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

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 7A, [(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(Do/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 (5B-8B) 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 (5A-8A) have long luminescence lifetimes which increase with increasing π expansion on the N,N spectator ligand. The Bphen complex, 8A, 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.

Ruthenium pincer complexes for light activated toxicity: Lipophilic groups enhance toxicity.

Nine ruthenium CNC pincer complexes (1-9) were tested for anticancer activity in cell culture under both dark and light conditions. These complexes included varied CNC pincer ligands including OH, OMe, or Me substituents on the pyridyl ring and wingtip N-heterocyclic carbene (NHC) groups which varied as methyl (Me), phenyl (Ph), mesityl (Mes), and 2,6-diisopropylphenyl (Dipp). The supporting ligands included acetonitrile, Cl, and 2,2'-bipyridine (bpy) donors. The synthesis of complexes 8 and 9 is described herein and are fully characterized by spectroscopic (1H NMR, IR, UV-Vis, MS) and analytical techniques. Single crystal X-ray diffraction results are reported herein for 8 and 9. The other complexes (1-7) are reported elsewhere. The four most lipophilic ruthenium complexes (6, 7, 8, and 9) showed the best activity vs. MCF7 cancer cells with complexes 6 and 9 showing cytotoxicity and complex 7 and 8 showing light activated photocytotoxicity. The distribution of these compounds between octanol and water is reported as log(Do/w) values, and increasing log(Do/w) values correlate roughly with improved activity vs. cancer cells. Overall, lipophilic wingtip groups (e.g. Ph, Mes, Dipp) on the NHC ring and a lower cationic charge (1+ vs. 2+) appears to be beneficial for improved anticancer activity.

Nanoformulation of Lipophilic Osmium Photosensitizers in Liposomes and Micelles as a General Strategy for Improving Reproducibility and Reducing Quenching†.

Nanoformulation of an osmium photosensitizer within liposomes and micelles is used to improve the water-solubility of this highly lipophilic molecule. This highlight report describes a recent paper by Cameron, Obaid and McFarland on this topic and discusses the context for this report. Nanoformulation has been explored as a strategy before, but this represents the first usage of this strategy with highly potent metal-based photosensitizers having phototherapeutic indices (PIs) in excess of 104 . The nanoformulation strategy is effective due to reducing aggregation and self-quenching of the photosensitizer molecules.

Factors that influence singlet oxygen formation vs. ligand substitution for light-activated ruthenium anticancer compounds.

This review focuses on light-activated ruthenium anticancer compounds and the factors that influence which pathway is favored. Photodynamic therapy (PDT) is favored by π expansion and the presence of low-lying triplet excited states (e.g. 3MLCT, 3IL). Photoactivated chemotherapy (PACT) refers to light-driven ligand dissociation to give a toxic metal complex or a toxic ligand upon photo substitution. This process is driven by steric bulk near the metal center and weak metal-ligand bonds to create a low-energy 3MC state with antibonding character. With protic dihydroxybipyridine ligands, ligand charge can play a key role in these processes, with a more electron-rich deprotonated ligand favoring PDT and an electron-poor protonated ligand favoring PACT in several cases.

Light-responsive and Protic Ruthenium Compounds Bearing Bathophenanthroline and Dihydroxybipyridine Ligands Achieve Nanomolar Toxicity towards Breast Cancer Cells.

We report new ruthenium complexes bearing the lipophilic bathophenanthroline (BPhen) ligand and dihydroxybipyridine (dhbp) ligands which differ in the placement of the OH groups ([(BPhen)2 Ru(n,n'-dhbp)]Cl2 with n = 6 and 4 in 1A and 2A , respectively). Full characterization data are reported for 1A and 2A and single crystal X-ray diffraction for 1A . Both 1A and 2A are diprotic acids. We have studied 1A , 1B , 2A , and 2B (B = deprotonated forms) by UV-vis spectroscopy and 1 photodissociates, but 2 is light stable. Luminescence studies reveal that the basic forms have lower energy 3 MLCT states relative to the acidic forms. Complexes 1A and 2A produce singlet oxygen with quantum yields of 0.05 and 0.68, respectively, in acetonitrile. Complexes 1 and 2 are both photocytotoxic toward breast cancer cells, with complex 2 showing EC50 light values as low as 0.50 µM with PI values as high as >200 vs. MCF7. Computational studies were used to predict the energies of the 3 MLCT and 3 MC states. An inaccessible 3 MC state for 2B suggests a rationale for why photodissociation does not occur with the 4,4'-dhbp ligand. Low dark toxicity combined with an accessible 3 MLCT state for 1 O2 generation explains the excellent photocytotoxicity of 2.

Singlet Oxygen Formation vs Photodissociation for Light-Responsive Protic Ruthenium Anticancer Compounds: The Oxygenated Substituent Determines Which Pathway Dominates.

Ruthenium complexes bearing protic diimine ligands are cytotoxic to certain cancer cells upon irradiation with blue light. Previously reported complexes of the type [(N,N)2Ru(6,6'-dhbp)]Cl2 with 6,6'-dhbp = 6,6'-dihydroxybipyridine and N,N = 2,2'-bipyridine (bipy) (1A), 1,10-phenanthroline (phen) (2A), and 2,3-dihydro-[1,4]dioxino[2,3-f][1,10]phenanthroline (dop) (3A) show EC50 values as low as 4 µM (for 3A) vs breast cancer cells upon blue light irradiation ( Inorg. Chem. 2017, 56, 7519). Herein, subscript A denotes the acidic form of the complex bearing OH groups, and B denotes the basic form bearing O- groups. This photocytotoxicity was originally attributed to photodissociation, but recent results suggest that singlet oxygen formation is a more plausible cause of photocytotoxicity. In particular, bulky methoxy substituents enhance photodissociation but these complexes are nontoxic ( Dalton Trans 2018, 47, 15685). Cellular studies are presented herein that show the formation of reactive oxygen species (ROS) and apoptosis indicators upon treatment of cells with complex 3A and blue light. Singlet oxygen sensor green (SOSG) shows the formation of 1O2 in cell culture for cells treated with 3A and blue light. At physiological pH, complexes 1A-3A are deprotonated to form 1B-3B in situ. Quantum yields for 1O2 (ϕΔ) are 0.87 and 0.48 for 2B and 3B, respectively, and these are an order of magnitude higher than the quantum yields for 2A and 3A. The values for Ï•Δ show an increase with 6,6'-dhbp derived substituents as follows: OMe < OH < O-. TD-DFT studies show that the presence of a low lying triplet metal-centered (3MC) state favors photodissociation and disfavors 1O2 formation for 2A and 3A (OH groups). However, upon deprotonation (O- groups), the 3MLCT state is accessible and can readily lead to 1O2 formation, but the dissociative 3MC state is energetically inaccessible. The changes to the energy of the 3MLCT state upon deprotonation have been confirmed by steady state luminescence experiments on 1A-3A and their basic analogs, 1B-3B. This energy landscape favors 1O2 formation for 2B and 3B and leads to enhanced toxicity for these complexes under physiological conditions. The ability to convert readily from OH to O- groups allowed us to investigate an electronic change that is not accompanied by steric changes in this fundamental study.

Cellular uptake of protic ruthenium complexes is influenced by pH dependent passive diffusion and energy dependent efflux.

The lipophilic vs. hydrophilic properties of three protic ruthenium compounds were studied as a function of pH. Specifically, we measured Log(Do/w) values for [(N,N)2Ru(6,6'-dhbp)]2+ complexes (where N,N = 2,2'-bipyridine (1A), 1,10-phenanthroline (2A), 2,3-dihydro-[1,4]dioxino[2,3-f][1,10]phenanthroline (3A) and 6,6'-dhbp is the diprotic 6,6'-dihydroxy-2,2'-bipyridine ligand) from pH 4.0 to 8.0. This study allowed us to demonstrate that as the ligand is deprotonated at higher pH values the resulting neutral charge on the complex improves its lipophilic properties. Thus, improved uptake by passive diffusion is expected with protic ligands on Ru(II). Furthermore, cellular studies have demonstrated that passive diffusion is the dominant pathway for cellular uptake. However, metabolic inhibition has also shown that energy dependent efflux reduces the amount of the ruthenium complex (as measured by mean fluorescence intensity) in the cells. These compounds have been shown by fluorescence microscopy to accumulate in the nuclei of cancer cells (MCF7, MDA-MB-231, and HeLa). Taken together, this data shows that uptake is required for toxicity but uptake alone is not sufficient. The greatest light activated toxicity appears to occur in breast cancer cell lines with relatively moderate uptake (MCF7 and MDA-MB-231) rather than the cell line with the greatest uptake of complex 3A (normal breast cell line MCF-10A).

Highly Active Ruthenium CNC Pincer Photocatalysts for Visible-Light-Driven Carbon Dioxide Reduction.

Five ruthenium catalysts described herein facilitate self-sensitized carbon dioxide reduction to form carbon monoxide with a ruthenium catalytic center. These catalysts include four new and one previously reported CNC pincer complexes featuring a pyridinol derived N-donor and N-heterocyclic carbene (NHC) C-donors derived from imidazole or benzimidazole. The complexes have been characterized fully by spectroscopic and analytic methods, including X-ray crystallography. Introduction of a 2,2'-bipyridine (bipy) coligand and phenyl groups on the NHC ligand was necessary for rapid catalysis. [(CNC)Ru(bipy)(CH3CN)](OTf)2 is among the most active and durable photocatalysts in the literature for CO2 reduction without an external photosensitizer. The role of the structure of this complex in catalysis is discussed, including the importance of the pincer's phenyl wingtips, the bipyridyl ligand, and a weakly coordinating monodentate ligand.

Sterically demanding methoxy and methyl groups in ruthenium complexes lead to enhanced quantum yields for blue light triggered photodissociation.

Ruthenium complexes containing a sterically congested metal center can serve as light activated prodrugs through photo-activated chemotherapy (PACT). In this work, we modified PACT agents containing 6,6'-dihydroxybipyridine (6,6'-dhbp) (Papish et al., Inorg. Chem., 2017, 56, 7519) by replacing it with a sterically bulky isoelectronic ligand, 6,6'-dimethoxybipyridine (6,6'-dmbp). The resulting complexes, [(phen)2Ru(6,6'-dmbp)]Cl2 (2OMe, phen = 1,10-phenanthroline) and [(dop)2Ru(6,6'-dmbp)]Cl2 (3OMe, dop = 2,3-dihydro-[1,4]dioxino[2,3-f][1,10]phenanthroline), have been fully characterized and display enhanced quantum yields for blue light triggered photodissociation of 0.024(6) and 0.0030(2), respectively. We have also synthesized 4OH = [(dmphen)2Ru(4,4'-dhbp)]Cl2 wherein dmphen = 2,9-dimethyl-1,10-phenanthroline and 4,4'-dhbp = 4,4'-dihydroxybipyridine. These ligands enhance steric bulk near the metal center and move the hydroxy groups further from the metal center, respectively. Complex 4OH displays a relatively low quantum yield of 0.0014(2). All of the new complexes (2OMe, 3OMe, 4OH) were tested in breast cancer cells (MDA-MB-231) and were non-toxic (IC50 > 100 µM). This has been interpreted in terms of unfavorable log(Do/w) values and furthermore photodissociation alone is insufficient for cytotoxicity. We also report the crystal structures of 4OH and 2OMe, the thermodynamic acidity of complex 4OH, and the redox potentials for all new complexes.

Nickel(ii) pincer complexes demonstrate that the remote substituent controls catalytic carbon dioxide reduction.

The first example of a CNC pincer ligand with a central pyridinol ligand is reported in a nickel(ii) complex. This metal complex can be protonated or deprotonated reversibly in situ to switch on or off the photocatalytic performance towards CO2 reduction. The O- substituent appears essential for catalysis.

Thermodynamic Acidity Studies of 6,6'-Dihydroxy-2,2'-bipyridine: A Combined Experimental and Computational Approach.

The organic ligand 6,6'-dihydroxy-2,2'-bipyridine (6,6'-dhbp) is frequently used to bind transition metals in order to form catalysts for many organic and inorganic transformations. 6,6'-dhbp exists in two tautomeric forms, the pyridinol tautomer and the amide (lactam) tautomer with each tautomer having two rotational conformers: cis or trans. Only the cis-pyridinol tautomer has the proper configuration to bind transition metals. The pendant OH (or O- groups when deprotonated) in 6,6'-dhbp typically do not bind the metal when forming the metal catalyst but can facilitate the proton transfer steps in the catalysis process. Electronic structure calculations were used to predict the stability of all possible isomers (including conformers and protonation states) in the gas phase and aqueous solution. These results have been compared to experimental data including UV-vis and NMR spectra as a function of pH. The pKa values for the 6,6'-dhbp ligand in the -2 to +2 structures were predicted, and these ligands show different behavior in the gas phase versus in aqueous solution.

Ruthenium (II) and Iridium (III) Complexes of N-Heterocyclic Carbene and Pyridinol Derived Bidentate Chelates: Synthesis, Characterization, and Reactivity.

We report the synthesis and characterization of new ruthenium(II) and iridium(III) complexes of a new bidentate chelate, NHCR'-pyOR (OR = OMe, OtBu, OH and R' = Me, Et). Synthesis and characterization studies were done on the following compounds: four ligand precursors (1-4); two silver complexes of these NHCR'-pyOR ligands (5-7); six ruthenium complexes of the type [η6-(p-cymene)Ru(NHCR'-pyOR)Cl]X with R' = Me, Et and R = Me, tBu, H and X = OTf-, PF6- and PO2F2- (8-13); and two iridium complexes, [Cp*Ir(NHCMe-pyOtBu)Cl]PF6 (14) and [Cp*Ir(NHCMe-pyOH)Cl]PO2F2 (15). The complexes are air stable and were isolated in moderate yield. However, for the PF6- salts, hydrolysis of the PF6- counter anion to PO2F2- during t-butyl ether deprotection was observed. Most of the complexes were characterized by 1H and 13C-NMR, MS, IR, and X-ray diffraction. The ruthenium complexes [η6-(p-cymene)Ru(NHCMe-pyOR)Cl]OTf (R = Me (8) and tBu (9)) were tested for their ability to accelerate CO2 hydrogenation and formic acid dehydrogenation. However, our studies show that the complexes transform during the reaction and these complexes are best thought of as pre-catalysts.

Ruthenium(ii) complexes of pyridinol and N-heterocyclic carbene derived pincers as robust catalysts for selective carbon dioxide reduction.

A new pincer ligand with N-heterocyclic carbene (NHC) and 4-pyridinol-derived rings supports ruthenium complexes for photocatalytic CO2 reduction. The methoxy group on the pyridine ring offers unique catalysis advantages not seen with the unsubstituted analog. Our best catalyst offers selective CO formation, ∼250 turnover cycles, and a 40 h lifetime.

Ruthenium Complexes are pH-Activated Metallo Prodrugs (pHAMPs) with Light-Triggered Selective Toxicity Toward Cancer Cells.

Metallo prodrugs that take advantage of the inherent acidity surrounding cancer cells have yet to be developed. We report a new class of pH-activated metallo prodrugs (pHAMPs) that are activated by light- and pH-triggered ligand dissociation. These ruthenium complexes take advantage of a key characteristic of cancer cells and hypoxic solid tumors (acidity) that can be exploited to lessen the side effects of chemotherapy. Five ruthenium complexes of the type [(N,N)2Ru(PL)]2+ were synthesized, fully characterized, and tested for cytotoxicity in cell culture (1A: N,N = 2,2'-bipyridine (bipy) and PL, the photolabile ligand, = 6,6'-dihydroxybipyridine (6,6'-dhbp); 2A: N,N = 1,10-phenanthroline (phen) and PL = 6,6'-dhbp; 3A: N,N = 2,3-dihydro-[1,4]dioxino[2,3-f][1,10]phenanthroline (dop) and PL = 6,6'-dhbp; 4A: N,N = bipy and PL = 4,4'-dimethyl-6,6'-dihydroxybipyridine (dmdhbp); 5A: N,N = 1,10-phenanthroline (phen) and PL = 4,4'-dihydroxybipyridine (4,4'-dhbp). The thermodynamic acidity of these complexes was measured in terms of two pKa values for conversion from the acidic form (XA) to the basic form (XB) by removal of two protons. Single-crystal X-ray diffraction data is discussed for 2A, 2B, 3A, 4B, and 5A. All complexes except 5A showed measurable photodissociation with blue light (λ = 450 nm). For complexes 1A-4A and their deprotonated analogues (1B-4B), the protonated form (at pH 5) consistently gave faster rates of photodissociation and larger quantum yields for the photoproduct, [(N,N)2Ru(H2O)2]2+. This shows that low pH can lead to greater rates of photodissociation. Cytotoxicity studies with 1A-5A showed that complex 3A is the most cytotoxic complex of this series with IC50 values as low as 4 µM (with blue light) versus two breast cancer cell lines. Complex 3A is also selectively cytotoxic, with sevenfold higher toxicity toward cancerous versus normal breast cells. Phototoxicity indices with 3A were as high as 120, which shows that dark toxicity is avoided. The key difference between complex 3A and the other complexes tested appears to be higher uptake of the complex as measured by inductively coupled plasma mass spectrometry, and a more hydrophobic complex as compared to 1A, which may enhance uptake. These complexes demonstrate proof of concept for dual activation by both low pH and blue light, thus establishing that a pHAMP approach can be used for selective targeting of cancer cells.

Crystal structure of (perchlorato-κO)(1,4,7,10-tetra-aza-cyclo-dodecane-κ4N)copper(II) perchlorate.

The crystal structure of the title salt, [Cu(ClO4)(C8H20N4)]ClO4, is reported. The CuII ion exhibits a square-pyramidal geometry and is coordinated by the four N atoms of the neutral 1,4,7,10-tetra-aza-cyclo-dodecane (cyclen) ligand and an O atom from one perchlorate anion, with the second perchlorate ion hydrogen-bonded to one of the amine N atoms of the cyclen ligand. Additional N-H⋯O hydrogen bonds between the amine H atoms and the coordinating and non-coordinating perchlorate groups create a three-dimensional network structure. Crystals were grown from a concentrated methanol solution at ambient temperature, resulting in no co-crystallization of solvent.

Iridium and Ruthenium Complexes of N-Heterocyclic Carbene- and Pyridinol-Derived Chelates as Catalysts for Aqueous Carbon Dioxide Hydrogenation and Formic Acid Dehydrogenation: The Role of the Alkali Metal.

Hydrogenation reactions can be used to store energy in chemical bonds, and if these reactions are reversible, that energy can be released on demand. Some of the most effective transition metal catalysts for CO2 hydrogenation have featured pyridin-2-ol-based ligands (e.g., 6,6'-dihydroxybipyridine (6,6'-dhbp)) for both their proton-responsive features and for metal-ligand bifunctional catalysis. We aimed to compare bidentate pyridin-2-ol based ligands with a new scaffold featuring an N-heterocyclic carbene (NHC) bound to pyridin-2-ol. Toward this aim, we have synthesized a series of [Cp*Ir(NHC-pyOR)Cl]OTf complexes where R = t Bu (1), H (2), or Me (3). For comparison, we tested analogous bipy-derived iridium complexes as catalysts, specifically [Cp*Ir(6,6'-dxbp)Cl]OTf, where x = hydroxy (4Ir ) or methoxy (5Ir ); 4Ir was reported previously, but 5Ir is new. The analogous ruthenium complexes were also tested using [(η6-cymene)Ru(6,6'-dxbp)Cl]OTf, where x = hydroxy (4Ru ) or methoxy (5Ru ); 4Ru and 5Ru were both reported previously. All new complexes were fully characterized by spectroscopic and analytical methods and by single-crystal X-ray diffraction for 1, 2, 3, 5Ir , and for two [Ag(NHC-pyOR)2]OTf complexes 6 (R = t Bu) and 7 (R = Me). The aqueous catalytic studies of both CO2 hydrogenation and formic acid dehydrogenation were performed with catalysts 1-5. In general, NHC-pyOR complexes 1-3 were modest precatalysts for both reactions. NHC complexes 1-3 all underwent transformations under basic CO2 hydrogenation conditions, and for 3, we trapped a product of its transformation, 3SP , which we characterized crystallographically. For CO2 hydrogenation with base and dxbp-based catalysts, we observed that x = hydroxy (4Ir ) is 5-8 times more active than x = methoxy (5Ir ). Notably, ruthenium complex 4Ru showed 95% of the activity of 4Ir . For formic acid dehydrogenation, the trends were quite different with catalytic activity showing 4Ir ≫ 4Ru and 4Ir ≈ 5Ir . Secondary coordination sphere effects are important under basic hydrogenation conditions where the OH groups of 6,6'-dhbp are deprotonated and alkali metals can bind and help to activate CO2. Computational DFT studies have confirmed these trends and have been used to study the mechanisms of both CO2 hydrogenation and formic acid dehydrogenation.

Crystal structure of 4'-bromo-2',5'-dimeth-oxy-2,5-dioxo-[1,1'-biphen-yl]-3,4-dicarbo-nitrile [BrHBQ(CN)2] benzene hemisolvate.

In the crystal of the title compound, C16H9BrN2O4·0.5C6H6, the mol-ecules stack in a centrosymmetric unit cell in a 2:1 stoichiometry with co-crystallized benzene solvent mol-ecules and inter-act via various weak inter-actions. This induces a geometry different from that predicted by theory, and is unique among the hemibi-quinones heretofore reported.

Crystal structures of bis- and hexakis[(6,6'-di-hydroxy-bipyridine)copper(II)] nitrate coordination complexes.

Two multinuclear complexes synthesized from Cu(NO3)2 and 6,6'-di-hydroxy-bipyridine (dhbp) exhibit bridging nitrate and hydroxide ligands. The dinuclear complex (6,6'-di-hydroxy-bipyridine-2κ(2) N,N')[µ-6-(6-hy-droxy-pyridin-2-yl)pyridin-2-olato-1:2κ(3) N,N':O (2)](µ-hydroxido-1:2κ(2) O:O')(µ-nitrato-1:2κ(2) O:O')(nitrato-1κO)dicopper(II), [Cu2(C10H7N2O2)(OH)(NO3)2(C10H8N2O2)] or [Cu(6-OH-6'-O-bpy)(NO3)(µ-OH)(µ-NO3)Cu(6,6'-dhbp)], (I), with a 2:1 ratio of nitrate to hydroxide anions and one partially deprotonated dhbp ligand, forms from a water-ethanol mixture at neutral pH. The hexa-nuclear complex bis-(µ3-bi-pyridine-2,2'-diolato-κ(3) O:N,N':O')tetra-kis-(6,6'-di-hydroxy-bipyridine-κ(2) N,N')tetra-kis-(µ-hydroxido-κ(2) O:O')bis-(methanol-κO)tetra-kis-(µ-nitrato-κ(2) O:O')hexa-copper(II), [Cu6(C10H6N2O2)2(CH4O)2(OH)4(NO3)4(C10H8N2O2)4] or [Cu(6,6'-dhbp)(µ-NO3)2(µ-OH)Cu(6,6'-O-bpy)(µ-OH)Cu(6,6'dhbp)(CH3OH)]2, (II), with a 1:1 NO3-OH ratio and two fully protonated and fully deprotonated dhbp ligands, was obtained by methanol recrystallization of material obtained at pH 3. Complex (II) lies across an inversion center. Complexes (I) and (II) both display intra-molecular O-H⋯O hydrogen bonding. Inter-molecular O-H⋯O hydrogen bonding links symmetry-related mol-ecules forming chains along [100] for complex (I) with π-stacking along [010] and [001]. Complex (II) forms inter-molecular O-H⋯O hydrogen-bonded chains along [010] with π-stacking along [100] and [001].

Studies of the pathways open to copper water oxidation catalysts containing proximal hydroxy groups during basic electrocatalysis.

Water oxidation can lead to a sustainable source of energy, but for water oxidation catalysts to be economical they must use earth abundant metals. We report here 2:1 6,6'-dihydroxybipyridine (6,6'-dhbp)/copper complexes that are capable of electrocatalytic water oxidation in aqueous base (pH = 10-14). Two crystal structures of the complex that contains 6,6'-dhbp and copper(II) in a ratio of 2:1 (complex 1) are presented at different protonation states. The thermodynamic acid dissociation constants were measured for complex 1, and these show that the complex is fully deprotonated above pH = 8.3 (i.e., under water oxidation conditions). CW-EPR, ENDOR, and HYSCORE spectroscopy confirmed that the 6,6'-dhbp ligand is bound to the copper ion over a wide pH range which shows how pH influences precatalyst structure. Additional copper(II) complexes were synthesized from the ligands 4,4'-dhbp (complex 2) and 6,6'-dimethoxybipyridine (complexes 3 and 4). A zinc complex of 6,6'-dhbp was also synthesized (complex 5). Crystal structures are reported for 1 (in two protonation states), 3, 4, and 5. Water oxidation studies using several of the above compounds (1, 2, 4, and 5) at pH = 12.6 have illustrated that both copper and proximal OH groups are necessary for water oxidation at a low overpotential. Our most active catalyst 1 was found to have an overpotential of 477 mV for water oxidation at a moderate rate of kcat = 0.356 s(-1) with a competing irreversible oxidation event at a rate of 1.082 s(-1). Furthermore, our combined work supports previous observations in which OH/O(-) groups on the bipyridine rings can hydrogen bond with metal bound substrate, support unusual binding modes, and potentially facilitate proton coupled electron transfer.

Ruthenium dihydroxybipyridine complexes are tumor activated prodrugs due to low pH and blue light induced ligand release.

Ruthenium drugs are potent anti-cancer agents, but inducing drug selectivity and enhancing their modest activity remain challenging. Slow Ru ligand loss limits the formation of free sites and subsequent binding to DNA base pairs. Herein, we designed a ligand that rapidly dissociates upon irradiation at low pH. Activation at low pH can lead to cancer selectivity, since many cancer cells have higher metabolism (and thus lower pH) than non-cancerous cells. We have used the pH sensitive ligand, 6,6'-dihydroxy-2,2'-bipyridine (66'bpy(OH)2), to generate [Ru(bpy)2(66'(bpy(OH)2)](2+), which contains two acidic hydroxyl groups with pKa1=5.26 and pKa2=7.27. Irradiation when protonated leads to photo-dissociation of the 66'bpy(OH)2 ligand. An in-depth study of the structural and electronic properties of the complex was carried out using X-ray crystallography, electrochemistry, UV/visible spectroscopy, and computational techniques. Notably, RuN bond lengths in the 66'bpy(OH)2 complex are longer (by ~0.3Å) than in polypyridyl complexes that lack 6 and 6' substitution. Thus, the longer bond length predisposes the complex for photo-dissociation and leads to the anti-cancer activity. When the complex is deprotonated, the 66'bpy(O(-))2 ligand molecular orbitals mix heavily with the ruthenium orbitals, making new mixed metal-ligand orbitals that lead to a higher bond order. We investigated the anti-cancer activities of [Ru(bpy)2(66'(bpy(OH)2)](2+), [Ru(bpy)2(44'(bpy(OH)2)](2+), and [Ru(bpy)3](2+) (44'(bpy(OH)2=4,4'-dihydroxy-2,2'-bipyridine) in HeLa cells, which have a relatively low pH. It is found that [Ru(bpy)2(66'(bpy(OH)2)](2+) is more cytotoxic than the other ruthenium complexes studied. Thus, we have identified a pH sensitive ruthenium scaffold that can be exploited for photo-induced anti-cancer activity.