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.聚吡啶钌配合物是光激活化疗（photoactivated chemotherapy, PACT）的优良候选体系，前提是它们在黑暗中保持稳定，且能高效发生配体光取代反应。本研究针对以天然氨基酸L-脯氨酸作为保护配体的钌基光激活化疗化合物展开探究，所涉及的配合物系列包括：Λ-[Ru(bpy)₂(l-prol)]PF₆（记为[1a]PF₆；其中bpy为2,2′-联吡啶，l-prol为L-脯氨酸）、Λ-[Ru(bpy)(dmbpy)(l-prol)]PF₆（记为[2a]PF₆与[2b]PF₆；dmbpy为6,6′-二甲基-2,2′-联吡啶）以及Λ-[Ru(dmbpy)₂(l-prol)]PF₆（记为[3a]PF₆）。合成含不对称脯氨酸配体的三异配配合物时，仅得到四种可能区域异构体中的两种，即[2a]PF₆与[2b]PF₆。对这两种异构体均进行了分离，并结合光谱学与密度泛函理论计算完成了表征。采用紫外-可见光谱法、圆二色谱法、质谱法以及氢核磁共振波谱法，在水（H₂O）与乙腈（MeCN）中对[1a]PF₆、[2a]PF₆、[2b]PF₆及[3a]PF₆四种配合物的光反应活性展开了研究。在水中，当氧气存在下进行可见光照射时，未发生配体光取代反应，但[1a]PF₆中的胺基被光氧化为亚胺。与预期相悖的是，在磷酸盐缓冲生理盐水（phosphate-buffered saline, PBS）中，通过引入两个（对应[2b]PF₆）或四个（对应[3a]PF₆）甲基取代基来增大空间位阻，并未引发配体光取代反应。不过，这一取代策略抑制了光氧化过程，这可能源于甲基取代基的给电子效应。此外，尽管[2b]PF₆在PBS中具有光稳定性，但[2a]PF₆经光照后会定量异构为[2b]PF₆。在纯乙腈中，[2a]PF₆与[3a]PF₆会发生非选择性的配体光取代，同时断裂L-脯氨酸与dmbpy配体；而无空间位阻的[1a]PF₆则表现出光稳定性。最后，在水-乙腈混合溶剂中，[3a]PF₆仅发生L-脯氨酸的选择性光取代，这证明了溶剂对该系列配合物光反应活性的调控作用。本文还讨论了溶剂极性与配位性能对聚吡啶钌配合物光化学性质的影响。