Study of minimum energy conformers of N-substituted derivatives of piperidine and pyrrolidine. Evidence of weak H-bonding by theoretical correlation with experimental NMR data

Four N-substituted piperidines and four N-substituted pyrrolidines were synthesized and characterized by common spectroscopic techniques. In order to investigate the dynamic behavior of these important heterocyclic building blocks, a conformational study was carried out, using suitable tools of computational chemistry. The comparison of computed and experimental NMR chemical shifts is now accepted as a valuable aid in the elucidation of structures and that was the strategy followed in the present study. After a conformational search by statistical methods, the lowest three minimum-energy conformers of each piperidine/pyrrolidine derivative were analyzed (24 conformers in total). The relative proportion of each conformer was estimated by thermodynamic calculations, involving the Boltzmann weighting factor; Pi. Using DFT methods, the geometry of each conformer was fully optimized and their chemical shifts (1H, 13C) were calculated. A very good coincidence between calculated and experimental data of both, 1H and 13C shifts was found, indicating that the theoretical geometries obtained were reliable enough for the study of structure-properties relationships. For all the conformers, specific weak unusual hydrogen bonding involving H–C instead of H–X (where X=electronegative atom) was observed. The nitrogen atom and the carbonyl oxygen participate in these interactions and could play an important role in the activity of these compounds and, therefore, they should be considered in the modeling of bioactive compounds. Furthermore, the good quality of theoretical/experimental data validates the theoretical methods used. The solvent effect (CDCl3 in this case) was found of small significance on the observed H-bonding.