On the Design of Effective Water‐Soluble Actinide‐Masking Ligands Through Ligand Structure Modulation

Abstract Water‐soluble actinide‐masking ligands are fundamentally important for achieving efficient lanthanide/actinide separation and for the development of water‐soluble f‐block complexes for bioimaging and radiopharmaceutical applications. However, the underlying design principles remain largely elusive, particularly in achieving a fine balance between ligand water solubility and metal affinity/selectivity. In this study, it is demonstrated that for the well‐established phenanthroline diimine ligand framework, topological modifications can preserve water solubility but introduce significant rotational energy barriers. These barriers, in turn, diminish both the metal‐binding affinity and selectivity. Conversely, non‐coordinating substituents play an unexpected role in modulating water solubility. Specifically, the incorporation of methylthio‐flanking groups is found to significantly impair the ligand's aqueous solubility. A combination of solution‐ and solid‐state coordination studies is employed to elucidate how structural modifications influence ligand‐metal interactions. Additionally, DFT calculations provided molecular‐level insights into the relationship between chemical structure, water solubility, and coordination behavior. This work offers valuable design guidelines for the development of hydrophilic ligands, with implications for selective f‐block element separation and the formulation of stable, water‐soluble f‐block complexes.