Molecular structure and gas-phase reactivity of zileuton and its N-dehydroxylated metabolite: two-layered ONIOM calculations

Abstract

The geometries of various tautomers and rotamers of R(+)-zileuton [(+)-1-(1-benzo[b]thien-2-ylethyl)-1-hydroxyurea], its metabolite (N-dehydroxyzileuton) in both anionic and protonated forms, were optimized using the two-layered ONIOM (B3LYP6-311+G(d,p): MNDO) method. The calculations showed that the neutral molecule should exist in two forms stabilized by an intramolecular hydrogen bond. The most stable conformer of R(+)-zileuton is non-planar with the OH hydrogen atom out of the plane of the heavy atoms. In the case of N-dehydroxyzileuton (R-enantiomer) the intramolecular electrostatic stabilization ia hydrogen bonding is less important in comparison to the parent zileuton. In contrast to the parent neutral molecules, ionization caused considerable geometric changes in the anions. Both conjugate bases are stabilized by intramolecular hydrogen bonding between N–H group and the negatively charged nitrogen and oxygen atoms. R(+)-zileuton is predicted to behave as an O-acid in the gas phase and N-dehydroxyzileuton behaves as a N-acid. R(+)-zileuton is a weak acid with calculated acidity of about 1484 kJ mol⁻¹. From our study we can conclude that R(+)-zileuton and N-dehydroxyzileuton are oxygen bases in the gas phase. The proton affinity of R(+)-zileuton was computed to be −914.6 kJ mol⁻¹.