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.