Microflow systems

A copper-free Sonogashira coupling reaction in ionic liquids and its application to a microflow system for efficient catalyst recycling, Org. Lett. 4, 10 (2002) 1691-1694. 

Another pilot plant, developed by at Kyoto University, was used for the Grignard exchange reaction at the same productivity as the batch reactor (10 m3) by adding only four microflow systems of the present scale (Wakami and Yoshida 2006). A multitubular reactor is the core element of the microprocessing plant (see Fig. 17). Stable yields of approximately 95% could be demonstrated for a 24-h run. 

Following similar trials with the formation of diarylbenzenes [63-65], the same research group has reported a multistep synthesis of photochromic diarylethenes using a microflow system that contained two linked micromixers and microreactors (MRi 2) [66]. Similarly to the previously reported linked microreactors, the reactors used in this setup were made of stainless steel tubes and T-shaped micromixers. Initial experiments were conducted in two steps in a continuous sequence to afford symmetrical octasubstitued diaryUiexafluoro cyclopentene (Scheme 29). 

Scheme 30 Synthesis of an unsymmetrical diarylethene using a multistep microflow system [66]...

Rahman MT, Fukuyama T, Kamata N et al (2006) Low pressure Pd-catalyzed carbonylation in an ionic liquid using a multiphase microflow system. Chem Commun 21 2236-2238... 

Fukuyama T, Rahman T, Kamata N et al (2009) Radical carbonylations using a continuous microflow system. Beilstein J Org Chem 5 No. 34... 

Nagaki A, Takabayashi N, Tomida Y et al (2009) Synthesis of unsymmetrically substituted biaryls via sequential lithiation of dibromobiaryls using integrated microflow systems. Beilstein J Org Chem 5 11... 

Ushiogi Y, Hase T, linuma Y et al (2007) Synthesis of photochromic diarylethenes using a microflow system. Chem Commun 28 2947-2949... 

The synthesis of diarylethenes from hetaryl bromides and octafluoro-cyclopentene using a microflow system allows the preparation of various symmetrical and unsymmetrical diarylperfluorocyclopentenes in 47-87% yields at 0°C (07CC2947). 

Flow-Based Systems Needle-type sensors with a fluid flowing over the sensor tip seem to resist biofouling and extend sensor lifetime.31 There are numerous methods that have been investigated for flow-based sensors, such as microperfusion systems,75 microdialysis,76 77 and ultrafiltration.78 Reduced fouling was found with an open microflow system where slow flow of protein-free fluid over the sensor surface at the implant site is effected.73 Different from the other flow-based sensors, the open microflow is controlled by the subcutaneous tissue hydrostatic pressure and does not require a pump. 

Nagaki et al. (2008) also demonstrated the use of sec-BuLi 84 in a microflow system for the anionic polymerization of styrene 88, as a means of attaining a high degree of control over the molecular weight distribution of the resulting polymer. Employing a solution of styrene 88 (2.0 M) in THF and sec-BuLi 84 (0.2 M) in hexane and a tubular reactor... 

Using a stainless-steel microreactor, Ushiogi et al. (2007) reported a microflow system capable of synthesizing unsymmetrical diarylethenes, a process that is notoriously difficult to achieve in conventional batch systems. As Scheme 62 illustrates, diarylethenes are of synthetic interest due to their ability to change color via a reversible switching between two distinct isomers, which occurs as a result of light absorption. 

Table 31 Comparison of the product distribution obtained in batch and microflow systems for the arylation of octafluorocyclopentene 213...

Haswell and coworkers carried out the Wittig reaction of 2-nitrobenzyl triphenylpho-sphonium bromide with methyl 4-formylbenzoate in a microflow system [17,18]. They used a borosilicate glass microreactor with T-shaped channels (width = 200 pm and depth = 100 pm), and the reagents were added via EOF by applying a constant... 

Condensation of 1,3-diketones with hydrazines or hydroxyamines was conducted in a microflow system to give pyrazoles and isoxazoles in good yields [22]. High-throughput synthesis of pyrrole by the Paal-Knorr condensation of ethanolamine and acetonylacetone was achieved using the CPC CYTOS Lab System [23], The running of the system for 165 min resulted in 714 g of the pyrrole (Scheme 4.14). 

Microwave irradiation has been proven useful in accelerating chemical reactions. A unique approach to multicomponent reactions - the combination of microwave irradiation and microreactors - was developed by Organ and Bremner [25]. The three-component coupling reaction of amino pyrazole with an aldehyde and diketone in a glass capillary tube microflow system (1180 pm i.d.) under microwave irradiation (170 W) proceeded smoothly to give the desired quinolinone in high yield (Scheme 4.16). Without microwave irradiation, the reaction efficiency was very low. 

In their pioneering work, Jensen et al. demonstrated that photochemical transformation can be carried out in a microfabricated reactor [37]. The photomicroreactor had a single serpentine-shaped microchannel (having a width of 500 pm and a depth of 250 or 500 pm, and etched on a silicon chip) covered by a transparent window (Pyrex or quartz) (Scheme 4.25). A miniature UV light source and an online UV analysis probe were integrated to the device. Jensen et al. studied the radical photopinacolization of benzophenone in isopropanol. Substantial conversion of benzophenone was observed for a 0.5 M benzophenone solution in this microflow system. Such a high concentration of benzophenone would present a challenge in macroscale reactors. This microreaction device provided an opportunity for fast process optimization by online analysis of the reaction mixture. 

Kitamori and coworkers reported the use of a Ti02-modified microchannel chip reactor (TMC, Pyrex glass chip, having branched channels 770 pm wide and 3.5 pm deep) for photocatalytic redox-combined synthesis of L-pipecolinic acid from L-lysine (Scheme 4.31) [45], Although both batch and microflow systems gave comparable yield and enantiomeric excess of the product, the conversion rate was significantly higher for the microflow reactor than for the batch system. 

Paddon et al. reported that a simple thin-layer flow cell having closely spaced electrodes (50 pm) does not require added electrolytes (Scheme 4.35) [49]. Such dose proximity of the electrodes allows the two diffusion layers of the electrodes to overlap or couple . Hence, ions generated at one electrode may act as the charge carrier, obviating the need to add electrolytes. A self-supported two-electron/two-proton reduction oftetra(ethoxycarbonyl)ethylene to tetra(ethoxycarbonyl)ethane in a microflow system was demonstrated as a model reaction. 

Yoshida and coworkers also developed a microreaction system for cation pool-initiated polymerization [62]. Significant control of the molecular weight distribution (Mw/Mn) was achieved when N-acyliminium ion-initiated polymerization of butyl vinyl ether was carried out in a microflow system (an IMM micromixer and a microtube reactor). Initiator and monomer were mixed using a micromixer, which was connected to a microtube reactor for the propagation step. The polymerization reaction was quenched by an amine in a second micromixer. The tighter molecular weight distribution (Mw/M = 1.14) in the microflow system compared with that of the batch system (Mw/M > 2) was attributed to the very rapid mixing and precise control of the polymerization temperature in the microflow system. 

Overalkylation can lead to tertiary alcohol formation by consecutive reaction [29]. Product quality demands to keep this impurity level <0.2%. Microreactor operation yielded the overalkylated alcohol follow-up product at 0.18%, whereas level of impurity for the batch process was 1.56% [29]. The reason is probably the lower back-mixing in the microflow system, with concentration profiles being less deteriorated from ideal that is, no excess of alkylating agent is generated locally to promote the follow-up reaction. 

In a detailed process optimization study, the impact of the type of micromixers and process parameters was determined [56]. As a result, a pilot with a Toray Hi-mixer connected to a shell and tube microheat exchanger was constructed. Continuous operation for 24 h was carried out to obtain pentafluorobenzene (PFB) after protonation (92% yield). In this time, 14.7 kg of the product was produced, that is, about 5 t/a. Thus, the industrial-scale production carried out using a batch reactor (10 m3) can be replaced by adding only four microflow systems of the scale investigated. The pilot plant produces 0.5 kg in 6h continuous operation, thus about 730kg/a (see Figure 5.19). The name of the industrial company was not disclosed. 

QCqmlfPFg] [C4C1im][Tf2N] Pd-phosphine carbene complex Pr3N 130-150 °C. Arylation of butyl acrylate with iodobenzene in a microflow-system with continuous recycling of the ionic liquid-catalyst phase product extracted with hexane. [77]... 

Figure 3.54 shows schematically a generic microflow system that might be used to synthesize fine chemicals from reactants on denuuid, or to produce individual doses of a reconstituted lyophilized drug for medical treatment. A multi-... 

Figure 3.54 Conceptual view of integrated microflow system employing FPW pumps, mixer, process sensor and insonicator to produce ultrasound-assisted chemical reactions. Heater would be deposited metal or polysilicon meanderline formed on a surface of the chamber.

Suga, S. Okajima, M. Fujiwara, K Yoshida, J., Cation flow method a new approach to electrochemical conventional and combinatorial organic syntheses using electrochemical microflow systems,./. Am. Chem. Soc. 2001, 123, 7941-7942... 

Using a micro reactor the impurity by over-alkylation was 0.18%, while the batch impurity was 1.56% [181]. This was possible due the lower back-mbdng in the microflow system. The optical purity of the microreactor product was 98.4% as compared with 97.9% at batch level. 

This book provides an outline of the concept of flash chemistry for conducting extremely fast reactions in a highly controlled manner using microflow systems. In the following chapters, we will discuss the background, the principles, and applications of flash chemistry. 

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