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 alkylcyclohe xanes (alkyl = Me, Et, isopropyl, t-butyl) has been carried out by usi ng the MNDO, AM1 and PM3 semiempirical methods. It is found that all t hree methods correctly predict, qualitatively, the conformational pref erences in alkylcyclohexanes, although the PM3 method underestimates t he conformational energy for the t-butyl group by as much as 13 kJ/mol . Both AM1 and PM3 overestimate the conformational energy of the nitro gen lone pair to the extent that it exceeds that of the isopropyl grou p and (in the case of PM3) the t-butyl group, thereby leading to erron eous predictions of favoured conformations in amines and azaheterocycl es. Thus, axial N-alkylpiperidines are predicted to be more stable tha n the equatorial conformers. Thus, application of the AM1 and PM3 meth ods to the conformational analysis of molecules containing amine funct ionalities is not recommended. Although the MNDO method gives a qualit ative account of the conformational analysis of such molecules, with t he exception of hexahydropyridazines and hexahydropyrimidines, the res ulting conformational energies and molecular geometries are in poor ag reement with experimental data.