Catalytic activation of oxygen-containing functional groups

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Chemical synthesis is a laborious practice but is invaluable in providing access to molecules that provide benefits to society and help answer scientific questions. While any molecule can be prepared with existing technology, the demand of time and resources is often unreasonable. Chemical reactions that build complexity or introduce important functionality into an organic molecule are most desirable. In contrast, non-constructive redox manipulation, functional group interconversion, and protection/deprotection steps serve only to prepare a molecule for key bond formations. To make synthesis a more efficient and environmentally friendly practice, we need new chemical reactions that are able to directly harness the unprotected functional groups that are prevalent in abundant feedstock molecules in their native oxidation state. Transition metal catalysis, and cross-coupling reactions in particular, has proven itself to be powerful tool for building molecular complexity that is orthogonal to more traditional nucleophile/electrophile reactions. Thus, while Grignard reactions are the single most common non-catalytic method used to form C-C bonds, their use is now dwarfed by Pd & Ni-catalyzed couplings. Given the abundance of oxygen-containing functional groups like alcohols, phenols, ketones, and carboxylic acids, there are surprisingly few strategies for using these substrates in catalytic coupling reactions. The overarching goal of this research proposal is to change this by implementing activation strategies that exploit the natural behaviour of these functional groups. In particular, 'shortcut' reactions are sought. These direct, single step reactions are designed to replace commonly employed multi-step synthetic procedures that require non-complexity building pre-activation steps. This research goal will be achieved by exploiting the dynamic behaviour of carbon-oxygen bond containing molecules. Six graduate students and ten undergraduate HQP will tackle this problem across three objectives. Activation pathways that weaken C-O bonds in situ are sought to enable alcohols, enols, and carboxylic acids to participate in coupling chemistry as readily as alkyl halides, vinyl triflates, and acid chlorides. Mild methods to manipulate the alcohol/ketone oxidation state (`borrowing hydrogen') will be exploited in the development of Grignard-like 1,2 additions without the requirement of stoichiometric metals. Lastly, strategies to render enones and non-oxygenated pi-systems transiently nucleophilic will be explored, providing a unique approach to formal C-H functionalizations. In solving these problems, HQP will receive world-class training in organic synthesis, catalysis, and modern chemistry technologies. Insights gained along the path to discovery will be generalized to arm chemists with new tools to better access the current and future medicines, materials, and performance chemicals Canadians rely on for their quality of life.