Initial Proton Transfer Research Articles

Mechanism of the Oxidative Ring-Closure Reaction during Gliotoxin Biosynthesis by Cytochrome P450 GliF.

During gliotoxin biosynthesis in fungi, the cytochrome P450 GliF enzyme catalyzes an unusual C-N ring-closure step while also an aromatic ring is hydroxylated in the same reaction cycle, which may have relevance to drug synthesis reactions in biotechnology. However, as the details of the reaction mechanism are still controversial, no applications have been developed yet. To resolve the mechanism of gliotoxin biosynthesis and gain insight into the steps leading to ring-closure, we ran a combination of molecular dynamics and density functional theory calculations on the structure and reactivity of P450 GliF and tested a range of possible reaction mechanisms, pathways and models. The calculations show that, rather than hydrogen atom transfer from the substrate to Compound I, an initial proton transfer transition state is followed by a fast electron transfer en route to the radical intermediate, and hence a non-synchronous hydrogen atom abstraction takes place. The radical intermediate then reacts by OH rebound to the aromatic ring to form a biradical in the substrate that, through ring-closure between the radical centers, gives gliotoxin products. Interestingly, the structure and energetics of the reaction mechanisms appear little affected by the addition of polar groups to the model and hence we predict that the reaction can be catalyzed by other P450 isozymes that also bind the same substrate. Alternative pathways, such as a pathway starting with an electrophilic attack on the arene to form an epoxide, are high in energy and are ruled out.

Mechanism of Nitrogen Reduction to Ammonia in a Diiron Model of Nitrogenase.

Nitrogenase is a fascinating enzyme in biology that reduces dinitrogen from air to ammonia through stepwise reduction and protonation. Despite it being studied in detail by experimental and computational groups, there are still many unknown factors in the catalytic cycle of nitrogenase, especially related to the addition of protons and electrons and their order. A recent biomimetic study characterized a potential dinitrogen-bridged diiron cluster as a synthetic model of nitrogenase. Using strong acid and reductants, the dinitrogen was converted into ammonia molecules, but details of the mechanism remains unknown. In particular, it was unclear from the experimental studies whether the proton and electron transfer steps are sequential or alternating. Moreover, the work failed to establish what the function of the diiron core is and whether it split into mononuclear iron fragments during the reaction. To understand the structure and reactivity of the biomimetic dinitrogen-bridged diiron complex [(P2P'PhFeH)2(μ-N2)] with triphenylphosphine ligands, we performed a density functional theory study. Our computational methods were validated against experimental crystal structure coordinates, Mössbauer parameters, and vibrational frequencies and show excellent agreement. Subsequently, we investigated the alternating and consecutive addition of electrons and protons to the system. The calculations identify a number of possible reaction channels, namely, same-site protonation, alternating protonation, and complex dissociation into mononuclear iron centers. The calculations show that the overall mechanism is not a pure sequential set of electron and proton transfers but a mixture of alternating and consecutive steps. In particular, the first reaction steps will start with double proton transfer followed by an electron transfer, while thereafter, there is another proton transfer and a second electron transfer to give a complex whereby ammonia can split off with a low energetic barrier. The second channel starts with alternating protonation of the two nitrogen atoms, whereafter the initial double proton transfer, electrons and protons are added sequentially to form a hydrazine-bound complex. The latter split off ammonia spontaneously after further protonation. The various reaction channels are analyzed with valence bond and orbital diagrams. We anticipate the nitrogenase enzyme to operate with mixed alternating and consecutive protonation and electron transfer steps.

Ultrafast Proton Transfer Pathways Mediated by Amphoteric Imidazole

Imidazole, being an amphoteric molecule, can act both as an acid and as a base. This property enables imidazole, as an essential building block, to effectively facilitate proton transport in high-temperature proton exchange membrane fuel cells and in proton channel transmembrane proteins, enabling those systems to exhibit high energy conversion yields and optimal biological function. We explore the amphoteric properties of imidazole by following the proton transfer exchange reaction dynamics with the bifunctional photoacid 7-hydroxyquinoline (7HQ). We show with ultrafast ultraviolet-mid-infrared pump-probe spectroscopy how for imidazole, in contrast to expectations based on textbook knowledge of acid-base reactivity, the preferential reaction pathway is that of an initial proton transfer from 7HQ to imidazole, and only at a later stage a transfer from imidazole to 7HQ, completing the 7HQ tautomerization reaction. An assessment of the molecular distribution functions and first-principles calculations of proton transfer reaction barriers reveal the underlying reasons for our observations.

Concerted primary proton transfer reactions in a thermophilic rhodopsin studied by time-resolved infrared spectroscopy at high temperature

The primary proton transfer reactions of thermophilic rhodopsin, which was first discovered in an extreme thermophile, Thermus thermophilus JL-18, were investigated using time-resolved Fourier transform infrared spectroscopy at various temperatures ranging from 298 to 343 K (25 to 70 °C) and proton transport activity analysis. The analyses were performed using counterion (D95E, D95N, D229E, and D229N) and proton donor mutants (E106D and E106Q) as well. First, the initial proton transfer from the protonated retinal Schiff base (PRSB) to D95 was identified. The temperature dependency showed that the proton transfer reaction in the intermediate states dramatically changed above 318 K (45 °C). In addition, the proton transfer reaction correlated well with the structural change from turn to β-strand in the protein moiety, suggesting that this step may be regulated by the rigidity of the loop region. We also elucidated that the proton transfer reaction from proton donor E106 to the retinal Schiff base occurred synchronously with the primary proton transfer from the PRSB to D95. Surprisingly, we discovered that the direction of proton transfer was regulated by the secondary counterion, D229. Comparative analysis of Gloeobacter rhodopsin from the mesophile, Gloeobacter violaceus, highlighted that the primary proton transfer reactions in thermophilic rhodopsin were optimized at high temperatures partly due to the specific turn to β-strand structural change. This was not observed in Gloeobacter rhodopsin and other related proteins such as bacteriorhodopsin.

Origin of Catalysis by Nitroalkane Oxidase.

The rate of proton abstraction of the carbon acid nitroethane by Asp402 is accelerated by a factor of 108 in the enzyme nitroalkane oxidase (NAO) relative to that by the organic base acetate ion in water. The Cα proton of nitroalkanes is known to exhibit an abnormal correlation between its acidity strength and the rate of deprotonation, with an unusually slow rate of deprotonation in water. This work examines the origin of NAO catalysis, revealing that the rate enhancement by the enzyme is due to transition-state stabilization, restoring the normal behavior of the linear free energy relationship of Bronsted acids. Interestingly, NAO employs the ubiquitous cofactor flavin adenosine diphosphate (FAD) to perform the subsequent oxidation. Does the FAD cofactor also affect the catalytic rate of the initial proton transfer process of the overall nitroalkane oxidation? Classical molecular dynamics and path-integral simulations using a reaction-specific combined quantum mechanics/molecular mechanics (QM/MM) approach were carried out to obtain the free energy reaction profiles, or the potentials of mean force, for the enzymatic reaction and for a model reaction in aqueous solution, as well as for the 2'-deoxy-FAD co-factor-modified NAO. Free energy perturbation calculations suggest that transition-state stabilization of the reactive fragment is the primary cause of the catalytic effect. It is found that the FAD cofactor plays a crucial role in increasing the Cα proton acidity, via specific hydrogen bonding and π-stacking interactions, although these factors have a smaller effect on the enhancement of the rate of deprotonation. Model QM calculations of the π-stacking complexes between the FAD isoalloxazine ring and the neutral and anionic nitroethane, respectively, reveal that the anionic π-stacking complex is more stable than the neutral one by 15.7 kcal/mol, and a net π-stacking energy of 17.3 kcal/mol is obtained. Hence, the isoalloxazine ring, in addition to serving as a very potent oxidizing agent via the formation of covalent intermediate structures, is able to exert a considerable amount of catalytic effect through noncovalent π-stacking interactions.

The Contribution of Proton-Donor pKa on Reactivity Profiles of [FeFe]-hydrogenases.

The [FeFe]-hydrogenases are enzymes that catalyze the reversible activation of H2 coupled to the reduction–oxidation of electron carriers. Members of the different taxonomic groups of [FeFe]-hydrogenases display a wide range of preference, or bias, for H2 oxidation or H2 production reactions, despite sharing a common catalytic cofactor, or H-cluster. Identifying the properties that control reactivity remains an active area of investigation, and models have emerged that include diversity in the catalytic site coordination environments and compositions of electron transfer chains. The kinetics of proton-coupled electron transfer at the H-cluster might be expected to be a point of control of reactivity. To test this hypothesis, systematic changes were made to the conserved cysteine residue that functions in proton exchange with the H-cluster in the three model enzymes: CaI, CpII, and CrHydA1. CaI and CpII both employ electron transfer accessory clusters but differ in bias, whereas CrHydA1 lacks accessory clusters having only the H-cluster. Changing from cysteine to either serine (more basic) or aspartate (more acidic) modifies the sidechain pKa and thus the barrier for the proton exchange step. The reaction rates for H2 oxidation or H2 evolution were surveyed and measured for model [FeFe]-hydrogenases, and the results show that the initial proton-transfer step in [FeFe]-hydrogenase is tightly coupled to the control of reactivity; a change from cysteine to more basic serine favored H2 oxidation in all enzymes, whereas a change to more acidic aspartate caused a shift in preference toward H2 evolution. Overall, the changes in reactivity profiles were profound, spanning 105 in ratio of the H2 oxidation-to-H2 evolution rates. The fact that the change in reactivity follows a common trend implies that the effect of changing the proton-transfer residue pKa may also be framed as an effect on the scaling relationship between the H-cluster di(thiolmethyl)amine (DTMA) ligand pKa and Em values of the H-cluster. Experimental observations that support this relationship, and how it relates to catalytic function in [FeFe]-hydrogenases, are discussed.

A water-soluble fluorescent probe for the determination of γ-glutamyltransferase activity and its application in tumor imaging

γ-glutamyltransferase (GGT), an important tumor marker, is highly expressed in tumor tissues, and precise detection of its activity provides a vital indicator for the diagnosis and treatment. In this work, a “lighting-on” probe (TCF-GGT) was elaborated to detect endogenous GGT with high selectivity and sensitivity. Dicyanomethyldifuranyl (TCF-OH) was employed as the fluorescence reporter and short peptide glutathione (GSH) worked as the GGT-active trigger, the introduction of which prevented the initial proton transfer of TCF-OH contributing to a blank sensing background. A bright red fluorescence could be switched on upon GGT catalytic hydrolysis, avoiding the potential interference from background. There displayed an excellent water-solubility, and little organic solvent was required during the exploration, which otherwise avoided the potential damage to enzyme and organism. TCF-GGT has been proved to be workable at cellular and organism level with highly effective imaging and a short metabolic cycle, which is expected to offer an alternative solution or reference to the early diagnosis and treatment of tumor.

NTO Degradation by Nitroreductase: A DFT Study.

NTO (5-nitro-1,2,4-triazol-3-one), an energetic material used in military applications, may be released to the environment during manufacturing, transportation, storage, training, and disposal. A detailed investigation of the possible mechanism for all steps of reduction of NTO by oxygen-insensitive nitroreductase, as one of the pathways for NTO environmental degradation, was performed by computational study at the PCM(Pauling)/M06-2X/6-311++G(d,p) level. Obtained results reveal an overall sequence for NTO transformation into ATO (5-amino-1,2,4-triazol-3-one) with the flavin mononucleotide (FMN) cofactor of nitroreductase. Reduction of the nitro group to the nitroso group and the nitroso group to the hydroxylamino group follow a similar mechanism that consists of the sequential electron and proton transfer from the flavin cofactor. The hydride transfer mechanism may contribute to reduction of the nitroso group by the anionic form of the reduced flavin cofactor. Reduction of 5-(hydroxylamino)-1,2,4-triazol-3-one by the neutral form of the reduced flavin is impossible, whereas reduction of the hydroxylamino group to the amino group occurs with the anionic form of the reduced cofactor by a mechanism involving an initial proton transfer from the hydroxonium ion followed by two electrons and one proton transfers from the flavin cofactor. Small activation energies and high exothermicity support the significant contribution of oxygen-insensitive nitroreductase and other enzymes, containing FMN as a cofactor, to NTO degradation in the environment.

Conformational Change of H64 and Substrate Transportation: Insight Into a Full Picture of Enzymatic Hydration of CO2 by Carbonic Anhydrase.

The enzymatic hydration of CO2 into HCO3 − by carbonic anhydrase (CA) is highly efficient and environment-friendly measure for CO2 sequestration. Here extensive MM MD and QM/MM MD simulations were used to explore the whole enzymatic process, and a full picture of the enzymatic hydration of CO2 by CA was achieved. Prior to CO2 hydration, the proton transfer from the water molecule (WT1) to H64 is the rate-limiting step with the free energy barrier of 10.4 kcal/mol, which leads to the ready state with the Zn-bound OH−. The nucleophilic attack of OH− on CO2 produces HCO3 − with the free energy barrier of 4.4 kcal/mol and the free energy release of about 8.0 kcal/mol. Q92 as the key residue manipulates both CO2 transportation to the active site and release of HCO3 −. The unprotonated H64 in CA prefers in an inward orientation, while the outward conformation is favorable energetically for its protonated counterpart. The conformational transition of H64 between inward and outward correlates with its protonation state, which is mediated by the proton transfer and the product release. The whole enzymatic cycle has the free energy span of 10.4 kcal/mol for the initial proton transfer step and the free energy change of −6.5 kcal/mol. The mechanistic details provide a comprehensive understanding of the entire reversible conversion of CO2 into bicarbonate and roles of key residues in chemical and nonchemical steps for the enzymatic hydration of CO2.

Nonequilibrium Dynamics of Proton-Coupled Electron Transfer in Proton Wires: Concerted but Asynchronous Mechanisms.

The coupling between electrons and protons and the long-range transport of protons play important roles throughout biology. Biomimetic systems derived from benzimidazole-phenol (BIP) constructs have been designed to undergo proton-coupled electron transfer (PCET) upon electrochemical or photochemical oxidation. Moreover, these systems can transport protons along hydrogen-bonded networks or proton wires through multiproton PCET. Herein, the nonequilibrium dynamics of both single and double proton transfer in BIP molecules initiated by oxidation are investigated with first-principles molecular dynamics simulations. Although these processes are concerted in that no thermodynamically stable intermediate is observed, the simulations predict that they are predominantly asynchronous on the ultrafast time scale. For both systems, the first proton transfer typically occurs ∼100 fs after electron transfer. For the double proton transfer system, typically the second proton transfer occurs hundreds of femtoseconds after the initial proton transfer. A machine learning algorithm was used to identify the key molecular vibrational modes essential for proton transfer: a slow, in-plane bending mode that dominates the overall inner-sphere reorganization, the proton donor–acceptor motion that leads to vibrational coherence, and the faster donor–hydrogen stretching mode. The asynchronous double proton transfer mechanism can be understood in terms of a significant mode corresponding to the two anticorrelated proton donor–acceptor motions, typically decreasing only one donor–acceptor distance at a time. Although these PCET processes appear concerted on the time scale of typical electrochemical experiments, attaching these BIP constructs to photosensitizers may enable the detection of the asynchronicity of the electron and multiple proton transfers with ultrafast two-dimensional spectroscopy. Understanding the fundamental PCET mechanisms at this level will guide the design of PCET systems for catalysis and energy conversion processes.

Using Electron-Transfer-Induced Proton Transfer to Control Binding Strength in H-Bond Dimers

An important goal in supramolecular chemistry is the development of stimuli-responsive systems in which the strength of the intermolecular interactions can be altered by external signals such as changes in light, temperature, pH or voltage of an electrode. Our group is exploring the latter possibility, primarily by trying to develop systems in which electron transfer perturbs the strength of H-bonding interactions between molecules. The underlying principle is straightforward: an oxidation that decreases the negative charge on a H-acceptor (A) or a reduction that decreases the positive charge on a H-donor (D) will weaken a H-bond. Alternatively, reduction that increases the negative charge on a H-acceptor or oxidation that increases the positive charge on a H-donor will increase the strength of a H-bond. However, in the latter case, it is possible that oxidation or reduction could also lead to full proton transfer. If this occurs across the H-bond, the primary H-bonds will remain, but the secondary H-bonds will change. This can lead to an increase in unfavorable secondary interactions, which would counteract the effect of the initial proton transfer. However, with proper design, proton transfer could lead to an increase in favorable secondary interactions, which would enhance the effect of initial transfer. The goal of this project is to do the latter. For this work, the 3 H-bond DAD array, 1, that contains a N-methyl-4,4'-bipyridinium or “monoquat” redox couple (see figure) has been synthesized. Compound 1 forms a three H-bond dimer with the non-electroactive ADA array, 2, in CH2Cl2. Typically, DAD-ADA arrays such as this have relatively weak association constants of ~102 M−1 in non-competitive solvents such as CH2Cl2 due to the three, favorable primary H-bonds (shown as solid, double-headed, green arrows in the figure) being counterbalanced by four unfavorable secondary interactions (shown as dashed, double-headed, red arrows). Preliminary NMR studies suggest stronger binding in this case (>103 M−1), probably due to the greater acidity of the amide NH’s in 1 because of the strongly electron-withdrawing nature of the pyridinium. In the absence of 2, initial cyclic voltammetry studies of 1 display the expected two, sequential, 1 e− reduction waves of the monoquat redox couple in CH2Cl2, corresponding to reduction of 1 to the radical and then the quinoidal anion. Addition of 2 results in no change in the E1/2 of the first reduction, but the second reduction shifts ~0.24 V positive. Further addition of 2 causes no additional change in the E1/2, consistent with a 1:1 complex. The 0.24 V positive shifts indicate a ~104 increase in binding strength upon overall 2 e− reduction of 1. Combined with the initial association constant of >103 M−1, this indicates an association constant of >107 M−1 in the fully reduced state. We believe the most likely explanation of such strong H-bonding in a 3 H-bond array is that the second reduction induces proton transfer across the central H-bond in the complex, thus converting the DAD-ADA array to a DDD-AAA array. The latter is expected to have significantly stronger H-bonding because all of the secondary interactions, in addition to the primary interactions, are favorable. If confirmed by further studies, the association constant in the reduced form would represent, to the best of our knowledge, the largest achieved to date in a redox-dependent H-bonding system, thereby demonstrating the utility of incorporating proton transfer to amplify the effect of electron transfer in these systems. Figure 1

Control of Bond Strength in H-Bond Dimers Via Proton Transfer Induced By Electron Transfer

An important goal in supramolecular chemistry is the development of stimuli-responsive systems in which the strength of the intermolecular interactions can be altered by external signals such as changes in light, temperature, pH or voltage of an electrode. Our group is exploring the latter possibility, primarily by trying to develop systems in which electron transfer perturbs the strength of H-bonding interactions between molecules. The underlying principle is straightforward: an oxidation that decreases the negative charge on a H-acceptor (A) or a reduction that decreases the positive charge on a H-donor (D) will weaken a H-bond. Alternatively, reduction that increases the negative charge on a H-acceptor or oxidation that increases the positive charge on a H-donor will increase the strength of a H-bond. However, in the latter case, it is possible that oxidation or reduction could also lead to full proton transfer. If this occurs across the H-bond, the primary H-bonds will remain, but the secondary H-bonds will change. This can lead to an increase in unfavorable secondary interactions, which would counteract the effect of the initial proton transfer. However, with proper design, proton transfer could lead to an increase in favorable secondary interactions, which would enhance the effect of initial transfer. The goal of this project is to do the latter. For this work, the 3 H-bond DAD array, 1, that contains a N-methyl-4,4'-bipyridinium or “monoquat” redox couple (see figure) has been synthesized. Compound 1 forms a three H-bond dimer with the non-electroactive ADA array, 2, in CH2Cl2. Typically, DAD-ADA arrays such as this have relatively weak association constants of ~102 M−1 in non-competitive solvents such as CH2Cl2 due to the three, favorable primary H-bonds (shown as solid, double-headed, green arrows in the figure) being counterbalanced by four unfavorable secondary interactions (shown as dashed, double-headed, red arrows). Preliminary NMR studies suggest stronger binding in this case (>103 M−1), probably due to the greater acidity of the amide NH’s in 1 because of the strongly electron-withdrawing nature of the pyridinium. In the absence of 2, initial cyclic voltammetry studies of 1 display the expected two, sequential, 1 e− reduction waves of the monoquat redox couple in CH2Cl2, corresponding to reduction of 1 to the radical and then the quinoidal anion. Addition of 2 results in no change in the E1/2 of the first reduction, but the second reduction shifts ~0.24 V positive. Further addition of 2 causes no additional change in the E1/2, consistent with a 1:1 complex. The 0.24 V positive shifts indicate a ~104 increase in binding strength upon overall 2 e− reduction of 1. Combined with the initial association constant of >103 M−1, this indicates an association constant of >107 M−1 in the fully reduced state. We believe the most likely explanation of such strong H-bonding in a 3 H-bond array is that the second reduction induces proton transfer across the central H-bond in the complex, thus converting the DAD-ADA array to a DDD-AAA array. The latter is expected to have significantly stronger H-bonding because all of the secondary interactions, in addition to the primary interactions, are favorable. If confirmed by further studies, the association constant in the reduced form would represent, to the best of our knowledge, the largest achieved to date in a redox-dependent H-bonding system, thereby demonstrating the utility of incorporating proton transfer to amplify the effect of electron transfer in these systems. Figure 1

Deprotection of N-Boc Groups under Continuous-Flow High-Temperature Conditions.

The scope of thermolytic, N-Boc deprotection was studied on 26 compounds from the Pfizer compound library, representing a diverse set of structural moieties. Among these compounds, 12 substrates resulted in clean (≥95% product) deprotection, and an additional three compounds gave ≥90% product. The thermal de-Boc conditions were found to be compatible with a large number of functional groups. A combination of computational modeling, statistical analysis, and kinetic model fitting was used to support an initial, slow, and concerted proton transfer with release of isobutylene, followed by a rapid decarboxylation. A strong correlation was found to exist between the electrophilicity of the N-Boc carbonyl group and the reaction rate.

Using Electron-Transfer-Induced Proton Transfer to Control Binding Strength in H-Bond Dimers

An important goal in supramolecular chemistry is the development of stimuli-responsive systems in which the strength of the intermolecular interactions can be altered by external signals such as changes in light, temperature, pH or voltage of an electrode. Our group is exploring the latter possibility, primarily by trying to develop systems in which electron transfer perturbs the strength of H-bonding interactions between molecules. The underlying principle is straightforward: an oxidation that decreases the negative charge on a H-acceptor (A) or a reduction that decreases the positive charge on a H-donor (D) will weaken a H-bond. Alternatively, reduction that increases the negative charge on a H-acceptor or oxidation that increases the positive charge on a H-donor will increase the strength of a H-bond. However, in the latter case, it is possible that oxidation or reduction could also lead to full proton transfer. If this occurs across the H-bond, the primary H-bonds will remain, but the secondary H-bonds will change. This can lead to an increase in unfavorable secondary interactions, which would counteract the effect of the initial proton transfer. However, with proper design, proton transfer could lead to an increase in favorable secondary interactions, which would enhance the effect of initial transfer. The goal of this project is to do the latter. For this work, the 3 H-bond DAD array, 1, that contains a N-methyl-4,4'-bipyridinium or “monoquat” redox couple (see figure) has been synthesized. Compound 1 forms a three H-bond dimer with the non-electroactive ADA array, 2, in CH2Cl2. Typically, DAD-ADA arrays such as this have relatively weak association constants of ~102 M−1 in non-competitive solvents such as CH2Cl2 due to the three, favorable primary H-bonds (shown as solid, double-headed, green arrows in the figure) being counterbalanced by four unfavorable secondary interactions (shown as dashed, double-headed, red arrows). Preliminary NMR studies suggest stronger binding in this case (>103 M−1), probably due to the greater acidity of the amide NH’s in 1 because of the strongly electron-withdrawing nature of the pyridinium. In the absence of 2, initial cyclic voltammetry studies of 1 display the expected two, sequential, 1 e− reduction waves of the monoquat redox couple in CH2Cl2, corresponding to reduction of 1 to the radical and then the quinoidal anion. Addition of 2 results in no change in the E1/2 of the first reduction, but the second reduction shifts ~0.24 V positive. Further addition of 2 causes no additional change in the E1/2, consistent with a 1:1 complex. The 0.24 V positive shifts indicate a ~104 increase in binding strength upon overall 2 e− reduction of 1. Combined with the initial association constant of >103 M−1, this indicates an association constant of >107 M−1 in the fully reduced state. We believe the most likely explanation of such strong H-bonding in a 3 H-bond array is that the second reduction induces proton transfer across the central H-bond in the complex, thus converting the DAD-ADA array to a DDD-AAA array. The latter is expected to have significantly stronger H-bonding because all of the secondary interactions, in addition to the primary interactions, are favorable. If confirmed by further studies, the association constant in the reduced form would represent, to the best of our knowledge, the largest achieved to date in a redox-dependent H-bonding system, thereby demonstrating the utility of incorporating proton transfer to amplify the effect of electron transfer in these systems. Figure 1

Conversion of a Weak Three H-Bond Dimer to a Strong Three H-Bond Dimer Using Electron Transfer Induced Proton Transfer

An important goal in supramolecular chemistry is the development of stimuli-responsive systems in which the strength of the intermolecular interactions can be altered by external signals such as changes in light, temperature, pH or voltage of an electrode. Our group is exploring the latter possibility, primarily by trying to develop systems in which electron transfer perturbs the strength of H-bonding interactions between molecules. The underlying principle is straightforward: an oxidation that decreases the negative charge on a H-acceptor (A) or a reduction that decreases the positive charge on a H-donor (D) will weaken a H-bond. Alternatively, reduction that increases the negative charge on a H-acceptor or oxidation that increases the positive charge on a H-donor will increase the strength of a H-bond. However, in the latter case, it is possible that oxidation or reduction could also lead to full proton transfer. If this occurs across the H-bond, the primary H-bonds will remain, but the secondary H-bonds will change. This can lead to an increase in unfavorable secondary interactions, which would counteract the effect of the initial proton transfer. However, with proper design, proton transfer could lead to an increase in favorable secondary interactions, which would enhance the effect of initial transfer. The goal of this project is to do the latter. In particular, 3-H-bond DAD-ADA arrays will be studied in which the DAD component contains a N-alkyl-4,4'-bipyridinium or “monoquat” redox couple (see figure). DAD-ADA arrays have relatively weak association constants (102 in non-competitive solvents such as CHCl3) due to the three favorable primary H-bonds (shown as solid double-headed arrows in the figure) being counterbalanced by four unfavorable secondary interactions (cross interactions shown as dashed double-headed arrows). As shown in the figure, reduction of the monoquat by one electron should lead to proton transfer, creating not only a strong ionic primary H-bond, but converting all the secondary H-bonds to favorable ones. Examples of similar ionic DDD-AAA complexes have been reported in the literature with association constants greater than 109, suggesting it may be possible see a binding enhancement on the order of 107 upon reduction in this system. Initial voltammetric studies with just monoquat itself (x = nothing) and the diimide ADA guest show a significant positive shift in the E1/2 of the second reduction of monoquat, but little to no shift in the first reduction in both acetonitrile and methylene chloride. The shift is larger in acetonitrile, consistent with it being due to proton transfer between the guest and the fully reduced monoquat. Currently, synthesis of the compete DAD array is underway, which will have X = NC(=O)R to make the H-donor a strongly donating amide NH. In contrast to the monoquat results, CV studies with this compound and the diimide ADA guest are expected to show a E1/2 shift in the first reduction that is significantly larger in methylene chloride than acetonitrile, indicating very strong H-bonding to the radical form. Figure 1

Influence of Solvent Relaxation on Ultrafast Excited-State Proton Transfer to Solvent.

A thorough understanding of the microscopic mechanism of excited-state proton transfer (ESPT) and the influence of the solvent environment on its dynamics are of great fundamental interest. We present here a detailed investigation of an ESPT to solvent (DMSO) using time-resolved broadband fluorescence and transient absorption spectroscopies. All excited-state species are resolved spectrally and kinetically using a global target analysis based on the two-step Eigen-Weller model. Reversibility of the initial short-range proton transfer producing excited contact ion pairs (CIP*) is observed unambiguously in fluorescence and must be explicitly considered to obtain the individual rate constants. Close inspection of the early dynamics suggests that the relative populations of the protonated form (ROH*) and CIP* are governed by solvent relaxation that influences the relative energies of the excited states. This constitutes a breakdown of the Eigen-Weller model, although the overall agreement between the data and the analysis using classical rate equations is excellent.

Using Redox-Induced Proton Transfer to Convert a Weak 3-H-Bond Dimer to a Strong 3-H-Bond Dimer

An important goal in supramolecular chemistry is the development of stimuli-responsive systems in which the strength of the intermolecular interactions can be altered by external signals such as changes in light, temperature, pH or voltage of an electrode. Our group is exploring the latter possibility, primarily by trying to develop systems in which electron transfer perturbs the strength of H-bonding interactions between molecules. The underlying principle is straightforward: an oxidation that decreases the negative charge on a H-acceptor (A) or a reduction that decreases the positive charge on a H-donor (D) will weaken a H-bond. Alternatively, reduction that increases the negative charge on a H-acceptor or oxidation that increases the positive charge on a H-donor will increase the strength of a H-bond. However, in the latter case, it is possible that oxidation or reduction could also lead to full proton transfer. If this occurs across the H-bond, the primary H-bonds will remain, but the secondary H-bonds will change. This can lead to an increase in unfavorable secondary interactions, which would counteract the effect of the initial proton transfer. However, with proper design, proton transfer could lead to an increase in favorable secondary interactions, which would enhance the effect of initial transfer. The goal of this project is to do the latter. In particular, 3-H-bond DAD-ADA arrays will be studied in which the DAD component contains a N-alkyl-4,4'-bipyridinium or “monoquat” redox couple (see figure). DAD-ADA arrays have relatively weak association constants (102 in non-competitive solvents such as CHCl3) due to the three favorable primary H-bonds (shown as solid double-headed arrows in the figure) being counterbalanced by four unfavorable secondary interactions (cross interactions shown as dashed double-headed arrows). As shown in the figure, reduction of the monoquat by one electron should lead to proton transfer, creating not only a strong ionic primary H-bond, but converting all the secondary H-bonds to favorable ones. Examples of similar ionic DDD-AAA complexes have been reported in the literature with association constants greater than 109, suggesting it may be possible see a binding enhancement on the order of 107 upon reduction in this system. Initial voltammetric studies with just monoquat itself (x = nothing) and the diimide ADA guest will be reported in this presentation, along with our synthetic progress in making the complete DAD array, which will have X = NC(=O)R to make the H-donor a strongly donating amide NH. Figure 1

SmI2(H2O)n Reduction of Electron Rich Enamines by Proton-Coupled Electron Transfer.

Samarium diiodide in the presence of water and THF (SmI2(H2O)n) has in recent years become a versatile and useful reagent, mainly for reducing carbonyl-type substrates. This work reports the reduction of several enamines by SmI2(H2O)n. Mechanistic experiments implicate a concerted proton-coupled electron transfer (PCET) pathway, based on various pieces of evidence against initial outer-sphere electron transfer, proton transfer, or substrate coordination. A thermochemical analysis indicates that the C-H bond formed in the rate-determining step has a bond dissociation free energy (BDFE) of ∼32 kcal mol-1. The O-H BDFE of the samarium aquo ion is estimated to be 26 kcal mol-1, which is among the weakest known X-H bonds of stable reagents. Thus, SmI2(H2O)n should be able to form very weak C-H bonds. The reduction of these highly electron rich substrates by SmI2(H2O)n shows that this reagent is a very strong hydrogen atom donor as well as an outer-sphere reductant.

Reactivity of the copper(iii)-hydroxide unit with phenols.

Kinetic studies of the reactions of two previously characterized copper(iii)-hydroxide complexes (LCuOH and NO2 LCuOH, where L = N,N'-bis(2,6-diisopropylphenyl)-2,6-pyridine-dicarboxamide and NO2 L = N,N'-bis(2,6-diisopropyl-4-nitrophenyl)pyridine-2,6-dicarboxamide) with a series of para substituted phenols (XArOH where X = NMe2, OMe, Me, H, Cl, NO2, or CF3) were performed using low temperature stopped-flow UV-vis spectroscopy. Second-order rate constants (k) were determined from pseudo first-order and stoichiometric experiments, and follow the trends CF3 < NO2 < Cl < H < Me < OMe < NMe2 and LCuOH < NO2 LCuOH. The data support a concerted proton-electron transfer (CPET) mechanism for all but the most acidic phenols (X = NO2 and CF3), for which a more complicated mechanism is proposed. For the case of the reactions between NO2 ArOH and LCuOH in particular, competition between a CPET pathway and one involving initial proton transfer followed by electron transfer (PT/ET) is supported by multiwavelength global analysis of the kinetic data, formation of the phenoxide NO2 ArO- as a reaction product, observation of an intermediate [LCu(OH2)]+ species derived from proton transfer from NO2 ArOH to LCuOH, and thermodynamic arguments indicating that initial PT should be competitive with CPET.

(Invited) Elucidating Hydrogen Oxidation/Evolution Kinetics in Base and Acid By Enhanced Activities at the Optimized Pt-Shell Thickness on the Ru Core

Hydrogen oxidation and evolution reactions are slower by two orders of magnitude in base than in acid on Pt and other metal catalysts.1It is important to understand the cause and to develop catalysts that are more active than Pt in base for advancing the performance of anion-exchange-membrane fuel cells and water electrolyzers. Here, we detail a four-fold enhancement in Pt mass activity that we achieved using single crystalline Ru@Pt core-shell nanoparticles with two-monolayer-thick Pt shells,2 which doubles the activity on Pt-Ru alloy nanocatalysts. For Pt specific activity, the 2-ML and 1-ML thick Pt shells, respectively, exhibited an enhancement factor of 3.1 and 2.3 compared to the Pt nanocatalysts in base, larger than the values of 1 and 0.4 in acid.3 To explain such behavior and the huge difference in acid and base, we performed kinetic analyses of polarization curves over a wide range of potential from -250 to 250 mV, which were measured in 1 M KOH and 1 M HClO4 using the gas diffusion electrode method.4 The results of fitting polarization curves in Fig. 2 indicate (1) H adsorption free energy, DGad, increases from bulk Pt to 2 ML and to 1 ML, consistent with the weakening trend found by DFT-calculated hydrogen binding energy (H-BE); (2) the Tafel-Volmer is still the dominant pathway as the activation barriers are lower for the Tafel than the Heyrovsky reaction (DG+T < DG+H) on all three catalysts. More importantly, the activation free energies increase the most for the Volmer reaction, e.g., from 177 to 352 meV (Fig. 3a), resulting in a switch of the rate-determining step from the Tafel- to the Volmer-reaction, and a shift to a weaker optimal H-BE. The shift makes bulk Pt less active than 1-ML Pt in base (red in Fig. 3b), while the 2-ML Pt with an intermediate H-BE remains near the top of volcano. For both acid and base, the H-BE is a descriptor of catalysts’ activities, however, the huge difference between acid and base (~100 times in scale on the left than the right y-axis in Fig. 3b) has to be caused by a factor not directly associated with the H-BE because it is a general phenomenon for various catalysts.1 The much higher activation barrier for the Volmer reaction in base than in acid indicates that the key is the proton interaction with water. Theoretical studies showed that the main contribution to the barrier for the Volmer reaction comes from initial proton transfer from water to the electrode,6 which is superfast along hydrogen bond network in acids.7 In base, OH- transport is slow, and the HO-H bond breaking/formation likely has a considerable activation barrier, differing from the virtually activation-less hydrogen bond breaking/formation for hydrated proton (H2O-H+) in acid. Acknowledgements This research was supported by the US Department of Energy, Division of Chemical Sciences, Geosciences and Biosciences Division under contract DE-SC0012704. References (1) Durst, J.; Siebel, A.; Simon, C.; Hasché, F.; Herranz, J.; Gasteiger, H. A. Energy Environ. Sci. 2014, 7(7), 2255. (2) Hsieh, Y.-C.; Zhang, Y.; Su, D.; Volkov, V.; Si, R.; Wu, L.; Zhu, Y.; An, W.; Liu, P.; He, P.; Ye, S.; Adzic, R. R.; Wang, J. X. Nat. Commun. 2013, 4, 2466. (3) Elbert, K.; Hu, J.; Ma, Z.; Zhang, Y.; Chen, G.; An, W.; Liu, P.; Isaacs, H. S.; Adzic, R. R.; Wang, J. X. ACS Catal. 2015, 5, 6764. (4) Wang, J. X.; Zhang, Y.; Capuano, C. B.; Ayers, K. E. Sci. Rep. 2015, 5, 12220. (5) Wang, J. X.; Springer, T. E.; Liu, P.; Shao, M.; Adzic, R. R. J. Phys. Chem. C 2007, 111(33), 12425. (6) Skúlason, E.; Karlberg, G. S.; Rossmeisl, J.; Bligaard, T.; Greeley, J.; Jónsson, H.; Nørskov, J. K. Phys. Chem. Chem. Phys. 2007, 9(25), 3241. (7) Guthrie, J. P. J. Am. Chem. Soc. 1996, 118 (51), 12886. Figure 1