The conformational free energies (-AG Β°) of a number of 4-substituted piperidines and piperidinium salts have been determined by the J-value method. For the 4-substituted piperidines (R = Me, Phenyl, CO2Et, Br, OH, F) the relative conformer energies are almost identical to those of the analogous cyclohexanes.
The methyl and phenyl compounds showed no change in the couplings on protonation, implying no change in the conformer energies. In contrast, in the remaining compounds with polar 4-substituents an almost constant stabilisation of the axial conformer of ca. 0.7 -0.8 kcal mol-1 was observed on protonation. In three cases (R = F, OH and Br) the conformational preference is reversed on protonation and the axial form is favoured.
The conformer energies of both the free bases and the piperidinium salts can be quantitatively predicted by molecular mechanics calculations using the COSMIC force-field, in which the electrostatic interactions are calculated by a simple Coulombic model with the partial atomic charges in the molecules given by the CHARGE2 routine, and an effective dielectric constant of five. The precise agreement obtained demonstrates conclusively that the electrostatic interactions between the substituents and the protonated nitrogen are the cause of the conformational changes on protonation, and that these can be modelled successfully using existing force-fields.