A complete thermodynamic study of the protonation and Cu^II complex formation equilibria of a series of α- and β-aminohydroxamic acids in aqueous solution was performed. The thermodynamic parameters obtained for the protonation of glycine-, (S)-α-alanine-, (R,S)-valine-, (S)-leucine-, β-alanine- and (R)-aspartic-β-hydroxamic acids were compared with those previously reported for γ-amino- and (S)-glutamic-γ-hydroxamic acids. The enthalpy/entropy parameters calculated for the protonation microequilibria of these three types of ligands are in very good agreement with the literature values for simple amines and hydroxamic acids. The pentanuclear complexes [Cu₅L₄H₋₄]²⁺ contain the ligands acting as (NH₂,N⁻)-(O,O⁻) bridging bis-chelating and correspond to 12-metallacrown-4 (12-MC-4) which are formed by self-assembly between pH 4 and 6 with α-aminohydroxamates (HL), while those with β- and γ-derivatives exist in a wider pH range (4–11). The stability order of these metallomacrocycles is β- ≫ α- > γ-aminohydroxamates. The formation of 12-MC-4 with α-aminohydroxamates is entropy-driven, and that with β-derivatives is enthalpy-driven, while with γ-GABAhydroxamate both effects occur. These results are interpreted on the basis of specific enthalpies or entropy contributions related to chelate ring dimensions, charge neutralization and solvation-desolvation effects. The enthalpy/entropy parameters of 12-MC-4 with α-aminohydroxamic acids considered are also dependent on the optical purity of the ligands. Actually, that with (R,S)-valinehydroxamic acid presents an higher entropy and a lower enthalpy value than those of enantiopure ligands, although the corresponding stabilities are almost equivalent. Moreover, DFT calculations are in agreement with a more exothermic enthalpy found for metallacrowns with enantiomerically pure ligands.

The binding constants of acetate and benzoate to a Pheha-based 15-metallacrown-5 have been determined by a fluorimetric indicator displacement assay demonstrating on a thermodynamic basis the stabilization effect arising from complexation of the less polar carboxylate into the hydrophobic pocket of the metallacrown scaffold.

We investigated, both in the solid state and in aqueous solution, the coordination environment and stability behavior of four macrocyclic ligands (three N₂S₂ and one N₃S₂) and of the corresponding Cu(II) complexes. The structural characterization in the solid state of the copper derivatives was performed by X-Ray Absorption Spectroscopy. Copper is found to be 4-fold coordinated with a CuN₂S₂ environment with different Cu–S distances depending on the size of the macrocyclic ring. The EXAFS technique has indicated that nitrogen and sulfur atoms are more preferable to oxygen atoms as donor systems, without the evidence of coordination of the carboxylic moieties to copper in the first shell. The joint EXAFS and XANES study of the copper(II) complex with the N₃S₂ ligand confirms the 4-fold coordination with an additional, long Cu–N interaction. The Cu²⁺ complexation constants for one ligand were determined in aqueous solution. The results indicate that the species [CuL], although isolated in the solid state, is not the most abundant at the pH of blood serum. Instead, at pH 7.4 the protonated [Cu(HL)]⁺ species was found to be the most relevant. The behaviour of the copper complexes in the presence of the strong copper chelating bioagent human serum albumin was also examined in order to gain information on the stability of these compounds in biological fluids.