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 O 2 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.