Site-specific binding of a water molecule to the sulfa drugs sulfamethoxazole and sulfisoxazole: a laser-desorption isomer-specific UV and IR study

To determine the preferred water molecule binding sites of the polybasic sulfa drugs sulfamethoxazole (SMX) and sulfisoxazole (SIX), we have studied their monomers and monohydrated complexes through laser-desorption conformer-specific UV and IR spectroscopy. Both the SMX and SIX monomer adopt a single conformer in the molecular beam. On the basis of their conformer-specific IR spectra in the NH stretch region, these conformers were assigned to the SMX and SIX global minimum structures, both exhibiting a staggered sulfonamide group and an intramolecular C-H center dot center dot center dot O=S hydrogen bond. The SMX-H2O and SIX-H2O complexes each adopt a single isomer in the molecular beam. Their isomeric structures were determined based on their isomer-specific IR spectra in the NH/OH stretch region. Quantum Theory of Atoms in Molecules analysis of the calculated electron densities revealed that in the SMX-H2O complex the water molecule donates an O-H center dot center dot center dot N hydrogen bond to the heterocycle nitrogen atom and accepts an N-H center dot center dot center dot O hydrogen bond from the sulfonamide NH group. In the SIX-H2O complex, however, the water molecule does not bind to the heterocycle but instead donates an O-H center dot center dot center dot O=S hydrogen bond to the sulfonamide group and accepts an N-H center dot center dot center dot O hydrogen bond from the sulfonamide NH group. Both water complexes are additionally stabilized by a C-ph-H center dot center dot center dot OH2 hydrogen bond. Interacting Quantum Atoms analysis suggests that all intermolecular hydrogen bonds are dominated by the short-range exchange-correlation contribution.