In George Orwell’s classic 1945 novella ‘Animal Farm’ the revolutionary livestock develop the slogan “Four legs good, two legs bad” to summarize their views on the farmer and other humans. As the novella progresses, we see that things cannot be simplified so readily, and so I was encouraged by the recent excellent article by Brianna Barbu in Chemical and Engineering News (February 12/19, 2024) showing that the mindset “earth-abundant metals good, precious metals bad” was a similar oversimplification when it came to making homogeneous catalysis greener. It was particularly heartening to see so many industrial process chemists interviewed alongside academics; showing the growing partnerships that now exist between the two groups, and highlighting the fact that industrial process chemistry requires staying at the forefront of academic research.
A recent ChemRxiv article mentioned in the C&ENews article, that I strongly encourage all interested in the details of this topic to read, was written by Prof. Bruce Lipshutz and his collaborators from Novartis (Lipshutz, B.; Gallou, F.; Luescher, M. The Impact of Earth-Abundant Metals as a Replacement for Pd in Cross Coupling Reactions. ChemRxiv 2024. DOI:10.26434/chemrxiv-2024-tc9hm). It clearly outlines the fallacy of a single set of ‘general’ reaction conditions then applying sustainability metrics to a catalytic metal element and extrapolating that conclusion to all possible applications of that metal. In this pre-print the authors show that catalyst loading has a major impact on any sustainability assessment and how their micellar methods enable Pd to be used at 10- to 100-fold lower levels compared to using an earth-abundant metal for the same transformation. This not only has a direct contribution to sustainability in the metal contribution, but also enables several secondary benefits such as a simplified work-up and waste disposal because one does not have so much metal to remove. They conclusively show that the metal cost is a tiny fraction of the total for most pharmaceutical applications; vastly outweighed by costs for the reacting substrates, solvents, reagents and materials.
For those interested in how to scale-up the micellar chemistry pioneered by Prof. Lipshutz there is another recent ChemRxiv article published by a consortium of industrial process chemists from the ACS Green Chemistry Institute Pharmaceutical Roundtable (Fox, R.; Bailey, D.; Obligacion, J.; Borlinghaus, N.; Braje, W.; Li, X.; Mukherjee, S.; Schoen, A.; Towne, T.; Vukelic, S. A Chemistry in Water Reproducibility Study: Learnings from a Pre-Competitive, Multi-Company Collaboration; preprint; Chemistry, 2023. https://doi.org/10.26434/chemrxiv-2023-mgww0). The authors report that many of the perceived barriers to adoption of aqueous surfactant methodology in Pharma are largely unfounded, but that like any new technology there is a learning curve, especially since the reactions can be quite substrate dependent. I also appreciate that they identified some reactions that perform equally well in water without the added surfactant, reminding us how important control experiments are to establish the necessity of each reaction component.
So far in this blog I’ve focused on replacing the metal to improve sustainability. A recent paper by a team in Norway explored replacing ligands prepared from petrochemical feedstocks with ligands prepared from renewable feedstocks (D. van der Westhuizen Catalysis Science & Technology 2023, 13, 6733). The authors were able to find potentially more sustainable alternatives to Beller’s ligand (cataCXium® A or Ad2-PnBu), but more importantly when reading the paper, it started to sink in just how fundamental a change in mindset and R&D work is needed to enable a genuinely sustainable future. Hard as it might be to admit, most of the current work in ‘sustainability’ is reducing the consumption and environmental consequences of using petrochemical feedstocks and rare metals rather than replacing or recycling them completely.
Of course, the most sustainable ligand is no ligand at all, which is why I’ve had a growing interest in the past couple of years around single-atom catalysts, however all studies that I was aware of were small scale demonstrations on model substrates. It was good therefore to recently see a group of Swiss academics evaluate a carbon-supported Pd single-atom catalyst in a pharmaceutically relevant Sonogashira−Hagihara coupling on a 2 L scale (~1 mole). The paper includes a comprehensive holistic lifecycle analysis of the reaction and demonstrates that these catalysts might offer significant improvements in sustainability assuming that the heterogeneous catalyst can be used 10-times before being replaced, and 98% of the metal recovered in regenerating a new batch of catalyst. There is still a lot of work to be performed on single-atom catalysts to reproducibly and economically scale up the preparation of this class of material and produce a portfolio of catalysts for different reaction types and substrates, but in my opinion this paper is positive step in opening this new class of catalyst to process chemists.
Finally, an illustration of just how fast this field is moving that before I sat down to write this article, I started my weekly literature review and saw an excellent ASAP article from a team of academics in New York City where they used mechanistic insights to identify a new class of phosphine ligands to promote the Ni-catalyzed Suzuki-Miyaura coupling (J. Yang J. Am. Chem. Soc. 2024. https://doi.org/10.1021/jacs.4c00370). In some cases, they were able to reduce the Ni loading below 1 mol % and still get isolated yields above 90% using a set of reaction conditions that process chemists might use for scale-up. The full scope of this new class of ligands remains to be seen, but this paper shows the increasing sophistication that is being brought to improve the range of catalytic conditions available for cross-coupling.
Full references
ProPhos
Yang, J.; Neary, M. C.; Diao, T. ProPhos: A Ligand for Promoting Nickel-Catalyzed Suzuki-Miyaura Coupling Inspired by Mechanistic Insights into Transmetalation. J. Am. Chem. Soc. 2024. https://doi.org/10.1021/jacs.4c00370.
Lipshutz Chem Rxiv 2024
Lipshutz, B.; Gallou, F.; Luescher, M. The Impact of Earth-Abundant Metals as a Replacement for Pd in Cross Coupling Reactions. ChemRxiv 2024. DOI:10.26434/chemrxiv-2024-tc9hm. This content is a preprint and has not been peer-reviewed.
Fox, R.; Bailey, D.; Obligacion, J.; Borlinghaus, N.; Braje, W.; Li, X.; Mukherjee, S.; Schoen, A.; Towne, T.; Vukelic, S. A Chemistry in Water Reproducibility Study: Learnings from a Pre-Competitive, Multi-Company Collaboration; preprint; Chemistry, 2023. https://doi.org/10.26434/chemrxiv-2023-mgww0.
Ligands from sustainable sources
Westhuizen, D. van der; C. Castro, A.; Hazari, N.; Gevorgyan, A. Bulky, Electron-Rich, Renewable: Analogues of Beller’s Phosphine for Cross-Couplings. Catalysis Science & Technology 2023, 13 (23), 6733–6742. https://doi.org/10.1039/D3CY01375H.
Single atom catalysis
Poier, D.; Akl, D. F.; Lucas, E.; Machado, A. R.; Giannakakis, G.; Mitchell, S.; Guillén-Gosálbez, G.; Marti, R.; Pérez-Ramírez, J. Reaction Environment Design for Multigram Synthesis via Sonogashira Coupling over Heterogeneous Palladium Single-Atom Catalysts. ACS Sustainable Chem. Eng. 2023, 11, 16935 (Swiss academics ETH and Friborg)
