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. © 2014 American Chemical Society.