Novel Synthetic Methodologies Exploiting Nitrogen-Containing Molecules

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Advances in the pharmaceutical or energy sectors are inherently linked to molecular synthesis. Consequently, it is critical to develop new tools to maximize efficiency and safety, while minimizing waste and environmental impact. Nitrogen (N) and nitrogen-based functionality play a key role in function, but are challenging with regards to synthesis and catalysis. Their basicity, natural nucleophilicity and reactive promiscuity are significant hurdles for any new synthetic method to jump. The overall goal of the research program is to address the challenges by developing novel, "outside of the box" synthetic methods, many of which flip nitrogen on its head and investigate its underexplored reactivity as an electrophile. C-H functionalization is an ideal synthetic strategy for incorporating nitrogen-based functionality (C-H?C-N). We will study complexes of sustainable first row transition metals for catalytic stereoselective amination reactions using novel chiral carbamate sulfilimine ligands. Such ligands having S-N bonds have yet to be explored in catalysis. As a new solution to stereoselective C-H functionalization, novel hypervalent iodine reagents will be developed that transfer a highly desired hydroxylamine (NH-OH) unit. The incorporation of hydroxylamine functionality is highly limited using current methods. We will explore new diazotization reactions that permit the synthesis of highly reactive diazonium electrophiles from aliphatic nitrogen compounds. The proposed method makes use of highly available amines derived from biosources, and represents a more sustainable route to synthesis. Importantly, the electrophiles can be applied toward the synthesis of compounds of interest in medicinal chemistry and energy storage. Furthermore, our proposal aims to exploit nitric oxide (NO), a toxic gas and pollutant, as a new reagent in both the synthesis of hydroxylamine-containing molecules and diazotisation that produces benign nitrogen (N2) as the sole waste. Finally, the reactivity of sulfilimines (S-N) and tetrazoles will be explored for applications in the deconvolution of therapeutic targets, where an electrophilic nitrogen will selectively trap protein nucleophiles. The proposed research takes advantage of modern techniques involving organometallic catalysis, continuous flow chemistry, photocatalysis, and electrochemistry to overcome challenges in molecular synthesis that are of paramount importance in the fields of pharmaceutical and energy sciences.