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Bimolecular excited-state proton-coupled electron transfer (PCET*) was observed for reaction of the triplet MLCT state of [(dpab)₂Ru(4,4′-dhbpy)]²⁺ (dpab = 4,4′-di(n-propyl)amido-2,2′-bipyridine, 4,4′-dhbpy = 4,4′-dihydroxy-2,2′-bipyridine) with N-methyl-4,4′-bipyridinium (MQ⁺) and N-benzyl-4,4′-bipyridinium (BMQ⁺) in dry acetonitrile solutions. The PCET* reaction products, the oxidized and deprotonated Ru complex, and the reduced protonated MQ+ can be distinguished from the excited state electron transfer (ET*) and the excited state proton transfer (PT*) products by the difference in the visible absorption spectrum of the species emerging from the encounter complex. The observed behavior differs from that of reaction of the MLCT state of [(bpy)₂Ru(4,4′-dhbpy)]²⁺ (bpy = 2,2′-bipyridine) with MQ⁺, where initial ET* is followed by diffusion-limited proton transfer from the coordinated 4,4′-dhbpy to MQ⁰. The difference in observed behavior can be rationalized based on changes in the free energies of ET* and PT*. Substitution of bpy with dpab results in the ET* process becoming significantly more endergonic and the PT* reaction becoming somewhat less endergonic.

Cancer cells utilize high basal levels of reactive oxygen species (ROS) to create conditions that facilitate rapid cell proliferation. This creates an Achilles heel, making cancer cells more susceptible than normal cells to cell death caused by a bolus dose of ROS. The common food preservative, tert-butylhydroquinone (tBHQ), generates ROS intracellularly via redox cycling. Herein, we tested the effect of combining tBHQ with a manganese porphyrin, compounds originally designed as super oxide dismutase mimetics which can also generate ROS intracellularly in cancer cells and have radioprotective effects under clinical investigation. We find that the combination treatment of tBHQ and the commercially available Mn(III) tetrakis(1-methyl-4-pyridyl)porphyrin pentachloride (MnTMPyP) is much more toxic to leukemic Jurkat lymphocytes than either compound alone, e.g., lowering the LC50 of tBHQ by two orders of magnitude to 1.0 μM. MnTMPyP acts as a catalyst to oxidize tBHQ, shown by UV-Vis spectroscopy. Flow cytometry analysis revealed that while 5 μM tBHQ decreases cell viability by less than 10% in 4 hours, the combination of 5 μM tBHQ and 12 μM MnTMPyP decreases viability by 60%, primarily by apoptosis. A clinically tested manganese porphyrin, Mn(III) meso-tetrakis(N-n-butoxyethylpyridinium-2-yl)porphyrin (Mn2BuOE), was as effective and more potent than MnTMPyP. We evaluated the cancer-targeting effect of tBHQ and Mn2BuOE in both Jurkats and a matched primary CD4 T cell line. The combination treatment induced significantly more cell death in cancerous Jurkats than in the normal CD4 cells. With the promise Mn2BuOE shows in pre-clinical studies and early clinical trials as adjunctive to radiotherapy, and the wide use of tBHQ in prepared food, the results shown here in CD4 cells suggest their combination may be an effective therapy to target cancer cells. Citation Format: Joseph P. LaMorte, Sandra Tamarin, Margueritte Lalo, David J. Sokoloski, Jared J. Paul, Aimee L. Eggler. The cancer targeting synergy of tertbutylhydroquinone and a manganese porphyrin. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4787.

This manuscript reports the reaction of the 3MLCT excited states of two luminescent chromophores, [(bpy)2Ru(OHbpy)]2+ and [(bpy)2Ru(OMebpy)]2+ (bpy = 2,2′-bipyridine, OHbpy = 4-hydroxy-2,2′-bipyridine, OMebpy = 4-methoxy-2,2′-bipyridine), with anthraquinone (AQ). A series of luminescence, electrochemical, spectrophotometric and transient absorption studies were done in order to determine free energies for the potential reaction paths between the photoexcited complexes and AQ. For the OMebpy complex, only excited state electron transfer (ET*) from the 3MLCT state of the complex to AQ was possible. However, for the OHbpy complex, the excited state could react with AQ via a variety of pathways including excited state electron transfer, ET*, excited state proton transfer (PT*) and excited state proton coupled electron transfer (PCET*). The thermodynamic analysis revealed that, for the OHbpy complex PT* was very endergonic and not a viable reaction pathway, however both ET* and PCET* could occur. Luminescence quenching studies revealed that both the OHbpy and the OMebpy excited complexes reacted with AQ (kq ~ 109 M−1s−1 for both). Transient absorption analysis showed that, for the OMebpy complex, no photoproducts escaped the encounter complex associated with the quenching reaction. The result is consistent with strong electrostatic association of the 3+/1- encounter complex. For the OHbpy complex transient absorption results clearly show the formation of PCET* products from the encounter complex. The result represents one of a small number of examples of excited states of chromophores reacting via proton coupled electron transfer within an encounter complex.

The development of metal complexes with ligands capable of proton transfer can result in significant advances in Proton Coupled Electron Transfer (PCET) chemistry, specifically understanding how these reactions occur mechanistically in the excited state. The synthesis of three ruthenium complexes containing asymmetric bipyridine ligands: [Ru(bpy)2(4bpyOH)]2+, [Ru(bpy)2(4bpyOMe)]2+, and [Ru(bpy)2(44′bpy(OH)(OMe))]2+ (bpy = 2,2′-bipyridine; 4bpyOH = 4-hydroxy-2,2′-bipyridine; 4bpyOMe = 4-methoxy-2,2′-bipyridine; 44′bpy(OH)(OMe) = 4-hydroxy-4′-methoxy-2,2′-bipyridine) are reported. These complexes were studied using both experimental and computational methods. These studies indicate that the methoxy-substitution gives similar electron-donating properties to the hydroxy-substitution, meaning that the methoxy-substitution is a good control when examining electron transfer in the absence of proton transfer. Potential versus pH diagrams show that [Ru(bpy)2(4bpyOH)]2+ has a RuIII/II reduction potential of 0.97 V vs. Ag/AgCl in aqueous acidic solution that decreases to 0.76 V vs. Ag/AgCl when deprotonated. The [Ru(bpy)2(44′bpy(OH)(OMe))]2+, with an additional methoxy-substituent, has a RuIII/II reduction potential that is slightly lower with a potential of 0.92 V vs. Ag/AgCl in acidic aqueous solution that decreases to 0.74 V vs. Ag/AgCl when deprotonated. These complexes are comparable to other hydroxy- and methoxy-substituted polypyridyl ruthenium complexes reported previously, showing the additive effects of hydroxy- and methoxy-substitutions on the reduction potential of the RuIII/II wave and spectroscopic shifts that occur as the ligand scaffold is altered.

The development of metal complexes with pH dependent ligands could lead to useful design principles in altering catalysis. We have synthesized the complex [Ru(bpy)(bpy(OH)2)2]2+ (bpy=2,2′-bipyridine, bpy(OH)2=4,4′-dihydroxy-2,2′-bipyridine) to better understand how the hydroxyl groups influence the electronic and structural properties of the complex as a function of protonation state. Both experimental and computational methods were utilized to study the complex in the protonated and deprotonated state. The most notable difference observed by X-ray diffraction studies, as well as by computational structural analysis, is the shortening of the modified ligand’s C–O bond length upon deprotonation due to increasing double bond character by resonance. Cyclic voltammetry studies of the complex revealed a 0.96V decrease in RuIII/II potential upon deprotonation. Only one ligand redox wave is observed when deprotonated, assigned to the unmodified bpy ligand. The absorption spectrum of protonated [Ru(bpy)(bpy(OH)2)2]2+ is similar to that of [Ru(bpy)3]2+ with typical metal to ligand charge transfer bands at approximately 460nm. Upon deprotonation, the absorption spectrum shifts dramatically, exhibiting a 4504cm−1 red shift from λmax=468nm to λmax=593nm in acetonitrile. Computational studies indicate that the bpy(O−)2 ligand’s orbitals heavily mix with the Ru d-orbitals, leading to mixed metal–ligand to ligand charge transfer transitions. Luminescence studies reveal absolute quenching of the excited state upon deprotonation in accordance with the energy gap law. These studies alongside results from the previously studied [Ru(bpy)2(bpy(OH)2)]2+ and [Ru(bpy(OH)2)3]2+ complexes, provide useful insight into the impact of increasing electron donation to the metal center.

Although much of the scientific community concerns itself with ideas of a sustainable future, very little of this interest and motivation has reached the classroom experience of the average chemistry major, and therefore, it is imperative to expose students to these ideas early in their careers. The focus of most undergraduate chemistry curricula rests on the preparation of the next generation of researchers, ensuring that students are capable and effective in the laboratory. A majority of laboratory experiences focus on building basic technical skill sets for chemists. However, little time is spent ensuring that students are aware of the impacts of their research, as it pertains to chemical waste and the sustainability of research, in general. At Villanova, an existing first-year undergraduate inorganic chemistry laboratory course was modified to promote novel ideas in research with an emphasis on life-cycle thinking and analysis in terms of sustainability. Initial results are reported, as well as an out...

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.

Attaining high oxidation states at the metal center of transition metal complexes is a key design principle for many catalytic processes. One way to support high oxidation state chemistry is to utilize ligands that are electron-donating in nature. Understanding the structural and electronic changes of metal complexes as higher oxidation states are reached is critical towards designing more robust catalysts that are able to turn over at high rates without decomposing. To this end, we report herein the changes in structural and electronic properties as [Ru(bpy)2(44′bpy(OH)2)]2+ is oxidized to [Ru(bpy)2(44′bpy(OH)2)]3+ (bpy = 2,2′-bipyridine; 44′bpy(OH)2 = 4,4′-dihydroxy-2,2′-bipyridine). The 44′bpy(OH)2 ligand is a pH-dependent ligand where deprotonation of the hydroxyl groups leads to significant electronic donation to the metal center. A Pourbaix Diagram of the complex reveals a pH independent reduction potential below pH = 2.0 for the Ru3+/2+ process at 0.91 V vs. Ag/AgCl. Above pH = 2.0, pH dependence is observed with a decrease in reduction potential until pH = 6.8 where the complex is completely deprotonated, resulting in a reduction potential of 0.62 V vs. Ag/AgCl. Spectroelectrochemical studies as a function of pH reveal the disappearance of the Metal to Ligand Charge Transfer (MLCT) or Mixed Metal–Ligand to Charge Transfer bands upon oxidation and the appearance of a new low energy band. DFT calculations for this low energy band were carried out using both B3LYP and M06-L functionals for all protonation states and suggest that numerous new transition types occur upon oxidation to Ru3+.

The development of metal complexes with pH dependent ligands could lead to useful design principles in altering catalysis. We have synthesized the complex [Ru(bpy)(bpy(OH)2)2]2+ (bpy = 2,2′-bipyridine, bpy(OH)2 = 4,4′-dihydroxy-2,2′-bipyridine) to better understand how the hydroxyl groups influence the electronic and structural properties of the complex as a function of protonation state. Both experimental and computational methods were utilized to study the complex in the protonated and deprotonated state. The most notable difference observed by X-ray diffraction studies, as well as by computational structural analysis, is the shortening of the modified ligand’s C–O bond length upon deprotonation due to increasing double bond character by resonance. Cyclic voltammetry studies of the complex revealed a 0.96 V decrease in RuIII/II potential upon deprotonation. Only one ligand redox wave is observed when deprotonated, assigned to the unmodified bpy ligand. The absorption spectrum of protonated [Ru(bpy)(bpy(OH)2)2]2+ is similar to that of [Ru(bpy)3]2+ with typical metal to ligand charge transfer bands at approximately 460 nm. Upon deprotonation, the absorption spectrum shifts dramatically, exhibiting a 4504 cm−1 red shift from λmax = 468 nm to λmax = 593 nm in acetonitrile. Computational studies indicate that the bpy(O−)2 ligand’s orbitals heavily mix with the Ru d-orbitals, leading to mixed metal–ligand to ligand charge transfer transitions. Luminescence studies reveal absolute quenching of the excited state upon deprotonation in accordance with the energy gap law. These studies alongside results from the previously studied [Ru(bpy)2(bpy(OH)2)]2+ and [Ru(bpy(OH)2)3]2+ complexes, provide useful insight into the impact of increasing electron donation to the metal center.

The development of pH switchable metal catalysts by choosing ligands with multiple protonation states would be a useful design principle. In order to better understand how such a system would work, interactions between the ligand and metal in the varying protonation states must be studied. In this work, we have synthesized para-hydroxyl-substituted terpyridine complexes of ruthenium, [Ru(tpy)(tpyOH)] 2+ and [Ru(tpyOH) 2 ] 2+ (tpy = 2,2′:6′,2″-terpyridine, tpyOH = 4′-hydroxy-2,2′:6′,2″-terpyridine), to determine how the protonation state affects the electronic properties of the complexes using UV–Vis spectroscopy and computational techniques. In addition, we have studied the electrochemical and structural properties of these complexes. Both complexes yield standard Metal to Ligand Charge Transfer (MLCT) electronic transitions in the visible region when in the protonated state. However, when deprotonated new electronic transitions from a filled molecular orbital consisting of a mixture of metal d and deprotonated pyridinolate ligand orbitals to empty ligand orbitals are observed. These transitions have been termed mixed metal–ligand to ligand charge transfer (M mix LCT). In deprotonated [Ru(tpy)(tpyO − )] + , containing only one deprotonatable group, the ligand only mixes with one of the three degenerate metal d orbitals to give one new mixed metal–ligand orbital. However, in deprotonated [Ru(tpyO − ) 2 ], the two pyridinolate groups are orthogonal to each other and each mix with a separate metal d orbital to give two new mixed metal–ligand orbitals. These results lead to the potential design principle for catalytic systems in which specific orbital interactions based on protonation state and orientation of the ligand can be tuned.

Water-oxidation catalysts (WOCs) can potentially be improved by installing pendant electron-donor groups that may also be proton donors or acceptors. We have modified one of the most well-studied WOCs with alkoxy or hydroxy substituents on the bidentate bipyridine ligand (N,N), thereby forming [(terpy)RuII(N,N)X] (X = Cl, H2O; terpy = 2,2′;6′,2"-terpyridine). A combination of NMR spectroscopy (particularly 15N chemical-shift data), UV/Vis spectroscopy, X-ray diffraction, and oxygen evolution data point to interesting and beneficial effects of an oxygenated group proximal to X. A methoxy group on the 2,2′-bipyridyl (bipy) ring cis to X = Cl is shown to facilitate ionization of the chloride ligand in aqueous acetone, perhaps by acceptance of a hydrogen bond from the aquo ligand. Hydrogen-bond donation of a proximal hydroxy group to a bound aquo ligand is shown by X-ray diffraction. Distinct differences in pKa values for the 4,4′- and 6,6′-dihydroxy bipy complexes are seen. In water oxidation driven by ceric ammonium nitrate, the 6,6′-dimethoxy species is somewhat faster and longer-lived than the analogue that lacks the oxygenated groups [a turnover number (TON) of 215 instead of 138 in 10 h, and a turnover frequency (TOF) of 0.36 min–1 instead of 0.23 over the same time period]. Taken together, oxygenated groups near the WOC active site are promising electron or proton donors and/or hydrogen-bond acceptors, and are the subject of further scrutiny.

We report highly active iridium precatalysts, [Cp*Ir(N,N)Cl]Cl (1-4), for water oxidation that are supported by recently designed dihydroxybipyridine (dhbp) ligands. These ligands can readily be deprotonated in situ to alter the electronic properties at the metal; thus, these catalyst precursors have switchable properties that are pH-dependent. The pKa values in water of the iridium complexes are 4.6(1) and 4.4(2) with (N,N) = 6,6'-dhbp and 4,4'-dhbp, respectively, as measured by UV-vis spectroscopy. For homogeneous water oxidation catalysis, the sacrificial oxidant NaIO4 was found to be superior (relative to CAN) and allowed for catalysis to occur at higher pH values. With NaIO4 as the oxidant at pH 5.6, water oxidation occurred most rapidly with (N,N) = 4,4'-dhbp, and activity decreased in the order 4,4'-dhbp (3)6,6'-dhbp (2) ≫ 4,4'-dimethoxybipyridine (4)bipy (1). Furthermore, initial rate studies at pH 3-6 showed that the rate enhancement with dhbp complexes at high pH is due to ligand deprotonation rather than the pH alone accelerating water oxidation. Thus, the protic groups in dhbp improve the catalytic activity by tuning the complexes' electronic properties upon deprotonation. Mechanistic studies show that the rate law is first-order in an iridium precatalyst, and dynamic light scattering studies indicate that catalysis appears to be homogeneous. It appears that a higher pH facilitates oxidation of precatalysts 2 and 3 and their [B(Ar(F))4](-) salt analogues 5 and 6. Both 2 and 5 were crystallographically characterized.

We have synthesized the complex [Ru(bpy)(2)(bpy(OH)(2))](2+) (bpy =2,2'-bipyridine, bpy(OH)(2) = 4,4'-dihydroxy-2,2'-bipyridine). Experimental results coupled with computational studies were utilized to investigate the structural and electronic properties of the complex, with particular attention paid toward the effects of deprotonation on these properties. The most distinguishing feature observed in the X-ray structural data is a shortening of the CO bond lengths in the modified ligand upon deprotonation. Similar results are also observed in the computational studies as the CO bond becomes double bond in character after deprotonating the complex. Electrochemically, the hydroxy-modified bipyridyl ligand plays a significant role in the redox properties of the complex. When protonated, the bpy(OH)(2) ligand undergoes irreversible reduction processes; however, when deprotonated, reduction of the substituted ligand is no longer observed, and several new irreversible oxidation processes associated with the modified ligand arise. pH studies indicate [Ru(bpy)(2)(bpy(OH)(2))](2+) has two distinct deprotonations at pK(a1) = 2.7 and pK(a2) = 5.8. The protonated [Ru(bpy)(2)(bpy(OH)(2))](2+) complex has a characteristic UV/Visible absorption spectrum similar to the well-studied complex [Ru(bpy)(3)](2+) with bands arising from Metal-to-Ligand Charge Transfer (MLCT) transitions. When the complex is deprotonated, the absorption spectrum is altered significantly and becomes heavily solvent dependent. Computational methods indicate that the deprotonated bpy(O(-))(2) ligand mixes heavily with the metal d orbitals leading to a new absorption manifold. The transitions in the complex have been assigned as mixed Metal-Ligand to Ligand Charge Transfer (MLLCT).

In many of the chemical steps in photosynthesis and artificial photosynthesis, proton coupled electron transfer (PCET) plays an essential role. An important issue is how excited state reactivity can be integrated with PCET to carry out solar fuel reactions such as water splitting into hydrogen and oxygen or water reduction of CO2 to methanol or hydrocarbons. The principles behind PCET and concerted electron–proton transfer (EPT) pathways are reasonably well understood. In Photosystem II antenna light absorption is followed by sensitization of chlorophyll P680 and electron transfer quenching to give P680+. The oxidized chlorophyll activates the oxygen evolving complex (OEC), a CaMn4 cluster, through an intervening tyrosine–histidine pair, YZ. EPT plays a major role in a series of four activation steps that ultimately result in loss of 4e−/4H+ from the OEC with oxygen evolution. The key elements in photosynthesis and artificial photosynthesis – light absorption, excited state energy and electron transfer, electron transfer activation of multiple-electron, multiple-proton catalysis – can also be assembled in dye sensitized photoelectrochemical synthesis cells (DS-PEC). In this approach, molecular or nanoscale assemblies are incorporated at separate electrodes for coupled, light driven oxidation and reduction. Separate excited state electron transfer followed by proton transfer can be combined in single semi-concerted steps (photo-EPT) by photolysis of organic charge transfer excited states with H-bonded bases or in metal-to-ligand charge transfer (MLCT) excited states in pre-associated assemblies with H-bonded electron transfer donors or acceptors. In these assemblies, photochemically induced electron and proton transfer occur in a single, semi-concerted event to give high-energy, redox active intermediates.

The particle acidity of secondary organic aerosol (SOA) created from ozonolysis of α-pinene in the presence of acidic inorganic seed aerosols was investigated using an indoor Teflon film chamber. Colorimetry integrated with a reflectance UV-Visible spectrometer was used for the first time to dynamically measure the aerosol acidity over time. An external calibration curve was produced based on the correlation between the proton mass (ng) collected on the filter, which was impregnated with metanil yellow, and the absorbance of the reflectance UV-Visible spectra for the protonated and the unprotonated metanil yellow on the filter. Using this calibration curve, the particle acidity of the submicron acidic sulfate aerosol coated with SOA was measured from the reflectance UV-Visible spectra of filter samples. The colorimetric analysis requires a short sampling time (less than 2 m) for SOA studies using the laboratory Teflon film chamber and eliminates extraction of the filter sample with water. Results show tha...

Structural changes between [OsIIL3]2+ and [OsIIIL3]3+ (L: 2,2′-bipyridine; 1,10-phenanthroline) and molecular and electronic structures of the OsIII complexes [OsIII(bpy)3]3+ and [OsIII(phen)3]3+ are discussed in this paper. Mid-infrared spectra in the ν(bpy) and ν(phen) ring stretching region for [OsII(bpy)3](PF6)2, [OsIII(bpy)3](PF6)3, [OsII(phen)3](PF6)2, and [OsIII(phen)3](PF6)3 are compared, as are X-ray crystal structures. Absorption spectra in the UV region for [OsIII(bpy)3](PF6)3 and [OsIII(phen)3](PF6)3 are dominated by very intense absorptions (e = 40 000–50 000 M−1 cm−1) due to bpy and phen intra-ligand π → π∗ transitions. In the visible region, relatively narrow bands with vibronic progressions of ∼1500 cm−1 appear, and have been assigned to bpy or phen-based, spin–orbit coupling enhanced, 1π → 3π∗ electronic transitions. Also present in the visible region are ligand-to-metal charge transfer bands (LMCT) arising from π(bpy) → t2g(OsIII) or π(phen) → t2g(OsIII) transitions. In the near infrared, two broad absorption features appear for oxidized forms [OsIII(bpy)3](PF6)3 and [OsIII(phen)3](PF6)3 arising from dπ–dπ interconfigurational bands characteristic of dπ5OsIII. They are observed at 4580 and 5090 cm−1 for [OsIII(bpy)3](PF6)3 and at 4400 and 4990 cm−1 for [OsIII(phen)3](PF6)3. The bpy and phen infrared vibrational bands shift to higher energy upon oxidation of Os(II) to Os(III). In the cation structure in [OsIII(bpy)3](PF6)3, the OsIII atom resides at a distorted octahedral site, as judged by ∠N–Os–N, which varies from 78.78(22)° to 96.61(22)°. Os–N bond lengths are also in general longer for [OsIII(bpy)3](PF6)3 compared to [OsII(bpy)3](PF6)2 (0.010 A), and for [OsIII(phen)3](PF6)3 compared to [OsII(phen)3](PF6)2 (0.014 A). Structural changes in the ligands between oxidation states are discussed as originating from a combination of dπ(OsII) → π∗ (bpy or phen) backbonding and charge redistribution on the ligands as calculated by natural population analysis.

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 ~0.3A) 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.

Excited-state proton-transfer dynamics between 7-hydroxy-4-(trifluoromethyl)coumarin and 1-methylimidazole base in toluene were studied using ultrafast pump–probe and time-resolved emission methods. Charge-transfer excitation of the hydroxycoumarin shifts electron density from the hydroxyl group to the carbonyl, resulting in an excited state where proton transfer to the base is highly favored. In addition to its the photoacid characteristics, the shift in the hydroxycoumarin electronic distribution gives it characteristics of a photobase as well. The result is a tautomerization process occurring on the picosecond time scale in which the 1-methylimidazole base acts as a proton-transfer shuttle from the hydroxyl group to the carbonyl.

The presence of the Zn2+ ion dramatically enhances the inhibition of trypsin and tryptase by amidine-modified benzimidazole inhibitors via coordination to both the catalytically active Ser195 hydroxyl and His57 imidazole residues of the enzyme and the nitrogens of the amidine-modified benzimidazole inhibitor (Janc, J. W.; Clark, J. M.; Warne, R. L.; Elrod, K. C.; Katz, B. A.; Moore, W. R. Biochemistry 2000, 39, 4792-4800). Some new 5-amidino-2-substituted benzimidazoles were synthesized and compared to known related molecules to explore systematically the metal-mediated inhibition of bovine trypsin as a function of coordinating groups and metal ions. These compounds take advantage of the favorable interaction between the amidine group on one side of the inhibitor and the Asp189 carboxylate in the binding pocket of the enzyme. The 5-amidino-2-substituted benzimidazoles all demonstrated similar inhibition constants (Ki) of 20-50 microM in the absence of metal ions. In the presence of Zn2+, inhibition increased to varying extents, depending upon the group substituted at the 2 position of the benzimidazole. The largest increase in inhibition in the presence of Zn2+ was seen with (5-amidino-2-benzimidazolyl)-2-benzimidazolylmethane with an apparent inhibition constant (Ki') of 0.37 +/- 0.06 nM, giving a 59,000-fold increase in inhibition when Zn2+ is present. Other metal ions, including Mn2+, Sc3+, and Hg2+, also increased the inhibition by several of the benzimidazole derivatives synthesized. The compound bis(2-benzimidazolyl)methane (BBIM) was also examined because it lacks the amidine group that provides a favorable hydrogen-bonding interaction with Asp189 in the binding pocket of trypsin. In the absence of metal ions, BBIM did not have a detectable affinity for trypsin; however, in the presence of Zn2+, a Ki' of 127 +/- 3 nM was observed. This result demonstrates that an affinity for the enzyme in the absence of metal ions is not required for potent metal-mediated inhibition, greatly expanding the possibilities for metal mediation of nonmetalloenzymes.

We have synthesized the complex [Ru(bpy(OH)(2))(3)](2+) (bpy(OH)(2) = 4,4'-dihydroxy-2,2'-bipyridine) containing ligands that can be readily deprotonated. Both experimental and computational techniques were utilized to perform a thorough analysis of the structural and electronic properties of the complex in both the protonated and deprotonated state. The complex [Ru(bpy(OMe)(2))(3)](2+) (bpy(OMe)(2) = 4,4'-dimethoxy-2,2'-bipyridine) was also synthesized and studied, because the bpy(OMe)(2) ligand has electron-donating properties like bpy(OH)(2), but does not contain deprotonatable groups. Cyclic voltammetry of [Ru(bpy(OH)(2))(3)](2+) yields a reversible Ru(III/II) wave that shifts 1.43 V to lower energy upon deprotonation of the complex. UV/Visible absorbance spectroscopy reveals several Metal-to-Ligand Charge Transfer (MLCT) transitions that shift to lower energy upon deprotonation of the complex. This observation is in contrast to mixed-ligand systems containing deprotonatable groups, such as [Ru(bpy)(2)(bpy(OH)(2))](2+) (bpy = 2,2'-bipyridine) that demonstrate different types of electronic transitions assigned as mixed Metal-Ligand to Ligand Charge Transfer (MLLCT). The more symmetrical nature of the tris-bpy(OH)(2) complex most likely prevents the metal molecular orbitals from significantly mixing with the molecular orbitals of the deprotonated ligand. Luminescence studies were carried out on [Ru(bpy(OH)(2))(3)](2+) and reveal a shift to lower energy and quenching of the excited state upon deprotonation in accordance with the energy gap law.