Catalysis
scale reactions, the risks can be (generally) safely managed and, in absolute terms, waste generation is minimal, but the process safety hazards and environmental impacts increase significantly upon scale-up. An optimized homogeneous EH process provides selective and quantitative (> 95%) conversion to the desired alcohol under controlled conditions and the catalyst can be removed by a simple precipitation step using a co-solvent or by distillation. Johnson Matthey’s survey of hydride reductions of esters reported in
Org.Proc.Res.Dev. confirms poor environmental metrics and E-factor values in the 30 to >100 range are common. Even with the difficulty of making exact like-for-like comparisons, JM estimates that similar transformations with homogeneous hydrogenation catalysts would reduce the sustainability metrics by a factor of five- to tenfold. As the pharmaceutical industry faces mounting pressure to achieve sustainability, the use of simpler catalytic processes is an unmissable opportunity to minimize the environmental impact of operations and improve green credentials. As highlighted in Figure 3, the possibility of using many of the simpler substrates ‘neat’ can further increase process efficiency. Despite the requirement to operate under hydrogen pressure, the benefits offered by the enhanced safety, simplicity and sustainability of homogeneous EH catalysts far outweigh the initial investment to explore this new technology. JM’s in-house R&D teams have demonstrated efficient turnover at hydrogen pressures as low as 5 bar, well within the pressure capabilities of most CMOs. The application of continuous flow technology, where higher pressure can be operated with a limited equipment footprint, will be another viable alternative.
A bright outlook
Homogeneous EH catalysis has a bright future in the fine chemicals industry, however, one major hurdle to its uptake is the ‘human factor’; in an industry where time pressure is overwhelming, chemists tend to rely on trusted, established technology, even when more effective alternatives become available. However, as molecules continue to become more structurally complex, environmental regulations continue to tighten, and health and safety policies become more stringent, the case for considering improved catalytic routes will become imperative. Johnson Matthey’s role in the homogeneous EH journey is twofold; first, to provide rapid access to high-quality, best-in-class technology and, second, to offer its extensive in-house expertise to support customer uptake optimization of EH within their specific processes.
Further information
E:
pharma@matthey.com References
Gusev catalysts Gusev et al. Angew. Chem. Int. Ed. 2013, 52, 2538 Gusev et al. Organometallics 2012, 31, 5239 Zanotti-Gerosa et al.,Chimica Oggi, July/August 2019, 37(4)
Reviews on EH Clarke Catal. Sci. Technol. 2012, 2, 241
Ikariya et al. ACS Catal. 2012, 2, 1718 Beller et al. Org. Process Res. Dev. 2014, 18, 289 Pidko et al. Chem. Soc. Rev. 2015, 44, 3808 Dub et
al.Nat. Rev. Chem. 2018, 2, 396 Pidkoet al. Chem. Soc. Rev. 2018, 47, 1459
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Figure 3: Substrate scope, molar substrate to catalyst loading (S/C), selectivity. Summer 2020
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