Flow microreactor, new methodology that can change the whole concept of conventional synthetic chemistry, has attracted a lot of attention from both academia and industry. This paper describes the progress and brief history of the flow microreactor research, and then discusses features of various flow reactors, reaction types suitable for flow microreactor, advantages over conventional batch reactors, and the future development in this field.
A flow-micro reactor can integrate the simple reactions to complete the molecular transformation consisting from many steps. Especially, it can set the most preferable reaction conditions including the temperature and the period to each reaction; the sequence of steps is also able to be planned precisely either in linear or parallel configuration. The method had already shown the great success in the flash chemistry, which uses reactive, unstable, and short-lived intermediates to perform the multi-step organic synthesis efficiently in the flow. On the other hand, a flow-micro reactor shows the efficiency in the classical one-pot reaction, as it can exclude the sensitive product from the starting substrate and the reagent by a flow. We introduced our recent results of the selective methylenation of telephthaldehyde and [6+1]type cycloheptane-ring synthesis using a micro-flow reactor. In addition, we show the Soai asymmetric autocatalysis and amplification reaction by a micro-flow system. The system show the high performance of the Soai reaction clearly and efficiently; the amplification of enantiomeric excess was observed clearly.
Micro-flow synthesis has advantages over conventional batch synthesis such as precise control of the reaction time (<1 sec) and temperature by rapid mixing and high heat and mass transfer. In addition, light-penetration efficiency can be improved in photo-reactions due to the thinness of micro-flow reactors. Moreover, scale-up can be readily achieved with high reproducibility either by continuous running or by numbering up of micro-flow reactors. Increasing number of highly efficient reactions and syntheses have been reported based on micro-flow technology in recent years. We have also developed efficient micro-flow photo-reaction, imidoylation, and acylation by taking the advantages of micro-flow technology. Herein, we wish to report our synthesis of bioactive vitamin D3, its analogues and α-aryl carbonyl compounds based on the micro-flow photo-reaction as well as the synthesis of diimine ligands for olefin polymerization catalysts and peptides based on the micro-flow imidoylation and acylation.
Continuous microflow synthesis is an innovative technology for chemical processes from small-scale synthesis to large-scale production. This technology enables fast and efficient mixing, rapid heating and cooling, strict temperature control, precise residence time control, and effective mass transfer. Moreover, once the reaction conditions are optimized for a small-scale operation, the same conditions are directly applicable to large-scale synthesis under the flow process. We successfully developed the alcohol dehydration process using microreactor and applied it to the large-scale production of saturated terpenoid pristane, which has been used as an adjuvant for monoclonal antibody production in mice. We then have been investigating to apply the advantageous features of the microfluidic systems to oligosaccharide synthesis. Our successful examples include α-sialylation, β-mannosylation, N-glycosylation on asparagine, α-selective glycosylation of 3-deoxy-d-manno-2-octulosonic acid (Kdo), and photo-bromination of toluene derivatives.
This article describes the highly efficient asymmetric photoreactions using flow microreactor. Organic photochemical reactions are highly effective methods forming complicated or distorted structures that cannot be obtained easily by conventional thermal reactions. On the other hand, photoreactions suffer from low reaction efficiency in common batch reactors owing to low light penetration. To solve this problem, microreactors have recently been fascinated. The asymmetric [2+2] photocycloadditions performed in both hand-made capillary reactors and purchased microreactors, and could be achieved higher diastereoselectivity and productivity than those in batch reactors. Additionally, the Paternò-Büchi type photoreactions in slug flow conditions with organic layer and unreactive layer (water or nitrogen gas) showed the unprecedented enhancement on reaction efficiency. These results demonstrate the good potential of micro flowreactor to achieve the efficient organic photoreactions not only in the lab scale chemistry but also in the process chemistry.
We studied catalytic photooxidation with molecular oxygen to improve the characteristics of the existing oxidation reactions and have found several oxidation methods using mild conditions. These oxidations are appealing in terms of green chemistry since they reduce waste, use molecular oxygen, and do not require heavy metals; however, longer reaction times were required to accomplish them in batch reactions. This is due to both a small specific interfacial area and a large decrease in the energy of light traveling through the reaction mixture. With these reaction characteristics in mind, we designed a glass continuous flow microreactor that can form a slug flow region on the chip and irradiate light effectively at a very close distance. In slug flow, internal circulation, accelerating the mixing of the gas and liquid phases and increasing the reaction rate, occurs within a slug. Furthermore, internal circulation flow prevents the liberation of precipitate on the channel walls and causing blockages in the channel. We examined the development of our aerobic photooxidation with our continuous flow microreactor that can form a slug flow region on the chip, and solved problems raised by using batch system as mentioned above. Although many reaction devices designed for photoreactions have been studied previously, the glass continuous flow microreactor, which had not been studied yet, is a very suitable reaction device for photoreactions. Here we report our detailed study of aerobic photooxidation with this microreactor.
High-pressure and high-temperature water including supercritical water with its unique properties is considered as a green solvent; a suitable replacement of conventional organic solvents. Until to the date, there were little successful examples to conduct organic reactions using high-pressure and high-temperature (HPHT) water in batch-wise method. Recently, we developed a high-pressure and high-temperature water microreaction system, which can be successfully used to conduct various organic reactions, resulted high yield and high selectivity of desired products within a very short reaction time. For instance, Claisen rearrangement can be achieved with almost quantitative yields within a few minutes in the absence of catalysts as well as any organic solvents at the reaction temperature and pressure of 250°C and 5 MPa, respectively. Furthermore, the microreaction system was also effective for palladium catalyzed cross coupling (Sonogashira coupling) and obtained almost 100% yields within the shortest reaction time of 0.1 s. The described system was advantageous in terms of the separation and purification of products due to the automatic separation of products from water. Successful application of the described microreaction system for various organic reactions without using any organic solvent make it a potential contender to the development of greener process not only in the small scale laboratory level but also will be extended to the industrial large scale production processes.
Heck carbonylation reaction is useful for obtaining various carbonyl-containing compounds. Since it usually requires a high pressure of toxic carbon monoxide and reaction is highly exothermic, it needs to take strict process management and safety planning. The use of a flow reactor in place of a large batch plant is expected to reduce not only the size of the apparatus, but the manufacturing costs. Furthermore, the easier control of the reaction under flow conditions could lead to a significant improvement of operational safety in manufacturing process. As a result of extensive studies of Heck carbonylation reaction with a flow reactor, we found that the reaction proceeded with a higher conversion rate under lower temperature and lower pressure conditions compared with the reaction using a batch autoclave reactor. These results would demonstrate that the flow Heck carbonylation reaction is favorable for environmental protection and safer manufacturing. In this paper, we introduce the applicability of a flow reactor to Heck carbonylation reaction and its mass production.
To predict the conditions for improving chemical reaction yield in a microreactor, the relationship between chemical reaction and molecular mixing was analyzed by Monte Carlo simulation. The targeted chemical reaction in the microreactor is the consecutive reaction, where k1 is the reaction-rate constant of the first stage, and k2 is the reaction-rate constant of the second stage. The non-dimensional Damkohler number Da is defined as the ratio of a chemical reaction time to a molecular mixing time. It was found that the reaction yield of main product was improved by using a microreactor when the ratio of the reaction rate constants is k1/k2>1. To validate the Monte Carlo simulation results described above, the validation experiments of four kinds of consecutive reactions were conducted using both the microreactor and the conventional batch method. It was found that the experimental results were good agreement with the predicted results by Monte Carlo simulation.
Flow reactor is a powerful tool to synthesize functional compounds at high yield rapidly and continuously. Many types of flow reactors have been developed all over the world so far. Micro reactors using micro-channels or capillary tubes can provide specific selectivity and high yield of the product, due to rapid mixing and thermal exchange in the limited space of micrometers. In addition of such physical effects of the micro reactor, catalyst-combined micro reactors chemically enhance the reaction efficiency and selectivity. Especially, micro reactors with Pd catalysts are widely applied to Pd-mediated flow reactions like hydrogenation, Heck reaction, Suzuki-Miyaura coupling, and so on. In order to achieve high throughput of flow reactor, Pd-immobilized epoxy monolith have been successfully prepared as the column reactor with high surface area and cavity volume. We also demonstrate fabrication of the Pd-immobilized epoxy monolith and actual examples of flow Heck reaction and Suzuki-Miyaura coupling using this column reactor.
In recent years, the micro-flow synthesis technologies have been attracting attention as the new technologies alternative to a batch reaction. Mainly, these technologies are being utilized in the field of the CMC by taking advantage of easy scale-up reactions. On the other hand, each company is exploring how to use these technologies in the field of medicinal chemistry. Although I have experienced for 20 years as medicinal chemist, I felt it was difficult to apply these technologies in the work-flow of medicinal chemistry. But in these few years, many interesting articles by medicinal chemists have been reported for example, the application of library synthesis. In this review, I will present the recent information of using flow-micro synthesis technologies as the view point of Medicinal Chemist.
Attention to microreactors and flow reaction technologies, in both academia and industry, has noticeably increased over the past decade. Although a large number of chemical reactions suitable for microstructured devices have been reported, there still exists a gap between laboratory and production scale. This review focuses on the use of microreactors in synthetic organic chemistry, aiming toward the production of chemical and pharmaceutical entities, through a survey of patents and other open information. The global movement of microreaction technologies is also discussed, from a viewpoint of the number of research articles and patent applications published worldwide. The goal of the present review is to provide an overview of the process development and scale-up studies in the fine chemical and pharmaceutical industries, and to illustrate an outlook for continuous-flow manufacturing as a cost effective, safe, green, and sustainable production method.