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Issue 11, 2000
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Molecular structure and gas-phase reactivity of zileuton and its N-dehydroxylated metabolite: two-layered ONIOM calculations

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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 [italic v (to differentiate from Times ital nu)]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.

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Article information


Submitted
08 Feb 2000
Accepted
03 Apr 2000
First published
08 May 2000

Phys. Chem. Chem. Phys., 2000,2, 2511-2514
Article type
Paper

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

M. Remko, P. D. Lyne and W. Graham Richards, Phys. Chem. Chem. Phys., 2000, 2, 2511
DOI: 10.1039/B001064M

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