Molecular Switches for any pH: A Systematic Study of the Versatile Coordination Behaviour of Cyclam Scorpionands

Abstract

Molecular switches have many potential applications in nanoscience and biomedicine. Transition metal complexes that can be switched from an inert, unreactive state to a catalytically active one by a simple change in conditions (e.g. pH shift) or by binding to a specific biomolecular target – so-called target-activated metal complexes (TAMCs) – hold particular allure as a means of harnessing the potent but at times indiscriminate reactivity of metal-based drugs. Towards this goal, we have prepared a series of ten structurally related ligands each of which bears a different pendant side-arm functional group off a common macrocyclic core. Copper(II) and nickel(II) complexes of these cyclam-based ‘molecular scorpionands’ have been prepared and characterised. X-ray crystal structures reveal a variety of binding modes between pendant side-arm and metal centre. Amine and triazole side-arms generally coordinate to the metal in the solid state via the pendant nitrogen atom, while carbonyl-containing side-arms (amide, urea, carbamate) and sulfonamide ligands either coordinate via their oxygen atoms, or do not coordinate to the metal. To investigate the switchability of side-arm coordination in solution, spectrophotometric pH titrations were carried out for all 20 metal complexes. Where pH changes trigger a change in the side-arm coordination and thence spectroscopic behaviour, pKa values have been calculated. Of the 20 complexes investigated, the majority undergo spectroscopic changes that are consistent with a switch in pendant coordination state at a specific pH. This ‘coordination switching’ is seen across a wide pH range with the different side-arm functionalities: four complexes (side-arm amines) have pKas at acidic pH (3.5–5), two (side-arm sulfonamides) around neutral pH (6–7.5), and six (side-arm amides, ureas and carbamates) at basic pH (10–13). Six complexes maintain their coordination state (bound or not bound) over the full pH range tested (2–13), while the remaining two undergo spectroscopic changes at high pH that are consistent with a change in protonation of a metal-bound water ligand. This ligand series represents a comprehensive model platform from which to build pH-switchable metal complexes for applications in nanoscience and biomedicine.