Daniel G. Nocera, Ph.D. - US grants

Metal cluster compounds are an important class of catalysts and are also of substantial current interest as models of species which exist at the metal surfaces when they are used as catalysts. Such cluster compounds absorb light strongly and the high-energy (excited state) species which are formed thereby are very reactive in bringing about chemical transformations of organic molecules. This research project is expected to provide information which is essential to effective use of metal clusters as catalysts for light-induced chemical reactions. The proposed research is focused on providing general guidelines for multielectron photochemistry beginning with two classes of transition metal compounds: multiply bonded metal- metal (M-n-M) dimers and hexanuclear clusters of Mo(II) and W(II). The excited states of these compounds are highly luminescent and long-lived. The factors governing the excited state dynamics of the hexanuclear clusters and the M-n-M dimers will be defined using electronic absorption, emission and time-resolved spectroscopies. Preliminary data indicate that the oxidation-reduction chemistry of these species is derived from the metal cores. The studies will be extended by using cyclic voltammetry, chronoamperometry and electrogenerated chemiluminescence (ecl) to identify reaction pathways. Of special importance are experiments in which ecl will be used to probe several mechanistic features of the hexanuclear cluster oxidation-reduction processes. The spectroscopic and electrochemical studies are complementary and will be used to define a framework in which to construct multielectron transformations of excited state metal clusters. Excited state reaction pathways that rely on redox reactions of small molecule reactants and organic substrates at electronically excited, coordinatively unsaturated metal cluster cores will be developed.

This award from the Chemistry Research Instrumentation Program will help the Department of Chemistry at Michigan State University purchase laser equipment. This equipment will be used in the following research activities: 1. Light Induced Charge Separation in Model and Biological Systems 2. Charge Separated Electron Transfer in Biomimetic Model Compounds 3. Solvent Dynamics of Non-Adiabatic Charge Separated Electron Transfer 4. Experimental and Theoretical Approaches to Specific Solvation of Charge Separated Electron Transfer Complexes 5. Proton Coupled Charge Separated Electron Transfer Lasers emit a narrow beam of coherent, powerful and nearly monochromatic electromagnetic radiation. This radiation is used in Chemistry to study a broad range of subjects, from the dynamics of proteins and nucleic acids to photoelectron transfer processes, and from interfacial chemistry to picosecond pulse shaping. Lasers are also useful in optics, communications, and engineering.

The proton coupled electron transfer and electron transfer reactions of photochemically prepared charge separated states of biomimetic assemblies will be addressed experimentally ad theoretically with the goal of suggesting efficient charge separating reaction networks. A homologous series of biomimetic compounds has been designed that permits a comparative study of electron transfer and proton coupled electron transfer reactions. Well characterized charge separated states of a series of these donor/acceptor complexes will be prepared optically by picosecond laser excitation. The competition between recombination and subsequent propagation of charge separated states will be monitored on the picosecond time scale by the use of time absorption spectroscopy. These experiments will permit the role of solvent dynamics, as well as energetics, on charge recombination steps to be explored. In accord with theoretical predictions that charge recombination occurring in the inverted electron transfer regime will be strongly affected by solvent dynamical properties, electron transfer rates of the biomimetic donor/acceptor complexes will be measured in solvents providing a wide range of dielectric relaxation times, as may be evocative of a protein environment. Analytic developments will focus on the consequences of solvent dynamical effects on rates in dielectrically complex solvents, and molecular dynamics simulations will be carried out to provide a detailed framework within which to interpret the experiments. As local solvation effects are important to biological electron transfer, laser induced fluorescence and time-of-flight mass spectrometry will be used to measure gas phase electron transfer rates of selectively solvated donor/acceptor complexes in supersonic jets. Electron transfer theories incorporating molecular dynamics simulations to characterize the role of specific solvation will be carried out to aid the experimental program. With the electron transfer chemistry elaborated, the role of proton motion on electron transfer will be investigated. A study of proton coupled electron transfer reactions has been initiated on a series of donor/acceptor pairs that are intramolecularly juxtaposed by a cyclic hydrogen bonded network of a dicarboxylic acid dimer or quinhydrone. Theoretical developments point to a significant proton/deuteron isotope effect on and an atypical temperature dependence of the electron transfer rate induced by proton motion. The effect of proton transfer mediation on electron transfer rates will be assessed in well defined experimental systems with the goal of elucidating these effects in the biological context.

The proton coupled electron transfer and electron transfer reactions of photochemically prepared charge separated states of biomimetic assemblies will be addressed experimentally ad theoretically with the goal of suggesting efficient charge separating reaction networks. A homologous series of biomimetic compounds has been designed that permits a comparative study of electron transfer and proton coupled electron transfer reactions. Well characterized charge separated states of a series of these donor/acceptor complexes will be prepared optically by picosecond laser excitation. The competition between recombination and subsequent propagation of charge separated states will be monitored on the picosecond time scale by the use of time absorption spectroscopy. These experiments will permit the role of solvent dynamics, as well as energetics, on charge recombination steps to be explored. In accord with theoretical predictions that charge recombination occurring in the inverted electron transfer regime will be strongly affected by solvent dynamical properties, electron transfer rates of the biomimetic donor/acceptor complexes will be measured in solvents providing a wide range of dielectric relaxation times, as may be evocative of a protein environment. Analytic developments will focus on the consequences of solvent dynamical effects on rates in dielectrically complex solvents, and molecular dynamics simulations will be carried out to provide a detailed framework within which to interpret the experiments. As local solvation effects are important to biological electron transfer, laser induced fluorescence and time-of-flight mass spectrometry will be used to measure gas phase electron transfer rates of selectively solvated donor/acceptor complexes in supersonic jets. Electron transfer theories incorporating molecular dynamics simulations to characterize the role of specific solvation will be carried out to aid the experimental program. With the electron transfer chemistry elaborated, the role of proton motion on electron transfer will be investigated. A study of proton coupled electron transfer reactions has been initiated on a series of donor/acceptor pairs that are intramolecularly juxtaposed by a cyclic hydrogen bonded network of a dicarboxylic acid dimer or quinhydrone. Theoretical developments point to a significant proton/deuteron isotope effect on and an atypical temperature dependence of the electron transfer rate induced by proton motion. The effect of proton transfer mediation on electron transfer rates will be assessed in well defined experimental systems with the goal of elucidating these effects in the biological context.

9311597 Nocera This proposal is motivated by the challenge of rationally designing magnetic substances. This research will exploit the structural control available in layered materials to study the interplay between molecular interactions and magnetic coupling. The intracrystalline environments of phosphate layered hosts will provide the scaffolding to position organic inorganic intercalants in well-defined relationships to the layers and to each other. Magnetic intercalates of layered phosphate and phosphonate hosts will be synthesized by redox and ion-exchange intercalation methods. Insertion of specially designed isostructural organic and inorganic sets of para- or diamagnetic guests will permit the probe of intralayer, layer-guest, guest-guest, and higher order magnetic interactions. In the case of paramagnetic intercalants, the roles of the open-shell orbitals' shape and alignment relative to the layers can be assessed in connection with quest orientation within the galleries. Finally, an exploratory path is outlined to assemble magnetic host layers about paramagnetic quests. As this proposal addresses structural issues of magnetic coupling, new strategies for the rational design of materials with magnetically tailored properties will emerge. Additionally, the structure- magnetism correlations assembled in this layered magnetic materials synthesis program will provide impetus for the development of new predictive structural theories of magnetism. Although the primary focus of the proposed work is synthetic, development of mechanistic models will be pursued as needed within an established collaboration with the condensed matter physics group at the University. ***

The proton coupled electron transfer and electron transfer reactions of photochemically-prepared, charge-separated biomimetic assemblies is under investigation from both a theoretical and experimental standpoint. A homologous series of biomimetic compounds has been designed that permits a comparative study of electron transfer and proton coupled electron transfer reactions. These experiments permit the role of solvent dynamics, as well as energetics, to be defined for electron transfer rates of the biomimetic donor/acceptor complexes in solvents providing a wide range of dielectric relaxation times, as may be evocative of a protein environment. With the electron transfer chemistry elaborated, a study of proton coupled electron transfer reactions has been initiated on a series of donor/acceptor pairs that are intramolecularly juxtaposed by a cyclic hydrogen bonded network of a dicarboxylic acid dimer or quinhydrone. The effect of proton transfer mediation on electron transfer rates is being assessed in well defined experimental systems, with the goal of elucidating these effects in the biological context. FAB-MS is used to characterize the large porphyrin-based biomimetic assemblies used in both the electron and proton-electron transfer studies.

Proton-coupled electron transfer (PCET) will be studied with the goal of understanding energy conversion in biological assemblies. The coupling of proton motion to charge separation is a basic bioenergetic mechanism. With the design and synthesis of new model compounds, a strategy has been developed that preserves features of charge separating networks in biological systems and permits the interrogation of the electron and proton dynamics. The key to our approach is to photoinduce electron transfer (ET) within a donor/acceptor pair that has a proton transfer (PT) network internal or external to the electron transfer pathway. For the case of the former, the proton interface may be symmetric or asymmetric. The electron transfer kinetics are defined by color changes associated with the donor/acceptor chromophores as monitored by time-resolved picosecond laser techniques. A significant advance in our approach is to design systems that have an optical and/or vibrational signature upon proton transfer. Thus, transient absorption or vibrational spectroscopy can be used to monitor the fate of the proton, in response to the ET and vice versa. These experimental measurements of PCET will be correlated with new theoretical approaches formulated to characterize the PCET phenomenon. The proposed program permits important PCET issues to be explored such as: What factors distinguish electron transfer followed by proton transfer from proton-coupled electron transfer? What structural/electronic features of the proton interface are important in governing the coupling between the electron and the proton? How will the energetics (reorganization, free energy) for charge transfer in an ET reaction be different in PCET with the additional charge arising from proton motion? Under what conditions will the rate of PCET be large compared with the ET rate? If a theory for these rates can be formulated, what will be its predictions that distinguish between these reaction pathways, and how can they be experimentally verified? These questions will be addressed in the biological context with our judiciously designed model systems. In the case of ET through symmetric interfaces, no formal proton transfer accompanies the electron. These systems shed light on hydrogen bond, electron transfer pathways in proteins like the cytochromes. For the case of asymmetric systems, ET may be accompanied by the transfer of a proton internal or external to the electron transfer pathway. These studies will provide insight into processes where proton bond making and breaking accompany electron transfer as is important in the small molecule activation (e.g., oxygen to water or water to oxygen) and proton translocation processes found in many enzymes and proteins such as cytochrome (c) oxidase and Photosystem II.

This award from the Chemistry Research Instrumentation and Facilities Program (CRIF), the Major Research Instrumentation (MRI) Program and the Office of Multidisciplinary Activities (OMA) will assist the Department of Chemistry at the Massachusetts Institute of Technology acquire nanosecond to sub-picosecond time-resolved laser instrumentation. This equipment will enhance research spanning the disciplines of inorganic, organic, and material chemistry. A sub-picosecond laser can provide important information about chemical reactivity. Its use may enable breakthroughs in our understanding of the properties of reactive and nonreactive molecules.

This award in the Inorganic, Bioinorganic, and Organometallic Chemistry Program supports research on two-electron transfer reactions by Dr. Daniel G. Nocera of the Chemistry Department, Massachusetts Institute of Technology. The goal of the research is to elucidate excited state reaction pathways for oxidation-reduction reactions occurring in two-electron steps at photoactivated metal centers. Each complex studied will contain two metal atoms in different oxidation states, linked by either single or multiple metal-metal bonds. In the case of single metal-metal bonded species, the oxidation states of the metals differ by two. For example, photoelimination of dihydrogen or dihalogen from hydrido halides of dirhodium bridged by difluorophospine ligands is expected to proceed through a Rh2(II,0) mixed valence intermediate that can be characterized. Additional complexes, including ones containing asymmetric ligands to stabilize the two-electron mixed valence centers, will be synthesized and studied. In the case of dimers linked by multiple bonds, two-electron mixed valency will be achieved by photogenerating a core with M-M+ character. Such species can be obtained from complexes with quadruple bonds or with an edge-sharing bioctahedral arrangement. Photoinitiated bond addition and atom transfer reactions for a variety of substrates will be explored.

Multielectron reactions are not well understood, but occur in many important processes, including photocatalysis, energy conversion, and information processing. The reactions studied here are unusual in that one photon promotes the movement of two-electrons. Understanding the mechanism of multielectron transfer should open the way to new reactions involving transition metals and small molecule phototransformations. Students involved in the project will experience both synthetic techniques and physical methods.

DESCRIPTION: (Adapted from the applicant's abstract) Proton-coupled electron transfer (PCET) is the basic mechanism by which the energy conversion processes in a remarkable variety of oxidases and reductases are effected. Small molecule activation, redox-driven proton pumps and enzymatic function derived from hydrogen atom abstraction all involve the coupling of an electron to proton motion. By studying PCET networks in biomimetic and natural systems, the authors intend to develop a framework in which PCET-derived structure/function relations of enzymes and proteins may be defined. With the design and synthesis of new model compounds, the authors may photo-induce electron transfer (ET) within a donor/acceptor pair that has a proton transfer (PT) network internal (e.g., salt bridge) or external (e.g., imine) to the electron transfer pathway. A key to their approach is the incorporation of independent optical and/or vibrational signatures for the electron transfer and the proton transfer events so that they can monitor the fate of the proton, in response to the electron and vice versa. With this development they can define the factors that distinguish synchronous and asynchronous transfer of the electron and proton, the structural/electronic features by which the proton and electron communicate with each other and how the energetics (e.g., reorganization, free energy) cause PCET to differ from an ET reaction. Against this mechanistic backdrop, they will undertake studies to directly measure the PCET pathway in ribonucleotide reductase (RNR). In this enzyme, an oxidizing hole traverses a putative 35 A inter-subunit (R1 and R2) pathway to arrive at an active site where the reduction of ribonucleotide to deoxyribonucleotide is catalyzed. They intend to break down the overall pathway by studying PCET within the individual R2 and R1 subunits. For the latter, they will focus on the 20-mer C-terminal peptide tail (R2C20) from the R2 subunit, which accounts for the predominate interaction required for subunit association. This peptide contains a tyrosine (Y356) that is thought to shuttle the hole from R1 to R2. A major focus of this proposal is to develop general photochemical methods to trigger the release of radical amino acids along PCET pathways of proteins and enzymes. Modification of the Y356 position of R2C20 with one of these newly synthesized tyrosyl photocages will enable them to generate Y356 radical upon laser excitation, while bypassing the normal radical generating process originating at the metallo-cofactor of R2. By turning the tyrosine radical on instantly, they can observe the transport of the hole along the PCET pathway into the R1 active site by transient absorption methods and correlate this transport to effector and substrate binding at R1. The pKa's and driving force of the PCET pathway can be modified with fluorotyrosines, allowing them to assess the relative importance of the contributions of the proton and electron to the PCET. The intein/extein technology of protein splicing provides a further opportunity to introducte the R2C20 C-terminal tail back into R2 with a photocaged fluorotyrosine at Y356. In this case, they will be able to study the PCET pathway through R2 by laser-generating Y356 radical, which can then propagate backwards to the tyrosine (Y122) proximate to the diiron cofactor of R2, the site from which overall PCET is initiated in RNR.

Daniel Nocera of the Massachusetts Institute of Technology is supported by the Inorganic, Bioinorganic, and Organometallic Chemistry Program to conduct research on the development of photoinduced multi-electron oxidation-reduction transformations. Dinuclear inorganic complexes in which the constituent metal centers differ by two units of oxidation state will be prepared and characterized. Photoinduced reactivity of these complexes will be studied. Specific systems selected for study include the photochemical production of dihydrogen from hydrohalic acids catalyzed by a newly discovered dirhenium photocatalyst, and related materials to be synthesized. Stereoelectronic factors that account for stabilization of two-equivalent mixed-valence complexes by diphosphazanes will be investigated and insights thus gained will be applied to design and synthesis of new two-unit mixed valence complexes.

The main thrust of the present proposal is on extending scientific understanding of two-electron photochemical processes and two-equivalent mixed-valence complexes, rather than on development of specific catalyic systems. However, the work has high potential of leading to future useful technological applications, such as design of energy-conversion photocycles, and activation of C-H bonds by multielectron photoredox transformations.

Daniel G. Nocera and Moungi G. Bawendi of MIT and Manoochehr M. Koochesfahani of Michigan State University are jointly supported by the Division of Chemistry, the Division of Chemical Transport Systems and the Office of Multidisciplinary Activities of the Mathematical and Physical Sciences Directorate for their interdisciplinary collaboration on new molecule-based optical diagnostic techniques to measure flow on small spatial scales. They will use newly synthesized fluorescent tracers based on caged laser dye molecules and nanocrystalline quantum dots to image flows at speeds of less than 1 mm/s. New optical techniques will be developed for the quantitative measurement of multivariable flow properties (e.g., flow velocity field, temperature, concentration) and transport in small dimensions. The diagnostics will interrogate important fundamental principles of flows in microchannels including transport to within 50-150 nm of surfaces. Understanding the flow behavior in microchannels is a key step in the development of active flow and mixing control on small spatial length scales. These principles defined from these flow studies will be incorporated in microchannels that contain Distributed Feedback (DFB) lasers as optical sensor elements. The integration of flow control and mixing with DFB architectures may lead to unprecedented analytical sensitivity on exquisitely small length scales. These principles are the underpinning of many emerging microdevice technologies, especially microsensors and microreactors.

Collaborative Research in Chemistry (CRC) awards are given to interdisciplinary teams of scientists working on problems of broad chemical interest. The emphasis in these awards is on new collaborative modes of research and training.

This conference award to Daniel G. Nocera, MIT, and Gregory H. Robinson, University of Georgia, is supported by the Chemistry Collaboratives and Special Projects Program. Nocera and Robinson will organize and host a meeting of the investigators currently funded by the Collaborative Research in Chemistry (CRC) Program. The goals of the meeting are to discuss multidisciplinary/interdisciplinary research and training issues and discuss best practices for international collaboration, publicity, and project evaluations. A workshop report will be produced and widely disseminated.

Proton-coupled electron transfer (PCET) is central to small-molecule activation processes, the function of redox-driven proton pumps and radical initiation and transport processes in biology. By examining PCET networks in model and natural systems, we aim to develop a mechanistic framework with which to interpret these processes. In doing so, we will contribute to an understanding of the structure/function relations of a variety of enzymes and proteins. This proposal seeks to elaborate PCET on three fronts: (1) The mechanism of PCET will be determined by undertaking timeresolved laser measurements on assemblies formed from a photoexcitable porphyrin donor (D) and acceptor (A) juxtaposed by a proton transfer interface (---[H+]---). The assemblies are designed to possess independent optical and vibrational signatures for electron and proton transfer events, thus allowing the fate of the proton in response to the electron and vice versa to be monitored by transient spectroscopies under a variety of conditions. These data and accompanying theoretical analysis will comprise a powerfully predictive framework for future interpretations of enzyme catalysis. (2) PCET will be studied in biological systems with the same mechanistic rigor that we have achieved in the foregoing model systems. The role of PCET in amino acid radical initiation and transport will be explored with the 35 A electron/proton coupled pathway in E. coli ribonucleotide reductase (RNR). Radicals will be generated from photoactive peptides or from non-natural amino acid photosensitizers, thereby bypassing the normal radical generation process originating at the diiron metallocofactor. The competency of these photoinitiated radicals at turning over RNR under various conditions (e.g., radical position along the pathway, variable effector and substrate concentrations) will be established using biochemical probes; the kinetics of radical transport will be investigated by transient laser spectroscopy. The combination of these steady-state and time-resolved studies should provide the most complete picture to date of PCET in a natural system. (3) The involvement of PCET in biological small molecule activation will be quantified with emphasis on bond-making and bond-breaking processes involving oxygen and water. PCET reactions will be investigated for protoporphyrin IX model cofactors that confine the delivery of protons and electrons in a face-to-face arrangement to bound O-O bonds and assembled oxygen atoms derived from water. These studies will provide direct insight into the PCET processes that are the underpinning of photosynthesis and respiration.

Professor Daniel Nocera of the Massachusetts Institute of Technology is supported by the Division of Chemistry for his research exploring how light can be used to drive multielectron transformations of small molecules with emphasis on energy related substrates. New insights into the design of multielectron reagents, of electronic structure predisposed to multielectron reactivity, and of the mechanism of multielectron transfer processes will emerge from this research. The development of two-electron mixed-valence chemistry holds similar promise for developing multielectron photoprocesses of small molecule activation and energy conversion.

Meeting global energy needs over the next century requires greater understanding of key fundamental science issues for the elaboration of new carbon-neutral energy conversion schemes. To understand the chemistry of the activation and use of small molecules of energy consequence, including carbon dioxide, nitrogen and methane, in addition to hydrogen, water and oxygen, new multielectron inorganic redox reactions will be investigated with the aim of understanding of the reactivity of metal complexes in electronic excited states beyond conventional one-electron transfer. The combination of synthesis with photochemistry and spectroscopy will give undergraduates, graduate students and postdocs a unique training experience in a forefront inorganic chemistry program.

Daniel G. Nocera, Moungi G. Bawendi, Klavs F. Jensen (Massachusetts Institute of Technology) and Manoochehr Koochesfahani (Michigan State University) are jointly supported to develop a microfluidic reactor for high throughput materials synthesis. This massively parallel system will allow for rapid mixing and extremely uniform segmentation, required for hydrothermal and solvatothermal synthesis. The microfluidic reactor will be fitted with sensors to provide information on chemical and physical phenomena underlying materials growth as well as allowing feedback optimization of the desired materials properties. New optical diagnostic techniques will allow microflows to be quantitatively measured. These data will allow for the control of reaction kinetics and growth processes for the creation of nanocrystals designed for optical sensing and water-splitting catalysts for solar energy conversion. The new microfluidic reactor system will enable the rapid synthesis and analysis of new materials, allowing many new compositions and combinations to be effectively studied.

This project is funded through the Collaborative Research in Chemistry Program (CRC) and provides collaborative training and research opportunities in chemistry, chemical engineering and mechanical engineering. The investigators also engage the public by discussing the role of basic scientific research in promoting societal sustainability.

This award by the Inorganic, Bioinorganic, and Organometallic Chemistry Program supports Professor Daniel G. Nocera at the Massachusetts Institute of Technology for the exploration of efficient, and potentially economical, storage of solar energy in the form of chemical bonds. Basic chemical systems will be designed to provide multiple (usually two or four) electron equivalents for the conversion of water or hydrochloric acid and light into high energy products (hydrogen and oxygen or hydrogen and chlorine). Cobalt and rhodium Pacman (tethered diphorphyrin ligands) and Hangman (ligand architectures in which an acid group is positioned in proximity to the metal-hydride site) motifs will be examined electrochemically and photochemically, respectively, for their ability to generate dihydrogen (H2). Cobalt porphyrinogen systems will also be employed for dihydrogen generation. Dr. Nocera has been successful in raising public awareness of the global energy problem and the role that chemistry can play in addressing the energy challenge by appearing on national news, TV, radio programs, and other broadcast venues. He has made significant contributions to curriculum development by producing energy teaching modules for WGBH-TV, the CATALYST Program, and Science News for Kids.

[unreadable] DESCRIPTION (provided by applicant): Proton coupled electron transfer (PCET) underpins primary metabolic steps involving energy transduction, radical initiation and transport and the activation of substrates at cofactors. By examining PCET networks in biomimetic and natural systems, we aim to develop a mechanistic framework in which to understand the structure/function relations of a variety of enzymes and proteins. At a practical level, an understanding of PCET can lead to the development of drugs that directly target reactive radical-based species that cause disease related to oxidative stress including cancer. A major effort will be devoted to the role of PCET in amino acid radical initiation and transport over the 35 [unreadable] electron/proton coupled pathway in E. coli ribonucleotide reductase (RNR). The research plan relies on newly created biochemical and biophysical methods. Radicals will be generated on photoactive peptides or from non-natural amino acids, thereby bypassing the normal radical generation process originating at the di-iron metallocofactor in the R2 subunit of RNR. The competency of these photoinitiated radicals at turning over substrate in the R1 subunit of RNR under various conditions (e.g., radical position along the pathway, variable effector and substrate concentrations) will be established using biochemical probes. New photopeptides will be designed to enable the photochemical intermediates of these "photoRNRs" to be observed and their kinetics for transport measured by transient laser spectroscopy. Non-natural fluorotyrosine amino acids will be exploited to tune the thermodynamics and kinetics of the electron and proton in radical transport by PCET. We will extend studies from the photoRNR R1 subunit and develop photoRNR R2 subunits by introducing photooxidants into the Y356-containing, C-terminal tail of the R2. In tackling the R2 subunit, we will initiate studies to understand the PCET mechanism by which anticancer/antiviral agents can target disease by regulation of RNR. The combination of these steady-state and time-resolved studies should provide the most complete picture to date of PCET in a natural system. The research plan will be extended by investigating the role of PCET in the activation of substrates at Hangman porphyrin constructs, which poise an acid-base functionality over the face of the redox platform. The Hangman construct is a faithful structural and functional model of heme hydroperoxidase enzymes, thus allowing us to examine the PCET mechanism and kinetics of Compound I and II formation. Experiments are presented that allow these kinetics to be measured by stopped-flow and time-resolved spectroscopy. By attaching electron donors and acceptors to the Hangman framework, we will be to examine the mechanism of PCET in which electron and proton transport is bi-directional. This type of transfer is common in biology, but has yet to be captured at a mechanistic level. The principles that emerge from these studies will be applied to explain the functions of a variety of enzymes and proteins that derive their activity from PCET. [unreadable] [unreadable] [unreadable]

The Chemical Catalysis Program of the Chemistry Division of the National Science Foundation will support the research program of Daniel Nocera at the Massachusetts Institute of Technology. Dr. Nocera and his students will investigate the development of catalysts for the photochemical activation of small molecules, including water and hydrogen halides, useful in the generation of solar fuels. The focus of the research is on the expansion of the reactivity of metal complexes to include multi-electron transfer processes for the activation of small molecules relevant to solar fuel production. A combination of synthetic, spectroscopic characterization, and photocatalytic cycle development studies will be pursued. The fundamental understanding resulting from this research will enable the development of solar based renewable energy schemes. Students will be trained in the fundamental science and the public issues relevant to these renewable energy questions. Outreach to the public forms a large part of the work of this research group.

With this award, the Chemical Catalysis Program of the Chemistry Division is funding Professor Daniel Nocera of Harvard University to study catalytic processes that can generate hydrogen from light and simple compounds. Fuels are compounds that react with an oxidant, usually oxygen, to release energy. At the molecular level, when a fuel is burned, the bonds in high energy compounds rearrange to form new bonds in lower energy compounds, and the energy released in this bond rearrangement is used to power our world. Most fuels in our society are derived from coal, oil and natural gas; namely fossil fuels, the bonds of which are rearranged with the bonds of oxygen to generate carbon dioxide and water, which enter the atmosphere. One way to avoid the formation of carbon dioxide is to cut the connection between fuels and carbon and to use hydrogen as a fuel. There are two sources of hydrogen that can be generated using solar irradiation: water or hydrohalic acid (for example, a hydrogen atom bonded to a chlorine atom); however, hydrogen cannot be generated by shining light directly on water or hydrohalic acid. A catalyst must be used that will capture the light and then act as an intermediary in the bond rearrangement reaction. Professor Nocera is developing new catalysts that can absorb light and then convert hydrohalic acids into hydrogen and elemental halogen. The new compounds, reactions and techniques resulting from this research are likely to impact realted areas of science and could result in new energy generation technologies. Professor Nocera continues to be involved in raising public awareness of the global energy problem and the role that science, and especially chemistry, can play in addressing the energy challenge. Research discoveries in this area are being conveyed to the public through a variety of forums including news media, radio programs, movies and other broadcast venues.

The Nocera group is developing new catalysts for photochemical HX splitting and, in parallel, is studying the mechanisms of such reactions. The storage of renewable energy in the form of fuels requires the rearrangement of bonds with low energy content to ones of high energy content, and bonds of important energy consequence are H-H, X-X and O=O. New metal compounds based on Rh, Ni, Fe and Mn are being synthesized that can provide insight into these energy conversion processes. Critical intermediates that promote the requisite bond activation are being studied using advanced spectroscopic techniques, including the application of time-resolved X-ray crystallography and nanoparticle-based time-resolved resonance Raman spectroscopy for the identification of the critical M-H and M-X intermediates, and magnetic resonance techniques (intermediate-field ENDOR, ELDOR-detected NMR and single-crystal polarized neutron diffraction) for the identification of M-O intermediates. With knowledge of the stereoelectronic properties of the critical intermediates, photocycles are being constructed to drive energetically uphill reactions, which are at the basis for renewable energy conversion.

Abstract Proton-coupled electron transfer (PCET) is a ubiquitous mechanism in biology, serving as the basis for mediating steps involving biosynthesis of both primary and secondary metabolites, radical generation and transport, and the activation of substrates at cofactors. The control of highly reactive radical intermediates is achieved via coupling proton and electron transfer processes. Management of radicals in biology is of particular relevance to human health, as enzymes operating by PCET are therapeutic targets with wide-ranging (RNR), which performs reversible long-range charge-transfer that spans 35 Å and two subunits (? and ?) upon applications including chemotherapy, anti-retroviral drugs and anti-inflammatory agents. The proposed research program seeks to define PCET at a detailed mechanistic level by focusing on ribonucleotide reductase every turnover. This process occurs via a pathway of redox-active amino acids, rendering RNR a paradigm for the study of PCET in biology. An interdisciplinary approach integrates a suite of experimental methods encompassing biochemistry, transient spectroscopy, synthesis and electrochemistry to target three specific aims. Owing to the sensitivity of the coupling between the proton and electron, we seek to define how conformational gating targets the PCET pathway. We will concentrate on tyrosine dyads and triads of the PCET pathway and introduce canonical and non-native point mutations to address the effects of driving force, electrostatic local environment and hydrogen bonding interactions involving these tyrosine clusters. In tandem with these biochemical inquiries, studies of cofacially aligned tyrosine model dyads will be investigated to direct link between allostery and radical transport. A second specific aim targets PCET across the ? | ? protein define how the energetics of radical generation are affected by stacking and hydrogen bonding. These studies will uncover how conformational gating controls RNR activity at an atomistic level and thus will establish a interface with the goal of identifying critical residues that mediate proton transfer attendant to radical transport. The subunit interface of RNR is a critical nexus of the PCET pathway and provides an access point for therapeutics designed to affect enzymatic function. The third specific aim seeks to understand the interplay between allosteric activation in ?2 and reduction of the Y122? cofactor, 35 Å away in ?2. To address this directly, we will embark on an investigation of the kinetics and thermodynamics of PCET through ? by employing new photo?2s. We will extend our studies to a RNR class featuring a (Mn Fe ) state to initiate forward PCET IV IV through the enzyme by photoinitiating the active state for radical generation. Together, the principles that emerge from addressing these specific aims will be applied to explain the functions of a variety of enzymes and proteins that derive their activity from PCET.

Abstract Proton-coupled electron transfer (PCET) is a ubiquitous mechanism in biology, serving as the basis for mediating steps involving biosynthesis of metabolites, radical generation and transport, and the activation of substrates at cofactors. The control of highly reactive radical intermediates is achieved by coupling proton and electron transfer processes. Management of radicals in biology is of particular relevance to human health, as enzymes operating by PCET are therapeutic targets with wide-ranging applications including chemotherapy, anti-retroviral and anti-bacterial drugs and anti-inflammatory agents. Of the enzymes that operate by PCET, ribonucleotide reductases (RNRs) are exceptional in their biological function and are paramount to health, as the enzymes produce the DNA building blocks for life. The central role of RNRs in nucleic acid metabolism has made the human RNR the target of five clinically used therapeutics that shut down the PCET pathway and, consequently, nucleotide reduction. The class Ia RNR is the exemplar of biological PCET; its function originates from a reversible long-range radical transport pathway that spans 35 Å and two subunits (? and ?) upon every turnover. An interdisciplinary approach integrates a suite of experimental methods encompassing biochemistry, steady-state and transient biophysical spectroscopies, synthesis, and electrochemistry to target three specific aims. Specific Aim 1 seeks to address the role of PCET in nucleotide reduction, both in the substrate activation phase involving the conserved radical at the ?top face? of the active site, as well as in the radical substrate reduction phase at the ?bottom face? of the active site. Work will be advanced by (i) leveraging newly developed selenocysteine incorporation methodologies to alter proton inventories and electron affinities, (ii) examining rate constants of individual steps using model compounds, and (iii) structurally capturing forward radical transport leading into the active site. As the coupling between the proton and electron along the radical transport pathway is the target of conformational gating by the enzyme, Specific Aim 2, is designed to identify amino acid networks that govern allosteric PCET regulation between the ? and ? subunits, and to rigorously define the structural dynamics at the interface that modulate RNR activity. This work is guided by new structural insights afforded from cryo-EM studies, which allow both the nature of subunit interactions and the networks of amino acids that connect the catalytic, specificity, and activity sites of the intact enzyme to be identified. The structural and temporal visualization of subunit dynamics that come from these studies will inform on the design of new small molecule therapeutics targeting the subunit interface. Specific Aim 3 will utilize biochemical and molecular biology innovations to elucidate initial events of radical transfer within the ?- subunit with a focus on a critical tryptophan within the PCET pathway. These data will contribute to an understanding of how the radical of RNR remains unreduced until required for activity, and the role of the protein structure in coordinating PCET within ? and relaying radicals to the ? subunit.

This award is jointly supported by the Major Research Instrumentation and the Chemistry Research Instrumentation Programs. Harvard University is acquiring a dual-source single crystal diffractometer equipped with high-flux Cu and Mo microfocus X-ray sources, an enhanced detector, and a cryogenic device to support the research of Professor Theodore Betley and colleagues Jarad Mason, Daniel Nocera, and Shao-Liang Zheng. In general, an X-ray diffractometer allows accurate and precise measurements of the full three-dimensional structure of a molecule, including bond distances and angles, and provides accurate information about the spatial arrangement of a molecule relative to neighboring molecules. The studies described here impact many areas, including organic and inorganic chemistry, materials chemistry, biochemistry, and catalysis. This instrument is an integral part of teaching as well as research and research training of undergraduate and graduate students in chemistry and biochemistry at this institution. The facility serves as a regional XRD resource benefitting students and faculty from primarily undergraduate institutions within the Commonwealth of Massachusetts and surround New England regions with impacts through active collaborations with researchers at Wellesley College.<br/><br/>The award is aimed at enhancing research and education at all levels. Research enabled by the instrument is focused on organic synthesis, photoredox catalysis, C-H bond oxidation and functionalization catalysis, organocatalysis, reactive intermediate isolation, chemotherapeutic development, small molecule activation, novel magnetic material synthesis, tunable metal-organic phase- change materials, barocaloric responsive materials, and porous network materials. Furthermore, the new diffractometer will be utilized in probing both photo excited state and thermally driven transformation during in situ diffraction collection.<br/><br/>This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.