Mechanistic Studies of Halenium-Alkene Additions for Chemical Catalysis

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With the support of the Chemical Catalysis Program in the Division of Chemistry, Professors Babak Borhan and James E. Jackson of Michigan State University are studying new methods to control the three-dimensional structure and "handedness" of products in reactions that generate carbon-halogen and carbon-nucleophile bonds in the same operation. The products of these reactions serve as important chiral building blocks for many applications, for example, for the synthesis of pharmaceutically active agents or of agrochemicals. The Borhan-Jackson teams are working to expand and refine methods to catalyze the formation of a wide range of compounds of a specific desired handedness from much simpler starting substances. Sophisticated analysis techniques will be brought to bear on the areas of study such that superior catalysts can be rationally designed, in contrast to the essentially trial-and-error approaches used in the past. Ultimately, it is anticipated that this work will lead to more efficient processes for the manufacture of chiral molecules of importance to science, engineering, medicine, and commerce. The broader impacts of the funded project will extend to allowing the two PIs and their coworkers to recruit, train, and scientifically stimulate high school and undergraduate students in the laboratory via programs such as Project SEED. The involvement of these early stage science students many of whom belong to groups underrepresented in the physical sciences, in a dynamic, international lab and learning community, has the potential to help diversify the pool of students considering future STEM (science, technology, engineering and mathematics)-based study and careers.Halofunctionalizations of alkenes have recently joined the list of broadly applicable and genuinely useful chemical transformations that can be achieved in an enantioselective manner using chiral catalysis. However, to date, the most effective catalysts for asymmetric halenium-alkene addition processes, for example the well-known cinchona alkaloid dimer (DHQD)2PHAL, have been identified largely on an empirical basis. This collaborative project focuses on detailed mechanistic analyses of important classes of halofunctionalization reactions with the goal of enabling the rational design of simplified and practical new catalysts that are both affordable and highly selective. The approach taken is multi-faceted and involves examination of reaction kinetics, isotopic label tracing, kinetic isotope effects, quantum chemical models, and spectroscopic and structural analyses, with particular attention to the interactions among substrate alkenes, halogenation agents, and catalyst reactive sites. With an emphasis on allylamides, the investigative team will survey intramolecular halocyclizations and intermolecular halofunctionalizations, derive rate laws for each class of reaction, and determine the factors that control the mechanistic pathways. The alkene additions of interest form two new stereocenters in one step, potentially giving rise to four structurally distinct chiral products, or even eight when both regiochemical possibilities may be accessed. Coming from simple olefinic starting materials, this diversity of complex, functional group rich products is valuable, but only if the selectivity can be controlled. This research aims to provide the intellectual foundation needed to achieve generalized catalyst and process design, accelerating discovery based upon mechanistic understanding. If successful, these collaborative experimental/mechanistic studies will provide a useful model for the design and development of stereoselective catalysts well beyond the halenium-alkene addition reactions under study here.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.