Cyclen Tetra-Amide Ligands as a Privileged Class of Ligands for Studying Second-Sphere Coordination Environments

We propose that derivatives of cyclen tetra-amides are a privileged class of ligands for large ions such as lanthanides that enable control over the second-coordination sphere environment of discrete complexes. We demonstrate this concept first through highlighting examples of lanthanide cyclen tetra-amide derivatives that provide control over three different second-sphere environments. Control over the second-coordination sphere is then leveraged to enable the first mechanistic and kinetic oxidation studies of a Eu^II-containing complex in solution. We observed oxidation rates that are dependent on the concentration of oxygen exposed to the Eu^II complex, with implications for quantifying hypoxia. Computational modeling of the inner- and second-sphere coordination environments demonstrates that the protonation state of the phosphonate pendant arms of the Eu^II complex controls the access of O₂ to the Eu^II innersphere via hydrogen bonding to second-sphere water. Together, these findings provide a clear picture of the mechanism of the slow oxidation of the Eu^II-containing complex in solution and serve as a step toward the quantification of hypoxia and rational design of future Eu^II-containing complexes for imaging hypoxia in vivo. We expect that the molecular insights described here will inspire the study of other such privileged ligands for overcoming hurdles of rational design.