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

The geometries of various tautomers and rotamers of R(+)-zileuton [(+)-1-(1 -benzo[b]thien-2-ylethyl)-1-hydroxyurea], its metabolite (N-dehydroxyzileut on) in both anionic and protonated forms, were optimized using the two-laye red ONIOM (B3LYP6-311+G(d,p): MNDO) method. The calculations showed that th e neutral molecule should exist in two forms stabilized by an intramolecula r hydrogen bond. The most stable conformer of R(+)-zileuton is non-planar w ith the OH hydrogen atom out of the plane of the heavy atoms. In the case o f N-dehydroxyzileuton (R-enantiomer) the intramolecular electrostatic stabi lization via hydrogen bonding is less important in comparison to the parent zileuton. In contrast to the parent neutral molecules, ionization caused c onsiderable geometric changes in the anions. Both conjugate bases are stabi lized by intramolecular hydrogen bonding between N-H group and the negative ly 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-dehydroxyzileut on are oxygen bases in the gas phase. The proton affinity of R(+)-zileuton was computed to be -914.6 kJ mol(-1).