Bridging Academia and Industry: Advancing Ni and Cu Catalysis for Pharmaceutical Applications

Transition metal-catalysed reactions are indispensable in pharma, for example, 80% of most used med chem reactions are palladium (Pd)-catalysed. However, Pd is not sustainable, especially on large manufacturing scale.

Nickel (Ni) and copper (Cu) catalysis are viable alternatives, Ni in particular offers unique advantages over other transition metals like Pd, including cost-effectiveness and greater abundance. These benefits make it an attractive choice for large-scale applications, especially in the pharmaceutical industry, where it can reduce production costs and environmental impact. However, Ni catalysis poses significant challenges due to its intricate and poorly understood mechanistic pathways, which hinder the full realisation of its potential.

AstraZeneca (AZ) has emerged as a leader in the innovative application of Ni catalysis on an industrial scale. Notably, AZ has implemented Ni catalysts in selected borylation reactions to replace Pd, achieving remarkable reductions in CO2 emissions. This shift aligns with the UN's Sustainable Development Goals and AZ’s Ambition Zero Carbon Strategy, and highlights the importance of Ni catalysis in sustainable manufacturing practices.

Despite these advancements, there is still much to learn about the inner workings of Ni catalysts, including the structures of active intermediates, rate-determining steps, and reaction pathways. Gaining deeper mechanistic insights is essential to refining Ni catalysis for more efficient and environmentally friendly applications, and broadening the scope of its impact.

To address these challenges, advanced analytical techniques such as mass spectrometry (MS) offer promising solutions. Pressurized sample infusion-electrospray ionisation-mass spectrometry (PSI-ESI-MS), in particular, stands out as a powerful tool for real-time reaction monitoring. This method is effective for continuous observation of catalytic intermediates and reaction kinetics with unparalleled sensitivity, enabling researchers to study reactions at catalyst loadings as low as 0.1%. PSI-ESI-MS has been successfully applied to Pd catalysis, illuminating critical steps such as oxidative addition and transmetalation.

Extending this methodology to Ni catalysis will provide valuable insights into its unique catalytic processes, facilitating the optimisation of reaction conditions and the development of tailored strategies to enhance its performance.