Activation of the Ir-N(pyridine) Bond in Half-Sandwich Tethered Iridium(III) Complexes

We present four new organometallic half-sandwich iridium(III) complexes of formula [Ir(η⁵:κ¹-C₅Me₄CH₂py)(N,N)](PF₆)₂, bearing a N,N-chelating ligand [ethylenediamine (en), 1; 1,3-diaminopropane (dap), 2; 2,2'-bipyridine (bipy), 3; 1,10-phenanthroline (phen), 4]; and a derivatized cyclopentadienyl ligand, C₅Me₄CH₂C₅H₄N, which forms an additional five-membered chelate. The latter is hemilabile, and the Ir-N(py) bond can be reversibly cleaved by various stimuli. The four complexes are unreactive toward hydrolysis at pH 7. Interestingly, 1 and 2 react with hydrochloric acid and formate, and speciation between closed and open tether complexes can be followed by ¹H NMR spectroscopy. Complex 1 binds to nucleobase guanine (9-ethylguanine, 9-EtG), yet interaction to calf-thymus DNA was not observed. New X-ray structures of closed tether complexes 1-4 and open tether complexes [Ir(η⁵-C₅Me₄CH₂pyH)(en)Cl](PF₆)₂ (1·HCl) and [Ir(η⁵-C₅Me₄CH₂py)(en)H]PF₆ (1·hyd) have been determined. Hydride capture is efficient for 1 and 2. The kinetics of Ir-H bond formation and hydride transfer in a model organic molecule have been investigated, revealing a strong dependence on the temperature. Coincubation of complex 1 with nontoxic concentrations of sodium formate decreases the IC₅₀ value in MCF7 breast cancer cells, indicating the possibility of intracellular activation of the Ir-N(py) tether bond to generate cytotoxic activity via iridium-mediated transfer hydrogenation.