NMR of some benzodiazepine drugs: Structure elucidation with lanthanide‐induced shifts of N‐1 substituted benzodiazepinones

Two 1,4‐benzodiazepinones of psychopharmacological interest, pinazepam (2) and prazepam (3), were studied in solution by 13 C and 1 H NMR. 1 H variable‐temperature experiments showed that the seven‐membered ring exists in a simple pseudo‐boat form at room temperature, but the energy barrier is higher in 3 (Δ G 405°c = 82.8 kJ mol −1 ) than in diazepam (1). Moreover, upon addition of LSR, the boat conformation is retained in the lanthanide ion‐substrate complex, as with 1 in the solid state. Using a concentration‐dependent shift technique and a computer‐assisted LIS method, the conformations of the N ‐branched side‐chain were investigated. Two preferred orientations were found for the propargyl group of 2, while three unequally populated conformations of the cyclopropyl moiety of 3 are distributed preferentially in the sterically unhindered space around the complex.