A General Design Strategy Enabling the Synthesis of Hydrolysis‐Resistant, Water‐Stable Titanium(IV) Complexes

Despite its prevalence in the environment, the chemistry of the Ti⁴⁺ ion has long been relegated to organic solutions or hydrolyzed TiO₂ polymorphs. A knowledge gap in stabilizing molecular Ti⁴⁺ species in aqueous environments has prevented the use of this ion for various applications such as radioimaging, design of water-compatible metal-organic frameworks (MOFs), and aqueous-phase catalysis applications. Herein, we show a thorough thermodynamic screening of bidentate chelators with Ti⁴⁺ in aqueous solution, as well as computational and structural analyses of key compounds. In addition, the hexadentate analogues of catechol (benzene-1,2-diol) and deferiprone (3-hydroxy-1,2-dimethyl-4(1H)-pyridone), TREN-CAM and THP^Me respectively, were assessed for chelation of the ⁴⁵ Ti isotope (t_1/2 =3.08 h, β⁺ =85 %, E_β+ =439 keV) towards positron emission tomography (PET) imaging applications. Both were found to have excellent capacity for kit-formulation, and [⁴⁵ Ti]Ti-TREN-CAM was found to have remarkable stability in vivo.