Influence of the Steric Bulk and Solvent on the Photoreactivity of Ruthenium Polypyridyl Complexes Coordinated to l‑Proline

Ruthenium polypyridyl complexes are
good candidates for photoactivated chemotherapy (PACT) provided that
they are stable in the dark but efficiently photosubstitute one of
their ligands. Here the use of the natural amino acid l-proline
as a protecting ligand for ruthenium-based PACT compounds is investigated
in the series of complexes Λ-[Ru­(bpy)2(l-prol)]­PF6 ([1a]­PF6; bpy = 2,2′-bipyridine
and l-prol = l-proline), Λ-[Ru­(bpy)­(dmbpy)­(l-prol)]­PF6 ([2a]­PF6 and
[2b]­PF6; dmbpy = 6,6′-dimethyl-2,2′-bipyridine),
and Λ-[Ru­(dmbpy)2(l-prol)]­PF6 ([3a]­PF6). The synthesis of the tris-heteroleptic
complex bearing the dissymmetric proline ligand yielded only two of
the four possible regioisomers, called [2a]­PF6 and [2b]­PF6. Both isomers were isolated
and characterized by a combination of spectroscopy and density functional
theory calculations. The photoreactivity of all four complexes [1a]­PF6, [2a]­PF6, [2b]­PF6, and [3a]­PF6 was
studied in water (H2O) and acetonitrile (MeCN) using UV–vis
spectroscopy, circular dichroism spectroscopy, mass spectrometry,
and 1H NMR spectroscopy. In H2O, upon visible-light
irradiation in the presence of oxygen, no photosubstitution took place,
but the amine of complex [1a]­PF6 was photooxidized
to an imine. Contrary to expectations, enhancing the steric strain
by the addition of two ([2b]­PF6) or four ([3a]­PF6) methyl substituents did not lead, in phosphate-buffered
saline (PBS), to ligand photosubstitution. However, it prevented photoxidation,
probably as a consequence of the electron-donating effect of the methyl
substituents. In addition, whereas [2b]­PF6 was photostable in PBS, [2a]­PF6 quantitatively
isomerized to [2b]­PF6 upon light irradiation.
In pure MeCN, [2a]­PF6 and [3a]­PF6 showed non-selective photosubstitution of both the l-proline and dmbpy ligands, whereas the non-strained complex
[1a]­PF6 was photostable. Finally, in H2O–MeCN mixtures, [3a]­PF6 showed
selective photosubstitution of l-proline, thus demonstrating
the active role played by the solvent on the photoreactivity of this
series of complexes. The role of the solvent polarity and coordination
properties on the photochemical properties of polypyridyl complexes
is discussed.