Organocatalysis has drastically advanced stereoselective chemical synthesis. From an underdeveloped niche area, it has become the most frequently applied approach to asymmetric synthesis. Organocatalysis is also developing into a technology, which can be used to make pharmaceuticals, scents, and other fine chemicals. However, the early stages of industrial chemistry, the upgrading of hydrocarbon-based alkenes, arenes, and alkanes, are still largely dominated by heterogeneous and transition metal catalysts. Here we will address the question if a selective, Early-Stage Organocatalysis (ESO) can be developed that directly delivers high-value substances from abundantly available hydrocarbon feedstock chemicals, while significantly saving energy and other resources. During the last few years, we have developed confined organic acids as a new catalyst class that features enzyme and zeolite-inspired active sites with well-defined pockets for selective substrate recognition and catalysis. These catalysts offer a widely tunable reactivity range, reaching extreme levels with turnover numbers exceeding 106 in challenging asymmetric carbon-carbon bond forming reactions, and approaching “magic acid” reactivity toward the activation of olefins. We now aim to take confined acid catalysis to another level by designing new, even more reactive acids that enable the utilization and valorization of steam-cracker-based hydrocarbons in selective organocatalysis. Specifically, we propose three aims: (1) Developing asymmetric olefin hydrofunctionalizations including hydrations and hydroarylations; (2) An early stage functionalization of simple arenes such as benzene and toluene via highly stereoselective and regioselective electrophilic aromatic substitution reactions; and, as the ultimate test of extreme reactivity, (3) we propose organocatalytic, asymmetric reactions of alkanes. The all-underlying goal will be the design and development of organocatalysts of the next generation.

The depleting reserves of precious metals within the Earth’s crust has made their replacement with more abundant first-row transition metals of paramount importance. Pincer-ligated cobalt complexes have shown a unique ability to recapitulate the reactivity of commonly employed iridium catalysts for arene C–H borylation but, notably, with complementary ortho-to-fluorine site selectivity. However, the lower activity and functional group tolerance of cobalt catalysts has precluded their use in more demanding late-stage applications, depriving chemists of the possibility to selectively functionalize fluoroarenes within complex molecules. “CobaltLSF” aims to unlock the full potential of Co-catalyzed arene C–H functionalization with the use of a novel carbene-containing NCN-pincer ligand that is designed to promote metal-ligand cooperation to address three main challenges: (1) chemoselectivity, by facilitating key steps such as C–H bond cleavage and bond-forming reductive elimination, improving the efficiency of desired catalytic processes over competing side-reactions; (2) site selectivity, through ligand-assisted C–H activation which is predicted to result in a rapidly reversible process that would reinforce ortho-to-fluorine selectivity; (3) direct C–H alkylation using olefin coupling partners, with the aim of expanding the bond-forming capabilities of cobalt catalysis beyond C–H borylation in the context of a green, waste-free method for installing alkyl chains. Alongside the development of (NCN)Co catalysts, their application to the late-stage functionalization (LSF) of fluoroarene-containing drugs will be examined and their chemo- and site selectivity benchmarked against known LSF methods, providing useful comparative data for end-users, such as medicinal chemists. Overall, the successful realization of the proposal is expected to have far-reaching implications for the use of carbene-containing pincer ligands in C–H functionalization with earth-abundant metals.