A Regenerable Catalyst For More Direct Chemical Synthesis

EPFL and ETH Zurich researchers within NCCR Catalysis have developed a palladium catalyst that can be recovered, regenerated and reused after an essential chemical reaction. The research could help make the synthesis of pharmaceuticals and other fine chemicals more efficient and sustainable.

Making complex molecules often means joining smaller chemical building blocks together, a process facilitated by catalysts, compounds that make such reactions possible or speed them up without being consumed themselves.

Many widely used reactions also require chemists to modify their starting molecules before joining them. These added chemical “handles” make the molecules reactive, but preparing them means extra steps and, often, additional waste.

An alternative is C–H functionalization, which modifies ubiquitous carbon-hydrogen bonds already present in a molecule. Such modifications provide a more direct route to the desired structures, but are currently based on the use of large amounts of precious metals as catalysts, such as palladium, which can neither be recovered nor recycled. Until now, this promising approach was not sustainable in the context of chemical production.

At NCCR Catalysis, a team led by Jérôme Waser at EPFL and Javier Pérez-Ramírez at ETH Zurich has now developed a reusable single-atom palladium catalyst for C-H functionalization, leading to the construction of carbon-carbon bonds, which are central to many pharmaceuticals and other fine chemicals. In this type of catalyst, palladium atoms are dispersed across a solid support and isolated from each other. That way, they keep high activity, but the solid catalyst can easily be recovered after the reaction by simple filtration.

To develop this new process, the team had to overcome significant challenges in catalyst stability, activity and recyclability:
Stability: The team first realized that the palladium was not bound tightly enough on many solid supports. That meant losing palladium during the reaction without a chance to recover it. Eventually, carbon nitride -a cheap organic support- was identified as uniquely able to prevent the loss of the precious metal.

Activity: Stability-activity trade-off is often a major challenge in catalysis: Here, the team realized that the now perfectly stable catalyst displayed very low activity and the organic transformation was extremely slow. The researchers found that adding a sprinkle of a phosphine compound activated the catalyst, without jeopardizing its stability and the C-H functionalization proceeded in yields up to 83%.

Recyclability: Although the solid catalyst was easy to recover, its activity dropped sharply after the first reaction. Employing X-ray absorption spectroscopy performed at the Paul Scherrer Institute, the researchers traced the loss of activity to iodide binding strongly to the palladium atoms and blocking their catalytic sites. Based on this knowledge, the team was able to design washing treatments for the catalyst which regenerated its reactivity for up to five cycles. They achieved a cumulative turnover number above 200, meaning that each molecule of catalyst could be used to generate more than 200 molecules of the product, one-order of magnitude higher than the currently best catalyst (20 turnovers).

The method still has limitations. The catalyst cannot simply be reused indefinitely, and repeated regeneration changes the support. But the work acts as a proof of concept that single-atom catalysts can carry out demanding C–H functionalization reactions while retaining the precious metal (in this case palladium), and that understanding how they deactivate can provide practical routes to regeneration.

“The work was very long and complex, as we have first to find conditions for the catalyst to be active but still stable, then understand why is was losing its activity, and find a way to reactivate it to recycle it,” says Waser. “It was possible only by combining the expertise in organic reactions of the EPFL group, with the expertise in heterogenous catalyst design of the ETHZ group.”

"This is a fantastic example of integration within NCCR Catalysis. Without this community and students ready to embrace an interdisciplinary view of science, this collaboration would probably never have happened. This shows that some of the best science emerges when working at the interface between disciplines.", adds Pérez-Ramírez