Photocatalysts Capable of Reoxidizing C-H Activation Catalysts Could Revolutionize Pharmaceutical Industry

KAUST has devised a light-based alternative method for the chemical process for construction of complex molecules. CREDIT: Alamy stock photo, Blue Sky.

Researchers from King Abdullah University of Science and Technology (KAUST) have demonstrated that a greener and simpler version of the C-H activation reaction can be carried out using light from a standard electric light bulb. According to the research team, this is one of the most innovative new reactions for the assembly of complicated chemical structures.

Generally, long and multi-step syntheses are needed to produce medicines that comprise of complex molecules. C-H activation is emerging as a powerful way to assemble these complex molecules in less steps than traditional approaches, making their synthesis more environmentally sustainable.

A research team headed by Professor Magnus Rueping (from the Physical Science and Engineering Division and who has joined the faculty and the KAUST Catalysis Center at the beginning of 2016) has now made the C-H activation a little greener.

Rueping and his colleagues have demonstrated that when combined with a carefully chosen pair of catalysts, light has the ability to drive the aromatic C-H activation reaction.

Despite the fact that C-H activation has been in somewhat limited use since the 1960s, it has become one of the hottest research topics over the past 10 years. Even though the reaction is employed for different purposes, one of its significant roles is to couple two organic molecules to form a new C-C bond, which is an important course of action while constructing carbon skeleton of a complex molecule.

In the recent past, chemists have come out with different metal catalysts with the ability to activate a specific C-H bond in molecules having numerous similar bonds. The catalyst disintegrates the target bond using one “arm” and subsequently seizes the reaction partner using the other, consequently joining the two to form a new C-C bond.

However, a minor defect in the reaction is that the catalyst transforms into an inactive, reduced state at the end of the matchmaking process. Therefore, the catalyst must be reoxidized for it to couple the next two molecules in the reaction flask.

One of the key challenges in many metal-catalyzed C-H functionalizations is the reoxidation of the metal catalyst. Until now, this reoxidation has been achieved by the addition of a large amount of an oxidant, often copper or silver salts or organic compounds, which represents an obstacle for industrial application on a larger scale.

Professor Magnus Rueping, KAUST

Chemists from the pharmaceutical industry are already interested in Rueping’s light-based alternative technique for reoxidation of the catalyst.

While working in a parallel area of chemical research, using light-activated photocatalysts to activate practical transformations in organic molecules through an oxidation process, know as single-electron transfer, Rueping and his team identified the potential of the photocatalysts to reoxidize C-H activation catalysts.

Instead of requiring large amounts of oxidant, only traces of the photocatalyst are required. The team tested the idea, and it worked.

Our initial results show that it is possible to replace the oxidants with catalytic amounts of a photocatalyst.

Professor Magnus Rueping, KAUST

One of the initial reactions the team mastered employing their light-based approach was a rhodium-catalyzed C-H activation to generate versatile organic molecules called ortho-olefinated Weinreb amides, which are useful building blocks for pharmaceuticals manufacture.

The biggest challenge in developing combined visible light photocatalysis and metal catalysis is to find the right set and combination of catalysts that neither interact with each other nor lead to undesired side reactions with the substrate or product.

Professor Magnus Rueping, KAUST

However, the expanding list of successful sample reactions indicates the potential to discover effective combinations. Additionally, a broad array of organic molecules can be coupled by employing the catalyst pairs. According to the research team, the fact that the light-activated photocatalyst can instantly react with its catalyst partner enables the oxidation-sensitive organic molecules to be successfully coupled.

A further benefit of Rueping’s protocol is that it can be used by any lab because the process does not mandate the use of any special lamps or other equipment. “The reactions are carried out using typical chemistry laboratory equipment and LEDs or compact fluorescents that can readily be bought at any good hardware store,” added Rueping. “We hope that our newly developed protocols also inspire other researchers to further develop this field.”

Despite the progress the team has already made, there are still many avenues to explore,” stated Rueping. “As in any exciting research project, the results generated more questions than answers. In particular, we are interested in obtaining a deeper understanding of the mechanism at play and in testing the boundaries of the combined photo- and metal-catalysis reactions.”

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