Rarely in chemistry does the opportunity to explore the chemistry of a new functional group appear. The pentafluorosulfanyl (SF5) group, one of the few new functional groups of the last 100 years, has the potential to dramatically impact both life sciences and materials chemistry. The SF5 group presents a square pyramid of sulfur-bound fluorines to receptors yet occupies a volume somewhat less than the tert-butyl group. The large dipole moment in the carbon-SF5 bond results in long range electrostatic interactions of the substrate molecule. As the core building blocks of an enormous number of biologically relevant molecules, the synthesis of aliphatic SF5 containing carbonyl compounds quickly and economically is invaluable. The stereochemistry of reactions of cyclic and acyclic SF5-containing aldehydes, ketones and oxocarbenium ions with nucleophiles will be elucidated. Both the steric effects and electrostatic interactions of pentafluorosulfanylation can be employed in the synthesis of carbohydrates, amino acids and azetidinones from SF5-containing building blocks. The broader impact. Of vital economic and social importance, the utility of many organofluorine compounds is plagued by both metabolic and environmental limitations. The ready availability of these new SF5-containing molecules can be the first step in replacing trifluoromethylated agrichemicals that persist in the environment with adverse effects on both humans and animals. As replacements in pharmaceutical agents, facile SF5 group metabolism to substances that are not immunologically or enzymatically toxic may expand the utility of anti-malarial or anxiolytic drugs. The proposed program trains the next generation of students in basic synthetic fluorochemical and physical organic chemistry. Students will utilize multi-dimensional NMR methods and ab initio computational techniques. Students engaged in this cross-disciplinary project will be prepared to join other scientists and engineers with multidisciplinary backgrounds and experience in research and problem-solving. Within the last three years, PI has mentored nine students from historically under represented groups. Of these students, to date, five have continued their studies in graduate school. The development of a new functional group and its applications in synthesis can have an impact on nearly all areas of organic chemistry and offers a uniquely American technology to our industries. The product of the proposed research clearly has direct applicability to the development of new building blocks for medicinal chemistry and materials science as well as the potential to illustrate new strategies for the control of asymmetry in synthesis, a basic requirement of 21st century preparative methods.

Project Report

Overview A combination of the novel steric effects and electrostatic interactions of the pentafluorosulfanyl unit has been used to direct the stereochemistry of reactions and the conformation of products of interest to medicinal chemists. Substitution of the apical fluorine of the SF5 group by an alkyl or aryl group to form a tetrafluorosulfanyl substituent have enabled the synthesis of polar crystals and photosensitive monomers with utility in materials research. The polar and steric effects of pentafluorosulfanyl substitution on the selectivity and reactivity have been investigated in the ketene imine cycloaddition reaction. Functionalized SF5-bearing beta-lactams have been tested for antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA). Alkyl and aryl tetrafluorosulfanes have been prepared by photochemical as well as normal radical addition processes to explore the effect of the tetrafluorosulfanyl group on reactivity and conformation. The influence of substituents on bonding in fluorinated hypervalent sulfur compounds has expanded our understanding of the electronic and photochemical behavior of these products. In particular, our appreciation of the photosensitivity of the new monomers has led to a proof-of-concept demonstration of the patterning of a novel negative resist deposited on a silicon wafer. Intellectual Merit. The relationship between structure and reactivity of aliphatic fluorinated hypervalent sulfur compounds was explored. The influence of steric demand, electronegativity and dipole moment on the physical properties, conformation, and selectivity of beta lactams, aldehydes, alkenes and alkanes containing fluorinated hypervalent sulfur was investigated. The application of the photosensitivity of the reactants on the selectivity and reactivity of aryl tetrafluorosulfanyl halides in was contrasted with the results of chemically initiated reactions. The dipolar properties of the novel aryl tetrafluorosulfanyl alkenes were used to prepare polar crystals with potential piezo- and pyroelectric properties. Broader Impacts Promotion of Teaching and Learning- As few as a half-dozen laboratories remain in the US to train students in the handling of extraordinarily reactive reagents such as bromine trifluoride, chlorine fluoride or fluorine, reagents essential to fluorochemical research. The proposed research will sustain our ability to train students in this crucial area of chemical technology and research. Participation of Under-represented Groups. The PI’s research group currently includes two students of color and two Latina students. The PI has previously mentored nine students from historically underrepresented groups (African-American, Latino, and Native American): Qaid N Foulks, Prince Acheampong, Justice Agyei, Fedena Fanord, Keesha Smith, Diana Ongiti, Marsha Charles-Pierre, Tracey Pacheco and Sanjay Sekor in studies related to the proposed work. Over the period of the project Juan Duran, Kirali Genao, Sandip Khatri, David Johnson and Matt Cerda were engaged in project-supported research activities. Of past students, four have continued graduate studies; Ms. Smith received her Ph. D in chemistry, Ms. Fanord received a McKnight Doctoral Fellowship at the University of South Florida and Ms. Genao recently was a MHRIT participant in Lille, France in 2012. Infrastructure for Research and Education. We operate and make available to the scientific community a dedicated laboratory equipped with the necessary infrastructure (monel pressure reactors, stainless steel storage vessels, metal vacuum lines, PTFE storage vessels and transfer systems, capacitance manometers, hi performance vacuum systems with corrosion resistant oils, isolated ventilation and secure storage) for the preparation, purification and characterization of both liquid and gaseous reactive fluorinated intermediates and synthons. Colleagues at MIT, University of Southern California and the Université de Rouen. Benefits to Society. As fluorine chemistry plays a central role in new product development as well as in current products, including those derived from materials science, agrochemical, biochemical and medicinal chemistry, six patent or provisional patent applications have been filed to enable the translation of this sponsored research to commercial applications. Of particular note is the potential of the chemically and physically robust hypervalent sulfur compounds to decompose in an environmentally benign manner.

National Science Foundation (NSF)
Division of Chemistry (CHE)
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Tingyu Li
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Suny at Albany
United States
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