The hybridization state of nitrogen as a conformational variable in biologically active molecules

Abstract

A survey of the conformations found in the crystal structures of central nervous system-active drugs and related nitrogen-containing structures shows that there is a continuous distribution of conformations from that typical of the sp³(N-torsion 120°) to that typical of the sp²(N-torsion 180°) hybridization state. In general the presence of an adjacent carbonyl group favours a planar geometry, while the lack of any conjugating group favours the tetrahedral state, but nitrogens with aromatic substituents cover the entire range between the two states. Other than those cases where the nitrogen has aromatic substituents or is in a sterically constrained ring-system (e.g., cage compounds), steric effects have relatively little influence on the conformation at nitrogen. In these cases calculations using various techniques suggest that simple non-bonded potential calculations may be the most practical approach to the evaluation of nitrogen geometry. Even in small molecules, however, calculated barriers to nitrogen inversion are generally low and poorly reproduced by either molecular orbital or classical calculations.