High-Precision Synthesis and Analysis of Deuterated Cycloalkene Isotopomers

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With the support of the Chemical Synthesis Program in the Division of Chemistry, Professors W. Dean Harman and Brooks Pate of the University of Virginia are studying ways to make and identify molecules with distinct three-dimensional structures that differ in the attachment of hydrogen (H) and its isotope deuterium (D = a hydrogen atom with an extra neutron) to specific carbon atoms. Professor Harman is using a metal complex to template the controlled addition of deuterium to organic molecules. Professor Pate is developing molecular rotational resonance spectroscopy techniques to identify the structural distinctions between molecules that only differ in the attachment of hydrogen and deuterium. While hydrogen and deuterium exhibit similar broad reactivity patterns, carbon-deuterium bonds are slightly stronger than carbon-hydrogen bonds and this difference can be used to alter how a fast a reaction occurs. By installing deuterium instead of hydrogen in specific portions of a molecule, the biological activity of the molecule can be adapted to provide opportunities for increased drug lifetime, reduced dosing, and improved safety margins. Common techniques used by organic chemists to identify the structures of molecules are insufficient for determining the attachment of a hydrogen and a deuterium at a single carbon atom. Molecular resonance spectroscopy is being developed to address this limitation. These activities will provide an interdisciplinary education for a diverse group of graduate and undergraduate students. Professors Harman and Pate are also actively pursuing opportunities to increase participation in chemistry by underrepresented groups through engagement in outreach activities.Owing to the deuterium kinetic isotope effect, compounds in which hydrogen atoms have been replaced with deuterium can show dramatically reduced rates of metabolism. To progress toward the goal of having accessible isotopologue building blocks for incorporation into the active pharmaceutical ingredient of existing or potential drugs, Professor Harman is developing strategies for the precise synthesis of isotopologues and stereoisotopomers of common cycloalkenes. The fundamental reactivity of aromatic molecules bound to tungsten complexes is being investigated to enable the precise, sequential addition of individual deuterium atoms to aromatic rings. Through this process, a variety of specific isomers can be generated in high purity, solely differentiated by the number, position, and three-dimensional location of the deuterium atoms. A key challenge to making isotopologue and stereoisotopomer building blocks is the inability to accurately determine their molecular geometry and extent of purity through conventional characterization methods. Professor Pate is addressing this limitation through the development of molecular resonance spectroscopy techniques for enantio-enriched isotopomers, an approach that his designed to accommodate high-throughput analysis. With the good synergy between the development of synthetic chemistry and of new complementary analytical techniques, this research will provide a strong, interdisciplinary training environment for graduate and undergraduate students.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.