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, there has been significant interest in understanding their coordination chemistry, particularly the delicate balance among their thermodynamic and redox stability, kinetic inertness, and efficient relaxation enhancement. Herein, we report a comprehensive investigation into the thermodynamic and redox stability, dissociation kinetics, and ¹H relaxivity of four Fe(III) complexes featuring hexadentate triaza-macrocycle triacetate ligands, with ring sizes ranging from 9 to 12. An increase in the cavity size of the macrocycles resulted in an increase in their thermodynamic and redox stability, with a maximum of log K_FeL = 33.6 for the 11-membered [Fe(UNTA)], followed by a slight decrease in the value for the 12-membered [Fe(DOTRA)]. From the dissociation kinetics of the complexes in a basic environment, it was observed that the order of inertness followed the size of the macrocycles with [Fe(DOTRA)] being the most inert complex with a t_1/2 of 1 × 10⁶ days at pH 7.4. Subsequently, the experimental results were validated through computational analysis. Employing the quantum theory of atoms in molecules and the interaction region indicator, we evaluated the shapes, volumes, and intramolecular interactions within the four Fe(III) complexes and confirmed the best size-match for the Fe(III) complex with the 11-membered macrocyclic triacetate ligand. Conversely, relaxivity exhibited the opposite trend of decreasing values with increasing ring size. This trend is attributed to the variations in electronic parameters. Notably, none of the complexes exhibited a coordinated water molecule, resulting in inherently low relaxivity.