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

Selected N-benzoylated piperazine compounds were synthesized to study their conformational behavior using temperature-dependent ¹H NMR spectroscopy. All investigated piperazines occur as conformers at room temperature resulting from the restricted rotation of the partial amide double bond. In the case of selected mono-N-benzoylated and unsymmetrically N,N′-substituted derivatives, the appearance of the ¹H NMR spectrum was further shaped by the limited interconversion of the piperazine chair conformations. Therefore, two different coalescence points T_C were determined and their resulting activation energy barriers ΔG^‡ were calculated to be between 56 and 80 kJ mol⁻¹. In most of the cases, T_C and ΔG^‡ for the amide site appeared to be higher than the corresponding values for the ring inversion. The influences of substituents on rotational and inversion barriers were analyzed by correlation to Hammett constants. The obtained results are discussed and interpreted in the context of literature data. An additional aryl substituent connected at the amine site led to reduced rotational and inversion barriers compared to the free secondary amine. To support and evidence the findings from the NMR analyses, single crystals of selected 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.

The influence of substituents on rotational and inversion barriers in benzoylpiperazines was investigated by dynamic NMR and the observed effects were quantified by correlation analyses using Hammett substituent parameters.