Guest exchange in a biomimetic Zn^II cavity-complex: kinetic control by a catalytic water, through pore selection, 2nd sphere assistance, and induced-fit processes

The kinetics of ligand exchange at a Zn^II center confined in a biomimetic environment is studied. The metal ion is bound to a TMPA unit covalently capping the calix[6]arene core. As such, the system is rigidified in a cone conformation open to the solvent at the large rim. At the small rim, the methyl groups of the anisole units lead to steric crowding, thus defining a small pore leading to the metal center. The exchange of an organic guest ligand (MeCN) for another (EtCN) is studied by ¹H NMR spectroscopy. It is shown that it is very slow under dry conditions (several hours at mM concentrations), but much faster in the presence of appreciable amounts of water. Kinetic analyses indicate that the exchange process involves the transient formation of an aqua complex that was independently synthesized and well characterized. Computer studies suggest that transient water coordination first occurs through the small rim pore, in exo-position. The water molecule then flips in endo-position, as the MeCN guest decoordinates and exits from the cavity through the large rim. This allows another organic guest ligand to get in, with release of the catalytic water to the solvent. Steered molecular dynamics simulations also show the assistance of the second coordination sphere of the metal ion for the exo/endo flipping process of the water ligand through H-bonding to the oxygenated small rim of the calixarene macrocycle. Importantly, it appeared that only water can play such a catalytic role, due to size selection by the pores defined by the calixarene small rim. From a biological point of view, it further substantiates the importance of water molecules and micro-environment on metal ion lability.