K. Frydenvang, L. Matzen, P. Norrby
1997
Citations
0
Influential Citations
19
Citations
Journal
Journal of The Chemical Society-perkin Transactions 1
Abstract
Low-temperature single-crystal structure determinations have been carried out on isoxazol-3-ol, 5-methyl-isoxazol-3-ol, isothiazol-3-ol and 5-methylisothiazol-3-ol, the heterocyclic ring systems used as carboxy group bioisosteres in numerous neuroactive analogues of 4-aminobutyric acid (GABA) and glutamic acid. All compounds form hydrogen-bonded dimers in the solid state. The OH · · · N hydrogen bonds are shorter in isoxazol-3-ols than in isothiazol-3-ols. The excess molecular van der Waals volume of the sulfur-containing ring systems as compared to the corresponding isoxazol-3-ols amounts to about 15%. The sulfur substitution significantly affects the position of the 5-substituents in relation to the heterocyclic ring. Such effects may contribute to the observed differences in pharmacological effects of the structurally related isoxazol-3-ol and isothiazol-3-ol amino acids. The geometries of the compounds have been optimized by ab initio calculations at the HF/6-31G* level, and in some cases also at the MP2/6-311G** level. The gas-phase calculations are in agreement with the experimental data, especially when correction for the effects of hydrogen bonding is made, as estimated using a complex between isoxazol-3-ol and formic acid. Calculated dipole moments of isoxazol-3-ols and isothiazol-3-ols are similar. Isoxazol-3-ol is more acidic than isothiazol-3-ol by 1.7 pKa unit as determined by 13C NMR titration, and the differences in acidity are believed to be one of the major factors causing the differences in the biological actions of isoxazol-3-ol amino acids and the corresponding isothiazol-3-ol analogues.