Reversible Creation of Non-Inherent Reactivity Patterns in Catalytic Organic Synthesis

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Current methods in organic synthesis only enable reactions at the most reactive bonds or at bonds predisposed by specific directing groups. Consequently, many less reactive bonds, including numerous C-H and C-C bonds, cannot be functionalized, enormously limiting the scope of possible transformations. To overcome these limitations, I propose Reverse&Cat, a revolutionary strategy using a novel method to change the reactivity pattern of molecules. This strategy combines the dynamic equilibrium mediated by the first catalyst and a functionalization reaction catalyzed by the second catalyst. The originality of the transformation stems from exploiting three simultaneous processes: (i) the dynamic exchange of one functional group (FG) for another FG that modulates the reactivity of the substrate; (ii) the functionalization of the temporarily activated bond; and (iii) the restoration of the initial FG. In essence, the processes (i) and (iii) – the components of the dynamic equilibrium – realize the novel concept of the temporary creation of non-inherent reactivity of a substrate. The program is divided in three phases, which will establish the full potential of the strategy. In phase A, I will develop a set of new reactions enabled by the bi-catalytic systems. I will exploit two types of reversible reactions: (1) reversible oxidation of alcohols, which delivers temporarily activated aldehydes/ketones, with the distinct reactivity of their C-H bonds; and (2) reversible retro-hydrofunctionalization of nitriles or their analogues, which delivers temporarily activated alkenes, containing allylic C-H and C=C bonds. In phase B, I will conduct detailed mechanistic studies to gain the mechanistic understanding and enable further rational development. In phase C, I will establish the utility of this new strategy in practical organic synthesis. Overall, the strategy will open a new dimension of reactivity, with prospective applications in production of fine-chemicals and materials.