Computational mechanistic elucidation of NIR-triggered acetonitrile Photorelease in a ruthenium Photocage

Photosubstitutionally active ruthenium polypyridyl complexes are very promising candidates for light-activated therapies used in the treatment of tumors. However, while an in-depth understanding of the molecular factors that govern ligand release is of fundamental importance for the design of efficacious photoactivatable Ru(II) complexes, mechanistic details remain under debate. Here, we report a comprehensive density functional theory (DFT) and time-dependent DFT (TD-DFT) investigation of the near-infrared (NIR) responsive complex THCRuACN, a prototypical photocage bearing a tridentate quinolinylpyridine ligand (THC) and acetonitrile (ACN). In absence of light, water can substitute acetonitrile through associative or dissociative pathways, with barriers comparable to those estimated to hamper the hydrolysis reactions in platinum-based drugs. The hypothesis that the photosubstitution reaction can occur with or without the involvement of triplet states with MC character has been fully explored. Computational outcomes reveal that under irradiation, population of both 3MLCT and 3MC excited states can occur and promote ligand release through a dissociative mechanism with a very low energy expense. Notably, acetonitrile dissociation is driven by the tridentate ligand distortion rather than elongation of the Ru–ACN bond. The ACN dissociation leads to the formation of a pentacoordinate Ru-complex that, after decaying into its ground state, reacts with a solvent water molecule completing the metal coordination sphere.