An ab Initio Computational Molecular Orbital Study of the Conformers of Muconaldehyde, and the Possible Role of 2-Formyl-2H-pyran in Bringing about the Conversion of a(Z,Z)-Muconaldehyde Structure to an (E,Z)-Muconaldehyde Structure

Abstract

To determine whether conformers of 2-formyl-2H-pyran (2F2HP) can serve as intermediates in the isomerization (Z,Z)-muconaldehyde-->(E,Z)-muconaldehyde--an essential step in the metabolic oxidation of benzene in which (E,E)-muconic acid is formed--we have carried out ab initio molecular orbital calculations at 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)-muconaldehyde have 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 (eZzZz)-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 (zEzZz)-muconaldehyde (step b). An alternative pathway links (zZzZz)-muconaldehyde with syn-axial-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'.

Insights into the Formation and Isomerization of the Benzene Metabolite Muconaldehyde and Related Molecules: Comparison of Computational and Experimental Studies of Simple, Benzo-Annelated, and Bridged 2,3-Epoxyoxepins

“…o -Xylylene derivative 10 furnishes an interesting contrast with muconaldehyde. The ( Z , Z )- and ( E , Z )-muconaldehydes are more stable than the 2 H -pyran-2-carbaldehyde isomer that can interconvert with them . Although the pyran isomer is a reasonable intermediate for this isomerization, catalyzed rearrangement is also a possibility for Z , Z - to E , Z -isomerization and seemingly a necessity for E , Z - to E , E -isomerization. , In contrast, closure of the o -xylylene derivative regenerates a benzene ring and produces 3,4-benzo-2 H -pyran-2-carbaldehyde ( 11 ) as the global minimum.…”

Chemistry of muconaldehydes of possible relevance to the toxicology of benzene.

“…The similarity in rate of isomerization for a range of solvent polarity suggests a thermally allowed electrocyclic process, as shown in Scheme 2, in which 2-formyl-2H-pyran interconnects (Z,Z)and (E,Z)muconaldehyde (3,9). Analogous reactions have been described, for example, the ringopening of 2-alkenyl-2H-pyrans at room temperature (11).…”

ATSDR evaluation of health effects of benzene and relevance to public health

“…0 4 a n d 0.24 ± 0.02 mg/g creatinine, or 0.24 ± 0.06 and 0.13 ± 0.07 mg/mg cotinine, respectively. Because of its relative importance in benzene toxicity, additional modeling studies, including molecular orbital studies, have been conducted to further describe how trans,trans-muconaldehyde is transformed to muconic acid (Bock, et al, 1994). Kenyon, et al (1995) compared their urinary profile of metabolites in B6C3F 1 mice after oral dosing with phenol with the results of Sabourin, et al (1989a) who administered a comparable oral dose of benzene to B6C3F 1 mice.…”