Structure over States: Planarity, Not Energy, Dictates Photoactivation in Ru(II) PACT Agents

Photoactivated chemotherapy (PACT) employs light to precisely control the activity of prodrugs, enabling spatial and temporal regulation of therapeutic effects while minimizing systemic toxicity. Transition-metal complexes, particularly Ru(II) polypyridyl compounds, have emerged as promising PACT agents due to their ability to undergo photodissociation via triplet excited states. However, rationalizing and predicting photosubstitution quantum yields remain challenging due to complex excited-state dynamics, solvent effects, and limitations of traditional modeling approaches. In this study, we synthesized nine Ru(II) complexes incorporating a monodentate thioether ligand, a terpyridine ligand, and various bidentate polypyridyl ligands. Upon red-light irradiation in aqueous solution, these complexes showed selective photosubstitution of the thioether by an aqua ligand. Despite similar absorption properties, these compounds exhibited markedly different photosubstitution quantum yields that static DFT calculations failed to explain. These modeling difficulties prompted us to develop a novel triplet-state molecular dynamics protocol using the GFN-xTB method, explicit solvation, and enhanced sampling techniques. Our approach enabled full simulations of the ligand exchange process on the triplet hypersurface and comparison to experimental data. It revealed that both <i>cis</i> and <i>trans</i> substitution of the thioether by a water molecule is possible; it was also able to distinguish between photoactive and photoinactive compounds. Unexpectedly, we found that the deviation from planarity of the bidentate ligand, rather than the energy levels of the different triplet excited states (³MLCT, ³MC) involved in the photosubstitution reaction, was the primary determinant of photosubstitution efficiency, as it promoted access to the <i>trans</i> photosubstitution pathway. Furthermore, our simulations uniquely identified whether dissociative, interchange, or associative mechanisms governed the reactivity of each complex. These results provide for the first time mechanistic insights into Ru(II)-based photosubstitution reactions in a solvent and offer a practical, scalable computational tool for designing next-generation PACT agents with optimized light-responsive properties.