Phenylazo-pyridine and Phenylazo-pyrazole Chlorido Ruthenium(II) Arene Complexes:  Arene Loss, Aquation, and Cancer Cell Cytotoxicity

Ru(II) η⁶-arene complexes containing p-cymene (p-cym), tetrahydronaphthalene (thn), benzene (bz), or biphenyl (bip), as the arene, phenylazopyridine derivatives (C₅H₄NN:NC₆H₅R; R = H (azpy), OH (azpy-OH), NMe₂ (azpy-NMe₂)) or a phenylazopyrazole derivative (NHC₃H₂NN:NC₆H₅NMe₂ (azpyz-NMe₂)) as N,N-chelating ligands and chloride as a ligand have been synthesized (1−16). The complexes are all intensely colored due to metal-to-ligand charge-transfer Ru 4d⁶−π* and intraligand π → π* transitions (ε = 5000−63 700 M^-1 cm^-1) occurring in the visible region. In the crystal structures of [(η⁶-p-cym)Ru(azpy)Cl]PF₆ (1), [(η⁶-p-cym)Ru(azpy-NMe₂)Cl]PF₆ (5), and [(η⁶-bip)Ru(azpy)Cl]PF₆ (4), the relatively long Ru−N(azo) and Ru−(arene-centroid) distances suggest that phenylazopyridine and arene ligands can act as competitive π-acceptors toward Ru(II) 4d⁶ electrons. The pK_a* values of the pyridine nitrogens of the ligands are low (azpy 2.47, azpy-OH 3.06 and azpy-NMe₂ 4.60), suggesting that they are weak σ-donors. This, together with their π-acceptor behavior, serves to increase the positive charge on ruthenium, and together with the π-acidic η⁶-arene, partially accounts for the slow decomposition of the complexes via hydrolysis and/or arene loss (t_1/2 = 9−21 h for azopyridine complexes, 310 K). The pK_a* of the coordinated water in [(η⁶-p-cym)Ru(azpyz-NMe₂)OH₂]²⁺ (13A) is 4.60, consistent with the increased acidity of the ruthenium center upon coordination to the azo ligand. None of the azpy complexes were cytotoxic toward A2780 human ovarian or A549 human lung cancer cells, but several of the azpy-NMe₂, azpy-OH, and azpyz-NMe₂ complexes were active (IC₅₀ values 18−88 μM).