Tautomeric Preference and Conformation Locking in Fenobam, Thiofenobam, and Their Analogues: The Decisive Role of Hydrogen Bond Hierarchy

Abstract

The crystal and molecular structures of the potential antidepressant drug fenobam and its derivatives are examined in terms of the preferred form among the two possible tautomeric structures. In this study, chemical derivatization has been utilized as a means to "experimentally simulate" the tautomeric preference and conformational variability in fenobam. Eight new derivatives of fenobam have been synthesized, and structural features have been characterized by single-crystal X-ray diffraction and NMR spectroscopy. The specific tautomeric preference found in all of these compounds and their known crystal forms have been construed in terms of the stabilizing intramolecular N−H•••O and N−H•••S hydrogen bonding. The hierarchy of intramolecular hydrogen bonds evidenced as the preference of the C−H•••O hydrogen bond over C−H•••N and that of the C−H•••N hydrogen bond over C−H•••S explains the two distinct conformations adopted by fenobam and thiofenobam derivatives. The relative energy values of different molecular conformations have been calculated and compared.

Determination of tautomeric preference of fenobam in solution by high‐resolution NMR spectroscopy

“…Thus, two near planar positional isomer forms of each tautomer (Table 2: tautomer I-1, tautomer I-2, tautomer II-1, and tautomer II-2) may locate at the lowest energy level due to the locking effect of intramolecular N-HÁÁÁO and C-HÁÁÁO hydrogen bonds. [16] These four structures were used as input files for further geometry optimization and energy calculation. The energy calculation reveals that two positional isomers of each tautomer hold very close energy level.…”

“…[10] Also, similar molecular conformation can also be observed in the structures of fenobam's fluoro analogues. [16] Moreover, the optimized molecular structures of tautomer II-1 and tautomer II-2 in DMSO were compared with the ones in the reported crystal structures of fenobam. All of them process very similar molecular conformation (ESI, Table S2) due to the locking effect of intramolecular N-HÁÁÁO or C-HÁÁÁO hydrogen bonds.…”

Tautomeric polymorphism of the neuroactive inhibitor kynurenic acid

“…Enolketo tautomers are the most frequently encountered and have been actively investigated, for example, in hydroxynicotinic acids (Dogra, 2005;Santos et al, 2009;Long et al, 2015Long et al, , 2016. Imide-amide tautomers are also recognized in sulfonamide drugs (Thomas et al, 2012(Thomas et al, , 2014Lill & Broo, 2014). Important APIs that have been studied with respect to tautomeric polymorphism include triclabendazole (Tothadi et al, 2012), omeoprazole (Bhatt & Desiraju, 2007) and ranitidine (Mirmehrabi et al, 2004).…”

Investigation of rotameric conformations of substituted imidazo-[1,2-a]pyrazine: experimental and theoretical approaches

“…During a literature survey, we found some reports on the conformational examination of organic compounds by mean of experimental and theoretical techniques, but the conformation of imidazo-[1,2-a]pyrazine has not been determined. [27][28][29][30][31][32] In this work, we have synthesized a series of imidazo- [1,2-a]pyrazine derivatives that exhibit different rotameric conformations. These rotameric conformations were further puried by column chromatography.…”