NMR-based investigations of acyl-functionalized piperazines concerning their conformational behavior in solution

Selected N-benzoylated piperazine derivatives were synthesized to study their conformational behavior using temperature-dependent ¹H NMR spectroscopy. All investigated piperazine compounds occur as conformers at room temperature resulting from the reduced rotation of the partial amide double bond. Furthermore, a second conformational shape was observed for selected mono-N-benzoylated and unsymmetrically N,N’-substituted derivatives due to the limited change of the piperazine chair conformation. Therefore, two different coalescence points T_C were determined and their resulting activation energy barriers ΔG^# were calculated to be between 50 and 70 kJ/mol. In most of the cases, T_C and ΔG^# for the amide site appeared to be higher as for the amine site. Furthermore, benzoate moieties with electron withdrawing substituents like nitro show a higher rotational barrier compared to electron-releasing substitutents like methoxy. An additional aryl substituent connected at the amine site led to a reduced rotational barrier compared to the free secondary amine. To support and evidence the findings from the NMR analyses, single crystals of piperazines were obtained and XRD analyses were performed. To underline the results, two potential Tgase 2 inhibitors were investigated showing energy barriers with similar values.