Monopicolinate Cross-Bridged Cyclam Combining Very Fast Complexation with Very High Stability and Inertness of Its Copper(II) Complex

The synthesis of a new cross-bridged 1,4,8,11-tetraazacyclotetradecane (cb-cyclam) derivative bearing a picolinate arm (H<b>cb</b>-<b>te1pa</b>) was achieved by taking advantage of the proton sponge properties of the starting constrained macrocycle. The structure of the reinforced ligand as well as its acid–base properties and coordination properties with Cu²⁺ and Zn²⁺ was investigated. The X-ray structure of the free ligand showed a completely preorganized conformation that lead to very fast copper­(II) complexation under mild conditions (instantaneous at pH 7.4) or even in acidic pH (3 min at pH 5) at room temperature and that demonstrated high thermodynamic stability, which was measured by potentiometry (at 25 °C and 0.10 M in KNO₃). The results also revealed that the complex exists as a monopositive copper­(II) species in the intermediate pH range. A comparative study highlighted the important selectivity for Cu²⁺ over Zn²⁺. The copper­(II) complex was synthesized and investigated in solution using different spectroscopic techniques and DFT calculations. The kinetic inertness of the copper­(II) complex in acidic medium was evaluated by spectrophotometry, revealing the very slow dissociation of the complex. The half-life of 96 days, in 5 M HClO₄, and 465 min, in 5 M HCl at 25 °C, show the high kinetic stability of the copper­(II) chelate compared to that of the corresponding complexes of other macrocyclic ligands. Additionally, cyclic voltammetry experiments underlined the perfect electrochemical inertness of the complex as well as the quasi-reversible Cu²⁺/Cu⁺ redox system. The coordination geometry of the copper center in the complex was established in aqueous solution from UV–vis and EPR spectroscopies