Continuous amination of aryl/heteroaryl halides using aqueous ammonia in a Teflon AF-2400 tube-in-tube micro-flow reactor

Significance 

Heteroaryl amines mostly synthesized by hydrogenation of nitroarenes is among the valuable class of organic molecules. Lately, its application has been extended to numerous fields including agrochemicals, materials and pharmaceutical industries. Presently, heteroaryl amines are mainly synthesized by transformation via nucleophilic amination of heteroaryl halides in the presence of an amination reagent such as ammonia.

However, even though ammonia is cheap and abundance in nature, its use as an amination reagent in the nucleophilic transformation of heteroaryl halides is very challenging. This can be attributed to several reasons like weaker nucleophilicity and its extreme corrosive, toxic and explosive nature both in gas and liquid concentration thus prompting the need of additional safety precautions. To this end, the development of more effective methods for overcoming the low reactivity of ammonia is highly desirable.

Among the available strategies for increasing the reactivity of ammonia, the use of transition metals catalysis has been advantageous considering the high availability of ammonia. Alternatively, recent studies have shown that continuous flow reactors are suitable for minimizing the associated hazards as well as enhancing the mixing control and thermal management as compared to other reactors. However, the consistency of the gas/liquid reactions has still remained a great challenge in numerous organic transformations. Therefore, researchers have been looking for suitable alternatives and have identified the reactor design involving a gas-permeable membrane Teflon AF-2400 as a promising solution.

To this note, a group of researchers: Chengwen Xue, Jiesheng Li, Jin Ping Lee and Professor Jie Wu at National University of Singapore together with Ping Zhang from Novartis Institute for Biomedical Research developed a one reactor system to investigate the feasibility of using ammonia as an amination reagent for nucleophilic transformations. Fundamentally, the authors developed a gas-permeable Teflon AF-2400 tube-in-tube system to achieve a consistent flow during the diffusion of ammonia to the reaction mixture. The inner and outer part of the tubing contained ammonia water and reaction solution respectively. Their main aim was to assess the feasibility of using ammonia produced from the aqueous ammonia for generating heteroaryl amines through amination of heteroaryl chlorides. Their research work is currently published in the research journal, Reaction Chemistry and Engineering.

From the experiments, the authors generated a wide range of substituted aryl/heteroaryl amines in high yield. On the other hand, no additional optimization was required as the method was much simple and safe to both the operators and the environment. Additionally, the authors were able to achieve a continuous flow of diffused ammonia from the ammonia source by using the Teflon AF-2400 tube-in-tube system.

In summary, the National University of Singapore researchers successfully demonstrated effective amination of heteroaromatic halides in a permeable Teflon membrane reactor using ammonia from aqueous ammonia source. Alternatively, the technology-enabled understanding of the distribution of both ammonia and water in the tube-in-tube reactor under numerous conditions such as elevated temperatures which would further allow synthetic reactions using aqueous ammonia. Altogether, the research work will advance various industries that involve nucleophilic amination using ammonia with minimal effects on the environment.

Continuous amination of aryl/heteroaryl halides using aqueous ammonia in a Teflon AF-2400 tube-in-tube micro-flow reactor - Advances in Engineering

Reference

Xue, C., Li, J., Lee, J., Zhang, P., & Wu, J. (2019). Continuous amination of aryl/heteroaryl halides using aqueous ammonia in a Teflon AF-2400 tube-in-tube micro-flow reactor. Reaction Chemistry & Engineering, 4(2), 346-350.

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