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 pKa*
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 (t1/2 = 9−21 h for azopyridine complexes, 310 K). The pKa* 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).