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  • 1 Kyoto University, Nishikyo-ku, Kyoto 615-8510, Japan
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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.

Abstract

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.

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 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.

Many reactions which are used in organic synthesis involve reactive intermediates, although in many other cases starting materials react directly into products. A method in which a reactive intermediate is generated in the presence of a reaction partner is often used. A reactive intermediate molecule is reacted immediately after generation individually. However, this method cannot be used if the reaction partner is incompatible with the conditions for generation of the reactive intermediate. Unlike transition states, reactive intermediates are local energy minima. Therefore, they have definite lifetimes, and they can be accumulated in solution in some cases. However, the flask chemistry is limited to reactive species whose lifetimes are over the order of minutes.

Based on the concept that an unstable short-lived reactive intermediate is generated in a flow microreactor system, we have been developing reactions that are very difficult or impossible to achieve by conventional flask reactions [1, 2]. In 2005, we named this chemistry flash chemistry [3]. In flash chemistry, the reaction partner is added within a second or less to selectively obtain the target product. Precise and very short-range reaction time control by space in the flow system is essential for flash chemistry. This perspective article describes the basic concept of time control by space, some examples that realized reactions which were difficult to achieve by conventional flask chemistry, and the future of flash chemistry.

2. How Can We Achieve Short Reaction Times?

To generate a short-lived reactive intermediate and react it with a subsequently added reaction partner, it is necessary to control the reaction time shorter than its lifetime. How can we control reaction time in a short range? First, let us consider the following thought experiment about a photoreaction because the light can be easily switched on and off in a short time (Figure 1).

Figure 1.
Figure 1.

A simple system for photochemical reactions

Citation: Journal of Flow Chemistry JFChem 7, 3-4; 10.1556/1846.2017.00017

Generally, photoreactions proceed only when light strikes a solution of a starting material. Therefore, it is easy to start and stop the reaction. To start the reaction, we just turn on the lamp placed beside the reactor. Light enters the solution through the transparent reactor wall, and the photoreaction proceeds. To stop the reaction, we turn off the lamp. However, the minimum time interval that the switch can be turned on and off by hand is the order of seconds, and it is virtually impossible to do it in a shorter time such as milliseconds.

How can we control reaction in a shorter time? The following discussion based on the analogy with a camera shutter may be useful. A lamp is always turned on, and a curtain is placed between the lamp and the reactor. The photoreaction can be simply started by turning up the curtain, and by turning it down, the photoreaction can be stopped. These operations are very similar to the motion of the mechanical camera shutter. In fact, such on–off operations of the shutter can be achieved in a considerably short time (called an exposure time). The exposure time of 1/500th or 1/1000th of a second has been achieved without problems. However, it does not seem easy to move a shutter curtain mechanically so quickly. How can the exposure time be made very short in a controlled way in real cameras?

To achieve very short exposure time, focal plane shutters are often used. In this type of shutter, there are two curtains: a first curtain and a second curtain. First, the first curtain moves and the optical path opens. Therefore, the light hits the photosensitive part 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.

When the exposure time is set to be shorter, the second curtain starts to move before the light hits the entire photosensitive part. This means that a slit through which light passes is formed between the first curtain and the second curtain and that the slit moves in front of the photosensitive part. For example, to realize an exposure time of 1/1000 s, the slit width is set to 1/10 of the width of the photosensitive portion, and the slit moves from one end to the other end of the photosensitive portion in 1/100 s. As 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. The exposure time is controlled with the spatial size of the slit 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 temporal length of the reaction with the spatial length.

Figure 2.
Figure 2.

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

Citation: Journal of Flow Chemistry JFChem 7, 3-4; 10.1556/1846.2017.00017

As described above, short reaction times can be achieved with relatively slow mechanical speed of the curtain with a slid by using test tube type reactors. To make large amounts of products, however, a long test tube reactor is required, and the slit also needs to be moved a long distance. The method of moving the slit is not practical from the viewpoint of chemical synthesis. The idea of moving the solution instead of moving the slide solves the problem. The bottom of the reactor is eliminated to make a flow type reactor, and the reaction solution is allowed to flow while the position of the slit is fixed. Moving the slit is equivalent to flowing the solution in front of the slit. Even in this case, the reaction time can be controlled by adjusting the width of the slit. This method has an advantage that an infinite amount of a starting material can be reacted, in principle, by continuously flowing the solution. This is a feature of reactions in a continuous flow mode.

3. In the Case Other than Photoreaction

3.1. Starting a Reaction by Mixing

There are many reactions other than photoreactions. Photoreactions are rather minor in chemical synthesis. Many reactions are initiated by mixing two or more reaction components. To stop the reaction, a quenching agent is often added to the reaction mixture. In such cases, the method of moving a slit cannot be used. To control reaction times of such reactions, the concept of controlling reaction time by space should be more generalized. In such cases, we control the residence time of the solution between the point where the reaction components are mixed and the point where the quenching agent is added. The distance between the two points corresponds to the width of the slit of the curtain. In other words, the reaction time can be controlled by changing the distance between two mixing points (Figure 3).

Figure 3.
Figure 3.

Control of reaction time by changing the distance between the inlet of a reagent and that of quencher in a flow system

Citation: Journal of Flow Chemistry JFChem 7, 3-4; 10.1556/1846.2017.00017

Then, how much shorter reaction time can be controlled by using this method? If the distance between the two mixing points is 10 mm and the flow speed (linear velocity) is 1 mm/s, the average residence time (the time the solution remains in the reactor) is 10 s. If the flow speed is increased to 1 m/s, the average residence time is 10 ms. The speed 1 m/s (3600 m/h) is a little bit slower than the speed at which the man is walking. The reaction time of millisecond order can be controlled at this flow speed. This is the principle that a very short reaction time can be achieved using a flow type reactor.

3.2. The Time Required for Mixing

There is, however, still a problem. It is mixing time. When starting the reaction by mixing two reaction components, the solution must be uniformly mixed before the reaction takes place. If the mixing is faster than the reaction, the reaction starts after the mixing and proceeds according to the kinetics. If the reaction is very 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.

It is generally said that mixing eventually occurs by molecular diffusion. The time required for molecular diffusion increases in proportion to the square of the diffusion distance. In a macro-scale batch reactor, the solution is stirred by mixing blades or a stirrer bar to divide the solution into small segments which in turn shortens the diffusion distance. However, the minimum segment size is usually on the order of 10 to 100 μm. If the diffusion distance is 100 μm, it takes a few seconds for molecular diffusion. Therefore, the reaction time on the millisecond order cannot be controlled using a macro batch reactor.

3.3. Micromixer

To solve such a problem of mixing, flash chemistry uses microspace. A micromixer is a mixer which makes a solution into a small segment by using microstructures to shorten the mixing time. There are various types of micromixers, which can realize short mixing times that cannot be achieved with macro reactors [4]. For example, T-shaped mixtures with the channel width of 200–500 μm are often used although the mixing efficiency strongly depends on the flow speed. The reaction time can be controlled to the order of millisecond by extremely fast micromixing. Figure 4 shows a typical reaction system consisting of a micromixer and a flow reactor. Therefore, both flow and micro are indispensable for flash chemistry.

Figure 4.
Figure 4.

Precise control of reaction time by using a flow system equipped with micromixers

Citation: Journal of Flow Chemistry JFChem 7, 3-4; 10.1556/1846.2017.00017

4. Flash Chemistry

4.1. What is Flash Chemistry

As mentioned above, flash chemistry is a synthetic chemistry that utilizes flow microreactors to control ultra-fast reactions to obtain desired products selectively. For example, flash chemistry enables effective use of unstable intermediates before they decompose even if such decomposition cannot be prevented by conventional flask reactions. Flash chemistry is a new way which greatly expands the possibilities of synthetic chemistry. Some typical examples of flash chemistry will be shown in the following sections.

4.2. Applications of Flash Chemistry in Homogeneous Reactions

Organolithium species are highly reactive compounds having a bond between carbon and lithium. Because the carbon bonded to lithium acts as a carbanion, organolithium species are often used in organic synthesis, in particular, for making carbon–carbon bonds. For carbon–carbon bond formation, carbonyl compounds are commonly used as reaction partners (electrophiles) of organolithium species.

Let us consider generating an organolithium species having a ketone carbonyl group in the same molecule and reacting it with a subsequently added electrophile such as aldehydes, which are more reactive than ketones. Such a process was considered to be impossible according to textbooks of organic chemistry. Indeed, when such an organolithium species is generated, the carbon bonded to lithium reacts with the ketone carbonyl carbon of another organolithium species to give a dimerized species before an electrophile is added to the solution. However, flash chemistry makes it possible to quickly generate organolithium species having ketone carbonyl groups, add an electrophile before it dimerizes, and quickly react it with the electrophile [5].

First, an aryl iodide having a ketone carbonyl group and a lithiation reagent (mesityllithium, MesLi) are mixed at the first micromixer to generate an aryllithium species having a ketone carbonyl group (Figure 5), which is reacted with an aldehyde at the second micromixer. The residence time between the two micromixers is 3 ms. By using this process, Pauciflorol F, one of natural polyphenols, can be easily synthesized. Notably, approximately 1 g of the compound can be synthesized by a 5 min operation, indicating that the productivity of flash chemistry is rather high.

Figure 5.
Figure 5.

Generation and reactions of aryllithiums bearing ketone carbonyl groups

Citation: Journal of Flow Chemistry JFChem 7, 3-4; 10.1556/1846.2017.00017

Similarly, unstable benzyllithiums bearing an aldehyde carbonyl group have also been successfully generated and reacted with subsequently added electrophiles [6]. Moreover, carbamoyllithiums species in which lithium is directly bonded to the carbon of the carbonyl group can be easily generated and reacted with subsequently added electrophiles [7].

Recently, further shortening of the reaction time to submilliseconds has been achieved (Figure 6) [8]. Anionic Fries rearrangement is an intramolecular reaction in which an aryllithium species reacts with a carbonyl group in the same molecule. This intramolecular rearrangement reaction is extremely fast, and therefore, it is difficult to get the product derived from unrearranged aryllithium species. However, shortening of the reaction time to 0.3 ms makes it possible.

Figure 6.
Figure 6.

Control of anionic Fries rearrangement

Citation: Journal of Flow Chemistry JFChem 7, 3-4; 10.1556/1846.2017.00017

4.3. Applications of Flash Chemistry to Catalyst Generation

Catalysts are often used in chemical synthesis. Generally, thermally stable compounds are used as catalysts, but the flash chemistry enables the use of short-lived unstable catalysts; a catalyst can be generated and added to a reaction mixture before it decomposes. After an active catalyst is added, the catalytic cycle starts to work to promote the catalytic reaction. The following example of Suzuki–Miyaura coupling using a flash-generated catalyst demonstrates the power of the present concept (Figure 7) [9].

Figure 7.
Figure 7.

Flash generation of an active catalyst

Citation: Journal of Flow Chemistry JFChem 7, 3-4; 10.1556/1846.2017.00017

The catalytic activity of a complex obtained by mixing tri-t-butylphosphine and palladium acetate at a ratio of 1:1 increases with the time after mixing. However, further increase causes a decrease in the catalytic activity. The maximum activity is obtained when the complex was added 0.33 s after mixing. Presumably, a highly active catalyst is formed from tri-t-butylphosphine and palladium acetate by mixing, but it decomposes very quickly. The activity of this catalyst is much higher than conventional catalysts. The present example demonstrates that flash chemistry changes the concept of catalyst and the chemistry of catalytic reactions.

4.4. Polymerization

Polymerization reactions for producing polymers from monomers are widely used in industry. Polymerization can be classified into chain-growth polymerization and step-growth polymerization, and flash chemistry is effective for chain-growth polymerization. Chain-growth polymerization is classified into anionic polymerization, radical polymerization, and cationic polymerization according to the nature of the growth end. In anionic polymerization, using an organolithium species as an initiator is popular in laboratory polymer synthesis. However, because it requires an extremely low temperature of −78 °C, anionic polymerization has been thought to be difficult to use in industry. However, when using a flow microreactor, anionic polymerization of styrene and methacrylates can be carried out at −30 °C or room temperature, which are readily accessible from a viewpoint of industrial production (Figure 8) [10]. Polymers with narrow molecular weight distribution can be synthesized, and the molecular weight can be easily controlled by changing the flow ratio of a monomer solution and an initiator solution at the mixer. Furthermore, block copolymers can be easily synthesized by adding the second monomer using the second micromixer before the growth end is decomposed. Alternatively, terminal functionalization is also easy by reacting the living growth end with various electrophiles.

Figure 8.
Figure 8.

Anionic flash polymerization of methyl methacrylate

Citation: Journal of Flow Chemistry JFChem 7, 3-4; 10.1556/1846.2017.00017

Flash chemistry is effective not only for anionic polymerization but also for cationic polymerization which is also chain growth polymerization. In conventional living cationic polymerization, it was necessary to add additives to stabilize the growth ends. However, based on flash chemistry, living cationic polymerization could be achieved without adding such 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 narrow molecular weight distribution. Alternatively, block copolymerization is possible by quickly adding the second monomer.

5. Industrial Applications

Because of fast flow rates, the productivity of flash chemistry is much larger than that is imagined from the small size of the reactor. In fact, production of several tons or hundred tons of chemicals per year can be attained by one flow path. Therefore, flash chemistry has been receiving great expectation from chemical and pharmaceutical industries. For example, it is written in their website that “Lonza uses an advanced approach to microreaction technology known as Flash Chemistry, where multiple steps of a traditional chemical process can be replaced by a single Flash Chemistry step.” [12] The pharmaceutical company, Novartis stated in their paper on lithiation of aryl halides followed by borylation that “the developed 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 microreactors 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 pharmaceuticals. Some commercial production plants have already been built and operated in industry. This field will be further developed and be used widely in industry. By making the impossible possible, we hope, flash chemistry using flow microreactors will change our life and society in the future.

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If the inline PDF is not rendering correctly, you can download the PDF file here.

  • 1.

    Books on flow microreactor synthesis: (a) Ehrfeld W.; Hessel V.; Löwe H. Microreactors; Wiley-VCH: Weinheim, 2000;

    (b) Hessel V. ; Hardt S.; Löwe H. Chemical Micro Process Engineering; Wiley-VCH Verlag: 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: Weinheim, 2009;

    (e) Microreactors in Organic Chemistry and Catalysis, 2nd Ed.; Wirth T., Ed.; Wiley-VCH Verlag: Weinheim, 2013.

  • 2.

    Reviews on flow microreactor synthesis: (a) Jähnisch K.; Hessel V.; Löwe H.; Baerns M. Angew. Chem. Int. Ed. 2004, 43, 406446;

    (b) Doku G. N. ; Verboom W.; Reinhoudt D. N.; van den Berg A. Tetrahedron 2005, 61, 27332742;

    (c) Watts P. ; Haswell S. J. Chem. Soc. Rev. 2005, 34, 235246;

    (d) Geyer K. ; Codée J. D. C.; Seeberger P. H. Chem. Eur. J. 2006, 12, 84348442;

    (e) deMello A. J. Nature 2006, 442, 394402;

    (f) Song H. ; Chen D. L.; Ismagilov R. F. Angew. Chem. Int. Ed. 2006, 45, 73367356;

    (g) Kobayashi J. ; Mori Y.; Kobayashi S. Chem. Asian. J. 2006, 1, 2235;

    (h) Brivio M. ; Verboom W.; Reinhoudt D. N. Lab Chip 2006, 6, 329344;

    (i) Mason B. P. ; Price K. E.; Steinbacher J. L.; Bogdan A. R.; McQuade D. T. Chem. Rev. 2007, 107, 23002318;

    (j) Ahmed-Omer B. ; Brandt J. C.; Wirth T. Org. Biomol. Chem. 2007, 5, 733740;

    (k) Watts P. ; Wiles C. Chem. Commun. 2007, 443467;

    (l) Fukuyama T. ; Rahman M. T.; Sato M.; Ryu I. Synlett 2008, 151163;

    (m) Hartman R. L. ; Jensen K. F. Lab Chip 2009, 9, 24952507;

    (n) McMullen J. P. ; Jensen K. F. Annu. Rev. Anal. Chem. 2010, 3, 1942;

    (o) Yoshida J. ; Kim H.; Nagaki A. ChemSusChem 2011, 4, 331340;

    (p) Wiles C. ; Watts P. Green Chem. 2012, 14, 3854;

    (q) Kirschning A. ; Kupracz L.; Hartwig J. Chem. Lett. 2012, 41, 562570;

    (r) McQuade D. T. ; Seeberger P. H. J. Org. Chem. 2013, 78, 63846389;

    (s) Elvira K. S. ; Solvas X. C.; Wootton R. C. R.; deMello A. J. Nat. Chem. 2013, 5, 905915;

    (t) Pastre J. C. ; Browne D. L.; Ley S. V. Chem. Soc. Rev. 2013, 42, 88498869;

    (u) Baxendale I. R. J. Chem. Technol. Biotechnol. 2013, 88, 519552;

    (v) Yoshida J. ; Nagaki A.; Yamada D. Drug Discovery Today Technol. 2013, 10, e53e59;

    (w) Fukuyama T. ; Totoki T.; Ryu I. Green Chem. 2014, 16, 20422050;

    (x) Myers R. M. ; Fitzpatrick D. E.; Turner R. M.; Ley S. L. Chem. Eur. J. 2014, 20, 1234812366;

    (y) Cambié D. ; Bottecchia C.; Straathof N. J. W.; Hessel V.; Noël T. Chem. Rev. 2016, 116, 1027610341;

    (z) Movsisyan M. ; Delbeke E. I. P.; Berton J. K. E. T.; Battilocchio C.; Ley S. V.; Stevens C. V. Chem. Soc. Rev. 2016, 45, 48924928;

    (aa) Kobayashi S . Chem. Asian J. 2016, 11, 425436;

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