Efficient C(sp³)−H Carbonylation of Light and Heavy Hydrocarbons with Carbon Monoxide via Hydrogen Atom Transfer Photocatalysis in Flow

Despite their abundance in organic molecules, considerable limitations still exist in synthetic methods that target the direct C−H functionalization at sp3-hybridized carbon atoms. This is even more the case for light alkanes, which bear some of the strongest C−H bonds known in Nature, requiring extreme activation conditions that are not tolerant to most organic molecules. To bypass these issues, synthetic chemists rely on prefunctionalized alkyl halides or organometallic coupling partners. However, new synthetic methods that target regioselectively C−H bonds in a variety of different organic scaffolds would be of great added value, not only for the late-stage functionalization of biologically active molecules but also for the catalytic upgrading of cheap and abundant hydrocarbon feedstocks. Here, we describe a general, mild and scalable protocol which enables the direct C(sp3)−H carbonylation of saturated hydrocarbons, including natural products and light alkanes, using photocatalytic hydrogen atom transfer (HAT) and gaseous carbon monoxide (CO). Flow technology was deemed crucial to enable high gas-liquid mass transfer rates and fast reaction kinetics, needed to outpace deleterious reaction pathways, but also to leverage a scalable and safe process.</p

Dual role of benzophenone enables a fast and scalable C-4 selective alkylation of pyridines in flow

The efficient C-4 selective modification of pyridines is a major challenge for the synthetic community. Current strategies are plagued with at least one drawback regarding functional group-tolerant electronic activation of the heteroarene, mild generation of the required alkyl radicals, regioselectivity, safety and/or scalability. Herein, we describe a fast, safe and scalable flow process which allows preparation of said C-4 alkylated pyridines. The process involves a photochemical hydrogen atom transfer (HAT) event to generate the carbon-centered radicals needed to alkylate the C-2 blocked pyridine. In a two-step streamlined flow process, this light-mediated alkylation step is combined with a nearly instantaneous inline removal of the blocking group. Notably, cheap benzophenone plays a dual role in the pyridine alkylation mechanism by activating the hydrocarbon feedstock reagents via a HAT mechanism, and by acting as a benign, terminal oxidant. The key role of benzophenone in the operative reaction mechanism has also been revealed through a combination of experimental and computational studies

Efficient C(sp³)−H Carbonylation of Light and Heavy Hydrocarbons with Carbon Monoxide via Hydrogen Atom Transfer Photocatalysis in Flow

Despite their abundance in organic molecules, considerable limitations still exist in synthetic methods that target the direct C−H functionalization at sp3-hybridized carbon atoms. This is even more the case for light alkanes, which bear some of the strongest C−H bonds known in Nature, requiring extreme activation conditions that are not tolerant to most organic molecules. To bypass these issues, synthetic chemists rely on prefunctionalized alkyl halides or organometallic coupling partners. However, new synthetic methods that target regioselectively C−H bonds in a variety of different organic scaffolds would be of great added value, not only for the late-stage functionalization of biologically active molecules but also for the catalytic upgrading of cheap and abundant hydrocarbon feedstocks. Here, we describe a general, mild and scalable protocol which enables the direct C(sp3)−H carbonylation of saturated hydrocarbons, including natural products and light alkanes, using photocatalytic hydrogen atom transfer (HAT) and gaseous carbon monoxide (CO). Flow technology was deemed crucial to enable high gas-liquid mass transfer rates and fast reaction kinetics, needed to outpace deleterious reaction pathways, but also to leverage a scalable and safe process.</p

Interfacing single-atom catalysis with continuous-flow organic electrosynthesis

The global warming crisis has sparked a series of environmentally cautious trends in chemistry, allowing us to rethink the way we conduct our synthesis, and to incorporate more earth-abundant materials in our catalyst design. “Single-atom catalysis” has recently appeared on the catalytic spectrum, and has truly merged the benefits that homogeneous and heterogeneous analogues have to offer. Further still, the possibility to activate these catalysts by means of a suitable electric potential could pave the way for a true integration of diverse synthetic methodologies and renewable electricity. Despite their esteemed benefits, single-atom electrocatalysts are still limited to the energy sector (hydrogen evolution reaction, oxygen reduction, etc.) and numerous examples in the literature still invoke the use of precious metals (Pd, Pt, Ir, etc.). Additionally, batch electroreactors are employed, which limit the intensification of such processes. It is of paramount importance that the field continues to grow in a more sustainable direction, seeking new ventures into the space of organic electrosynthesis and flow electroreactor technologies. In this piece, we discuss some of the progress being made with earth abundant homogeneous and heterogeneous electrocatalysts and flow electrochemistry, within the context of organic electrosynthesis, and highlight the prospects of alternatively utilizing single-atom catalysts for such applications