Unexpected Role of Ru(II) Orbital and Spin Contribution on Photoinduced Ligand Exchange: New Mechanism To Access the Photodynamic Therapy Window

Abstract

A series of 12 Ru­(II) complexes of the type [Ru­(tpy)­(L)­(CH3CN)] n+, 1–12, containing the tridentate tpy ligand (tpy = 2,2′:6′,2″-terpyridine) and various bidentate ancillary ligands, L, were synthesized and evaluated for their ability to photodissociate CH3CN, a model for nitrile-containing drugs. Although the bidentate ligands chosen display a similar degree of steric bulk around the metal center in the ground state, the photosubstitution efficiencies of 1–12 vary by approximately an order of magnitude. The complexes containing the most electron-donating bidentate ligands, 8–11, exhibit the larger quantum yield values for ligand exchange in water. Complexes 8–11 also possess the smallest energy gap between the ground state and the lowest energy triplet metal-to-ligand charge transfer (3MLCT) excited state. In addition, density functional theory calculations indicate that a large degree of ligand character is present in their highest occupied molecular orbitals (HOMOs) and in their 3MLCT excited states. These results show that ligand mixing affects the π-backbonding ability of the metal center in the excited state, increasing the quantum yields of nitrile ligand dissociation. Linear relationships were observed between the quantum yield of ligand exchange and both the Mulliken spin density on the metal center in the excited state and the percent of Ru­(d) character in the ground state HOMO. These findings, driven by the presence of π-donating ancillary ligands that enhance excited state reactivity, can be used to design new complexes with higher quantum yields for the release of nitrile-containing drugs and biological probes without affecting their stability in the dark.

Trifluoromethyl substitution enhances photoinduced activity against breast cancer cells but reduces ligand exchange in Ru(ii) complex

“…In a series of 12 complexes of the type [Ru(tpy)(L)(CH 3 CN)] n+ (tpy ¼ 2,2 0 :6 0 ,2 00terpyridine), where L represents a neutral (n ¼ 2) or an anionic (n ¼ 1) bidentate ligand, the quantum yields for the photosubstitution of the CH 3 CN ligand for a water solvent molecule upon 400 nm irradiation, F 400 , resulted in the unexpected increase of ligand exchange with the increasing electrondonating character of the bidentate ligand, despite the lower 3 MLCT energy across the series. 42 Calculations revealed that as the p-donating ability of the bidentate ligand increased, the relative amount of metal character in the highest occupied molecular orbital (HOMO) decreased. As such, a strong inverse correlation between the % Ru(d) character of the HOMO and the F 400 values was observed.…”

NIR‐Absorbing RuII Complexes Containing α‐Oligothiophenes for Applications in Photodynamic Therapy

“…Some of these and related systems have been altered further by introducing a central metal ion into the tetrapyrrolic scaffold to enhance the chemical, photophysical, and biological characteristics of the parent PSs. [29,30] Design of the next generation of PSs has been focused on extending the absorption window to include NIR wavelengths (700-900 nm) [31][32][33][34] and to alter the excited state properties of the molecules to exploit oxygen-independent mechanistic pathways to achieve phototoxic effects in hypoxia. [35][36][37][38][39][40] Ru II polypyridyl complexes are particularly attractive scaffolds for PS design because the photophysics of these complexes is wellestablished [41][42][43][44][45][46][47] and polypyridyl ligand combinations can be chosen to systematically manipulate the excited state dynamics in a rational and consistent manner.…”

“…Various Ru II -based NIR scaffolds are known, but their phototoxic effects on cells were not reported. [31][32][33][34]50] Generally, the 1 O 2 quantum yields are low (and PDT effects thus poor) for metal complexes with lowenergy triplet metal-to-ligand charge transfer ( 3 MLCT) excited states due to efficient intersystem crossing (ISC) that competes effectively with 1 O 2 sensitization. [46] To circumvent this issue, we aimed to design Ru II -based NIR complexes with 3 ILCT states that are lower in energy than the 3 MLCT states and much longer lived, due to their organic 3 ππ* character.…”

“…We hypothesized that combining the PDT‐active ligand in TLD1433 with a Ru II NIR‐absorbing scaffold would generate NIR PDT effects with high potency that might extend to hypoxia. Various Ru II ‐based NIR scaffolds are known, but their phototoxic effects on cells were not reported [31–34,50] . Generally, the 1 O 2 quantum yields are low (and PDT effects thus poor) for metal complexes with low‐energy triplet metal‐to‐ligand charge transfer ( 3 MLCT) excited states due to efficient intersystem crossing (ISC) that competes effectively with 1 O 2 sensitization [46] .…”

“…Design of the next generation of PSs has been focused on extending the absorption window to include NIR wavelengths (700–900 nm) [31–34] and to alter the excited state properties of the molecules to exploit oxygen‐independent mechanistic pathways to achieve phototoxic effects in hypoxia [35–40] . Ru II polypyridyl complexes are particularly attractive scaffolds for PS design because the photophysics of these complexes is well‐established [41–47] and polypyridyl ligand combinations can be chosen to systematically manipulate the excited state dynamics in a rational and consistent manner.…”