2-Substituted N-acyl-piperidine is a widespread and important structural
motif, found in approximately 500 currently available structures, and present in nearly
30 pharmaceutically active compounds. Restricted rotation of the acyl substituent in
such molecules can give rise to two distinct chemical environments. Here we
demonstrate, using NMR studies and density functional theory modeling of the lowest
energy structures of 5-acyl-6,7-dihydrothieno[3,2-c]pyridine derivatives, that the amide
E:Z equilibrium is affected by non-covalent interactions between the amide oxygen and
adjacent aromatic protons. Structural predictions were used to design molecules that promote either the E- or Z-amide
conformation, enabling preparation of compounds with a tailored conformational ratio, as proven by NMR studies. Analysis of
the available X-ray data of a variety of published N-acyl-piperidine-containing compounds further indicates that these molecules
are also clustered in the two observed conformations. This finding emphasizes that directed conformational isomerism has
significant implications for the design of both small molecules and larger amide-containing molecular architectures.