Melanie Sarah Sanford - US grants

This award from the Division of Chemistry (CHE) supports a Research Experience for Undergraduates (REU) site led by Brian Coppola and Melanie Sanford at the University of Michigan. The research projects supported in this site are in broad areas of chemistry. Undergraduates will be recruited to this site primarily from institutions that lack infrastructure to support undergraduate research, including students from underrepresented groups. The site will support fourteen students per summer in a ten week program. A sample of the projects that undergraduates will work on include: (1) ultrafast laser spectroscopy of solvation dynamics; (2) the study of nickel-based catalysts for chain-growth polymerizations; (3) two-photon spectroscopy of novel materials; (4) the formation and study of semifluorinated alkylsiloxane self-assembled monolayers; (5) the study of CH activation with Pt(II) diimine catalysts (6) the study of the kinetics for ligand attachment to dendritic nanoparticles. In addition to conducting research during the summer, the students participating in this program will participate in a number of professional development activities, and will have expanded opportunities for presentation of research at national disciplinary meetings.

Young scientists need exposure to modern research methods and tools as part of their training. This REU site aims to provide cutting-edge research training in the chemical sciences, with a strong emphasis on areas of science with important societal impacts. Undergraduate researchers participating in this site will have significant, hands-on access to sophisticated research tools. The diverse student cohort participating in research at this site will be well-prepared for graduate school, and eventual employment as part of the country's technical workforce.

DESCRIPTION (provided by applicant): This proposal describes the development of general and selective Pd-catalyzed methods for the ligand-directed conversion of unactivated arene and alkane carbon-hydrogen bonds into new functional groups. Aims 1 and 2 focus on exploring new methods for C-H bond fluorination and trifluoromethylation, utilizing readily available and inexpensive fluoride and trifluoromethyl starting materials. A key objective is to identify novel (and potentially broadly applicable) reactivity modes for the Pd-catalyzed introduction of fluorinated groups into organic molecules. Aim 3 seeks to develop methods that use readily available dioxygen as the terminal oxidant for converting C-H bonds into diverse functional groups. Aim 4 focuses on developing widely applicable asymmetric catalytic C-H functionalization reactions. All of these aims will be tackled by taking advantage of the Sanford group's expertise in new reaction development/optimization, in detailed mechanistic investigations, and in the synthesis/characterization of reactive organopalladium intermediates. The reactions developed herein will find application in the synthesis/diversification of pharmaceutical candidates, natural products, positron emission tomography (PET) imaging agents, and biological probes.

This CAREER award by the Inorganic, Bioinorganic and Organometallic Chemistry program supports work by Professor Melanie Sanford at University of Michigan, Ann Arbor to study the fundamental chemical reactivity of high oxidation state late transition metal complexes including complexes of Pd(IV), Ni(III) and Ni(IV). The proposed studies will provide insights into new modes of reactivity for carbon-heteroatom bond-forming transformations at metal centers, which could ultimately facilitate the industrial synthesis of fine and/or commodity chemicals.

This research will focus on mechanistic aspects of how these metals promote reactions that form of new
chemical bonds. The award also supports the development and dissemination of a new model for advanced undergraduate laboratory experiments in catalysis. The proposed laboratory experiments will incorporate modern aspects of the field (for example, the olefin metathesis reaction, the subject of the 2005 Nobel Prize in Chemistry), and are designed to transition the students from a traditional laboratory course to a highly authentic research-like laboratory experience. This new course format is expected to increase undergraduate participation in research and ultimately in scientific career paths. Additionally, the proposed research
projects will provide broad training for diverse undergraduate and graduate students in
mechanistic and synthetic inorganic chemistry.

The Department of Chemistry at the University of Michigan will upgrade a 600 MHz nuclear magnetic resonance (NMR) spectrometer and equip it with solid state NMR capabilities with support from the Chemistry Research Instrumentation and Facilities: Multi User (CRIF:MU) program. The instrument will be employed in several biophysical and biomaterials and synthetic chemistry projects requiring high field SSNMR including: The high field SSNMR will be used in studies of polymorphic organic compounds, nanomaterials, reactive intermediates, interactions of small molecules with phospholipid bilayers, molecular organization of bone materials, molecular dynamics of proteins in nanocrystals and fuel cell membranes.

Nuclear Magnetic Resonance (NMR) spectroscopy is the most powerful tool available to chemists for the elucidation of the structure of molecules. It is used to identify unknown substances, to characterize specific arrangements of atoms within molecules, and to study the dynamics of interactions between molecules in solution. Access to state-of-the-art NMR spectrometers is essential to chemists who are carrying out frontier research. The results from these NMR studies will have an impact in synthetic organic chemistry, organometallic chemistry, biophysical chemistry and materials chemistry.

This award from the Division of Chemistry (CHE) supports the renewal of a successful Research Experiences for Undergraduates (REU) site at the University of Michigan (UM) Ann Arbor for the summers of 2008-2010. This site will be managed by Brian Coppola with assistance from Melanie Sanford both from the Department of Chemistry at UM. Thirteen individuals from around the United States, typically rising sophomores and juniors, will comprise the central component of this site. Eight students will be supported by NSF-REU, three will be supported by University funds, and two will be supported by the Intel Corporation, a leader in the computing and communcations industry. The REU students have access to all of the research groups associated with the chemistry department, including interdisciplinary programs in materials chemistry, chemical biology, life science, medicinal chemistry, and environmental chemistry. In addition to departmental seminars and symposia other non-research program activities include: training on laboratory safety and environmentally safe laboratory practices, the use of on-line Chemistry library resources (SciFinder, Beilstein, etc.), ethics, chemical instrumentation, field trips to local chemical industry, mentoring for applying to graduate school, and career mentoring including science career options, job searches, interview preparation and resume writing. Each research group will require oral presentations as a natural part of their scientific activities and all students will write a final progress report. Finally, a regional research symposium will be held at one of the REU Site-holding schools where undergraduates from across the area will gather to present their work.

This award is funded under the American Recovery and Reinvestment Act of 2009 (Public Law 111-5).

With this award from the Chemistry Research Instrumentation and Facilities Multiuser Program (CRIF:MU), Professor Carol A. Fierke from the University of Michigan and colleagues Adam J. Matzger, John Montgomery, Vincent L. Pecoraro and Melanie S. Sanford will acquire a single crystal X-ray diffractometer with a strong copper source to obtain high-resolution structural information in diverse fields including synthetic organic chemistry, materials science and inorganic chemistry. This instrument will support education and research in complexes from metallacrowns producing soft materials; determination of absolute and relative stereochemistry of molecules important in catalytic reactions; in synthesis and characterization of biological properties of fluorinated proteins; in mechanistic studies of late metal complexes with high oxidation states; and in metal-organic frameworks.

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 will impact a number of areas, including chemistry, materials chemistry and biochemistry. This instrument will be an integral part of teaching as well as research.

This award in the Division of Chemistry supports research by Professor Melanie Sanford at the University of Michigan to investigate the mechanism, scope, selectivity, and ligand effects in stoichiometric reactions involving Pd(III) and Pd(IV) intermediates. The reactivity and selectivity profiles discovered will enable the rational design of new catalytic transformations. Palladium is an extremely important transition metal that is widely used in homogeneous catalytic transformations for the construction of carbon-carbon and carbon-heteroatom bonds. These reactions have found extensive application in the synthesis of pharmaceuticals, natural products, fine chemicals, and commodity chemicals. The proposed research will demonstrate the feasibility of diverse organometallic reactions (including C-H activation, migratory insertion, and nucleopalladation) at appropriately designed high oxidation state palladium complexes. Ultimately, the novel reactivity and selectivity profiles established herein will enable the rational design of new catalytic transformations.

The PI and coworkers will expand an outreach program for high school students called "Science Saturdays", which promotes broader participation in the physical sciences by exposing students to an authentic research-like experience, to another site in Michigan. This laboratory trains a diverse set of students (29 total PhD students and post-docs since 2003), of whom 17 are women and 3 are members of underrepresented minority groups. Graduate and undergraduate students working on this project will receive interdisciplinary training in inorganic synthesis, inorganic reaction mechanisms, and synthetic organic chemistry.

The NSF Sustainable Energy pathways (SEP) Program, under the umbrella of the NSF Science, Engineering and Education for Sustainability (SEES) initiative, will support the research program of Prof. Levi Thompson and co-workers at the University of Michigan Ann Arbor to develop new non-aqueous redox flow battery chemistries for sustainable energy storage devices. Electricity accounts for ~40% of the energy consumed in the U.S. and most is derived from non-renewable resources including fossil and nuclear fuels. Pathways to greater energy sustainability will require the use of renewable resources. The lack of reliable, low-cost energy storage is one of the key challenges to large-scale integration of renewables, with their intermittency, into the grid. This Sustainable Energy Pathways (SEP) project will deliver the transformative scientific and engineering outcomes needed to demonstrate cost-competitive, non-aqueous redox flow batteries (RFBs) for grid storage applications. The research has three objectives. Objective 1: Detailed structure-composition-function relationships will be developed for metal beta-diketonate complexes in organic and ionic liquid electrolytes. These relationships will be used to identify the most promising chemistries for characterization of the kinetics and mechanisms at engineered electrodes. Objective 2: The results will be used to design and fabricate small-scale flow cells to evaluate large-scale RFB relevant performance characteristics. Objective 3: An integrated sustainable design and assessment framework will be developed and used to guide the research and evaluate sustainability performance across the electrochemistry, device, and grid integration levels. The results will be compared to those for other storage technologies.

This SEP research project will consider the scientific, technical, environmental, economic, and societal issues associated with energy storage, and establish a new sustainable energy pathway for advancing fundamental battery chemistries to large-scale RFBs for utility scale storage. The students, post-doctoral scholars and other researchers participating in the project will be part of an interdisciplinary team working on technology that address key societal and economic and environmental challenges facing our nation. On completion, they will be well prepared for leadership positions in industry, government, and/or academia.

The chemistries developed in this SEP project will provide the basis for RFBs with an attractive combination of benefits including low cost when compared to other energy storage solutions being considered for grid applications; flexibility in design due to the decoupled energy and power (like fuel cells); simplified thermal management leading to enhanced safety; little or no self-discharge resulting in high efficiencies; and modularity allowing easy scaling, maintenance and modification. The introduction of sustainable, low-cost RFB-based energy storage technologies will improve the integration of intermittent renewable energy sources such as wind and solar into the electricity grid and significantly reduce emissions of greenhouse gases and other pollutants produced from fossil resources including coal and natural gas.

In this project funded by the Chemical Catalysis program of the Chemistry Division, Professor Melanie Sanford of The University of Michigan focuses on the development of new catalysts that can ultimately be used for the synthesis of pharmaceuticals and agrochemicals via more efficient, direct, and environmentally friendly processes. To meet this challenge, the project will establish a more detailed scientific understanding of the challenging steps of the catalysis processes. In addition, new catalysts based on less toxic and earth abundant elements will be explored and developed. In addition, an outreach program led by Professor Sanford (UM FEMMES, Females Excelling More in Mathematics, Engineering, and Science) exposes middle school girls from Ann Arbor and surrounding communities to hands-on science activities. The broader impacts of this work include potential societal benefits from the discovery of more efficient catalysts and catalysts derived from less toxic, earth abundant metals. This project serves as a training ground for undergraduate and graduate students for careers at the interface of catalysis, inorganic and organic chemistry.

The research focuses on detailed mechanistic studies of the challenging steps of the catalytic cycle, primarily alkyl-heteroatom bond-forming reductive elimination processes. Ligands will be designed to stabilize the reacting metal centers (high valent Pd, Ni, and Cu complexes) in order to investigate the scope, mechanism, and stereochemical outcomes of these processes.

University of Michigan chemistry professors Brian Coppola and Melanie Sanford co-direct the Research Experiences for Undergraduates (REU) Site in Interdisciplinary Chemistry, funded by the Chemistry Division of NSF. This is a continuation of a long established program that began in 1989. In this renewal, 15 students from around the United States, recruited primarily from settings where individuals do not have the opportunity to carry out graduate-level research, spend 10 weeks engaged as full-fledged participants in the department's research groups. There is a recruiting emphasis on women and students from underrepresented groups.
Additional activities (lectures, workshops, trips, and social events), offered jointly with other programs on- and off-campus, provide a broad integration into scientific and professional communities. A regional poster session is the culminating activity each summer.

Students participate in a diverse collection of modern research problems centered in the interdisciplinary chemical programs in the University of Michigan chemistry department, including chemical biology, organometallics, energy, sustainability, surface science, sensors, optics and imaging, RNA biochemistry, and ultrafast dynamics. The REU students have access to all of the research groups in the chemistry department, including interdisciplinary groups. REU students produce publishable results. The experience also gives participants confidence to remain in science, pursue graduate education, and ultimately to join the technically-trained workforce in academia, industry, or government laboratories.

Project Summary: Radiotracers containing [18F]-labeled electron-rich aromatic rings are among the most highly sought-after PET imaging agents. For example, the development of a clinical synthesis of 6-[18F]fluoro- L-DOPA has been a challenging and high-profile target in the PET community for more than 20 years. Despite the great importance of [18F]-labeled electron rich arenes, there are very few radiosynthesis methods for accessing these structures. The grant builds on an existing collaboration between the physical sciences (Chemistry, Sanford) and life sciences (Radiology/Medical Imaging, Scott) at the University of Michigan, bringing their collective expertise to bear on this problem. The overall objective of the proposed research is to address this critical need by developing nucleophilic radiofluorination methods that (a) enable radiochemists to 18F-label electron rich aromatic rings starting from readily available, stable precursor molecules and (b) can be automated, validated, and translated to radiochemistry manufacturing facilities for use by non-chemists to synthesize clinical radiotracer doses. The central hypothesis of this application is that copper mediated radiofluorination methods will uniquely enable this team to achieve these objectives. The proposed research will develop Cu-mediated methods for radiolabeling (mesityl)(aryl)iodonium salts (Aims 1 and 2) as well as aryl iodides, aryl boronic acids and aryl stannanes (Aim 3) with 18F?. The work is significant because it entails development of novel methods for the synthesis of previously inaccessible (or difficult to access) 18F-labeled PET radiotracers of clinical interest: 4-[18F]fluoro-m-hydroxyphenethylguanidine ([18F]4F-MHPG; cardiac regional nerve density), 6-[18F]fluoro-L-DOPA ([18F]F-DOPA; dopaminergic pathway), [18F]2'-methoxyphenyl- (N-2'-pyridinyl)-p-fluoro-benzamidoethylpiperazine ([18F]MPPF; 5-HT1A receptor), (4- [18F]fluorophenyl)triphenylphosphonium chloride ([18F]BFPET; mitochondrial voltage sensor), [18F]octreotide ([18F]TOC; somatostatin 2 receptors in, for example, neuroendocrine tumors); pre-clinical interest: new radiotracers for the GAT-1 GABA transporter and dopamine D3 receptor, and targets of interest to the pharmaceutical industry (BACE, orexin receptors). These goals will be accomplished through a variety of innovations including: (a) the development of novel copper-mediated methods for the nucleophilic radiofluorination of electron rich arenes (including new methods for the generation and utilization of Ag18F), (b) the mechanistically-driven optimization of these new radiofluorination reactions and (c) translation of these methods to clinically validated radiosyntheses (automated synthesis of cGMP-compliant clinical doses). Overall, this project will deliver four novel Cu-mediated methods for synthesizing 18F-labeled radiotracers and validated clinical synthesis of numerous important radiotracers. Both of these deliverables will expand the utility of PET imaging for the detection, treatment, and prevention of disease.

Organometallic Chemistry of High Valent Nickel

Transition metal catalysts are used to manufacture many important products, including life-saving pharmaceuticals, crop-protecting agrochemicals, and electronic materials. The cost and sustainability of these products are directly impacted by the development of new catalysts that are less expensive, that generate less waste, and that operate under milder conditions. A particularly important goal for the field is to replace catalysts that are based on rare and expensive precious metals (e.g. palladium) and towards those derived from inexpensive and more readily available metals (e.g., nickel). Often, however, the more desirable inexpensive metals have very different (and often problematic) properties, that make them difficult to use for these important applications. In this project Dr. Sanford and her research group are conducting detailed studies of nickel catalysts. The overall goal of this work is to determine how to control the properties of nickel catalysts to enable them to perform as well or better than their palladium analogues. Dr. Sanford is also actively involved in outreach activities that seek to increase the participation of women in science and engineering. For example, she is working with programs that engage middle-school aged girls in scientific activities and that train diverse graduate students for careers in science/technology.

With funding from the Chemical Catalysis Program of the Chemistry Division, Dr. Sanford of the University of Michigan is studying the fundamental organometallic chemistry of high valent nickel intermediates [i.e., nickel(III) and nickel(IV) complexes]. Despite their potential relevance to a wide variety of important Ni-catalyzed cross-coupling and C-H functionalization reactions, the synthesis and reactivity of organometallic nickel(III) and nickel(IV) compounds has not been systematically explored. The current work is focused on establishing the feasibility and mechanisms of a variety of transformations at nickel(III) and nickel(IV) centers using both model systems and catalytic intermediates. The reactivity and selectivity profiles that are being established herein are expected to have a transformative impact on the design and optimization of new high valent Ni-catalyzed transformations. Dr. Sanford is also actively engaged in outreach programs aimed at broadening participation of women in science at the K-12, undergraduate, graduate, and faculty levels. Furthermore, her project is training a diverse group of scientists in the interdisciplinary areas of inorganic and organic synthesis, inorganic reaction mechanisms, electrochemistry, and catalysis. A well-trained and diverse scientific workforce is essential for continued advances in innovation and technology in the 21st century.

PROJECT SUMMARY Overall, this program will develop a variety of new metal-catalyzed synthetic methods for the construction and late-stage diversification of biologically relevant molecules. The proposed work encompasses many different types of chemical reactions but is unified by two central themes. First, it focuses on developing transformations that provide access to new chemical space and/or that streamline the synthesis of existing structures. Second, the proposed efforts are guided by detailed mechanistic analysis and organometallic chemistry. A first project continues the Sanford group's long-standing efforts in developing new approaches to carbon? hydrogen bond functionalization. The traditional approach in this area focuses on the discovery of highly selective reactions, in which the catalyst, substrate, and reaction conditions are tailored to convert a single, specific C?H bond into a new functional group. While successful, this approach is limited by a disproportionate focus on relatively simple substrates that contain only one ?reactive? C?H site. The proposed efforts will contribute to shifting this paradigm by targeting reactions in which a single starting material is converted into multiple C?H functionalization products. This will provide access to new structures that are of high interest in medicinal chemistry. Additionally, it will provide a wealth of mechanistic data about the factors responsible for reactivity and selectivity that will be used to drive next-generation catalyst design and new reaction discovery. A second project will target the development of new metal-catalyzed cross coupling reactions. Notably, cross- coupling is among the most widely used transformations in organic synthesis. The proposed efforts present a unified approach to target three central challenges associated with modern cross-coupling methods: (1) the use of abundant carboxylic acid-derived electrophiles as coupling partners; (2) elimination of the requirement for added base; and (3) the invention of reactions that form new types of bonds, with a focus on introducing fluorine- containing functional groups that are of high value in medicinal chemistry. All three goals will be accomplished in an integrated fashion via a common mechanistic foundation. A third project leverages the Sanford group's expertise in organometallic chemistry, mechanistic analysis, and catalytic reaction development to identify and tackle an emerging challenge in organic synthesis. SF5- substituted (hetero)aromatic rings are gaining increasing prominence as entities for integration into drug candidates. However, despite the growing significance of this functional group, synthetic methods for accessing aryl?SF5 derivatives remain extremely limited. This proposal outlines fundamental studies of the synthesis and reactivity of metal?SF5 complexes (species that are currently unprecedented). These studies will then be used to drive the development of catalytic aryl?SF5 coupling reactions.

Abstract: Radiotracers containing [18F]-labeled electron-rich aromatic rings are among the most highly sought- after PET imaging agents but have been historically challenging to synthesize. Recent efforts have sought to improve the late-stage labeling of (hetero)arenes with [18F]fluoride. In particular, transition metal-mediated reactions using high molar activity [18F]fluoride have changed the way radiochemists form C?18F bonds, and copper-mediated radiofluorination (CMRF) has proven one of the most versatile of approaches. In the previous award, we reported 10 new CMRF reactions, validated them for Good Manufacturing Practice (GMP), and used them to synthesize FDA-approved clinical doses. However, despite many successes, several key challenges remain for the widespread clinical application of CMRF: (a) many important organic scaffolds are incompatible with existing CMRF processes, (b) yields of automated CMRF methods are typically moderate and thus unsuitable for commercial distribution, and (c) disposable cassette technologies are not available for CMRF on automated radiosynthesizers, limiting radiotracer production for routine clinical use. All of these challenges will be addressed in this renewal proposal. The overall objective is to develop robust methods for clinical production of diverse PET radiotracers. Our central hypothesis is that CMRF is uniquely positioned to enable us to achieve this goal. The proposed research will identify new reactions to radiofluorinate scaffolds that are incompatible with existing CMRF (Aim 1), use cutting edge machine learning techniques to improve automated CMRF yields (Aim 2), and develop cassette technologies for reliable GMP production of clinical radiotracers using CMRF (Aim 3). The research is significant because it entails development of methods for radiolabeling bioactive molecules containing functionality that is incompatible (or low yielding) with existing CMRF (heterocycles like pyridine and morpholine, drug molecules like GW405833), as well as optimized automated methods and cassettes for radiotracers that have been challenging to access for decades (e.g. [18F]FDOPA). The viability of the proposed efforts is supported by extensive preliminary results that provide groundwork for the exciting new research directions. Our team has been collaborating for 7 years and our expertise in transition metal catalysis (Sanford), radiochemistry (Scott), and machine learning (Doyle) uniquely positions us to accomplish the proposed research. The project goals will be accomplished through a variety of innovations including: (1) developing methods for labeling challenging electron-rich (hetero)arenes from new precursors (C?H bonds, aryl halides), (2) the first application of machine learning to radiochemistry, and (3) development of automated cassettes for conducting CMRF using the newest generation of radiosynthesizers designed for plug-and-play production. Overall, this project will deliver multiple new methods for synthesizing 18F-labeled radiotracers that are inaccessible using existing methods, and validated clinical syntheses of important radiotracers. All of these deliverables will expand the utility of PET imaging for the detection, treatment, and prevention of disease.