Complex formation and stability of westiellamide derivatives with copper(II)

Abstract

The Cu^II coordination chemistry of three synthetic analogues of westiellamide (H₃L^wa) with an [18]azacrown-6 macrocyclic structure and imidazole (H₃L¹), oxazole (H₃L²), or thiazole (H₃L³) heterocyclic donors in addition to the peptide groups, is reported. The N_heterocycle–N_peptide–N_heterocycle binding sites are highly preorganized for the coordination to Cu^II ions. The stability constants of mono- and dinuclear Cu^II complexes of H₃L¹, H₃L², and H₃L³, obtained by isothermal titration microcalorimetry, are reported. EPR and NMR spectroscopy as well as electrospray ionization mass spectrometry (ESI-MS) were used to characterize the complexes formed in solution. The stabilities of the mononuclear and dinuclear Cu^II complexes of the three ligands are in the range of 10⁵ M⁻¹, but there are subtle differences; specifically the oxazole-derived ligand has, in contrast to the other two macrocycles, a negative formation entropy for coordination to the first Cu^II ion and a higher stability for complexation to a second Cu^II center in comparison with the first Cu^II center (cooperativity). Differences between the three ligands are also apparent in terms of the formation mechanism. With the oxazole-based ligand H₃L², NMR spectroscopy, EPR spectroscopy, and ESI-MS indicate the formation of a ligand–Cu^II 2:1 intermediate, and this may explain the differences in the formation entropy as well as the cooperativity.