibrium mixtures, suggest that the operative pathway is via step a, with little to choose between steps b and b'.
Introduction Like many polycyclic aromatic hydrocarbons,benzene is extremely toxic, and ita metabolism is the subject of extensive research (1-4). The presence in urine of one of its metabolic oxidation products, (E$)-muconic acid, Le., HOOCCH=CHCH=CHCOOH with the double bonds in the trans (E)configuration, is widely used as an indicator of benzene exposure (5). The pathway by which this is formed is of considerable interest because it can evidently compete successfully with the other reaction pathways by which benzene is converted into phenol, the dihydrol, or various conjugates (6). Starting from benzene, 1 in Scheme 1, it has been proposed (7) that the benzene oxide/oxepin, 2/3,tautomeric mixture is formed first in an initial epoxidation by the microsomal monooxygenase system, followed by a second epoxidation in which the oxepin, 3, is converted into 2,3-epoxyoxepin, 4, which then undergoes ring fission to give (2,Z)-muconaldehyde, 5, i.e., with both double bonds in the cis (2)configuration. Successive isomerization reactions, (Z,Z)-S (E,Z)-6 (E,E)-7, give the appropriate aldehyde, which upon oxidation yields (E,E)-
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+ Philadelphia College of Textiles and Science.
*8 The Fox Chaw Cancer Center. Rutgers University. Present addreee: Department of Chemistry,
University of North Carolina at Charlotte, Charlotte, NC 28223. Abstract published in Advance ACS Abstracts, June 1, 1994. A preliminaryaccount of this work was presented at the 16th Austin Symposiumon Molecular Structure,Universityof Texaaat Austin, Austin, TX, March 21-23, 1994, Abstract WM3, p 61.
muconic acid, 8. There is ample experimental evidence for this sequence of isomerization reactions and for the oxidation of the aldehyde to the acid (7, a), but the epoxyoxepin has never been observed. To circumventthe extremely high-energy barrier otherwise associated with the isomerization reactions (9),catalysis probably occurs under experimental conditions (lo),or, in the case of the Z,Z E,Z reaction, the formation of 2-formyl-W-pyran structures as intermediates (10)-although their participation has not been demonstrated. In broad outline, ab initio molecular orbital calculations at the MP2/6-31G*//RHF/6-31G*level which we have reported in a recent publication (11)support the above reaction pathway. Model reactions simulating the microsomal monooxygenase system show the formation of benzene oxide and the epoxyoxepin to be very favorable exothermic processes. Ring fission of the epoxyoxepin gives (eZzZz)-muconaldehyde, e or z denoting trans or cis configurations about the carbon-carbon single bonds, respectively. This step is also exothermic, with an activation energy of 16.5 kcal mol-l. The half-reaction time at the temperatures employed in the experimental studies (7) would thus be very short,
