Does the Exception Prove the Rule? A Comparative Study of Supramolecular Synthons in a Series of Lactam Esters

In this paper a series of simple lactam esters and carboxylic acids is studied with respect to their overall conformation and hydrogen bonding patterns. In total, eight lactams featuring Nα-substitution have been synthesized. Additionally, the molecular structures of related lactam esters have been considered. The length of the amide bonds does not seem to be majorly influenced by different substituents unless the electron withdrawing N-Boc-protection group is introduced, resulting in a higher susceptibility towards hydrolytic ring opening. As known from other lactams, the Nα ester moiety of the title compounds can be in an axial or equatorial conformation. Smaller ester groups were found to prefer equatorial positions, while larger ones occupy axial sites. N-substitution seems to promote axial conformations of the respective Nα group, with enantholactams being the only studied exception. In addition to the two common amide packing motifs, i.e. the R22(8) amide dimer (NH∙∙∙O/NH∙∙∙O) and the C(4) amide chain, a third graph-set was found: the R22(8) NH∙∙∙O/CH∙∙∙O=C heterodimers. In general, there seems to be a tendency for medium- sized lactams as well as lactams with small esters to form R22(8) amide dimers. Larger esters and enantholactam esters lead to C(4) amide chains. In this respect the formation of R22(8) N-H∙∙∙O/C-H∙∙∙O=C heterodimers should be seen as a remarkable exception.