Catalysis

Sustainable chemical catalysis

The pharmaceutical industry is highly dependent on catalysts made from scarce elements. For example, palladium complexes dominate the catalysts available for forming carbon-carbon bonds via cross-coupling reactions. These reactions are fundamental to modern (small molecule) drug discovery (Rayadurgam et al., 2021). The chemical industry has made substantial efforts to address the challenges posed by the cost and scarcity of catalytic species based on precious metals, primarily by developing processes for reclaiming these metals. However, it would be preferable to use cheaper, more abundant metals in the first place. Promising examples include cobalt, copper, nickel, and iron (Chirik and Morris, 2015). Collectively, these are known as base metals. Base metals typically have a lower environmental impact than precious metals (Nuss and Eckelman, 2014).

Base metal catalysis represents a pivotal shift from the pursuit of purely performance-based catalyst design towards more sustainable alternatives in chemical manufacturing (Hutchings, 2007), offering a viable solution to the challenges posed by the scarcity and cost of precious metals (Maes et al., 2016). Recent advancements highlight the potential of base metals in driving reactions traditionally dominated by precious metals. Innovations in this field have demonstrated that commercially available metal salts and well-defined metal complexes can perform efficiently as catalysts, marking a significant step forward in the development of more sustainable catalytic practices (Tamang and Findlater, 2019). This approach not only mitigates the reliance on limited precious metal resources but also opens up the possibility of new substances and reactions being discovered (Nair et al., 2019).

Modern catalysis in the pharmaceutical industry

The pharmaceutical industry predominantly relies on precious metal-based catalysts, with palladium in particular vital to cross-coupling reactions, hydrogenation, hydrogenolysis, and for benzyl/carboxybenzyl deprotection. Due to the ubiquitous yet specialised roles of precious metals for synthesising crucial pharmaceutical compounds, finding viable alternatives is not straightforward. Challenges arise from the need for comparable selectivity, potentially requiring a complete or partial redesign of large-scale processes if an alternative route is chosen. Even minor alterations in production processes for pharmaceuticals can necessitate revisiting associated registration files, incurring additional expenses and regulatory hurdles. These considerations underscore the complex landscape of adopting alternative methods in the pharmaceutical industry while striving to address the issues related to precious metals' availability, cost, and sustainability (Bullock et al., 2020; Lopez and Padrón, 2022).

Ideally, new chemistry (and new catalysts) are developed and implemented early in the development of an active pharmaceutical ingredient (API). This avoids some of the aforementioned issues. The design of robust, cheap catalysts without supply chain concerns requires substantial planning. It must also be considered that the ligands used in combination with metals such as palladium can sometimes be more expensive than the metals themselves, with less opportunity for recovery. Some innovative examples of sustainable catalysis are listed below:

• Immobilised rhodium: Asymmetric hydrogenation catalysed by a rhodium complex supported on a polar ionic liquid phase through electrostatic interactions (Geier et al., 2018).

• Cobalt: Asymmetric hydrogenation, replacing rhodium (with the highest carbon footprint of the metals shown in the above periodic table) with cobalt (which has a carbon footprint of production 4000 times less than rhodium) (Friedfeld et al., 2018).

• Nickel: Cross coupling replacing palladium with nickel (Hansen et al., 2016).

• Iron: Cross coupling to synthesise a blood clotting agent (Andersen et al., 2014).