Counterintuitive Impact of Polar Solubilizing Group Functionalization on Ligand Solubility and f-Block Element Affinity

The design of multidentate hydrophilic ligands with high binding affinity and selectivity is fundamentally important for efficient metal separation and the development of highly stable radiopharmaceuticals. A widely adopted strategy involves introducing water-solubilizing groups into originally effective lipophilic ligands, aiming to preserve the metal-binding affinity while imparting aqueous solubility. In this work, we demonstrate that such an intuitive solubilization approach can fail if an appropriate hydrogen-bonding network is not established. Using a phenanthroline diimine ligand system as a model, we reveal, at a molecular level, how inter- and intramolecular hydrogen bonding critically influences both water solubility and metal affinity. This is supported by a comprehensive suite of spectroscopic titrations, single-crystal X-ray diffraction, and DFT calculations. To the best of our knowledge, this is the first in-depth study to correlate molecular structure and hydrogen-bonding interactions with overall ligand solubility and metal affinity/selectivity. The insights gained here offer valuable guidance for the rational design of hydrophilic ligands in applications ranging from nuclear waste remediation to f-block-metal-based radiopharmaceuticals and contrast agents.