Periodic Reporting for period 3 - RuCat (New Horizons in C–H Activation: the ‘Real-World Molecules’ Challenge)
Reporting period: 2022-09-01 to 2024-02-29
Over the last two decades a new type of synthetic approach called C-H activation has been proposed to address this challenge. In this approach, molecules can be built in a more straightforward and flexible manner, by ‘simply’ breaking (ie activating) C-H bonds in precursors and installing the desired functionality or molecular scaffold in place of the hydrogen. However, the field of C‒H activation is significantly behind in achieving this aim: most biologically active molecules contain several polar and/or delicate functionalities (‘real world’ molecules), whereas most C‒H activation methods use harsh conditions, incompatible with delicate groups, and catalysts that tend to poison in the presence of polar groups.
This project aims at developing a new class of tools, based on ruthenium catalysts, to allow C-H activation in complex molecules, under mild conditions while avoiding catalyst poisoning. These catalysts will be expanded to be able to replace the hydrogen in chosen C-H bonds with a variety of substituents, thus maximizing its impact in streamlining the synthesis of pharmaceuticals, agrochemicals and other related compounds. This in turn will lead to a better capacity for synthesising and exploring the properties of novel molecules as well as affording more sustainable processes.
One line is dedicated to the synthesis of novel ruthenium complexes and the study of their physicochemical properties. This line is essential to discover new catalytic activities.
The second line has explored the application of these novel ruthenium complexes as catalyst for the C-H activation and functionalization of aromatic compounds. This line of work has focused on developing tools that: 1) perform at room temperature, instead of the typically found requirements of >100 °C; 2) can be applied to molecules bearing complex functionalities, including biologically active molecules, a process called late-stage functionalization; 3) replace the hydrogen in the C-H bond with functionalities of high utility, be it because of their properties interacting in biological systems or because they are themselves amenable to further easy modification; 4) allow for selecting a particular C-H bond in molecules that contain many C-H bonds.
Finally, the third line of research has focused on developing mechanistic understanding on how these ruthenium complexes operate, and how to modulate their reactivity by design. These studies involve organometallic chemistry, kinetic studies, computational studies and also the use of machine learning (ie artificial intelligence).
By the end of the project, we expect that a broad library of new ruthenium catalysts and associated highly selective transformations will be possible. Furthermore, we expect the mechanistic understanding on how these catalysts operate and how they can be modified to increase specificity and reactivity will be broadly applicable to other catalysts and other transformations beyond ours. Similarly, the mechanistic tools that we develop in the context of this project, will be of use broadly to other areas of catalysis.