The best of both worlds – Integrating reactive distillation with continuous flow processing

At present, continuous flow technology is highly recognized as a valuable enabling technique due to its improved heat and mass transfer compared to batch reactors. This feature arises from miniaturization of reactors and integration of highly effective mixing elements. The ever-increasing popularity of flow equipment furthermore arises from its modularity and small footprint. Consequently, multi-step chemical syntheses can be developed by combining several types of flow reactors – and potentially – traditional batch equipment in order to perform multiple transformations in an uninterrupted sequence. In fact, the integration of common batch processes has recently been identified as an underexplored means to perform important unit operations in a continuous fashion.

Reactive distillation is such a unit operation that is used to both generate reagents or reaction products and separate them from unwanted materials. This concept is significant in industrial settings, with multiple applications in biodiesel refining, fragrance production and petrochemical processes. However, readily available approaches that integrate reactive distillation with continuous flow synthesis of small bioactive molecules at the laboratory scale are scarce.

To this effect, Prof. Marcus Baumann, from the School of Chemistry at University College Dublin reported a novel approach that considered the aforementioned limitations and aimed at developing a simple solution that may find every-day use in chemical laboratories within both academic and industrial settings. Specifically, he focused on developing a continuous flow platform that could integrate reactive distillation with modern flow reaction technology. His work is currently published in the research journal, Reaction Chemistry & Engineering.

In brief, his work encompassed the use of a Hickman distillation apparatus that was operated in a continuous fashion by withdrawing reaction products generated by reactive distillation while concurrently replenishing the starting material. This miniaturized system was trialed by studying the generation of cyclopentadiene – a simple and versatile compound widely used as a building block in organic synthesis.

Professor Baumann’s approach allowed for the on-demand generation of cyclopentadiene through a high-temperature cracking process from its readily available dimeric precursor. Crucially for this approach, the Hickman still head has an overflow mechanism, meaning that only small quantities of about 1 mL of this unstable and highly malodourous cyclopentadiene species accumulate at any given time. This is being regulated by the constant withdrawal of cyclopentadiene from the set-up, while starting material is being replenished through a separate pump. In an application, the production of a small selection of different tetrahydroquinolines that are important drug-like structures was demonstrated through a continuous cycloaddition reaction sequence. The presented setup thus linked reactive distillation and subsequent tetrahydroquinoline synthesis in a process that effectively generated multigram quantities of desired reaction products within one hour without exposure of the operator to the hazardous cyclopentadiene intermediate.

In summary, a facile yet general set-up was devised that allows reactive distillation processes to be integrated with continuous flow synthesis. This novel approach successfully united a readily available Hickman microdistillation setup with state-of-the-art flow reactor technology to bring about the effective and safe synthesis of drug-like tetrahydroquinolines in high chemical yields.