Acid-base equilibria of 1,4-benzodiazepine 4-oxides by spectrophotometry

Chlordiazepoxide (a 1,4-benzodiazepine 4-oxide) is an anxiolytic/hypnotic drug in clinical use. It was reported to be predominantly protonated at the N-oxide oxygen in acidic aqueous solutions at pH << 4.6 (pKa). We have studied the acid-base equilibria of three 1,4-benzodiazepine 4-oxides (chlordiazepoxide, diazepam 4-oxide, and nordiazepam 4-oxide) by ultraviolet-visible spectrophotometry. The results indicate that chlordiazepoxide is not protonated at the N-oxide oxygen, but rather at the nitrogen of an imine bond between C2 carbon and its nitrogen substituent in acidic media.