Metal-Free Functionalization of Electron Rich Aromatic Systems: ortho-Quinone Methides, Aza-ortho-Xylylenes, and N,N-Dialkylaniline N-Oxides in Synthesis

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The Chemical Synthesis Program of the Chemistry Division supports the project by Professor William Chain. Professor Chain is a faculty member in the Department of Chemistry & Biochemistry at the University of Delaware. He is developing new classes of reactions that that are facilitated by reversing the normal polarity and hence reactivity of molecules. Reversing the polarity means that molecules that normally behave as if they are negatively charged behave as if they are positively charged. The change facilitates the formation of a wide array of new carbon-carbon, carbon-oxygen, carbon-nitrogen, and carbon-sulfur bonds that lie at the heart of chemical structures that serve many purposes in industrial, chemical, and medical applications. Professor Chain's research group provides the highest level of education and training for students at all ages. It also offers opportunities for students typically underrepresented in science. Professor Chain is actively engaged in outreach activities in local elementary, middle, and high schools to promote science education and engagement of students in science disciplines. These activities include summer research internships in Professor Chain's laboratory for promising high school seniors. These internships encourage student interest in university studies and careers in the sciences. An array of aromatic substitution reactions have been described since the seminal work of Charles Friedel and James Crafts in the mid to late 1800's. Despite this body of work, there are still limitations in electron-rich settings; functionalization of electron-rich aromatic systems can be controlled by virtue of a temporary inversion of reactivity. Generating and engaging highly reactive intermediates in a controlled and predictable manner by an umpolung strategy is a critical tool set in organic synthesis. Synthetic strategies in this regard are the manipulation of latent aromatic compounds and/or the temporary engagement of heteroatom-bound electron pairs and harnessing these energetic structures to form congested carbon-carbon and carbon-heteroatom bonds. This award explores two reactivity manifolds available to phenols and anilines. In the first reactivity manifold, silyl-protected phenols and anilines are converted to ortho-quinone methides (QOMs) and aza-ortho-xylylenes (AOXs). These protected species are mixed with silyl enol ethers or silyl ketene acetals to release both the electrophilic and nucleophilic participants in conjugate addition reactions by treatment with easily dispensed and handled fluoride sources. In the second reactivity manifold, anilines are oxidized to the corresponding N-oxides, which facilitates an array of bond formations that take advantage of the excision of the weak N-O bond. By virtue of these mild reaction conditions, the scope and capability of umpolung reactions with electron rich aromatic rings is expanded. The educational plan includes outreach to local elementary, middle, and high schools with integration of high school students into the research program in as research interns.