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Acids to drugs - catalytic access to paracetamol

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The image shows a part of the reaction pathway, in which the catalyst is attached to the reacting molecule. This was achieved through quantum chemical calculations of the reaction. (© Giovanni Di Mauro / CeMM)

Among the many pharmaceuticals in use every day, one of the most well-recognized substances is the century-old pain killer Paracetamol. Paracetamol is part of a family of compounds, the so-called para-aminophenols, which also includes other biologically active molecules, such as Diloxanide Furoate, which is used against amoeba infections, or the beta blocker Practolol. These molecules are typically synthesised using harsh acids, in processes that involve the formation of considerable amounts of waste (in the form of undesired byproducts).

The research group of Nuno Maulide, CeMM Adjunct Principal Investigator and Professor at the University of Vienna, has now discovered a novel method of chemical synthesis to access Paracetamol and related molecules through a catalytic process that is extremely selective and generates little waste. This is enabled by a rearrangement reaction, in which specific atoms of a given molecule change positions, while no atoms are released as waste. Additionally, here, using an inexpensive selenium-based catalytic system avoids the use of expensive (and often scarce) metal catalysts.

While undertaking mechanistic studies to understand the exact pathway of the reaction at hand, the authors uncovered a complex yet organised cascade of elemental steps, in which the catalyst and the starting material exchange one atom back and forth without breaking their engagement. Then, after completing the transformation and yielding the final product, the catalyst is released and can engage another molecule of the starting material to be taken through the rearrangement sequence.

This newly developed method bears great potential in enabling chemists to rethink the way in which para-aminophenols are made, while simultaneously deepening their understanding of chemical reactivity. This broadly applicable, easy-to-use synthetic tool opens up wide perspectives for the preparation of valuable compounds under inexpensive and benign conditions.

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The study "Redox‐Neutral Selenium‐Catalysed Isomerisation of para‐Hydroxamic Acids into para‐Aminophenols" was published online on Angewandte Chemie on 24 March 2021. DOI: https://doi.org/10.1002/anie.202100801

Authors: Hsiang‐Yu Chuang, Manuel Schupp, Ricardo Meyrelles, Boris Maryasin, Nuno Maulide.