A Caveat Concerning the Use of the AM1 and PM3 Semiempirical Methods in Calculating Conformational Preferences in Acyclic Amines and Saturated Azaheterocycles

A theoretical investigation of the conformational analysis of several acyclic amines, N- alkylated saturated azaheterocycles and alkylcyclohexanes (alkyl = Me, Et, isopropyl, t-butyl) has been carried out by using the MNDO, AM1 and PM3 semiempirical methods. It is found that all three methods correctly predict, qualitatively, the conformational preferences in alkylcyclohexanes, although the PM3 method underestimates the conformational energy for the t-butyl group by as much as 13 kJ/mol. Both AM1 and PM3 overestimate the conformational energy of the nitrogen lone pair to the extent that it exceeds that of the isopropyl group and (in the case of PM3) the t-butyl group, thereby leading to erroneous predictions of favoured conformations in amines and azaheterocycles . Thus, axial N-alkylpiperidines are predicted to be more stable than the equatorial conformers. Thus, application of the AM1 and PM3 methods to the conformational analysis of molecules containing amine functionalities is not recommended. Although the MNDO method gives a qualitative account of the conformational analysis of such molecules, with the exception of hexahydropyridazines and hexahydropyrimidines, the resulting conformational energies and molecular geometries are in poor agreement with experimental data.