“Impossible” Chemistries Based on Flow and Micro

Home , Flow chemistry, Reactive intermediate

Perspectives

Jun-ichi Yoshida*, Heejin Kim and Aiichiro Nagaki Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Nishikyo-ku, Kyoto 615-8510, Japan

Received: 31 July 2017; accepted: 04 September 2017

This perspective article discusses the basic concept of time control by space based on flow and micro, some examples that realized extremely fast reactions which were difficult to achieve by conventional flask chemistry, and the future of this fascinating chemistry. Keywords: Flash chemistry, flow chemistry, microreactor, residence time, organolithium

1. Introduction

According to the French expression “Impossible n'est pas français,” French people consider that nothing is impossible. It is presumably because they have a strong belief that the impossible can be made possible. The title suggested by the editor is “impossible” chemistry based on flow and micro. This perspective article focuses on the reactions that were considered impossible due to the short lifetime of intermediates. We will show here that some of such reactions have been made possible by Figure 1. A simple system for photochemical reactions the reaction time control in a very short range using flow microreactors, and we will look into the future of this exciting field of chemical synthesis. the reaction. To start the reaction, we just turn on the lamp placed Many reactions which are used in organic synthesis involve re- beside the reactor. Light enters the solution through the transpar- active intermediates, although in many other cases starting mate- ent reactor wall, and the photoreaction proceeds. To stop the re- rials react directly into products. A method in which a reactive action, we turn off the lamp. However, the minimum time intermediate is generated in the presence of a reaction partner is interval that the switch can be turned on and off by hand is the often used. A reactive intermediate molecule is reacted immedi- order of seconds, and it is virtually impossible to do it in a ately after generation individually. However, this method cannot shorter time such as milliseconds. be used if the reaction partner is incompatible with the conditions How can we control reaction in a shorter time? The following for generation of the reactive intermediate. Unlike transition discussion based on the analogy with a camera shutter may be states, reactive intermediates are local energy minima. Therefore, useful. A lamp is always turned on, and a curtain is placed be- they have definite lifetimes, and they can be accumulated in solu- tween the lamp and the reactor. The photoreaction can be simply tion in some cases. However, the flask chemistry is limited to re- started by turning up the curtain, and by turning it down, the active species whose lifetimes are over the order of minutes. photoreaction can be stopped. These operations are very similar – Based on the concept that an unstable short-lived reactive in- to the motion of the mechanical camera shutter. In fact, such on termediate is generated in a flow microreactor system, we have off operations of the shutter can be achieved in a considerably been developing reactions that are very difficult or impossible to short time (called an exposure time). The exposure time of achieve by conventional flask reactions [1, 2]. In 2005, we 1/500th or 1/1000th of a second has been achieved without named this chemistry flash chemistry [3]. In flash chemistry, the problems. However, it does not seem easy to move a shutter reaction partner is added within a second or less to selectively curtain mechanically so quickly. How can the exposure time be obtain the target product. Precise and very short-range reaction made very short in a controlled way in real cameras? time control by space in the flow system is essential for flash To achieve very short exposure time, focal plane shutters are chemistry. This perspective article describes the basic concept of often used. In this type of shutter, there are two curtains: a first time control by space, some examples that realized reactions curtain and a second curtain. First, the first curtain moves and the which were difficult to achieve by conventional flask chemistry, optical path opens. Therefore, the light hits the photosensitive part and the future of flash chemistry. such as a film or a charge-coupled device (CCD). Then, the second curtain moves to block the light path. However, as described above, there is a limit to moving the curtain mechanically quickly. 2. How Can We Achieve Short Reaction Times? When the exposure time is set to be shorter, the second curtain To generate a short-lived reactive intermediate and react it with starts to move before the light hits the entire photosensitive part. a subsequently added reaction partner, it is necessary to control This means that a slit through which light passes is formed be- the reaction time shorter than its lifetime. How can we control re- tween the first curtain and the second curtain and that the slit action time in a short range? First, let us consider the following moves in front of the photosensitive part. For example, to realize thought experiment about a photoreaction because the light can an exposure time of 1/1000 s, the slit width is set to 1/10 of the be easily switched on and off in a short time (Figure 1). width of the photosensitive portion, and the slit moves from one Generally, photoreactions proceed only when light strikes a so- end to the other end of the photosensitive portion in 1/100 s. As lution of a starting material. Therefore, it is easy to start and stop a result, the light of 1/1000 s is applied to the entire photosensitive part. If the slit width is reduced to 1/20, an exposure time of 1/2000 s can be achieved with the same speed of the curtains. * Authors for correspondence: [email protected] The exposure time is controlled with the spatial size of the slit

DOI: 10.1556/1846.2017.00017 J. Flow Chem. 2017, 7(3–4), 60–64 © 2017 The Author(s). This article is published with Open Access at www.akademiai.com First published online: 26 November 2017 J. Yoshida et al. width without changing the operating speed of the curtain. In this way, it is possible to control a very short time with a relatively slow mechanical operation. Let us consider how to control the reaction time of a photoreaction based on the concept of the camera shutter. A lamp is placed next to a long reactor like a test tube, and a curtain with a slit is placed between the lamp and the reactor. The curtain is moved along the reactor at a constant speed. The slit moves from the top of the reactor to the bottom of the reactor. In this case, the time that the light hits the reaction solution, i.e., the reaction time, can be controlled by changing the slit width (Figure 2). In other words, time can be controlled by space. This is the basic idea of flash chemistry. Flash chemistry is characterized by controlling the tem- poral length of the reaction with the spatial length. As described above, short reaction times can be achieved with Figure 3. Control of reaction time by changing the distance between relatively slow mechanical speedofthecurtainwithaslidby the inlet of a reagent and that of quencher in a flow system using test tube type reactors. To make large amounts of products, however, a long test tube reactor is required, and the slit also the average residence time is 10 ms. The speed 1 m/s needs to be moved a long distance. The method of moving the (3600 m/h) is a little bit slower than the speed at which the slit is not practical from the viewpoint of chemical synthesis. The man is walking. The reaction time of millisecond order can idea of moving the solution instead of moving the slide solves be controlled at this flow speed. This is the principle that a the problem. The bottom of the reactor is eliminated to make a very short reaction time can be achieved using a flow type flow type reactor, and the reaction solution is allowed to flow reactor. while the position of the slit is fixed. Moving the slit is equiva- 3.2. The Time Required for Mixing. There is, however, lent to flowing the solution in front of the slit. Even in this case, still a problem. It is mixing time. When starting the reaction the reaction time can be controlled by adjusting the width of the by mixing two reaction components, the solution must be slit. This method has an advantage that an infinite amount of a uniformly mixed before the reaction takes place. If the mixing starting material can be reacted, in principle, by continuously is faster than the reaction, the reaction starts after the mixing flowing the solution. This is a feature of reactions in a continu- and proceeds according to the kinetics. If the reaction is very ous flow mode. fast and the mixing time is comparable to or longer than the reaction time, it is not possible to control the reaction by the kinetics. 3. In the Case Other than Photoreaction It is generally said that mixing eventually occurs by molecular 3.1. Starting a Reaction by Mixing. There are many diffusion. The time required for molecular diffusion increases in reactions other than photoreactions. Photoreactions are rather proportion to the square of the diffusion distance. In a macro- minor in chemical synthesis. Many reactions are initiated by scale batch reactor, the solution is stirred by mixing blades or a mixing two or more reaction components. To stop the stirrer bar to divide the solution into small segments which in reaction, a quenching agent is often added to the reaction turn shortens the diffusion distance. However, the minimum seg- mixture. In such cases, the method of moving a slit cannot be ment size is usually on the order of 10 to 100 μm. If the diffu- used. To control reaction times of such reactions, the concept sion distance is 100 μm, it takes a few seconds for molecular of controlling reaction time by space should be more diffusion. Therefore, the reaction time on the millisecond order generalized. In such cases, we control the residence time of cannot be controlled using a macro batch reactor. the solution between the point where the reaction components 3.3. Micromixer. To solve such a problem of mixing, flash are mixed and the point where the quenching agent is added. chemistry uses microspace. A micromixer is a mixer which The distance between the two points corresponds to the width makes a solution into a small segment by using of the slit of the curtain. In other words, the reaction time can microstructures to shorten the mixing time. There are various be controlled by changing the distance between two mixing types of micromixers, which can realize short mixing times points (Figure 3). that cannot be achieved with macro reactors [4]. For example, Then, how much shorter reaction time can be controlled by T-shaped mixtures with the channel width of 200–500 μm are using this method? If the distance between the two mixing often used although the mixing efficiency strongly depends on points is 10 mm and the flow speed (linear velocity) is 1 mm/s, the flow speed. The reaction time can be controlled to the the average residence time (the time the solution remains in order of millisecond by extremely fast micromixing. Figure 4 the reactor) is 10 s. If the flow speed is increased to 1 m/s, shows a typical reaction system consisting of a micromixer

Figure 2. Control of reaction time by changing a slit width: moving a slit or moving a solution?

61 “Impossible” Chemistries

Figure 5. Generation and reactions of aryllithiums bearing ketone carbonyl groups

carbamoyllithiums species in which lithium is directly bonded Figure 4. Precise control of reaction time by using a flow system to the carbon of the carbonyl group can be easily generated equipped with micromixers and reacted with subsequently added electrophiles [7]. Recently, further shortening of the reaction time to submilli- and a flow reactor. Therefore, both flow and micro are seconds has been achieved (Figure 6) [8]. Anionic Fries rear- indispensable for flash chemistry. rangement is an intramolecular reaction in which an aryllithium species reacts with a carbonyl group in the same molecule. This intramolecular rearrangement reaction is ex- 4. Flash Chemistry tremely fast, and therefore, it is difficult to get the product de- 4.1. What is Flash Chemistry. As mentioned above, flash rived from unrearranged aryllithium species. However, chemistry is a synthetic chemistry that utilizes flow microreactors shortening of the reaction time to 0.3 ms makes it possible. to control ultra-fast reactions to obtain desired products 4.3. Applications of Flash Chemistry to Catalyst selectively. For example, flash chemistry enables effective use of Generation. Catalysts are often used in chemical synthesis. unstable intermediates before they decompose even if such Generally, thermally stable compounds are used as catalysts, decomposition cannot be prevented by conventional flask but the flash chemistry enables the use of short-lived reactions. Flash chemistry is a new way which greatly expands unstable catalysts; a catalyst can be generated and added to a the possibilities of synthetic chemistry. Some typical examples of reaction mixture before it decomposes. After an active flash chemistry will be shown in the following sections. catalyst is added, the catalytic cycle starts to work to 4.2. Applications of Flash Chemistry in Homogeneous promote the catalytic reaction. The following example of Reactions. Organolithium species are highly reactive compounds Suzuki–Miyaura coupling using a flash-generated catalyst having a bond between carbon and lithium. Because the carbon demonstrates the power of the present concept (Figure 7) [9]. bonded to lithium acts as a carbanion, organolithium species are The catalytic activity of a complex obtained by mixing tri-t- often used in organic synthesis, in particular, for making carbon– butylphosphine and palladium acetate at a ratio of 1:1 in- carbon bonds. For carbon–carbon bond formation, carbonyl creases with the time after mixing. However, further increase compounds are commonly used as reaction partners causes a decrease in the catalytic activity. The maximum ac- (electrophiles) of organolithium species. tivity is obtained when the complex was added 0.33 s after Let us consider generating an organolithium species having mixing. Presumably, a highly active catalyst is formed from a ketone carbonyl group in the same molecule and reacting it tri-t-butylphosphine and palladium acetate by mixing, but it with a subsequently added electrophile such as aldehydes, decomposes very quickly. The activity of this catalyst is much which are more reactive than ketones. Such a process was higher than conventional catalysts. The present example dem- considered to be impossible according to textbooks of organic onstrates that flash chemistry changes the concept of catalyst chemistry. Indeed, when such an organolithium species is gen- and the chemistry of catalytic reactions. erated, the carbon bonded to lithium reacts with the ketone 4.4. Polymerization. Polymerization reactions for producing carbonyl carbon of another organolithium species to give a polymers from monomers are widely used in industry. dimerized species before an electrophile is added to the solu- Polymerization can be classified into chain-growth polymerization tion. However, flash chemistry makes it possible to quickly and step-growth polymerization, and flash chemistry is effective generate organolithium species having ketone carbonyl for chain-growth polymerization. Chain-growth polymerization is groups, add an electrophile before it dimerizes, and quickly re- classified into anionic polymerization, radical polymerization, and act it with the electrophile [5]. cationic polymerization according to the nature of the growth end. First, an aryl iodide having a ketone carbonyl group and a In anionic polymerization, using an organolithium species as an lithiation reagent (mesityllithium, MesLi) are mixed at the initiator is popular in laboratory polymer synthesis. However, first micromixer to generate an aryllithium species having a because it requires an extremely low temperature of −78 °C, ketone carbonyl group (Figure 5), which is reacted with an anionic polymerization has been thought to be difficult to use in aldehyde at the second micromixer. The residence time be- industry. However, when using a flow microreactor, anionic tween the two micromixers is 3 ms. By using this process, polymerization of styrene and methacrylates can be carried out at Pauciflorol F, one of natural polyphenols, can be easily syn- −30 °C or room temperature, which are readily accessible from a thesized. Notably, approximately 1 g of the compound can be viewpoint of industrial production (Figure 8) [10]. Polymers with synthesized by a 5 min operation, indicating that the produc- narrow molecular weight distribution can be synthesized, and the tivity of flash chemistry is rather high. molecular weight can be easily controlled by changing the flow Similarly, unstable benzyllithiums bearing an aldehyde car- ratio of a monomer solution and an initiator solution at the mixer. bonyl group have also been successfully generated and reacted Furthermore, block copolymers can be easily synthesized by with subsequently added electrophiles [6]. Moreover, adding the second monomer using the second micromixer before

62 J. Yoshida et al.

Figure 6. Control of anionic Fries rearrangement

pharmaceutical company, Novartis stated in their paper on lithiation of aryl halides followed by borylation that “the de- veloped metalation platform embodies a valuable complement to existing methodologies, as it combines the benefits of Flash Chemistry (chemical synthesis on a time scale of <1 s) with remarkable throughput (g/min) while mitigating the risk of blockages.” [13] Other examples showing the superiority of flash chemistry using flow microreactors in chemical and pharmaceutical manufacturing have also been reported [14].

6. Conclusion As described above, flash chemistry using flow microreac- Figure 7. Flash generation of an active catalyst tors makes it possible to control chemical reactions that are very difficult or impossible in a conventional flask. Some reactions that have been supposed to be impossible according to organic chemistry textbooks are now possible by controlling the time to be extremely short. Therefore, flash chemistry opens a new possibility of chemistry and chemical synthesis. Such chemistry is noticed not only as laboratory chemical synthesis but also as a major innovation for industrial production of functional materials, agricultural chemicals, and pharmaceu- ticals. Some commercial production plants have already been built and operated in industry. This field will be further devel- Figure 8. Anionic flash polymerization of methyl methacrylate oped and be used widely in industry. By making the impossible possible, we hope, flash chemistry using flow the growth end is decomposed. Alternatively, terminal microreactors will change our life and society in the future. functionalization is also easy by reacting the living growth end with various electrophiles. Open Access. This is an open-access article distributed under Flash chemistry is effective not only for anionic polymeri- the terms of the Creative Commons Attribution-NonCommercial zation but also for cationic polymerization which is also chain 4.0 International License (https://creativecommons.org/licenses/ growth polymerization. In conventional living cationic poly- by-nc/4.0/), which permits unrestricted use, distribution, and merization, it was necessary to add additives to stabilize the reproduction in any medium for non-commercial purposes, growth ends. However, based on flash chemistry, living cat- provided the original author and source are credited, a link to the ionic polymerization could be achieved without adding such CC License is provided, and changes - if any - are indicated. additives [11]. By controlling the polymerization time to be short and by adding a terminating agent before the growth end is decomposed, it is possible to obtain a polymer having a nar- References row molecular weight distribution. Alternatively, block copo- 1. Books on flow microreactor synthesis: (a) Ehrfeld, W.; Hessel, V.; lymerization is possible by quickly adding the second Löwe, H. Microreactors; Wiley-VCH: Weinheim, 2000; (b) Hessel, V.; Hardt, S.; Löwe, H. Chemical Micro Process Engineering; Wiley-VCH Verlag: monomer. Weinheim, 2004; (c) Yoshida, J. Flash Chemistry, Fast Organic Synthesis in Microsystems; Wiley-Blackwell: Oxford, 2008; (d) Micro Process Engineering, Hessel, V.; Renken, A.; Schouten, J. C.; Yoshida, J., Eds.; Wiley-VCH Verlag: 5. Industrial Applications Weinheim, 2009; (e) Microreactors in Organic Chemistry and Catalysis, 2nd Ed.; Wirth, T., Ed.; Wiley-VCH Verlag: Weinheim, 2013. Because of fast flow rates, the productivity of flash chemis- 2. Reviews on flow microreactor synthesis: (a) Jähnisch, K.; Hessel, V.; try is much larger than that is imagined from the small size of Löwe, H.; Baerns, M. Angew. Chem. Int. Ed. 2004, 43, 406–446; (b) Doku, G. the reactor. In fact, production of several tons or hundred tons N.; Verboom, W.; Reinhoudt, D. N.; van den Berg, A. Tetrahedron 2005, 61, 2733–2742; (c) Watts, P.; Haswell, S. J. Chem. Soc. Rev. 2005, 34, 235–246; of chemicals per year can be attained by one flow path. There- (d) Geyer, K.; Codée, J. D. C.; Seeberger, P. H. Chem. Eur. J. 2006, 12, 8434– fore, flash chemistry has been receiving great expectation 8442; (e) deMello, A. J. Nature 2006, 442, 394–402; (f) Song, H.; Chen, D. L.; Ismagilov, R. F. Angew. Chem. Int. Ed. 2006, 45, 7336–7356; (g) from chemical and pharmaceutical industries. For example, it Kobayashi, J.; Mori, Y.; Kobayashi, S. Chem. Asian. J. 2006, 1,22–35; (h) is written in their website that “Lonza uses an advanced ap- Brivio, M.; Verboom, W.; Reinhoudt, D. N. Lab Chip 2006, 6, 329–344; (i) proach to microreaction technology known as Flash Chemis- Mason, B. P.; Price, K. E.; Steinbacher, J. L.; Bogdan, A. R.; McQuade, D. T. Chem. Rev. 2007, 107, 2300–2318; (j) Ahmed-Omer, B.; Brandt, J. C.; Wirth, try, where multiple steps of a traditional chemical process can T. Org. Biomol. Chem. 2007, 5, 733–740; (k) Watts, P.; Wiles, C. Chem. be replaced by a single Flash Chemistry step.” [12] The Commun. 2007 , 443–467; (l) Fukuyama, T.; Rahman, M. T.; Sato, M.; Ryu, I.

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