Ring inversion barrier of diazepam and derivatives: An ab initio study

Systematic ab initio calculations were performed to investigate the ring in version process of various 1,4-diazepines including diazepam, N-1-desmethyl diazepam, and 3-methyl-N-1-desmethyldiazepam. The diazepine ring adopts a s hape of a boat; owing to asymmetric substitution two such boats are possibl e in mirror image relation to each other. In the present study both structu ral and solvent effects were investigated on the energetics of ring inversi on of nine diazepine derivatives. The calculated ring inversion barriers fo r diazepam (17.6 kcal/mol) and N-1-desmethyldiazepam (10.9 kcal/mol) are in good agreement with the corresponding experimental data. In the cases of d iazepam and N-1-desmethyldiazepam, the calculated minimum energy path of th e ring inversion is asymmetric contrary to the fact that the terminals (M a nd P conformers) are equienergetic. (C) 1999 Wiley-Liss, Inc.