Fluoride Coordination in Metal Complexes: Thermodynamic, Kinetic and Structural Insights for Sensing and Diagnostic Applications

Anion recognition by metal complexes represents a challenge in coordination chemistry, with major implications in diagnostic and sensing fields. Recently, research attention has focused on the fluoride anion, which plays a fundamental role in medical imaging, such as chemical exchange saturation transfer (CEST) and positron emission tomography (PET). In this work, we investigated the fluoride binding to metal complexes of paramagnetic Gd3+ and its diamagnetic analogue Y3+ with a series of polyaminocarboxylate ligands with different structures and hydration states (i.e. EGTA, OBETA, EDTA). By combining low-resolution 1H NMR relaxometry with high-resolution 19F NMR spectroscopy, we demonstrated that F- can displace one or more inner-sphere water molecules, leading to the formation of ternary adducts and dimeric structures. The latter are generally challenging to observe in solution. The proton relaxation enhancement (PRE) method was employed to determine the association constants, while 19F NMR line-shape analysis elucidated the fluoride exchange dynamics, showing that an associative mechanism is typically preferred by bis-hydrate complexes. Complementary DFT calculations supported our proposed structures, accurately reproducing ¹⁹F NMR chemical shifts and JY-F coupling constants. These findings enhance our understanding of the thermodynamic, kinetic, and structural properties behind fluoride coordination. Notably, this multi-technique approach can also be applied to investigate biologically relevant interactions between NMR-active inorganic anions and macromolecular systems, such as metalloproteins with paramagnetic centres. Ultimately, this methodology directly supports the rational design of next-generation anion-sensitive molecular probes and high-performance contrast agents for medical imaging.