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Acid-catalyzed nucleophilic substitution and racemization of 3-methoxy-N-desmethyldiazepam enantiomers in methanol

pKa1 values of 3-methoxy-N-desmethyldiazepam in acetonitrile and methanol containing various acid concentrations were determined by spectrophotometry to be 3.5 and 1.3, respectively. Temperature-dependent racemization of enantiomeric 3-methoxy-N-desmethyldiazepam in methanol containing 0.5 M H2SO4 was studied by circular dichroism spectropolorimetry and the racemization reactions were found to follow apparent first-order kinetics. Thermodynamic parameters of the racemization reaction were found to be: Eact = 18.8 kcal/mol, and at 25°C: ΔH‡ = 18.3 kcal/mol, ΔS‡ = −14.8 entropy unit, and ΔG‡ = 22.7 kcal/mol, respectively. The racemization had an isotope effect (kH/kD) of 1.6 at 42°C. Based on the results of this report and those of earlier reports by other investigators, a nucleophilically solvated C3 carbocation intermediate resulting from either a P (plus) or an M (minus) conformation is proposed to be an intermediate and responsible for the stereoselective nucleophilic substitution and the subsequent racemization of 3-methoxy-N-desmethyldiazepam enantiomers. © 1993 Wiley-Liss, Inc.