Direct Functionalization of Heteroarenes using Phosphorus

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Direct functionalization converts chemically inert C-H bonds into chemically malleable C-R bonds (R = B, C, N, O, Cl, Br, I). Controlled functionalization in this manner is highly important in synthetic science, as it creates the building blocks necessary for countless man-made goods, from pharmaceuticals to polymers, electronics and agrochemicals. Catalysts that enable this transformation are largely based on expensive nonrenewable precious metals, including palladium and iridium, sourcing of which has significant environmental and geopolitical issues. Finding sustainable alternatives based on cheap and earthabundant p-block elements, including phosphorus, has become increasingly urgent. We propose exploiting the multiple coordination sites offered by p-block clusters to catalyze the direct functionalization of heteroarenes, including pyridine, in one convenient step. About 60% of FDA approved pharmaceuticals alone feature a nitrogen heterocycle, such as pyridine.PRELIMINARY RESULTS: We have prepared and characterized the first example of a boron functionalized group 15 Zintl cluster. Compound 1 was found to be a very active catalyst for the addition of H-B bonds, hydroboration, across pyridines in a selective 1,4-fashion. Interestingly, it was also found that upon aqueous work-up of the reaction, the pyridine was reformed and H2 gas eliminated. These findings reveal that clusters can act as catalysts to add H-B bonds across pyridines, and re-aromatization and H2 elimination are strong driving forces. Re-aromatization in this hydroboration transformation is undesirable. Can we turn this negative into a positive? HYPOTHESIS: In our preliminary results, upon aqueous work-up we lose the hydride installed during the catalytic hydroboration. But if a nucleophile other than hydride is installed, and an H atom lost during rearomatization we would metathesis a C-H bond for a C-R bond. Compared to other catalysts that convert C-H bonds to C-R bonds on heteroarenes, our catalysts are based on the cheap and sustainable p-block element phosphorus. Polyphosphorus clusters are attractive platforms as catalysts because they can be structurally related to the heterogenous material red phosphorus.[6] Red phosphorus is very inexpensive and sustainable, but difficult to study. Catalytic transformations established with [P7] clusters will be extended to larger polyposphides, for example [P16] and [P21] systems, and then with red phosphorus itself. Studies with the molecular clusters allow for in situ studies, reaction optimizations, and mechanistic invesigations. While, red phosphorus-based catalysts open the door to industry translation and high recyclability / stability. OVERALL AIM: Establish phosphorus-based materials as catalysts for direct functionalization of heteroarenes.We will achieve our overall aim by meeting three Objectives:Objective A: Using [P7] catalysts activate B-R bonds with phosphorus/boron-based clusters.Objective B: Using pyridines as a prototype, close the catalytic cycle and optimize catalytic conditions.Objective C: Develop catalysis with larger polyphosphorus materials.TRAINING OFFERED: multi-nuclear NMR, XRD diffraction, computational chemistry, inert-atmosphere synthesis, organometallic chemistry, and mechanistic studies.