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

Abstract

Copper-catalyzed azide-alkyne cycloadditions represent a class of chemical reactions belonging to the broader group of socalled "click reactions." In this context, the copper-catalyzed azide-alkyne cycloaddition (CuAAC), which contributed to Sharpless being awarded his second Nobel Prize in 2022, has assumed a primary role in synthetic chemistry. It is widely recognized as a privileged method for the preparation of triazole moieties, which are important scaffolds, particularly in the synthesis of active pharmaceutical ingredients (APIs). CuAAC reactions are characterized by high regio-and stereoselectivity, as well as 100% atom economy, resulting in minimal waste generation. This advantage is often highlighted through the evaluation of 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 synthesized. In this context, Life Cycle Assessment (LCA) emerges as a powerful tool capable of evaluating the overall environmental impact of a chemical process. In the present work, for the first time, the sustainability aspects of a series of CuAAC procedures have been investigated using LCA. This approach enables identification of the most environmentally friendly procedures among those examined, as well as the critical process stages that limit their overall sustainability.