Solvent Instead of Toxic Reagents: Chemists Develop Environmentally Friendly Method for Synthesising Aniline Derivatives

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An international team of researchers, including chemists from HSE University and the A.N. Nesmeyanov Institute of Organoelement Compounds of the Russian Academy of Sciences (INEOS RAS), has developed a new method for synthesising aniline derivatives—compounds widely used in the production of medicines, dyes, and electronic materials. Instead of relying on toxic and expensive reagents, they proposed using tetrahydrofuran, which can be derived from renewable raw materials. The reaction was carried out in the presence of readily available cobalt salts and syngas. This approach reduces hazardous waste and simplifies the production process, making it more environmentally friendly. The study has been published in ChemSusChem.

Anilines are compounds in which a nitrogen atom is bonded to an aromatic ring. This structure makes the molecule both stable and easily modifiable: reactions can occur at the nitrogen atom and on the aromatic ring, while the core framework remains intact. As a result, the basic structure can give rise to a wide variety of derivatives with diverse properties—from painkillers and decongestants to dyes, polymers, and electronic materials.

Aniline derivatives are typically produced using alkyl halides—reagents with chlorine or bromine atoms attached to a carbon chain. Although this method is reliable, it has several drawbacks: alkyl halides are expensive and toxic, and their use generates waste that requires careful disposal. Moreover, these substances corrode the metal of industrial reactors and pipelines, leading to faster equipment degradation and failure.

Fig. 1. New aniline alkylation reaction using tetrahydrofuran (THF). Instead of toxic reagents, the reaction employs THF, which can be obtained from renewable raw materials. The process relies on readily available cobalt salts and syngas, making it both cost-effective and environmentally friendly. This method enables selective production of compounds with either one or two alkyl substituents.

© Team of the HSE Faculty of Chemistry

Scientists at the A.N. Nesmeyanov Institute of Organoelement Compounds of the Russian Academy of Sciences and HSE University have proposed a new method for synthesising aniline derivatives. Instead of using alkyl halides, they employed tetrahydrofuran (THF)—a common solvent that typically serves only as a reaction medium and does not participate in the reaction. In the new method, however, THF acted as a reactant: its ring opened to form an intermediate compound, which then reacted with aniline to produce N-alkylanilines.                                                                                                                                                                           

The reaction was catalysed by cobalt salts—a more abundant and affordable alternative to the noble metals typically used as catalysts. The scientists also employed syngas, a mixture of hydrogen and carbon monoxide. While syngas is commonly used industrially to produce fuels and methanol, in this case it helped initiate the desired transformations and replaced more hazardous reagents. Under these conditions, the researchers successfully obtained the target compounds with high efficiency.

Evgeniya Podyacheva

'The method has proven to be highly versatile. By adjusting the reaction conditions, it is possible to produce compounds with either one or two carbon chains. This is significant because these different variants have applications across a wide range of fields,' explains Evgeniya Podyacheva, Associate Professor at the Joint Department of Organoelement Chemistry with the Nesmeyanov Institute of Organoelement Compounds of the Russian Academy of Sciences.

Moreover, the researchers successfully synthesised a compound used in the production of tetracaine, a well-known local aesthetic. This demonstrates that the method is suitable not only for laboratory experiments but also for pharmaceutical manufacturing.

Denis Chusov

'We have shown that a common solvent can be transformed into a valuable reagent. Using THF, which can be derived from biomass, makes the process more sustainable and less reliant on non-renewable resources. In addition, the method reduces waste and eliminates the need for toxic reagents. In the future, it can be extended to synthesise other aniline derivatives that are in high demand in medicine, materials science, and electronics,' says Denis Chusov, Professor at the Joint Department of Organoelement Chemistry with the Nesmeyanov Institute of Organoelement Compounds of Russian Academy of Sciences of the HSE Faculty of Chemistry.