Synthesis, Dynamic NMR Characterization, and XRD Study of 2,4-Difluorobenzoyl-Substituted Piperazines

Five different 2,4-difluorobenzamide derivatives were synthesized and fully characterized by 1H/13C/19F/2D NMR spectroscopy using DMSO-d6 as solvent and MS. All compounds occur as rotation conformers resulting from the partial amide double bond with a solvent-dependent coalescence point. Temperature-dependent 1H NMR techniques, as well as EXSY, were applied to determine the rate constants of exchange, and the resulting activation energy barriers were calculated. Regarding the N,N-diacylated piperazine, both conformers (syn and anti) were found in solution, whereas only the anti-conformer was found in the crystals. This result was verified by an XRD analysis. Single crystals of N,N-bis(2,4-difluorobenzoyl)piperazine 3b (monoclinic, space group P21/c, a = 7.2687(3), b = 17.2658(8), c = 6.9738(3) Å, β = 115.393(2)°, V = 790.65(6) Å3, Z = 4, Dobs = 1.530 g/cm3) were obtained from a saturated chloroform solution.