A Light-Promoted Innate Trifluoromethylation of Pyridones and Related N-Heteroarenes.

We report a practical, light-mediated perfluoroalkylation using Langlois' reagent (sodium trifluoromethylsulfinate) that proceeds in the absence of any photocatalyst or additives. This method has allowed for the facile functionalization of pyridones and related N-heteroarenes such as azaindole. This protocol is operationally simple, uses readily available materials, and is tolerable for electron-neutral and -rich functional pyridones. Cyclic voltammetry was utilized as a mechanistic probe, and preliminary data suggest the reaction may involve an electrophilic radical mechanism.

Exploring the Role of H-Bonding in Organic Electrochemistry - From Supramolecular Applications to Mechanistic Investigations.

H-bonds can exert a substantial impact on the course of organic electrode reactions due to their ability to stabilize charged intermediates and products formed during these reactions, as well as facilitate proton-coupled electron transfer (PCET) reactions. This has fundamental implications for the mechanism of organic electrode reactions, but also practical impact in supramolecular chemistry and potentially synthetic electrochemistry. My group's main focus has been on the supramolecular applications, using electron transfer to alter the strength of H-bonds to create highly redox-responsive H-bond dimers. Initially we sought to avoid proton transfer because we feared that would lead to irreversible electrochemistry. However, inevitably proton transfer did show up, but, to our surprise, did not lead to irreversible electrochemistry. To explain this, we developed a new mechanism, the "wedge scheme", that shows how H-bonding can facilitate reversible electron and proton transfer. This insight recently led us to a new PCET-based design strategy for the creation of our most highly redox-responsive H-bond dimers yet.

An Active-Site Sulfonate Group Creates a Fast Water Oxidation Electrocatalyst That Exhibits High Activity in Acid.

The storage of solar energy in chemical bonds will depend on pH-universal catalysts that are not only impervious to acid, but actually thrive in it. Whereas other homogeneous water oxidation catalysts are less active in acid, we report a catalyst that maintained high electrocatalytic turnover frequency at pH values as low as 1.1 and 0.43 (kcat =1501±608 s-1 and 831±254 s-1 , respectively). Moreover, current densities, related to catalytic reaction rates, ranged from 15 to 50 mA cm-2 mM-1 comparable to those reported for state-of-the-art heterogeneous catalysts and 30 to 100 times greater than those measured for two prominent literature homogeneous catalysts at pH 1.1 and 0.43. The catalyst also exhibited excellent durability when a chemical oxidant was used (CeIV , 7400 turnovers, TOF 0.88 s-1 ). Preliminary computational studies suggest that the unusual active-site sulfonate group acts a proton relay even in strong acid, as intended.

Redox-Responsive H-Bonding: Amplifying the Effect of Electron Transfer Using Proton-Coupled Electron Transfer.

A new strategy to create highly redox-responsive H-bond dimers based on proton-coupled electron transfer is proposed that capitalizes on the importance of secondary H-bonds in determining overall binding strength in H-bond dimers. Electron transfer induced proton transfer across a H-bond can be used to significantly strengthen the overall binding by both creating strong ionic H-bonds and changing the secondary H-bonds from unfavorable to favorable. The viability and potency of this approach are demonstrated with an electroactive DAD (A = H-acceptor, D = H-donor) array, H(MQ+)H, paired with an electroinactive ADA array, O(NH)O. NMR titration of H(MQ+)H with O(NH)O in 0.1 M NBu4PF6/CD2Cl2 gives a Kassoc of 500 M-1, typical of DAD-ADA dimers. However, upon two-electron reduction in 0.1 M NBu4PF6/CH2Cl2, cyclic voltammetry studies indicate a 1.8 × 105 increase in binding strength, corresponding to a very large Kassoc of 9 × 107 M-1. The latter value is typical of DDD-AAA H-bond dimers, consistent with proton transfer across the central H-bond upon reduction.

Click chemistry-facilitated comprehensive identification of proteins adducted by antimicrobial 5-nitroimidazoles for discovery of alternative drug targets against giardiasis.

Giardiasis and other protozoan infections are major worldwide causes of morbidity and mortality, yet development of new antimicrobial agents with improved efficacy and ability to override increasingly common drug resistance remains a major challenge. Antimicrobial drug development typically proceeds by broad functional screens of large chemical libraries or hypothesis-driven exploration of single microbial targets, but both strategies have challenges that have limited the introduction of new antimicrobials. Here, we describe an alternative drug development strategy that identifies a sufficient but manageable number of promising targets, while reducing the risk of pursuing targets of unproven value. The strategy is based on defining and exploiting the incompletely understood adduction targets of 5-nitroimidazoles, which are proven antimicrobials against a wide range of anaerobic protozoan and bacterial pathogens. Comprehensive adductome analysis by modified click chemistry and multi-dimensional proteomics were applied to the model pathogen Giardia lamblia to identify dozens of adducted protein targets common to both 5'-nitroimidazole-sensitive and -resistant cells. The list was highly enriched for known targets in G. lamblia, including arginine deiminase, α-tubulin, carbamate kinase, and heat shock protein 90, demonstrating the utility of the approach. Importantly, over twenty potential novel drug targets were identified. Inhibitors of two representative new targets, NADP-specific glutamate dehydrogenase and peroxiredoxin, were found to have significant antigiardial activity. Furthermore, all the identified targets remained available in resistant cells, since giardicidal activity of the respective inhibitors was not impacted by resistance to 5'-nitroimidazoles. These results demonstrate that the combined use of click chemistry and proteomics has the potential to reveal alternative drug targets for overcoming antimicrobial drug resistance in protozoan parasites.

Redox-Responsive Dimerization in a Ferrocene-Ureidopyrimidone Supramolecular Assembly.

Ureidopyrimidones (UPy's) are well-known to dimerize via 4 strong H-bonds in noncompetitive solvents. Although UPy dimers have been widely studied, there are few examples of UPy's containing redox-active groups, and even fewer in which oxidation/reduction has been shown to affect dimerization. In this study, a thorough electrochemical investigation of a UPy with a ferrocene attached to the 6-position of the pyrimidone ring, UPy(Fc), demonstrates that strong and reversible redox-control of dimerization is possible in the UPy system. 1H NMR shows that the reduced UPy(Fc) is fully dimerized under electrochemical conditions in CH2Cl2. Cyclic voltammetry (CV) shows that oxidation of the ferrocene to the ferrocenium converts the dimer to another species with a less positive E1/2, and that reduction of this species reforms the dimer in a chemically reversible fashion. Analysis of the scan rate and concentration dependence of the CV's along with the relative diffusion coefficient measurements strongly suggest that the oxidized form is the monomer. Simulation of the CV data gives a Kdis of 2.1 × 10-6 M in the reduced state and 12 M in the oxidized state. This large redox dependence is likely due to oxidation creating both electrostatic repulsion between monomers and greatly decreasing the H-accepting ability of the pyrimidone.

Use of an electrochemically-induced proton-coupled electron transfer reaction to control dimerization in a ureidopyrimidone 4 H-bond array.

Cyclic voltammetric and spectroelectrochemical evidence is presented showing that the H-bonded dimer formed from a ureidopyrimidone derivative containing a phenylenediamine redox couple can be reversibly broken apart at mM concentrations in CH2Cl2 by an electrochemically induced proton-coupled electron transfer reaction.

The effect of glassy carbon surface oxides in non-aqueous voltammetry: the case of quinones in acetonitrile.

Glassy carbon (GC) electrodes are well-known to contain oxygenated functional groups such as phenols, carbonyls, and carboxylic acids on their surface. The effects of these groups on voltammetry in aqueous solution are well-studied, but there has been little discussion of their possible effects in nonaqueous solution. In this study, we show that the acidic functional groups, particularly phenols, are likely causes of anomalous features often seen in the voltammetry of quinones in nonaqueous solution. These features, a too small second cyclic voltammetric wave and extra current between the two waves that sometimes appears to be a small, broad third voltammetric wave, have previously been attributed to different types of dimerization. In this work, concentration-dependent voltammetry in acetonitrile rules out dimerization with a series of alkyl-benzoquinones because the anomalous features get larger as the concentration decreases. At low concentrations, solution bimolecular reactions will be relatively less important than reactions with surface groups. Addition of substoichiometric amounts of naphthol at higher quinone concentrations produces almost identical behavior as seen at low quinone concentrations with no added naphthol. This implicates hydrogen bonding and proton transfer from the surface phenolic groups as the cause of the anomalous features in quinone voltammetry at GC electrodes. This conclusion is supported by the perturbation of surface oxide coverage on GC electrodes through different electrode pretreatments.

Nitrotriazole- and imidazole-based amides and sulfonamides as antitubercular agents.

Twenty-three 3-nitrotriazole-based and 2-nitroimidazole-based amides and sulfonamides were screened for antitubercular (anti-TB) activity in aerobic Mycobacterium tuberculosis H37Rv by using the BacTiter-Glo (BTG) microbial cell viability assay. In general, 3-nitrotriazole-based sulfonamides demonstrated anti-TB activity, whereas 3-nitrotriazole-based amides and 2-nitroimidazole-based amides and sulfonamides were inactive. Three 3-nitrotriazole-based sulfonamides (compounds 4, 2, and 7) demonstrated 50% inhibitory concentration (IC50), IC90, and MIC values of 0.38, 0.43, and 1.56 µM (compound 4), 0.57, 0.98, and 3.13 µM (compound 2), and 0.79, 0.87, and 3.13 µM (compound 7), respectively. For 3-nitrotriazole-based sulfonamides, anti-TB activity increased with lipophilicity, whereas the one-electron reduction potential (E1/2) did not play a role. 2-Nitroimidazole-based analogs, which were inactive in the BTG assay, were significantly more active in the low-oxygen assay and more active than the 3-nitrotriazoles. All active nitrotriazoles in the BTG assay were similarly active or more potent (lower MIC values) against resistant strains, with the exception of compounds 2, 3, 4, and 8, which demonstrated greater MIC values against isoniazid-resistant strains. Five 3-nitrotriazole-based sulfonamides demonstrated activity in infected murine J774 macrophages, causing log reductions similar to those seen with rifampin. However, some compounds caused toxicity in uninfected macrophages. In conclusion, the classes of 3-nitrotriazole-based amides and sulfonamides merit further investigation as potential antitubercular agents.

Electrochemical evidence for intermolecular proton-coupled electron transfer through a hydrogen bond complex in a p-phenylenediamine-based urea. Introduction of the "wedge scheme" as a useful means to describe reactions of this type.

The electrochemistry of several p-phenylenediamine derivatives, in which one of the amino groups is part of an urea functional group, has been investigated in methylene chloride and acetonitrile. The ureas are abbreviated U(R)R', where R' indicates the substituent on the N that is part of the phenylenediamine redox couple and R indicates the substituent on the other urea N. Cyclic voltammetry and UV-vis spectroelectrochemical studies indicate that U(Me)H and U(H)H undergo an apparent 1e(-) oxidation that actually corresponds to 2e(-) oxidation of half the ureas to a quinoidal-diimine cation, U(R)(+). This is accompanied by proton transfer to the other half of the ureas to make the electroinactive cation HU(R)H(+). This explains the observed irreversibility of the oxidation of U(Me)H in both solvents and U(H)H in acetonitrile. However, the oxidation of U(H)H in methylene chloride is reversible at higher concentrations and slower scan rates. Several lines of evidence suggest that the most likely reason for this is the accessibility of a H-bond complex between U(H)(+) and HU(H)H(+) in methylene chloride. Reduction of the H-bond complex occurs at a less negative potential than that of U(H)(+), leading to reversible behavior. This conclusion is strongly supported by the appearance of a more negative reduction peak at lower concentrations and faster scan rates, conditions in which the H-bond complex is less favored. The overall reaction mechanism is conveniently described by a "wedge scheme", which is a more general version of the square scheme typically used to describe redox processes in which proton transfer accompanies electron transfer.

The Effect of H-bonding and Proton Transfer on the Voltammetry of 2,3,5,6-Tetramethyl-p-phenylenediamine in Acetonitrile. An Unexpectedly Complex Mechanism for a Simple Redox Couple.

The voltammetry of 2,3,5,6-tetramethyl-p-phenylenediamine, H2PD, has been studied and compared to that of its isomer N,N,N'N'-tetramethyl-p-phenylenediamine, Me2PD. Both undergo two reversible electron transfer processes in acetonitrile that nominally correspond to 1e- oxidation to the radical cations, Me2PD+ and H2PD+, and a second 1e- oxidation at more positive potentials to the quinonediimine dications, Me2PD2+ and H2PD2+. While the voltammetry of Me2PD agrees with this simple mechanism, that of H2PD does not. The second voltammetric wave is too small. UV/Vis spectroelectrochemical experiments indicate that the second wave does correspond to oxidation of H2PD+ to H2PD2+ in solution. The fact that the second wave is not present at all at the lowest concentrations (5 µM), and that it increases at longer times and higher concentrations, indicates that H2PD+ is not the initial solution product of the first oxidation. A number of lines of evidence suggest instead that the initial product is a mixed valent, H-bonded dimer between one H2PD in the the full reduced, fully protonated state, H4PD2+, and another in the fully oxidized, fully deprotonated state, PD. A mechanism is proposed in which this dimer is formed on the electrode surface through proton transfer and H-bonding. Once desorbed into solution, it breaks apart via reaction with other H2PD's, to give 2 H2PD+, which is the thermodynamically favored species in solution.

Synthesis and electrochemistry of 2-ethenyl and 2-ethanyl derivatives of 5-nitroimidazole and antimicrobial activity against Giardia lamblia.

Infections with the diarrheagenic pathogen, Giardia lamblia, are commonly treated with the 5-nitroimidazole (5-NI) metronidazole (Mz), and yet treatment failures and Mz resistance occur. Using a panel of new 2-ethenyl and 2-ethanyl 5-NI derivatives, we found that compounds with a saturated bridge between the 5-NI core and a pendant ring system exhibited only modestly increased antigiardial activity and could not overcome Mz resistance. By contrast, olefins with a conjugated bridge connecting the core and a substituted phenyl or heterocyclic ring showed greatly increased antigiardial activity without toxicity, and several overcame Mz resistance and were more effective than Mz in a murine giardiasis model. Determination of the half-wave potential of the initial one-electron transfer by cyclic voltammetry revealed that easier redox activation correlated with greater antigiardial activity and capacity to overcome Mz resistance. These studies show the potential of combining systematic synthetic approaches with biological and electrochemical evaluations in developing improved 5-NI drugs.

Electrochemically controlled hydrogen bonding. Electrolyte effects in an oxidation-based arylurea-amide system.

Oxidation of a dimethylaminophenyl-substituted urea leads to a > 2000-fold increase in binding strength between the urea and a diamide guest in 0.1 M NBu4B(C6F5)4/CH2Cl2. The strength of this interaction is obscured when NBu4ClO4 or NBu4PF6 is used as the electrolyte due to competition between the neutral guest and the electrolyte anion for H-bonding to the urea cation.

Voltammetry of quinones in unbuffered aqueous solution: reassessing the roles of proton transfer and hydrogen bonding in the aqueous electrochemistry of quinones.

Cyclic voltammetry studies are reported for two representative quinones, benzoquinone and 2-anthraquinonesulfonate, in buffered and unbuffered aqueous solution at different pH's. While the redox reaction of quinones in buffered water is well described as an overall 2 e-, 2 H+ reduction to make the hydroquinone, a much better description of the overall reaction in unbuffered water is as a 2 e- reduction to make the strongly hydrogen-bonded quinone dianion, which will exist in water as an equilibrium mixture of protonation states. This description helps to unify quinone electrochemistry by bridging the apparent gap between the redox chemistry of quinones in water and that in aprotic organic solvents, where quinones undergo two sequential 1 e- reductions to form the quinone dianion.

Electrochemically controlled hydrogen bonding. Redox-dependent formation of a 2:1 diarylurea/dinitrobenzene2- complex.

[reaction: see text] The electrochemistry of 1,2-dinitrobenzene (1,2-DNB), 1,3-dinitrobenzene (1,3-DNB), and 1,4-dinitrobenzene (1,4-DNB) is strongly affected by the presence of 1,3-diphenylurea. In DMF, the second reduction potential of all three DNBs shifts substantially positive in the presence of the urea, indicating very strong hydrogen bonding to the dianions. With 1,2- and 1,3-DNB, the hydrogen bonding leads to irreversible chemistry, likely due to proton transfer from the urea to the dianions. No such irreversible behavior is observed with 1,4-DNB. Instead, the second reduction shifts into the first reduction, producing a single, reversible, two-electron cyclic voltammetric wave at high urea concentrations. Computer simulations show that the changes in wave shape accompanying this process are well accounted for by the stepwise formation of a 1:1 and 2:1 1,3-diphenylurea/DNB2- complex, with sequential binding constants of approximately 5.5 x 10(4) M(-1) and approximately 4.0 x 10(3) M(-1) in DMF.

Electrochemically controlled hydrogen bonding. Nitrobenzenes as simple redox-dependent receptors for arylureas.

Reduction of nitrobenzene derivatives in the presence of arylureas in aprotic solvents results in large positive shifts in potential of the nitrobenzene(0/)(-) cyclic voltammetry wave with little change in wave shape. This behavior is indicative of reversible hydrogen bonding between nitrobenzene radical anions and arylureas. Computer fitting of the cyclic voltammetry of 4-nitroaniline, NA, plus 1,3-diphenylurea in DMF shows essentially no binding between urea and NA in the oxidized state (K(ox) < 1 M(-)(1)), but very strong binding in the reduced state (K(red) = 8 x 10(4) M(-)(1)), along with very rapid rates of hydrogen bond formation (k(f)'s approximately 10(8)-10(10) M(-)(1) s(-)(1)), making this system a fast on/off redox switch.

Development of chemical sensors based on redox-dependent receptors: N,N'-dimethyldiazapyrenium-modified electrodes.

Electrodes modified with Nafion films containing 2,7-dimethyldiazapyrenium (DAP2+) were prepared and characterized with voltammetry by themselves and in the presence of organic substrates. The large, planar, electron-poor aromatic surface in DAP2+ facilitates pi-stacking interactions with other planar aromatic molecules, particularly those that are negatively charged or electron-rich. Previous studies showed that the reduction of DAP2+ decreases the strength of these interactions, making the binding redox-dependent, and resulting in negative shifts in the E(1/2) of DAP2+/+. This study shows that the redox-dependent binding ability of DAP2+ is retained in Nafion, but the selectivity is considerably different. Most significantly, the electron-rich, neutral aromatic compounds that produced small shifts in the E(1/2) of DAP2+/+ in solution cause much larger shifts, up to -110 mV, with the modified electrodes. With indole as a substrate, Nernstian behavior is observed (-60 mV shift per log[indole]) between 10 and 0.5 mM.