The Timeless Relevance of Size-Match Selectivity in Macrocyclic Fe(III) Complexes

Given the recent emergence of Fe(III) complexes as promising MRI contrast agents, significant interest has grown in understanding their coordination chemistry, particularly the delicate balance between thermodynamic and redox stability, kinetic inertness, and efficient relaxation enhancement. Among the most widely employed macrocyclic systems for Fe(III) coordination is functionalized 1,4,7-triazacyclononane (TACN). However, it is well-established that the small Fe(III) ion exhibits a preference for 6-membered chelate rings and, consequently, larger distances between macrocyclic N-donors to form stable complexes. In this work, we present a comprehensive investigation into the thermodynamic and redox stability, dissociation kinetics, and 1H relaxivity of four Fe(III) complexes. These feature hexadentate triacetate ligands derived from triazamacrocycles with ring sizes ranging from 9- to 12-membered, allowing us to systematically evaluate the impact of increasing the macrocyclic cavity size. The experimental results were subsequently validated through computational analysis. Employing Quantum Theory of Atoms in Molecules and the Interaction Region Indicator, we evaluated the shape, volumes, and intramolecular interactions within the four Fe(III) complexes. A key finding revealed that the stability of the Fe(III) complexes peaks with the ligand derived from the 11-membered ring, indicating optimal accommodation of the small Fe(III) ion. However, the most kinetically inert complex was observed with the 12-membered ring ligand. Conversely, relaxivity exhibited an opposite trend, decreasing with increasing ring size. This trend is attributed to variations in electronic parameters. Notably, none of the complexes exhibited a coordinated water molecule, resulting in inherently low relaxivity.