Nitrogen inversion in cyclic amines and the bicyclic effect

The hitherto unsolved problem of the origin of the unusually high nitrogen inversion - rotation (NIR) barriers in 7-azabicyclo[2.2.1]heptanes (the bicyclic effect) was examined using the natural bond orbital (NBO) approach. Reinvestigating the NIR barrier for tropane by DNMR, we found that NIR barriers increase smoothly on going from nitrogen-bridged bicyclic systems of a larger ring size to the smaller ring homologous systems. The experimental NIR barriers are reproduced with good accuracy using the MP2/6-31G* level of theory. The NBO analysis for these and other azabicycles led to the conclusion that the height of these barriers is mostly determined by the energy of the σ-orbitals of the C_α-C_β bonds as well as the nitrogen lone pair. Thus, the bicyclic effect is actually an extreme case of a common C_α-N - C_α tripyramid geometry - NIR barrier dependence for N-bridged bicyclic amines. By establishing the rate-determining role of the C_α-N - C_α tripyramid fragment for NIR, we have derived the first sufficiently accurate quantitative correlations amine geometry - NIR barrier for monocyclic as well as bicyclic N-H and N-Me amines (i.e., for an amine set which also includes the bicyclic effect systems).