Clicking the sustainability: Nobel-awarded copper catalysed azide-alkyne cycloadditions (CuAAC) through Life Cycle Assessments analysis

Abstract

Copper-catalysed azide–alkyne cycloaddition (CuAAC) reactions represent a class of chemical tranformations belonging to the broader group of so-called “click reactions.” CuAAC, which contributed to Sharpless being awarded his second Nobel Prize in 2022, has emerged as a key tool in synthetic chemistry. It is widely recognised as a privileged method for preparing triazole moieties, which are important scaffolds, particularly in the synthesis of active pharmaceutical ingredients (APIs). CuAAC reactions are characterised by high regio- and stereoselectivity, as well as 100% atom economy, resulting in minimal waste generation. This advantage is often highlighted by evaluating green chemistry metrics. However, such metrics do not always provide a fully comprehensive assessment of the advantages and drawbacks of a specific synthetic pathway, as they mainly focus on the amount of waste generated relative to the amount of product synthesised. Under these circumstances, life cycle assessment (LCA) emerges as a powerful tool capable of evaluating the overall environmental impact of a chemical process. In this study, the sustainability characteristics of a series of CuAAC procedures have been investigated using LCA, and the data have been validated through uncertainty analysis. This approach enables identification of the most environmentally friendly procedures among those examined, as well as identification of the critical process stages that limit overall sustainability.