Ruthenium Complexes with Protic Ligands: Influence of the Position of OH Groups and π Expansion on Luminescence and Photocytotoxicity

Abstract

Protic ruthenium complexes using the dihydroxybipyridine (dhbp) ligand combined with a spectator ligand (N,N = bpy, phen, dop, Bphen) have been studied for their potential activity vs. cancer cells and their photophysical luminescent properties. These complexes vary in the extent of π expansion and the use of proximal (6,6'-dhbp) or distal (4,4'-dhbp) hydroxy groups. Eight complexes are studied herein as the acidic (OH bearing) form, [(N,N)₂Ru(n,n'-dhbp)]Cl₂, or as the doubly deprotonated (O^- bearing) form. Thus, the presence of these two protonation states gives 16 complexes that have been isolated and studied. Complex 7_A, [(dop)₂Ru(4,4'-dhbp)]Cl₂, has been recently synthesized and characterized spectroscopically and by X-ray crystallography. The deprotonated forms of three complexes are also reported herein for the first time. The other complexes studied have been synthesized previously. Three complexes are light-activated and exhibit photocytotoxicity. The log(D_o/w) values of the complexes are used herein to correlate photocytotoxicity with improved cellular uptake. For Ru complexes 1-4 bearing the 6,6'-dhbp ligand, photoluminescence studies (all in deaerated acetonitrile) have revealed that steric strain leads to photodissociation which tends to reduce photoluminescent lifetimes and quantum yields in both protonation states. For Ru complexes 5-8 bearing the 4,4'-dhbp ligand, the deprotonated Ru complexes (5_B-8_B) have low photoluminescent lifetimes and quantum yields due to quenching that is proposed to involve the ³LLCT excited state and charge transfer from the [O₂-bpy]^2- ligand to the N,N spectator ligand. The protonated OH bearing 4,4'-dhbp Ru complexes (5_A-8_A) have long luminescence lifetimes which increase with increasing π expansion on the N,N spectator ligand. The Bphen complex, 8_A, has the longest lifetime of the series at 3.45 μs and a photoluminescence quantum yield of 18.7%. This Ru complex also exhibits the best photocytotoxicity of the series. A long luminescence lifetime is correlated with greater singlet oxygen quantum yields because the triplet excited state is presumably long-lived enough to interact with ³O₂ to yield ¹O₂.

Keywords: anticancer; highly conjugated ligands; light activation; luminescence; protic ligands; ruthenium.

Figure 1

Ru complexes herein can utilize both PACT and PDT pathways. (a) Schematic showing the excited states typically involved in PACT and PDT. ¹MLCT and ³MLCT are shown here for concise presentation, but singlet oxygen formation often occurs via ³ILCT and other excited states (e.g., ³LLCT), especially with highly conjugated organic ligands. (b) A specific example showing PACT and PDT for a Ru(II) complex; thus, the complex is a dual PDT/PACT agent (e.g., complexes 1_A–4_A herein). (c) Complexes 5_A–8_A used herein are solely PDT agents due to a lack of steric strain near the metal center. The co-ligands in 1_A–8_A are defined in Figure 2.

Figure 2

Ruthenium complexes 1–8 are used in the current study. Complexes 1_A–4_A, [(6,6′-dhbp)Ru(N,N)₂]Cl₂, are shown in the top left, along with their basic deprotonated forms, 1_B–4_B, which are neutral species. Complexes 5_A–8_A, [(4,4′-dhbp)Ru(N,N)₂]Cl₂, are shown in the top right, along with their basic deprotonated forms, 5_B–8_B, which are neutral species. The N,N co-ligands used herein are shown in the bottom box.

Figure 3

Molecular diagrams for 7_A crystallized as [(dop)₂Ru(4,4′-dhbp)]Cl₂(H₂O)₃. In both views of 7_A, water solvent and chloride counter anions have been removed for clarity. In the right-hand view, hydrogen atoms are hidden for clarity. Ellipsoids are shown at 50% probability. Molecular diagrams of 3_A and 6_A (from prior publication [28]) are included for comparison. Grey = carbon, white = hydrogen, red = oxygen, blue = nitrogen, teal = ruthenium.

Figure 4

Rationalizing the trends in Φ_Δ of compounds 5_A–8_A in terms of their photoluminescence (PL) dynamics. (a) Steady-state PL spectra of 8_A and 8_B in deaerated acetonitrile excited at their corresponding absorption peak wavelengths (483 nm and 525 nm, respectively). (b) Comparison of the time-resolved PL dynamics of 8_A and 8_B excited at 404 nm. (c) Time-resolved PL dynamics of 5_A–8_A excited at 404 nm. (d) Time-resolved PL dynamics of 5_B–8_B excited at 404 nm.

Figure 5

(a) Steady-state PL spectra of 3_A and 3_B excited at at their corresponding absorption peak wavelengths (467 nm and 529 nm, respectively). (b) Comparison of the time-resolved PL dynamics of 3_A and 3_B excited at 404 nm. (c) Time-resolved PL dynamics of 1_A–4_A excited at 404 nm. (d) Time-resolved PL dynamics of 1_B–4_B excited at 404 nm.

Figure 6

Correlation between the PL lifetime and singlet-oxygen QY (Φ_Δ). (a) Φ_Δ of compounds 5_B–8_B in aerated acetonitrile as a function the fast PL dynamics lifetime of these compounds in deaerated acetonitrile. The line shows calculated ϕ_Δ assuming the transfer time from ³MLCT to ³O₂ equals 0.240 µs (from the analysis in (b)). (b) Data in (a) plotted on the reciprocal scales to determine the “average” ³MLCT to ³O₂ transfer time. (c) Φ_Δ of compounds 4_A–8_A in aerated acetonitrile as a function the fast PL dynamics lifetime of these compounds in deaerated acetonitrile. The line shows calculated Φ_Δ assuming the transfer time from ³MLCT to ³O₂ equals 0.884 µs. (d) Φ_Δ of compounds 1_B–3_B in aerated methanol (CD₃OD) as a function the fast PL dynamics lifetime of these compounds in deaerated acetonitrile.