Flow Chemistry Case Studies

Taylor-vortex membrane reactor for continuous gas-liquid reactions

Abstract: A unique Taylor-vortex membrane reactor (TVMR) design for continuous gas-liquid reactions is presented in this work. The reactor consists of a cylindrical rotor inside a stationary concentric cylindrical vessel, and a flexible system of equispaced baffle rings surrounding the rotor. This restricts the annular cross section to a small gap between the baffles and the rotor, and divides the annulus into 18 mixing zones. The baffles support a 6 m long PFA tubular membrane that is woven around the rotor.

An Eight-Step Continuous-Flow Total Synthesis of Vitamin B1

Abstract:  This study reports on an integrated eight-step continuous-flow synthesis of vitamin B1 from commercially available 2-cyanoacetamide. The proposed continuous-flow process is based on advances in chemistry, engineering, and equipment design, and affords improved performance and safety compared with batch-mode manufacturing. Several challenges were precisely investigated and controlled, including mixing, unexpected clogging, solvent switches, an exothermic reaction, and the prevention of side reactions, using various micro-channel flow reactors, mixers, separators, and continuous filters. Vitamin B1 was produced with a separated yield of 47.7% and high purity, with a total residence time of about 3.5 h. This eight-step continuous-flow protocol enables technology involving up to six of the key principles of green chemistry. Hence, the application of flow technology is of paramount importance for improving security, reducing waste, and, in particular, improving the efficiency of batch operations that require several days for manufacturing.  

A Scalable Balz-Schiemann Reaction Protocol in a Continuous Flow Reactor

Abstract:  The demand for aromatic fluorides is steadily increasing in the pharmaceutical and fine chemical industries. The Balz-Schiemann reaction is a straightforward strategy for preparing aryl fluorides from aryl amines, via the preparation and conversion of diazonium tetrafluoroborate intermediates. However, significant safety risks exist in handling the aryl diazonium salts when scaling up. In order to minimize the hazard, we present a continuous flow protocol that has been successfully performed at a kilogram scale that eliminates the isolation of aryl diazonium salts while facilitating efficient fluorination. The diazotization process was performed at 10 °C with a residence time of 10 min, followed by a fluorination process at 60 °C with a residence time of 5.4 s with about 70% yield. The reaction time has been dramatically reduced by introducing this multi-step continuous flow system.

Development of a Horizontal Dynamically Mixed Flow Reactor for Laboratory Scale-Up of Photochemical Wohl–Ziegler Bromination

Abstract:  Flow reactors with enhanced mixing are of interest to the pharmaceutical industry for a range of photochemical applications. Taylor–Couette (vortex, dynamically mixed) reactors have been reported to have intensified mixing and have been used with heterogeneous systems. Our photochemical workflow has previously been demonstrated for the development of a photochemical Wohl–Ziegler process and scale-up in flow using a plug flow reactor (PFR). In this work, a 20 mL dynamically mixed Autichem, Ltd. prototype photochemical DART reactor (Taylor–Couette reactor) was paired with four custom Kessil PR160L 400 nm lamps. The reactor was evaluated as a 500 g scale-up option for the bromination of ethyl 4-methylbenzoate. Herein we describe our workflow moving from a Pacer International Photochemistry LED Illuminator (HTS system) to the photochemical DART reactor in the scale-up of the synthesis of ethyl 4-(bromomethyl)benzoate via a radical bromination process.

High-Throughput Exploration of a Thioxanthone-catalyzed Photoredox C-O Coupling

Abstract:  Using High-Throughput Experimentation (HTE), a visible light-mediated etherification method was developed, employing the organic photocatalyst thioxanthen-9-one (TXO) and a commercially available, air-stable nickel source. Design of Experiments (DoE) techniques were utilized in conjunction with HTE to identify optimal reaction conditions which are mild, cost-effective, robust and therefore suitable for use in an industrial setting. A diverse substrate scope was prepared via parallel synthesis and selected examples were demonstrated on a 4.2 mmol scale in batch. Furthermore, the reaction was successfully performed on an 83 mmol scale, utilizing a standard jacketed reactor and Kessil PR160L lamps.

Ruthenium-Catalyzed Ester Reductions Applied to Pharmaceutical Intermediates

Abstract:  Ruthenium pincer complexes were synthesized and used for catalytic ester reductions under mild conditions (∼5 bar of hydrogen). An experimental design approach was used to optimize the conditions for yield, purity, and robustness. Evidence for the catalytically active ruthenium dihydride species is presented. Observed intermediates and side products, as well as time-course data, were used to build mechanistic insight. The optimized procedure was further demonstrated through scaled-up reductions of two pharmaceutically relevant esters, both in batch and continuous flow.

Design of a Kilogram Scale, Plug Flow Photoreactor Enabled by High Power LEDs

Abstract:  A simple and inexpensive photoreactor with a throughput of kilograms of material per day has been developed. This achievement was enabled by using high-power Light Emitting Diodes (LEDs) to provide high light density, leading to minimization of the footprint of the reactor. A study of the impact of tube diameter enabled maximization of the photon absorbance without increasing photocatalyst loading. Further optimization of reaction conditions using a design of experiments (DoE) elucidated reaction sensitivities that allowed the reaction rate, yield, and productivity to be maximized upon scale-up. The reactor has been operated continuously for 6 h leading to reaction performance that provided 12 kg of material per day at 90% conversion.

A Continuous Stirred-Tank Reactor (CSTR) Cascade for Handling Solid-Containing Photochemical Reactions

Abstract:  Visible-light photoredox reactions have been demonstrated to be powerful synthetic tools to access pharmaceutically relevant compounds. However, many photoredox reactions involve insoluble starting materials or products that complicate the use of continuous flow methods. By integrating a new solid-feeding strategy and a continuous stirred-tank reactor (CSTR) cascade, we realize a new solid-handling platform for conducting heterogeneous photoredox reactions in flow. Residence time distributions for single phase and solid particles characterize the hydrodynamics of the heterogeneous flow in the CSTR cascade. Silyl radical-mediated metallaphotoredox cross-electrophile coupling reactions with an inorganic base as the insoluble starting material demonstrate the use of the platform. Gram-scale synthesis is achieved in 13 h of stable operation.

Photons as a 21st century reagent

Abstract:  A pharmaceutical industry viewpoint on how the fundamental laws of photochemistry are used to identify the parameters required to implement photochemistry from lab to scale. Parameters such as photon stoichiometry and light intensity are highlighted within to inform future publications.

Teaching and Learning 

Flow chemistry experiments in the undergraduate teaching laboratory: synthesis of diazo dyes and disulfides

By embedding flow technology in the early phases of academic education, students are exposed to both the theoretical and practical aspects of this modern and widely-used technology. Herein, two laboratory flow experiments are described which have been carried out by first year undergraduate students at Eindhoven University of Technology. The experiments are designed to be relatively risk-free and they exploit widely available equipment and cheap capillary flow reactors. The experiments allow students to develop a hands-on understanding of continuous processing and gives them insights in both organic chemistry and chemical engineering. Furthermore, they learn about the benefits of microreactors, continuous processing, multistep reaction sequences and multiphase chemistry. Undoubtedly, such skills are highly valued in both academia and the chemical industry.