Karla Frydenvang, Lisa Matzen, Per-Ola Norrby, Frank A. Sløk, Tommy Liljefors, Povl Krogsgaard-Larsen and Jerzy W. Jaroszewski
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.