Simulating Metal Complex Formation and Ligand Exchange: Unraveling the Interplay between Entropy, Kinetics, and Mechanisms on the Chelate Effect

Metal coordination is ubiquitous in Nature and central in many applications, ranging from nanotechnology to catalysis and environmental chemistry. Complex formation results from the subtle interplay between different thermodynamic, kinetic, and mechanistic contributions, which remain largely elusive to standard experimental methodologies and challenging for typical modeling approaches. Here, considering some prototypical metal complexes between Cd(II) and Ni(II) with various amine ligands, we present a comprehensive atomistic-level description of their chemical equilibrium, complex formation, and ligand exchange dynamics in aqueous solution, providing an excellent agreement with available association constants and formation rates spanning several orders of magnitude. This is achieved through an effective molecular simulation approach that combines finely tuned interatomic potentials with state-of-the-art enhanced sampling and kinetics techniques. Worthy of note, the nature of the chelate effect, a fundamental concept in coordination chemistry, is fully unravelled through the comparative analysis of the ligand binding reactions of monodentate and bidentate ligands in octahedral complexes. Results provide a complete picture illustrating all the concurrent contributions to this phenomenon, such as entropy, dissociation rates, and ligand binding mechanisms, in some cases contradicting previously held beliefs. This study represents a step forward for the in silico design and applications of coordination complex systems.