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FEATURE ARTICLE

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Recent advances in micro reaction technology Charlotte Wiles*a and Paul Watts*ab

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Received 5th January 2011, Accepted 8th March 2011 DOI: 10.1039/c1cc00089f It is the intention of this review to provide the reader with a survey of the current literature pertaining to the use of micro reactors in synthetic chemistry; recent advances are briefly discussed, with references provided to assist with further reading on this rapidly growing research topic.

Introduction Since the mid nineteen nineties, academic researchers have been investigating the use of micro reactors as tools for chemical research;1 however, in the intervening fifteen years research has spread to the wider chemical community, with several contract manufacturers now using this technology for the production of high value intermediates/products and even degree level courses taught on the subject.2 For those of you new to this discipline, you may be questioning what is a micro reactor? These are commonly classed as devices in which synthetic transformations are performed within structures with lateral dimensions of typically less than 1 mm; they can also be termed microstructured reactors or flow reactors. The scale that reactions are performed on is key to the advantages of this technology, affording access to a series of unique properties which are unattainable through the use of conventional batch reactors. The first of these advantages is the rapid mixing that occurs due to the short diffusion distances within such devices,3,4 as such high purity products can be obtained via suppression of side reactions that occur due to poor mixing or aging in batch reactors.5 The second advantage is the efficient thermal transfer, with heat transfer a

Chemtrix BV, Burgemeester Lemmensstraat 358, 6163 JT, Geleen, The Netherlands. E-mail: [email protected]; Tel: +44 (0)1482 466459 b The Department of Chemistry, The University of Hull, Cottingham Road, HU6 7RX, UK. E-mail: [email protected]; Tel: +44 (0)1482 465471

Dr Charlotte Wiles is the Chief Technology Officer at Chemtrix BV, and has been actively researching within the area of micro reaction technology for ten years, starting with a PhD entitled ‘Micro reactors in organic chemistry’, which she obtained from The University of Hull in 2003. In the past decade she has authored many scientific papers and review articles, recently co-authoring a book on the subject ‘Micro reaction technology in organic synthesis’. More recently, she has tailored her experience to the development and evaluation of commercially available continuous flow reactors, systems and peripheral equipment. 6512

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coefficients of the order of 6  104 W m 2 K 1 compared with B100 W m 2 K 1 for batch vessels.6 Consequently reaction exotherms can be readily dissipated, enabling highly energetic materials to be synthesised in a safe manner; examples of which are described herein. Combining these unique physical features within bench-top equipment, the chemist now has a new way of performing synthetic reactions, at steady-state, which enables the evaluation of temperature and pressure effects to be performed with ease and with a high degree of reproducibility. With this in mind, users have more recently begun to report the extraction of kinetic information derived from such systems.7,8 Compared to the conventional practice of slowing down reactions or adapting plant infrastructure in order to maintain a process under thermal control, continuous flow reactors employ superior heat management which enables reaction conditions previously deemed too dangerous to be employed on a production scale. Therefore fast, exothermic reactions can be intensified due to rapid mixing and efficient thermal management and slow reactions can be improved by employing higher temperatures and pressures when compared to batch processes.9 Opening up the ‘processing window’10,11 available to the chemist therefore enables the investigation of new synthetic routes utilising, for example, low boiling solvents and less catalytic material, generating cleaner by-product free materials. In addition, the ability to implement electrochemical and photochemical activation has been increased by the development of easy to use lab-scale equipment providing additional tools to the modern synthetic chemist. Dr Paul Watts is a reader in organic chemistry at The University of Hull and since graduating from the University of Bristol, where he completed a PhD in bio-organic natural product synthesis, he has led the Micro Reactor group at Hull. In this role he has published more than 70 papers, and he regularly contributes to the field by way of invited book chapters, review articles, and keynote lecturers on the subject of micro reaction technology in organic synthesis.

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Whilst the low system volumes can be perceived as a disadvantage when looking to prepare large quantities of material, the fact that such devices can be safely operated continuously, and un-attended, means that small footprint systems can be used to generate production scale volumes of material; at the same time as being flexible enough to respond to changes in the market or supply chain, examples of which will be given later. For those new to the field one of the most frequently ask questions about micro reactors is ‘don’t you block the channels?’. As can be expected from systems containing mm to mm size features, these systems do not tolerate particles well and although systems have been designed to synthesise nanoparticles,12 polymeric microspheres13 and for crystallisations;14 in the main, micro reactors are not tolerant to particulates where the particle size exceeds 10% of the smallest dimension in the system. With this in mind, it is important to think about the reaction that you are performing and to select a solvent and concentration that means the reactants, intermediates and products remain in solution—this may mean selecting a solvent that you would not have previously considered in batch, but as the reactor can be readily pressurised and heated, you can now select a solvent based on wider criteria than the boiling point! In order to demonstrate the advantages associated with micro reaction technology, a series of examples have been selected; these range from single phase reactions to multiphase and multistep examples. In addition, unit operations such as separations, purifications and crystallisations are described owing to their importance in the wider picture of chemical production.

1.0. 1.1

Liquid-phase reactions Nitrations

The exothermic and corrosive nature of nitration reactions means that numerous research groups have investigated their performance under flow conditions as a means of increasing the process safety associated with this transformation.15,16 Investigating the exothermic nitration of 2-ethylhexanol to afford the diesel additive 2-ethylhexylnitrate, Chen et al.17 fabricated a sixteen channel stainless steel micro reactor. Employing a mixed acid solution (74% H2SO4 and 24% HNO3), a biphasic reaction mixture resulted upon addition of the alcohol, and the reaction products were collected and cooled offline prior to analysis by GC-FID. Utilising electrical heating, the authors investigated the reaction at 25 to 40 1C, whereas the commercial process is maintained at 15 1C, observing conversions of 60 to 82%. Further investigations into increased HNO3 concentration enabled the authors to obtain the target nitrate in 97.2% conversion with a reaction time of 7.2 s (35 1C). Using commercially available glass micro reactors (Corning Incorporated), Reintjens and co-workers18 demonstrated selective nitration using neat HNO3. Synthesising an undisclosed product, the researchers report that a 150 ml reactor was used to generate the target compound at a rate of 13 kg h 1, with intrinsic safety levels not attainable using conventional batch This journal is

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Scheme 1 Synthesis of a pharmaceutically interesting intermediate via continuous flow azidation.

methodology. Operating eight reactors in parallel enabled the scale to be increased to 100 kg h 1 which equates to a theoretical throughput of 800 tonnes annum 1. Whilst the details of the reaction were not disclosed, the investigation illustrates the ease with which flow processes can be scaled to achieve production-scale quantities whilst retaining a relatively small system footprint. 1.2 Azidations Whilst azides represent a synthetically useful functional group, the hazards associated with their preparation have limited their production and use. Kopach et al.19 demonstrated the development of a continuous flow reactor suitable for the synthesis of 1-(azidomethyl)-3,5-bis(trifluoromethyl)benzene 1 from the respective chloride 2, as illustrated in Scheme 1, as a means of circumventing the hazards associated with the build-up of hydrazoic acid in the headspace of batch reaction vessels. Using a stainless steel tube reactor (dimensions = 1.59 mm (o.d.)  0.64 mm (i.d.)  63.1 m (long), volume = 20 ml), the authors investigated the reaction at a series of temperatures. Introducing heat into the system, by placing the reactor in a GC oven, the authors identified 90 1C as the optimal temperature at a residence time of 20 min; affording 1 in 97.3% conversion. Operating the reactor continuously for 2.8 h enabled the authors to produce 25 g of 1-(azidomethyl)-3,5-bis(trifluoromethyl)benzene 1 in 94% isolated yield; after partitioning between heptane and water. Employing trimethylsilylazide (0.4 M in THF), Nieuwland et al.20 investigated the effect of reaction time (5–30 s) and temperature (60–80 1C) on the azidation of alkyl halides, using HCl in EtOAc/acetone as a quench solvent. Using this approach, the authors identified a reaction time of 10 s and a reactor temperature of 80 1C as being optimal for the transformation. In an example which demonstrates the increased reactor safety associated with micro reactors, Brandt and Wirth21 performed the synthesis of carbamoyl azides in the presence of an excess of in situ prepared IN3 3 (Scheme 2),

Scheme 2 Illustration of the protocol used for the flow synthesis of carbamoyl azides.

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whereby subsequent thermal rearrangement of the isocyanate 4 in the presence of IN3 3 afforded the target carbamoyl azide 5. In order to safely quench any residual IN3 3 or organic azides formed, the reaction products were collected in an aqueous solution of sodium thiosulfate and the products extracted into DCM. Using this approach, the authors successfully reacted a series of aldehydes, affording the target products in isolated yields of 21 to 44%.

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1.3

Fluorinations

Owing to the increased biological uptake of pharmaceutical agents containing fluorine substituents, efficient synthetic methods are sought for the introduction of fluorine into small organic compounds. A recent example reported by Seeberger et al.22 demonstrated the efficient synthesis of fluorinated alcohols, aldehydes and carboxylic acids using diethylamino sulfur 6 (DAST) in a PTFE tube reactor (volume = 16 ml). Employing a reaction time of 16 min and a temperature of 70 1C (5 bar), the authors were able to isolate the target fluorinated compound in yields ranging from 40 to 100% (Scheme 3). Subsequently, Baumann et al.23 demonstrated the tolerance of their flow methodology towards vinyl iodides, ethers and epoxides, with electron deficient aldehydes readily fluorinated at 80 1C. 1.4

Grignard reactions

Employing a commercially available tubular reactor (Vapourtec), Rencurosi and co-workers24 demonstrated the reaction of a series of carbonyl containing compounds with Grignard reagents as a means of synthesising substituted alcohols. Using the developed methodology, the authors extended their investigation to evaluate the synthesis of (rac)-Tramadol 7 (Scheme 4). Using a PTFE tube reactor, the authors reacted (rac)-2-((dimethylamino)methyl)-cyclohexanone 8 (0.25 M) with 3-methoxyphenylmagnesium bromide 9 (1.2 eq.) at room temperature for a period of 33 min. Under the aforementioned conditions, the authors were able to isolate the target compound in 96% yield as a diastereomeric mixture (8 : 2). The high degree of reaction control obtained under flow conditions has been shown to be advantageous in particular for the Grignard reaction, as a means of suppressing side reactions and increasing product purity whilst decreasing reaction times.

Scheme 4 Synthetic approach used in the synthesis of (rac)-Tramadol 7 under flow conditions.

1.5 Cycloadditions Due to the ease with which complex scaffolds can be prepared, and diversity introduced, cycloadditions have been widely studied under flow conditions. Using a combination of flow reactors and the H-cubes system, Baumann and co-workers25 demonstrated the generation of azomethine ylides and their dipolar cycloaddition reaction to afford a series of 3-nitropyrrolidines 10 (60–120 1C), which were subsequently chemoselectively hydrogenated (60 1C) to the respective amines in high yield (Scheme 5)—a core motif found in biologically active compounds such as nicotine, L-proline, levetiracetam and vildagliptin. Employing a microcapillary flow disk (MFD) containing eight parallel reaction channels, each with a dimension of 180–220 mm, Mackley and co-workers26 investigated the Diels–Alder reaction of maleic anhydride 11 and isoprene 12 to afford the cycloadduct 3a,5,7a-trimethyl-3a,4,7,7a-tetrahydro-isobenzofuran-1,3-dione 13 owing to its potential as a pharmaceutically interesting scaffold (Scheme 6).

Scheme 5 Illustration of the continuous flow synthesis of 3-nitropyrrolidines and their subsequent hydrogenation.

Scheme 3 Illustration of the performed in a PTFE flow reactor.

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fluorinations

Scheme 6 Illustration of the Diels–Alder reaction performed in a MFD reactor.

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Scheme 7 Model reaction used to demonstrate the Diels–Alder cycloaddition at high temperatures and pressures.

Employing MeCN as the reaction solvent, the authors introduced isoprene 12 (18.0 M) and maleic anhydride 11 (9.0 M) from separate inlets and warmed the reactor to 60 1C using an immersion bath. Varying the reaction time between 28 and 118 min, the authors were able to perform the cycloaddition to afford yields ranging from 85 to 98%. Under the optimal conditions, this route enabled the authors to produce the cycloadduct 13 at an impressive rate of 1.05 kg day 1. Utilising a high temperature (300 1C) and pressure (200 bar) stainless steel tubular reactor, Kappe et al.27 were able to expand the processing window usually employed by research chemists. Employing the cycloaddition of 2,3-dimethylbutadiene 14 and acrylonitrile 15 as a model reaction (Scheme 7), the authors were able to demonstrate dramatic reductions in reaction time as a result of performing the reaction under continuous flow. Using toluene as the reaction solvent, the authors observed incomplete conversion to 3,4-dimethylcyclohex-3-enecarbonitrile 16 with quantitative conversion obtained at 250 1C (200 bar) and a reaction time of 5 min. In a subsequent article, the authors reported exchange of toluene for solvents such as MeCN and THF which enabled facile product isolation.28 Okafor and co-workers29 recently performed a detailed investigation into the performance of a micro reactor towards the cycloaddition of isoamylene and a-methylstyrene to afford indane compounds used in the synthesis of musk fragrances. Employing a tube reactor containing silica beads, immersed in a thermostatted bath, the authors investigated the acid catalysed cycloaddition. At 35 1C, the authors identified no reaction up to 72% H2SO4 concentration, using 98 wt% catalyst the authors were able to convert 96% of the reactants in 30 min. Compared to batch reactions where high speed mixing was required, the packed-bed reactor afforded efficient mixing of the biphasic reactant streams and represents a scalable technique for the production of such cyclic intermediates. Focusing on the hetero Diels–Alder reaction of nitrosodienophiles to afford 3,6-dihydro-1,2-oxazine scaffolds, Stevens and co-workers30 investigated the advantages associated with performing the reaction under continuous flow conditions. Using the reaction of 2-nitrosotoluene 17 and cyclohexadiene 18, the authors firstly investigated the effect of solvent, evaluating acetone, MeOH, THF, MeCN and DMF (Scheme 8a). This enabled the authors to conclude that the reaction was relatively insensitive to solvent polarity, obtaining the target compound in >92% yield at 95 1C (47 min) for all solvents investigated. In addition to the HDA transformations described, the authors also investigated the generation of acylnitroso-species by introducing a pre-mixed solution of diene and hydroxamic acid and an oxidant solution into the reactor. Employing a reaction time of almost 2 h, the authors were able to generate the nitrosodienophile intermediate and react it with the diene in situ, to afford the respective cycloadduct in high yield; without the need for additives or metal catalysts (Scheme 8b). This journal is

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Scheme 8 Schematic illustrating (a) the hetero Diels–Alder reaction of nitroso species and (b) the in situ generation of nitroso dienophiles.

1.6 Oxidations Owing to the use of reduced reaction temperatures, the synthetic versatility of the Swern–Moffatt oxidation is often over-looked at a process-scale due to the costs associated with maintaining reactors under cryogenic conditions. With this in mind, several authors have reported investigations into performing the reaction under continuous flow with the main advantage cited as the ability to perform the reaction at higher reaction temperatures whilst maintaining, or even improving, product selectivity in the case of testosterone 19 (Scheme 9).31,32 With more recently, examples of semi-continuous processes being reported as key steps in the synthesis of heptenulose.33 Using the cheap and readily available oxidant KMnO4 20, Sedelmeier and Ley et al.34 demonstrated the ability to perform oxidations under continuous flow, with efficient downstream processing of MnO2 slurries. Reporting the oxidation of alcohols and aldehydes to carboxylic acids in a FEP tubular flow reactor (volume = 14 ml), the authors were able to develop a scalable technique affording the target acids in high to excellent yield (71–98%) with reaction times ranging from 10 to 30 min at room temperature. By application of ultrasound pulses, the authors were able to prevent the MnO2 slurries from aggregating and blocking the device. In the absence of ultrasound, fouling of the reactor was observed at the point of mixing, retarding continuous operation. In an extension to this, the authors investigated the basic potassium permanganate 20 Nef oxidation, generalised in Scheme 10. Employing the nitroalkane (0.25 M) and KOH (0.3 M) as a methanolic solution as one reactant stream and aqueous KMnO4 20 (0.20 M) as the second stream, the authors were able to prepare the respective carbonyl compound in yields ranging from 58 to 95% with reaction times of 5 to 8 min (at room temperature).

Scheme 9

Schematic illustrating the oxidation of testosterone 19.

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Scheme 10 Illustration of the KMnO4 20 promoted Nef oxidation performed under continuous flow.

Scheme 13 Schematic illustrating a homogeneous Suzuki coupling performed using a glass coil reactor.

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a recent review by Parmar and co-workers42 providing background into the types of reactions investigated.

Scheme 11 Illustration of a 4-hydroxy-TEMPO 21 catalysed bleach 22 oxidation.

Where more selective oxidations are required, oxidants such as TEMPO 21 have been successfully employed, as illustrated in Scheme 11, for the bleach 22 oxidation of alcohols to aldehydes.35,36 Other homogeneous oxidants employed under flow conditions include oxone37 and iron nitrate,38 with Rutjes et al.39 using the periodic acid/H2SO4 for the oxidative deprotection of p-methoxyphenyl protected amines. 1.7

Reductions

Unlike oxidations, until recently few reductions had been performed under continuous flow conditions however that trend is changing with researchers adapting techniques used in batch, such as Dibal-H,40 as well as developing new methodologies. An example of the latter was recently published by Sedelmeier et al.41 who demonstrated the lithium tert-butoxide 23 mediated, transition metal free, reduction of ketones (Scheme 12). Employing IPA as the reaction solvent, the authors pumped a solution of ketone (0.3–0.4 M) and 10 mol% LiOtBu 23 through a tube reactor at 180 1C (160 bar), for a fixed period of time, prior to passing the reaction mixture through a scavenger cartridge containing a tosyl-functionalised resin. Using this approach, the authors identified a reaction time of 30 min as being optimal for the conversion of aromatic and aliphatic ketones to the respective 11 or 21 alcohol. Conversions ranged from 84 to 99%, with halogenated ketones experiencing B5% dehalogenation. 1.8

Coupling reactions

Transition metal catalysed C–C bond forming reactions form one of the most widely studied classes of reaction that have been performed under continuous flow conditions, with

Scheme 12 Illustration of the transition metal free reduction of ketones performed under continuous flow conditions.

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Suzuki–Miyaura coupling. Employing microwave heating, Wilson et al.43 demonstrated a Suzuki coupling reaction in a borosilicate glass coil reactor (volume = 10 ml). Using EtOH as the reaction solvent and triethylamine 24 as the base, the authors investigated the synthesis of 4-(benzofuran-2-yl)benzaldehyde 25 via the PdCl2(PPh3)2 26 catalysed coupling of 4-bromobenzaldehyde 27 with benzofuran-2-yl boronic acid 28 (0.11 M) (Scheme 13). Optimal conditions were found to be a flow rate of 0.25 ml min 1 (residence time = 8 min) and a reactor temperature of 140 1C, affording the coupling product 25 in 84% yield. Repeating the reaction using conventional heating, analogous results were obtained confirming that this was not a microwave effect. Heck coupling. Using a PTFE tube reactor, Wirth et al.44 evaluated the efficacy of a series of catalysts (10 mol%) towards the Heck reaction of iodobenzene 29 with methyl acrylate 30 in the presence of triphenylphosphine (Scheme 14). Employing a reactor temperature of 70 1C the authors were able to conclude that Pd(PPh3)4 was the best catalyst under the flow conditions investigated, affording methyl cinnamate 31 in 62% yield. The authors subsequently investigated the effect of inserting perfluorodecalin into the reaction stream, affording a biphasic droplet system, which resulted in a 29% increase in yield; attributed to an increase in mixing efficiency within the reactor. Larhed et al.45 more recently reported the vinylation of boronic acids within a PTFE reactor (volume = 2 ml) as an extension to previous examples of continuous flow Heck reactions. Using Pd(OAc)2 32 (1.1  10 2 M) as the catalyst and dppp as the ligand (1.1  10 2 M), the authors investigated the reaction of a series of arylboronic acids (0.5 M) with vinyl acetate 33 (5.0 M) in DMF, with a reaction time of 2 min and a reactor temperature of 150 1C (Scheme 15). Under the aforementioned conditions, the reaction products were obtained in yields ranging from 42–86% for thirteen vinyl derivatives depending on the boronic acid under investigation.

Scheme 14 Illustration of the Heck reaction used to probe the efficacy of catalysts under flow conditions.

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Scheme 15 General reaction scheme illustrating the vinylation of aryl boronic acids under flow conditions.

Sonogashira coupling. In a recent example, Fukuyama et al.46 reported the development of an automated micro reaction system for the rapid optimisation of continuous flow reactions. Using the Sonogashira coupling reaction as a model (Scheme 16) the authors screened reaction temperature (70–110 1C) and time (20–60 min), using offline HPLC analysis to quantify the formation of the metalloproteinase inhibitor 34. Performing the reaction screen, the authors were able to identify a reaction time of 60 min and a temperature of 110 1C as being the optimal, afford the target compound 34 in 88% conversion. Repeating the screen, this time varying the acetylene 35 ratio, a time of 20 min, temperature of 120 1C and 1.25 eq. of acetylene 35 was found to be optimal. With this information in hand, the authors operated the reactor for 8 h affording 14 g of 34 (84% yield), further increases in scale were met by employing a larger residence time unit; providing access to (R)-3-(1H-indol-3-yl)-2-(5-(p-tolylethynyl)thiophene2-sulfonamido)propanoic acid 34 at a throughput of 18.8 g h 1. Murahasi coupling. Having demonstrated a wide array of lithiation reactions performed under continuous flow conditions, Yoshida and co-workers47 recently extended their investigations to incorporate lithiation and Murahasi couplings in a single fluidic process, with the aim to suppress the competing reaction that is known to readily occur between the ArLi and the by-product BuX; whilst promoting the slower cross coupling reaction between the two aryl halides. By combining a screen of Pd-based catalysts, with the spatial control obtained within continuous flow reactors, the authors were able to rapidly develop a flow process for the cross-coupling reaction illustrated in Scheme 17. The reactor comprised of three micromixers,

Scheme 17 Illustration of the H–Li exchange and subsequent Murahasi coupling reactions performed under flow conditions.

connected to a series of tube reactors (internal diameter = 1000 mm) maintained at different temperatures using thermostatted baths. In the first part of the reactor the 4-methoxyphenyllithium 36 was prepared via the reaction of 4-bromoanisole 37 (0.314 M in THF, 7.5 ml min 1) with n-BuLi 38 (1.57 M in hexane, 1.5 ml min 1) with a reaction time of 2.6 s. The Ar–Li 36 was subsequently fed into a second micromixer where it was mixed with a solution of bromobenzene 39 (0.523 M in THF) and catalyst (26.2 mM in THF, 3.0 ml min 1) prior to quenching in a third micromixer with MeOH (5.0 ml min 1). Using this approach, the authors investigated the effect of reaction time and temperature on the Murahashi coupling reaction, observing a dramatic decrease in the target product, 4-methoxybiphenyl 40, with decreasing reactor temperature. The reaction products were collected (1 min) and poured into water prior to extraction with diethyl ether and purified using a combination of flash chromatography and gel permeation chromatography. Using this approach, the optimal reaction conditions were found to be 0 1C and 2.6 s for the lithiation and 50 1C and 16 s for the coupling reaction performed in the presence of PEPPSI-SIPr; affording the target bi-aryl 40 in >90% yield (15.6 g h 1); with small quantities of by-products 41 and 42. Employing a series of ortho-, para- and metasubstituted halides, the authors were able to demonstrate the generality of the aforementioned conditions enabling the cross-coupling of aryl halides in yields ranging from 20 to 93% depending on the halide employed. A single example of the use of sec-BuLi for the H–Li exchange was also demonstrated, enabling the coupling of thiophene and 2-bromopyridine in 80% yield with a reaction time of 94 s. Other examples of metal-catalysed coupling reactions performed under continuous flow conditions include the Stille coupling48 and the Buchwald–Hartwig reaction,49 both of which have shown increased purity profiles as a result of employing flow reactor technology. 1.9 Esterifications

Scheme 16 Schematic of the Sonogashira coupling reaction used to demonstrate an automated micro reaction system.

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Kappe and co-workers50 have over the years performed a significant amount of research into the advantages associated with the performance of synthetic reactions, under what is conventionally termed ‘extreme’ conditions. Throughout this research, the authors have identified that it is possible to perform reactions in the absence of catalysts and/or promoters. One such example that demonstrates the novel conditions Chem. Commun., 2011, 47, 6512–6535

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Scheme 20 Schematic illustrating the reaction pathway used for the synthesis of 5-hydroxymethylfurfural 48 under flow conditions.

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Scheme 18 Illustration of the (a) esterification and (b) transesterification reactions performed using supercritical alcohols as promoters and solvent. Scheme 21 Synthesis of tri-substituted pyridines from aminodienones.

Scheme 19 Illustration of the in situ preparation of diazomethane 46 under flow conditions.

accessible within flow reactors was the catalyst-free esterification (Scheme 18a)/transesterification (Scheme 18b) reaction recently reported.27 Due to the high ionic product of supercritical alcohols (TCEtOH = 268 1C, PCEtOH = 61 bar; TCMeOH = 239 1C, PCMeOH = 81 bar), the solvent acts as a catalyst, promoting the reaction. Ethyl benzoate 43 was synthesised in 87% yield from benzoic acid 44 at 300 1C (120 bar) and a residence time of 12 min. With this in mind, the authors subsequently performed a transesterification, isolating methyl-3-phenylpropanoate 45 in 85% yield when a reaction time of 8 min and a temperature of 350 1C was employed; compared with no reaction at 200 1C. Alongside those examples utilising acid or base catalysts, researchers have also demonstrated the in situ generation of diazomethane 46 and its use in the synthesis of methyl benzoate (Scheme 19). Using commercially available Diazalds 47, Stark et al.51 screened the effect of reactor temperature (0–85 1C) with a fixed reaction time of 5 s, observing decreasing product formation at temperatures above 50 1C; attributing this to decomposition. Through developing a continuous process it was the authors aim to increase the safety associated reactions that are currently prohibited at a process scale. 1.10

Dehydrations

In efforts towards increasing the cleanliness and efficiency of the synthesis of 5-hydroxymethylfurfural 48 (Scheme 20), due to its promise as a synthetically useful building block, Loebbecke and co-workers52 recently demonstrated the use 6518

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of a glass micro reactor (dimensions = 1200 mm  300 cm) containing passive mixing elements along the length of the reactor. Employing reaction conditions of 0.1 M HCl, 185 1C reactor temperature maintained under 17 bar and a reaction time of 1 min, the authors were able to generate 5-hydroxymethylfurfural 48 in 97% conversion and 76–81% selectivity; depending on the wt% of fructose 49 employed (10–50%). Utilising such a short reaction time enabled the authors to avoid extensive rehydration minimising the formation of levulinic acid and formic acid as observed in batch. In an example of continuous flow cyclodehydrations, Bagley and co-workers53 reported the ability to take reactions from commercial micro reactors to mesoscale production using a microwave flow reactor. Using the Bohlmann–Rahtz reaction, summarised in Scheme 21, the authors were able to synthesise tri-substituted pyridines 50 from aminodienones 51. Initially investigating the reaction in a batch microwave reactor, the authors screened a series of solvents—finding a mixture of toluene and AcOH (5 : 1) afforded quantitative conversion in 2 min at 100 1C. With this information in hand, the reaction was transferred to a glass micro reactor whereby 0.1 M solutions of various aminodienones were evaluated at a range of reaction times at 100 1C. Using this approach, the authors obtained the target compounds in >98% conversion with a reaction time of 4 min. Finally, the authors employed a 10 ml glass column reactor, filled with sand to prevent backmixing, observing that the target pyridines could be obtained in >98% conversion with a reaction time of 2 min (100 1C) under microwave irradiation. Conventional heating was subsequently applied to a steel tube reactor (5 ml), which afforded analogous conversions and a throughput of 0.25 mmol min 1. 1.11 Reductive aminations Soloshonok and co-workers54 reported a detailed investigation into the use of a continuous flow reactor for the biomimetic reductive amination of fluorinated carbonyl compounds as a means of accessing amines and amino acids of biomedical importance. Using a column reactor packed with silicaabsorbed DBU 52, the authors were able to perform 1,3-proton shift reactions by percolating solutions of fluorinated imines (10 mol% in hexane : MeCN (4 : 1)) through the reactor at 50 1C (Scheme 22). The reaction products were collected at a rate of 1 drop s 1 and all UV active fractions collected; the yield and This journal is

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Scheme 24 Thermal rearrangement of substituted furfuryl alcohols performed under flow conditions.

Scheme 22 Generalisation of the biomimetic reductive aminations performed using silica-supported DBU 52.

ee was subsequently determined. Employing this technique, the authors obtained comparable yields to those reported using conventional methodologies (87–95%) however increases in ee were obtained using the flow protocol (90–95% cf. 77–97%), an observation attributed to the ease of base removal and product isolation. 1.12

Rearrangements

With the advent of commercially available flow equipment with wide operating windows, the number of atom efficient rearrangement reactions reported in the literature has increased dramatically over the past 5 years; however, examples can still be found using in-house fabricated equipment. Claisen. One such example was reported by Jia and Zhou et al.55 in 2009, whereby a stainless steel tube reactor (dimensions = 170 mm (i.d.)  1.2 m (long)) immersed in an oil bath afforded access reaction temperature of 220 1C and times of 8 to 24 min. Employing a solution of 4-chlorophenyl ether 53, the authors investigated the effect of time and temperature on the formation of 2-allyl-4-chlorophenol 54 (Scheme 23). Performing the reaction at 220 1C, the authors were able to convert 82% of 53 to 54; representing a 68% increase when compared to a batch reaction performed at reflux. To confirm the cleanliness of the process, the crude reaction mixture was analysed by 1H NMR spectroscopy, which revealed the presence of only the target phenol 54 and un-reacted starting material 53. Gratified by this result, the authors evaluated a series of rearrangements, obtaining the target phenolic derivatives in moderate to high conversion. Razzaq, Glasnov and Kappe56 also demonstrated the Claisen rearrangement under continuous flow conditions (240 1C), using the X-Cube flashTM (ThalesNano) to investigate the effect of solvent, pressure and additive on the conversion of 2-allylphenol to (E)-2-(prop-1-enyl)phenol.

Scheme 23 Model Claisen rearrangement performed under flow conditions.

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Using inductive heating, Kirschning and co-workers57 demonstrated the ability to perform the rearrangement of 1,4-bis(allyloxy)naphthalene at 170 1C, in 85% yield; which represents an increase of 23% compared to a conventionally heated system. A recent example of a rearrangement reaction performed under flow conditions exploited the conversion of furfuryl alcohols to 4-hydroxy-2-cyclopentenones, which form valuable intermediates in the synthesis of natural products. Employing a tubular reactor, Ulbrich, Kreitmeier and Reiser58 were able to demonstrate the applicability of continuous flow processing as a means of accessing the multigram scale synthesis of such intermediates. Using a steel tube reactor (internal dimension = 0.75 mm, volume = 1. 77 ml), immersed in a 240 1C bath, reaction times in the range of 1 min were explored for the transformation (Scheme 24). Newman–Kwart. Using the Newman–Kwart rearrangement, researchers at Eli Lilly reported the ability to synthesise an O-thiocarbamate 55, from a bisaryl-phenol 56 under flow conditions (Scheme 25). Using this approach, provided the researchers with access to thiol 57 in kilogram quantities, required as a project moved from early phase discovery to further development moving towards phase I clinical trials. Employing dimethoxyethane as the solvent, the authors were able to replace tetradecane or diglyme as the solvent making the product 55 easier to isolate via a heptane solvent switch. Pumping a mixture of bisaryl-phenol 56 in DME (5 volumes), the authors investigated the reaction in a 60 m stainless steel tube reactor housed within a GC oven. Performing the reaction under 70–77 bar of pressure at 300 1C, the authors employed a residence time of 7.6 min (flow rate = 7.5 ml min 1) which afforded 99.1% conversion of 56 to 55 with 0.6% residual phenol 56 and 0.3% of an unknown impurity. Distilling off the DME and addition of heptane as an antisolvent was found to initiate crystallisation affording the product 55 in 93% yield and 99.2% purity. In accordance with the authors original goal, the system developed was capable of synthesising 1.5 kg of 55 in a 24 h period. Fischer indolisation. As part of a project evaluating continuous flow radiosyntheses, Wahab and co-workers59 evaluated the Fischer indolisation under flow conditions as a means of developing a facile route to the indole core. Employing glacial acetic acid as the reaction solvent and H2SO4 as the catalyst, the authors were able to access simple indoles in moderate to high chromatographic yield at a reaction temperature of 105 1C and throughputs of 1.9–2.3 mg h 1. Using a continuous flow microwave reactor, Bagley and co-workers60 were able to indolise phenyl hydrazine 58 and Chem. Commun., 2011, 47, 6512–6535

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Scheme 27 Illustration of the key steps employed in the synthesis of 6,6,5-configured spiropiperidines.

Scheme 25 Schematic illustrating the Newman–Kwart rearrangement performed under flow conditions.

conditions, providing access to dihydropyrimidine-2-thiones (DHPMs) at a throughput of 0.32 mmol h 1. Using a packed-bed reactor, Brasholz and co-workers63 recently demonstrated the base catalysed 61 synthesis of 6,5,5-spiropiperidines followed by their rearrangement to afford 6,6,5-configured spiropiperidines; selected due to their use as building blocks towards the synthesis of histrionicotoxin alkaloids (Scheme 27).

2.0.

Photochemistry

Whilst in its infancy, compared to chemical flow processes, the number of photochemical transformations performed under flow conditions is growing, with early examples of benzopinacol formation (mg h 1 scale)64 superceded by techniques suitable for the multi g h 1 scale synthesis of cycloaddition products65 and even photosensitised diastereodifferentiation.66 Employing standard commercially available light sources, Oelgemo¨ller and co-workers67 focused on the photodecarboxylative benzylation of phthalimide (Scheme 28) as a means of providing access to 3-arylmethyleneisoindolin-1-ones upon dehydration. With problems observed with this reaction using

Scheme 26 An example of a Fischer indolisation performed under flow conditions.

cyclohexanone 59 to afford 2,3,4,9-tetrahydro-1H-carbazole 60 in 91% yield at a throughput of 2 g h 1 (Scheme 26). Other rearrangements. The Hofmann rearrangement has also been shown to be dramatically improved by performance under flow conditions, with Ley and co-workers61 reporting a 25-fold decrease in reaction time when compared to an optimised batch process, providing access to a synthetically useful core motif. As a means of scaling successful microwave reactions, Kappe and Orru et al.62 reported the Dimroth rearrangement under microwave-assisted continuous flow 6520

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Scheme 28 Schematic illustrating the addition of phenylacetates to phthalimide 62 and dehydration to afford 3-arylmethyleneisoindolin1-ones 63.

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conventional photochemistry, including the formation of the product as a potassium salt and significant by-product formation upon dehydration, the authors investigated the reaction using a microstructured reactor. Irradiating the phthalimide 62 solution, in a mixture of acetone and pH 7 buffer, in the presence of phenyl acetate (3.0 eq.), the authors obtained the target addition products in o97% yield (2 h, 300 nm) with low diastereoselectivity. In a batch process, the acid catalysed dehydration was performed using catalytic quantities of sulfuric acid in DCM, affording high selectivity towards the E-isomer. Employing a Xenon lamp (500 W, 280 nm) and an in-house fabricated glass : ionomer film reactor (channel dimensions = 2.5 mm (wide)  60 mm (long)), Maeda et al.68 investigated the [2 + 2] and [2 + 3] photocycloaddition of 2-(2-alkenyloxymethyl)-naphthalene-1-carbonitriles. Analysing the reaction products by NMR spectroscopy, the authors observed that the uniform irradiation of the contents of the micro channel reactor afforded a dramatic reduction in reaction time from 240 min in batch to 1 min. As a result of reducing the irradiation time, the authors were able to isolate the 1,2-adduct in 96% selectivity, illustrating that when fast reversible reactions and slow irreversible reactions co-exist, micro reactors offer a facile method for the synthesis of materials via the former synthetic pathway. Using a series of UV-LEDs as the light source, Ryu and co-workers69 demonstrated increased reaction efficiency compared to the Paterno–Buchi reaction performed using a 300 W Mercury lamp. Employing six UV-LED light sources, the authors performed the [2 + 2] cycloaddition of cyclohexen2-one 64 with vinyl acetate 33 to afford the cycloadduct 65 depicted in Scheme 29. Within a micro channel device (dimensions = 1000 mm (wide)  200 mm (deep)  56 cm (long)), the authors obtained a 200-fold increase in energy efficiency compared to a Mercury lamp and a 10-fold increase compared to blacklights. With the developed protocol in hand, the authors also demonstrated the generality of the technique by varying the acetate used, affording an array of substituted cyclohexanone derivatives. Other examples from the group include the black light promoted selective halogenation of cycloalkenes, reporting the efficient mono-bromination using Br2 and chlorinations using Cl2 and SOCl2 within a biphasic reaction system70 and the Barton nitrite photolysis used for the high-throughput synthesis of a steroid 66 (Scheme 30). With a view towards synthetic production using flow photochemistry, Freitag and co-workers71 have reported the construction of multipass flow reactors as a means of increasing photochemical efficiency without the need for large irradiated areas. Incorporation of in-line IR enabled the authors to re-circulate the reaction mixture until conversion had reached

Scheme 29 Illustration of the Paterno–Buchi reaction performed in a photochemical micro reactor.

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Scheme 30 Illustration of the Barton nitrite photolysis used in the synthesis of a complex saturated alcohol.

a pre-set level, at which point an automatic valve opened and diverted the reaction mixture to a collection vessel. In addition to single-phase photochemical transformations, continuous flow reactors have also been applied to heterogeneous photochemical reactions, using TiO2 coated channels to perform reductions,72 oxidations,73 alkylations74 and cyclisations.75

3.0.

Electrochemistry

Electroorganic synthesis represents an atom efficient tool for the formation of complex molecular architectures. The techniques use has however been somewhat limited to small scale syntheses due to the difficulties associated with successful scale-up. Using flow cells, several authors have begun the task of addressing the physical problems that have limited application of this technology, namely an inhomogeneous electric field and energy loss due to Joule heating; with the overall aim being to develop the technology to a stage that it can be used for production of chemicals.76,77 One of the most important aspects of electrochemical flow chemistry is efficient incorporation of electrodes into the devices, an area that numerous authors have investigated with techniques ranging from plate electrodes78 to micro-imprinted electrodes79 or grooved electrodes.80 Of the reactions studied, oxidations represent the most widely investigated, with early examples by Suga et al.81 demonstrating the potential of the technique dubbed ‘cation flow’ for the formation of C–C bonds (Fig. 1). Subsequently, Atobe and co-workers82 developed a flow reactor in which anodic oxidation and nucleophilic reaction of the cation could be performed. By positioning the anode and cathode parallel to one another down the length of the reaction channel, the authors introduced an electrolytic solution containing the nucleophile along the cathodic portion of the reactor and the substrate solution along the anodic part. Using this approach, the cation was formed at the anode and the nucleophilic reaction at the interface between the reactant Chem. Commun., 2011, 47, 6512–6535

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In an extension to this, the authors investigated the reductive coupling of benzyl bromide with a series of olefins, to afford the C–C coupling products in high yield and excellent selectivity.89 From the examples provided it can be seen that electrochemical transformations on the micro-scale have potential to significantly transform how synthetic reactions are performed; opening up, for the first time, the ability to apply electrochemistry in production scenarios.

Fig. 1 Illustration of the reactor configuration used for the electrochemical generation of cations under continuous flow.

streams. This approach was found to be particularly successful as oxidation of the nucleophile was not observed. Selecting 2,2,2-trifluoroethanol as the solvent, the authors were able to oxidise methyl pyrrolidinecarboxylate and subsequently react the cation with allyltrimethylsilane to afford methyl-2-allylpyrrolidine-1-carboxylate in 59% yield; compared with 6% yield (36% conversion) in a bulk preparative scale experiment. More recently, Yoshida and co-workers83 have demonstrated the ability to perform the Friedel–Crafts alkylation of dimethoxy-substituted aromatics and allylsilanes; observing that an improved product distribution could be obtained under flow with reduced polyalkylation. The [4 + 2] cycloaddition of a series of N-acyl iminium ions derived from a-silyl carbamates was also demonstrated, with the authors identifying the ability to react the cations with a series of styrene-based dienophiles (Scheme 31) in high yield without the formation of the polymeric products obtained in batch. Authors have also demonstrated the iodination of diand tri-substituted aromatics, via the generation of I+ from molecular I2 using a Pt plate electrode.84 Compared to batch, the use of a flow reactor enabled the authors to reduce the proportion of di-iodinated products formed. In addition to those examples utilising electrolytes, a series of examples have featured in the literature where reactions have been performed in the absence of intentionally added electrolytes.85–87 One such example was the electrochemical reduction of 4-nitrobenzyl bromide 67 to afford the homocoupling product 1,2-bis(4-nitrophenyl)ethane 68 (Scheme 32) in 92% conversion with only 6% competing dehalogenation.88

Scheme 31 Synthesis of [4 + 2] adducts under continuous flow.

Scheme 32 Illustration of the electrolyte-free electrochemical reduction of 4-nitrobenzyl bromide 67.

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4.0.

Multi-phase reactions

One area of synthetic chemistry that has potentially the most to benefit from continuous processing is that of multi-phase reactions. Be it liquid–liquid (l–l), gas–liquid (g–l) (Section 6.1), liquid–solid (l–s) (Sections 4.1–4.3) or gas–liquid–solid (g–l–s) (Section 6.2), numerous permutations have been demonstrated under continuous flow with most examples reporting synthetic advantages that stem from the improved phase contacting obtained.90 The use of immiscible liquid phases has also been demonstrated as a means of dealing with insoluble reaction products. During the synthesis of Indigo 69 (Scheme 33), via the aldol reaction of acetone and 2-nitrobenzaldehyde 70, McQuade and co-workers91 observed the formation of a precipitate. Introducing an immiscible carrier phase into the tubular reactor, the authors were able to synthesise Indigo 69 without fouling of the reactor. Wirth and co-workers44 recently demonstrated the rate enhancement of reactions performed under segmented flow conditions, with the use of droplets as individual reaction vessels also reported by Huck et al.92 4.1 Heterogeneously catalysed reactions With catalysts becoming increasingly more complex and expensive, the ability to recover and re-use is an important consideration when devising a synthetic process. One method for simplifying this step is the use of solid-supported catalytic materials which enables facile separation of the catalyst from the solution phase reactants and products. Should incomplete conversion occur however, additional purification will still be required to isolate the target compound. In addition to those examples of click chemistry using homogeneous catalysts under flow conditions, examples have also been performed using copper-in-charcoal in packed-bed reactors and even copper tube reactors. Employing a Cu–C as a catalyst, Fuchs and Kappe et al.93 were able to gain mechanistic insight into copper(I)-catalysed azide–alkyne cycloadditions by performing reactions within a continuous flow reactor (X-Cubes, ThalesNano). Using the reaction between benzyl azide and phenyl acetylene as a model, the

Scheme 33 Indigo 69 synthesis under continuous flow.

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authors investigated the effect of reaction time and temperature on the triazole synthesis, finding that a 12 s residence time within the packed bed and a temperature of 170 1C afforded the target compound in 99% isolated yield. Attempts to increase the system productivity by increasing reagent throughput were however met with increased leaching of Cu from the charcoal support. Analysis of the reaction products by ICP-MS enabled this phenomena to be quantified, with the authors observing increased leaching in the presence of organic bases (38.6 mg Cu) at 1.5 ml min 1; indicating that the reaction was in fact homogeneously catalysed, with the charcoal operating a release and recapture mechanism. With the quantities of Cu found in the target compounds far exceeding those permitted in pharmaceuticals, the authors positioned a scavenger cartridge within the flow system, containing QuadraPure TU, which was found to sequester the free Cu. The reaction has also been investigated using a copper tube reactor (Conjure, Accendo) where the surface of the reactor was found to promote a series of cycloadditions—showing varying degrees of Cu leaching depending on the solvent employed. Using typical azide concentrations of 0.1 M and a reactor temperature of 150 1C, Bogdan and James94 were able to synthesise a series of macrocycles in yields ranging from 28 to 80% with reaction times of 5 min (Scheme 34). Using a capillary reactor (internal diameter = 1.7 mm) Shore, Tsimerman and Organ95 evaluated the gold-film catalysed, microwave-assisted benzannulation of aromatic carbonyls and alkynes, as generalised in Scheme 35. Owing to the relatively poor adhesion of Au on glass surfaces, the capillaries were initially coated with a transparent Ag film which upon coating with Au, afford a stable catalytic surface. To perform a reaction, the authors pumped a solution of carbonyl (1 eq.) and alkyne (3 eq.) in 1,2-dichlorobenzene through the reactor at a flow rate of 25 ml min 1. Under microwave irradiation, the authors observed 90% conversion

Scheme 34 Illustration of a typical flow cyclisation performed in a Cu tube reactor.

to the target product at 240 1C, reducing to 68% at 190 1C; with batch reactions requiring 6 h to afford comparable conversions. To identify if this was a microwave or flow effect, the reaction was repeated using an oil bath (190 1C), whereby only 14% conversion was obtained. The authors postulate that this effect may be due to the formation of localised hot-spots upon microwave irradiation, giving rise to super-heating. Using the optimised method, the authors were able to vary the alkyne substitution and the heteroatom, observing little effect on the yield of the reaction (40–78%). Performing the reactions on 700 ml slugs of reactants, the authors were able to generate 70–80 mg of each target product in 35 min, with larger scale experiments performed to demonstrate synthetic utility of the technique. Increasing the reactant concentration three-fold, the authors were able to produce the benzannulation products at a throughput of 0.5 g h 1. Under comparable microwave-assisted conditions, the authors have also demonstrated the ability to catalyse the Suzuki–Miyaura and Heck reactions.96 Whilst osmium catalysts have been widely employed in the dioxygenation of alkenes, Park and Kim97 developed a novel Pd-based magnetic nanoparticle 71 capable of not only catalysing the reaction but also being readily isolated from the reaction mixture by application of a magnetic field (0.51 G). Employing a PDMS micro reactor containing reaction channels with dimensions of 300 mm (wide)  52 mm (deep)  32 cm (long), the authors investigated the dioxygenation of cyclohexenylbenzene 72 under continuous flow. Using a working solution comprising of the olefin 72 (0.2 M) and PhI(OAc)2 73 (1.2 eq.) in DMF/AcOH (1 : 2) and 3.5 mol% of Pd catalyst 71, the authors investigated the effect of reaction time and temperature by re-circulating the reaction mixture through the device using a peristaltic pump. Using this approach, the authors were able to obtain (1S,2S)-1-phenylcyclohexane1,2-diyl diacetate 74 in 89% yield in 14 min at 50 1C. Exploring a series of alkenes, the authors found the method to be general and the separation of the catalyst 71 effective with no Pd detected in the reaction product upon analysis by ICP-AES; with the same aliquot of catalyst 71 remaining active for the duration of the investigation (Scheme 36). One of the most widely studied reactions using heterogeneous catalysis within flow reactors is the Knoevenagel condensation (Scheme 37), with authors demonstrating the use of packed-beds with pressure-driven flow98 and electroosmotic flow,99

Scheme 36 Use of Pd magnetic nanoparticles 71 as a heterogeneous catalyst towards the dioxygenation of alkenes.

Scheme 35 General scheme outlining the microwave-assisted benzannulation reactions performed in a wall-coated capillary reactor.

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Scheme 37 General schematic illustrating the Knoevenagel condensation performed using heterogeneous catalysis under flow conditions.

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Scheme 38 Continuous flow hydrogenation of methyl-2-chloro-6methylisonicotinate 75.

wall-coated reactors,100 zeolite catalysts101 and monoliths.102 With all of the techniques demonstrating the ability to synthesise a,b-unsaturated compounds in high yield and purity; with no degradation of the catalyst material. Employing catalyst filled cartridges, the H-cubes has been widely reported throughout the scientific literature for continuous flow hydrogenations. Examples include the reduction of nitro, nitriles, debenzylations and reductive alkylations, with researchers reporting the reversal of ee for the enantioselective hydrogenation103 and the hydrogenation of methyl-2-chloro-6methylisonicotinate 75 to piperidine 76 (Scheme 38).104 4.2

Heterogeneous biocatalysis

In addition to the use of chemical heterogeneous catalysts within micro reactors, examples have also been demonstrated for the efficient exploration of immobilised biocatalysts. Using commercially available Novozyme 435 immobilised lipase biocatalyst, Woodcock et al.105 reported the flow synthesis of a series of alkyl esters in high yield and purity. More recently, Mugo and Ayton106 demonstrated the synthesis of butyl laurate using a capillary reactor, wall-coated with Candida antarctica lipase B; achieved via the well known glutaraldehyde method. The activity of the enzyme modified surface was measured spectrophotometrically using the hydrolysis of p-nitrophenyl butyrate which confirmed the activity to be 0.9 U mg 1. To perform reactions, a solution of lauric acid (0.015 M) and n-butanol in hexane or heptane was pumped through a heated (50 1C) capillary at a flow rate of 1 ml min 1, affording a residence time of 38 s. The reaction products were collected and periodically analysed offline using GC-MS. Investigating the effect of acid to alcohol ratio, the authors identified optimal conversions at a 1 : 3 ratio; obtaining >95% conversion to butyl laurate over a 9 h period, with no side products observed. The authors propose that whilst from a production perspective this approach is not likely to be adopted, there is potential for the use of this technology in mass spectrometry as a derivatisation tool for the study of lipidomics. Again employing an immobilised Lipase 77, Wiles and co-workers107 were able to perform the chemo-enzymatic epoxidation of alkenes using either urea–hydrogen peroxide 78 or H2O2 as the oxidant. When compared to a batch process the flow methodology was advantageous as the enzyme was able to be employed at a higher processing temperature without degradation (Scheme 39). With research drivers of lower running costs and investment costs whilst gaining competitive advantages through technology, Karge et al.108 developed a biocatalytic process for the synthesis of a key intermediate in the production of Vitamin A 79 (Scheme 40). Utilising Chirazyme L2-C2 80, the authors were 6524

Scheme 39 Schematic illustrating the chemo-enzymatic protocol employed for the continuous flow synthesis of epoxides.

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Scheme 40 Illustration of the biocatalytic acylation used in the synthesis of a Vitamin A 79 precursor 82.

able to quantitatively acylate the diol 81 to afford 82 at a throughput of 10 g min 1. Employing an EDTA pre-column to purify the feedstock, the authors report the ability to perform the flow reaction over 100 days without observing a reduction in system performance. In addition to packed-bed reactors, examples of polymeric monoliths109 (Scheme 41) and derivatisation of channel

Scheme 41 Example of a typical biocatalytic deacylation reaction performed under flow conditions.

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Scheme 42 Biocatalytic enantioselective hydrolysis performed under continuous flow conditions.

walls110 (Scheme 42) have also been reported for the successful incorporation of biocatalytic surfaces in micro reactors. In a comparable manner to chemical catalysts, the use of immobilised enzymes is a cost effective method for their recycle and re-use. In addition to their application as catalysts in synthetic transformations, biocatalysts have also featured in the development of continuous flow resolutions of chiral material, as demonstrated by the work of Maeda et al.111 and Urge et al.112 Authors have even demonstrated the combination of catalytic and biocatalytic materials in a single device as a means of performing two-step reactions. To this end, Spain et al.113 combined zinc powder and a mutase biocatalyst within a tube reactor to convert nitrobenzene to 2-nitrophenol, via the hydroxylamine intermediate, extending the investigation to the synthesis of N-[2-(4-amino-3-hydroxyphenyl)-2hydroxy-1-hydroxymethylethyl]-2,2-dichloroacetamide from chloramphenicol. 4.3

Non-catalytic solid–liquid reactions

In addition to the use of immobilised catalysts, researchers have also demonstrated the use of stoichiometric reagents within packed bed reactors as a means of obtaining product selectivity currently not attainable in stirred batch reactors. A recent example of this was communicated by Venturoni and co-workers114 who demonstrated the use of a polymersupported pyridine hydrobromide 83 in the preparation of a-bromoketones which were subsequently reacted with 3-amino-6-chloropyridazine to afford imidazopyridazines as

Scheme 43 General synthetic protocol employed for the synthesis of the imidazopyridazine scaffold under flow conditions.

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illustrated in Scheme 43. Employing a reaction time of 13 min the authors observed the formation of mono- and di-brominated products, however reducing the reaction time to 5 min, the target a-bromoketones were obtained in quantitative yield and selectivity. Another example is the use of a silica-supported analogue of Jones reagent, developed as a means of preventing copper contamination of the reaction products. When used in conventional batch reactions, Jones reagent is an efficient oxidising agent which readily converts alcohols to their respective carboxylic acid. Employing the reagent under flow conditions, Wiles and co-workers115 were able to selectively isolate either the aldehyde or carboxylic acid by simply tuning the residence time of the alcohol within the flow reactor. Using this approach, fifteen alcohols were converted into the respective aldehyde and carboxylic acid; obtaining all products in quantitative yield and excellent purity. Consumption of the oxidant was also visually indicated with the orange reagent turning green upon exhaustion.

5.0.

Multi-step/multi-component flow reactions

An early example of multi-step reactions performed under continuous flow conditions was the Ciprofloxacin 84 synthesis reported by Schwalbe and co-workers (Scheme 44).116 Expanding their investigations into the use of trimethylaluminium in the continuous synthesis of amide bonds, Seeberger and co-workers117 applied the technique in a key step of Efaproxiral 85 (Scheme 45) synthesis, disclosing that the use of a flow reactor enabled the transformation to be performed in 2 min at 125 1C. During their research into the development of new reaction pathways, McQuade et al.118 developed a continuous synthetic route for the preparation of Ibuprofen 86 (Scheme 46). Using a PFA tube reactor, the authors devised a pathway comprising of a Friedel–Crafts acylation, followed by a 1,2-aryl migration and finally an ester hydrolysis to furnish the target compound 86 in 68% yield and 96% purity. Purification of the crude material was then performed resulting in a 51% yield and 99% purity. Employing a series of polymer-supported reagents and catalysts, Ley and co-workers119 have demonstrated the

Scheme 44 Schematic illustrating the reaction steps employed for the continuous flow synthesis of Ciprofloxacin 84 and its analogues.

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Scheme 45 Illustration of the synthesis of Efaproxiral 85 performed under flow conditions.

Scheme 47 Illustration of the use of multiple solid-supported reagents and catalysts for the synthesis of the API Gleevac.

Scheme 46 Schematic illustrating the reaction pathway selected for the continuous flow synthesis of Ibuprofen 86.

continuous flow synthesis of a series of pharmaceutically relevant compounds, with the synthesis of Imatinib 87 being their most recent (Scheme 47). Performing three discrete reaction steps, the authors were able to isolate the API 87 in an overall yield of 32% (95% purity). By combining discretely performed flow reactions in series, Venturoni and co-workers114 were able to demonstrate the synthesis of Casein Kinase I inhibitors. To achieve this, the authors firstly performed the arylation of a picoline derivative using n-BuLi 38 and a series of esters. With this material in hand, the second flow reaction involved the selective a-bromination using a solid supported analogue 83 as previously described. Upon removal of the alcoholic solvent, the a-bromoketone was dissolved in DMF and reacted with a chloropyrazine substrate, in a third reactor to afford an imidazo[1,2-b]pyridazine (52–82% yield). The final step of the reaction displacement of the chlorine to introduce structural diversity was achieved by reaction of the 6526

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imidazo[1,2-b]pyridazine in EtOH with 2 eq. of amine at 177 1C for 1.6 h. Passing the reaction products through a scavenger column, residual amine was removed and the target compounds obtained in high yield after recrystallisation (Fig. 2). In addition to the use of micro reactors for the synthesis of small organic molecules for use in the fine chemical or pharmaceutical industries, the technology has also been applied to polymerisations120 giving rise to well-defined organic polymers. Frey et al.121 reported the use of a microstructured reactor to perform living anionic polymerisation to afford novel and tailored end functionalised polystyrenes. They introduced styrene and sec-BuLi into a micromixer (internal volume = 15 ml), followed by reaction in a tube reactor (internal diameter = 0.7 mm) prior to the addition of a termination reagent at a T-mixer. As Fig. 3 illustrates, various termination agents were evaluated, affording an array of end functionalised polystyrenes. By varying the mixer temperature (25–60 1C) and the residence time (6 to 12 s), the authors were able to evaluate

Fig. 2 Illustration of the Casein Kinase I inhibitor scaffold synthesised under flow conditions.

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Scheme 49 Illustration of the model reaction used to demonstrate the high-throughput screening of catalysts using online UHPLC.

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Fig. 3 Illustration of the termination agents used in the flow synthesis of end functionalised polystyrenes.

the effect on molecular weight and the molecular weight distribution, enabling the realisation of customised polystyrenes with pre-defined physical properties. Using a newly developed sequence of polymerisation and termination, the authors propose that the methodology is suited to a wide range of monomers that are polymerisable by carbanionic polymerisation. The application of continuous flow to multi-step organic synthesis was recently reviewed by Webb and Jamison122 and Stevens et al.,123 readers are directed to these reviews for additional examples on this subject. 5.1

Automated reaction screening

Using a borosilicate glass micro reactor (channel dimensions = 120 mm (wide)  55 mm (deep)  0.26 or 13.20 cm (long); volume = 0.14 or 7.02 ml) van Hest, Rutjes and co-workers124 recently demonstrated automated reaction screening for the Swern–Moffatt oxidation. Investigating the effect of reaction time and temperature, the authors were able to comprehensively survey the oxidation of benzyl alcohol to benzaldehyde, identifying a mixing time of 32 s and a reactor temperature of 70 1C as being optimal; 150 1C higher than conventional batch processes. Performing the reaction under the identified optimal conditions, the authors were able to synthesise the oxidation product in 96% yield. Selecting the Heck reaction of 4-chlorobenzotrifluoride 88 and 2,3-dihydrofuran 89 as a model system (Scheme 48), Jensen and co-workers125 developed an integrated process for the selfoptimisation of reactions performed on the micro and meso scale. Using the ‘black-box’ Nelder–Mead Simplex method, the authors demonstrated the ability to integrate feedback into the reaction optimisation process enabling a dramatic increase in speed compared to conventional DoE approaches. Identifying Pd(OAc)2 32, tert-butyl-MePhos 90 as the ligand and n-BuOH as the best reagents, the authors optimised the Heck reaction between 4-chlorobenzofluoride 88 and 2,3-dihydrofuran 89, observing that the reaction reached optimal conversion in 10 min at 90 1C. Using a meso-reactor

Scheme 48 Illustration of the Heck reaction used to demonstrate the development of a self-optimising micro reactor.

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(volume = 7 ml, Corning) and a HPLC gradient mixer filled will stainless steel ball bearings (to ensure good mixing), the authors employed nine reaction conditions similar to those evaluated on the micro scale, as a means of comparing the efficiency of method translation. Using this approach, the authors obtained comparable conversions on the 50-fold larger device however further work is required to investigate identical conditions on both a micro and meso scale in order to validate this principle of up-scaling. Utilising a capillary based micro reactor interfaced to ultra high performance liquid chromatography (UHPLC), Floreancig and Weber et al.126 demonstrated the development of a high-throughput screening system for homogeneous catalysts—focussing on the evaluation of catalyst efficacy towards the Friedel–Crafts addition into an acyliminium ion, as illustrated in Scheme 49. Connecting the capillary reactor to an autoinjector, the authors were able to introduce the catalyst and reactant solution into a continuous carrier stream affording small, discrete reaction zones within the capillary. Employing a reaction time of 1 h, the slugs were detected using an online UV/Vis detector and subsequently analysed by UHPLC (6 min analytical method). Using this approach, the authors evaluated the effect of a series of Lewis and Bronsted acids along with reaction temperature (0 to 40 1C) and molar ratio (0 to 2.0 eq.). Performing reactions in triplicate, the authors were able to demonstrate the screening power of their technique whereby 18 catalysts were assessed in 6 h temperature 1; which enabled the identification of Er(OTf)3 as the most efficient catalyst. In addition to providing a rapid technique for the screening of catalysts using low volumes of reactants (400 mg reaction 1), the methodology proved to be reproducible for the transformation studied, with the optimum catalyst shown to be effective on a large-scale also. Along with single phase reaction screening, researchers have begun to report the performance of reactions within single droplets. An example of this was recently communicated by Zagnoni and Cooper127 where the principle of an electronic shift register was used to serially form, store and retrieve water microdroplets from an oil carrier phase using a PDMS device with post production fluorophilic modification of the channel network. By applying pressure patterns, in the range of 0 to 200 Pa, the authors were able to create and alternate two w/o droplet populations at a double-T junction, affording ABAB droplet trains. This passive system has the potential to be used for the controlled positioning of emulsions, enabling the strategic creation of interfaces to be performed and the construction of serial droplet arrays, which could be used to generate artificial lipid bilayers and study diffusion processes. In addition, the strategic positioning of reagent containing droplets has the potential to afford a method for the controlled Chem. Commun., 2011, 47, 6512–6535

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performance of discrete chemical reactions further increasing the number and type of addressable reactions screened under flow conditions.128 Stemming from a more analytical perspective, Ismagilov et al.129,130 recently communicated the development of a ‘Slipchip’, a device which enables high-throughput screening to be performed without the need for expensive liquid handling. The device developed consists of two glass plates containing wells or ducts, which serve as reagents reservoirs or fluidic channels when, sandwiched on top of one another. By dragging the surface of the upper plate horizontally across the lower plate, the reservoirs move in and out of contact with one another creating channels for reactant transportation; upon contacting, the reagents can then mix and react. Using this principle, the authors have been able to perform protein crystallography and immunoassays in a parallel fashion and indicate the systems potential for the performance of highthroughput synthetic reactions.

6.0. 6.1

Reactions employing a gaseous component Gas–liquid reactions

In addition to enabling access to less conventional operating conditions, the use of continuous flow reactor technology has also opened up the availability of gas–liquid reactions to the synthetic chemist.131 In a recent communication, O’Brien et al.132 reported the construction of a gas–liquid reactor for the ozonolysis of alkenes comprising of a semi-permeable tube (Teflon AF-2400) housed within a gas-tight vessel. To perform the target reaction, a solution of the alkene was pumped through the tubing, at a flow rate equivalent to a 1 h reaction time, and the vessel filled with ozone 91. Upon exiting the reactor, the reaction mixture was quenched using polymersupported triphenylphosphine in MeOH and the target compounds isolated by filtration and solvent evaporation— after testing with peroxide strips. The crude materials were subsequently purified by silica gel chromatography to afford the target ketones in moderate to high yield (57 to 95%). Using a falling-film reactor, Steinfeldt and co-workers133 reported the ozonolysis of acetic acid vinyl ester, with Hubner et al.134 subsequently reporting an ozonolysis as a key reaction step in the synthesis of pharmaceutical intermediates

Scheme 51 Pd-catalysed Heck aminocarbonylation.

Scheme 52 Illustration of the (a) conventional and (b) improved route to isocyanates.

(Scheme 50). Commercial units are also now available for this synthetically useful, but previously hazardous reaction. Using a silicon–glass micro reactor (reaction channel = 400 mm (wide)  400 mm (deep)  43.0 cm (long)), Buchwald and co-workers135 evaluated a series of Pd-catalysed Heck aminocarbonylations, as illustrated in Scheme 51. Employing reactor temperatures in the range of 116 to 160 1C, the authors were able to efficiently convert a series of aryl halides into the respective amide in moderate to high yield (32 to 83%), with an emerging pressure trend enabling the synthesis of a-keto amides. Employing a Pd-catalysed carbonylation, Takebayashi and co-workers136 were able to develop a synthetic protocol for the conversion of nitrobenzenes into isocyanates, avoiding the need for a phosgenation step (Scheme 52). Targeting the compounds due to their use in thermoplastic manufacture, the authors sought a clean and efficient method for the synthesis of isocyanates. Using pressures of o1 MPa, the authors were able to exploit the efficient mass transfer obtained at the gas–liquid interface to perform the reductive carbonylation. Other examples of gas– liquid reactions include chlorinations,137 selective fluorinations138 and hydrogenations.139 6.2 Gas–liquid–solid reactions As observed for liquid–solid reactions, gas–liquid–solid reactions can also be performed under flow conditions employing the solid reagent or catalyst in a packed-bed,140 as a monolith (sol–gels) or as a wall-coat141 expanding the processing conditions available to the researcher.

7.0.

Scheme 50 Illustration of the continuous flow synthesis of a Vitamin D precursor.

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Inorganic chemistry

In addition to the dramatic uptake of the technology in the area of synthetic chemistry, the past five years has seen growth in the area of inorganic chemistry142 with researchers focussing on the preparation of metals,143 metal oxides and semiconductors. This journal is

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In a recent example, Maeda et al.144 demonstrated the use of several micro reactors, combined with online detection, for the development of a combinatorial synthesis system used for the preparation of CdSe nanoparticles. Using this approach, the authors were able to rapidly evaluate three reaction parameters, temperature, time and additive concentration; enabling the elucidation of underlying mechanisms that affect the size, shape and colour of the resulting nanoparticles. Employing relatively low reactor temperatures (270 1C) and short reaction times (5 s) the authors were able to generate nanoparticles with a target peak wavelength of 480–510 nm (blue–green) and by increasing the reactor temperature (300 1C), time (60 s) and additive proportion (20 wt%) the wavelength could be tuned to 570–600 nm (orange). By embedding a series of replicate within their study, the authors were able to confirm that the system was reproducible for the same stock solution; with slight variations observed when different raw material batches were used. Employing droplet based flow, Lee and co-workers145 were able to fuse droplets of Cd(NO3) and Na2S within a silicone oil continuous phase to obtain a super-saturated solution of CdS from which nanoparticles were precipitated. Compared to batch techniques, a blue-shift was observed which indicates the formation of smaller particles. Owing to the excellent control over molecular weight distribution obtained for polymers and semiconductors prepared under continuous flow conditions, a large proportion of work has been undertaken into the continuous flow preparation of metal oxide nanoparticles. In an early example, Jensen and co-workers146 evaluated the effect of reactor design, flow velocity, reaction time and flow type on the formation of SiO2 particles using the Stober process. Comparing segmented flow with laminar flow, the authors were able to conclude that segmented flow offered a facile means of obtaining narrow particle size distributions when compared with laminar flow; whereby axial dispersion led to a large size variation. The flow synthesis of TiO2 nanoparticles was also studied by Wang and co-workers147 via the hydrolysis and condensation of titanium tetraisopropoxide. By varying the flow rate of two reactant solutions, the authors were able to generate a stable laminar interface at which particle growth occurred. Collecting the nanoparticles offline and subjecting them to analysis by UV-Vis and TEM, the authors were able to generate TiO2 as the anatase polymorph. Using a spinning disk reactor, Raston et al.148 demonstrated the ability to rapidly mix reagents under plug flow, tuning particle size as a function of rotating speed (500 to 2500 rpm). Investigating the preparation of superparamagnetic Fe3O4 nanoparticles, the authors were able to obtain 5–10 nm particles with a narrow particle size distribution and a high saturation magnetisation. Employing a microwave flow reactor, Bondioli and co-workers149 developed a techniques for the preparation of monodisperse, spherical nanoparticles of zirconia via the hydrolysis and condensation of tetran-propylzirconate. From these examples alone, it can be seen that flow chemistry also has processing advantages to offer the inorganic chemist. This journal is

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8.0.

Up-scaling

In a recent article by Laird,150 the role the chemist has to play in the success of process scaling is discussed, with the author stating that ‘for robust and efficient scale-up it is important to choose good syntheses and this is often the decision of the chemist rather than the engineer’. Whilst this is true for conventional up-scaling, where processes are translated from discovery on the mg-scale to kilogram to tonne scales, with changes in surface to volume ratio, dosing time and heating and cooling efficiencies.151 With continuous flow processes, scalable concepts are available which enable up-scaling to be achieved with no (or minimal) changes to the reactors employed. As a result, the implementation of engineered reactors in discovery has the potential to ease the scaling of a synthetic route through the various stages as a successful reaction performed on a mg-scale can be used without change on a production-scale. With this in mind, the researcher for the first time has the ability to generate synthetic methodology that can be directly applied to production should the material need to be taken forward within industry—opening up new and exciting opportunities for the research and process chemist, particularly with respect to the types of reactions that can be safely performed at scale.152 Whilst several of the key chemical reactions described have had elements of up-scaling within the investigations, here follows a series of examples selected to illustrate the advantages of up-scaling with continuous flow reactors. Togashi et al.153 demonstrated the parallelization of micro reactors for the nitration of phenol. Employing quartz micro reactors, housed within a Hastelloy holder, the authors reported the operation of twenty reactors in four banks of five. Devising a manifold with accurate flow distribution, the authors were able to obtain mono-nitrated phenol in 88.1% conversion at a 20-fold increased throughput compared with a single reactor. Operating such a unit continuously, the authors calculated that the system would have a throughput of 72 tonne annum 1. In 2002, Schwalbe and co-workers154 reported the Paal–Knorr synthesis under continuous flow (Scheme 53). More recently, Rutjes et al.155 demonstrated the reaction of acetonylacetone 92 and 2-aminoethanol 93 in a micro reactor, subsequently scaling the reaction to four meso reactors capable of producing 2-(2,5-dimethyl-1H-pyrrol-1-yl)ethanol 94 at a throughput of 55 g h 1. Fukase et al.156 recently demonstrated the application of methodology developed for the dehydration of b-hydroxyketones to the synthesis of the natural product pristane 95. Employing p-TsOH 96 as the acid catalyst, the authors were able to synthesise the target compound 95 at a rate of 5 kg week 1, sufficient to meet the current market demands for the immunoactivating agent (Scheme 54).

Scheme 53 Illustration of the Paal–Knorr synthesis of 2-(2,5-dimethyl-1H-pyrrol-1-yl)ethanol 94.

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Fig. 4 Illustration of nitrate esters synthesised in an automated micro reactor.

Scheme 54 Illustration of the synthetic route employed for the flow synthesis of Pristane 95.

Scheme 55 Illustration of the model reaction used to probe reaction kinetics under flow conditions.

Lo¨we et al.157 reported the use of a 600 ml stainless steel micro channel (channel dimensions = 500 mm (wide)  300 mm (deep)  40 cm (long)) with a PEEK cover plate for the synthesis of 1,3-dimethylimidazolium triflate. Owing to the highly exothermic nature of the reaction, overheating of the reaction mixture can lead to poor quality, discoloured ionic liquids. By performing the reactions in a micro reactor, fitted with a heat exchanger, the authors were able to increase the throughput of material processing when compared to more conventional methods of production. In addition to being tools for the production of ionic liquids, microstructured devices have also been used to probe the kinetics of such reactions. Recently, Wang and Lo¨we et al.158 reported the derivation of kinetic information from a micromixer and tubular reactor, for the butylation of 1-methylimidazole 97 (Scheme 55), with the reaction yield determined using an offline bromine titration. To investigate the reaction, the molar ratio of 1-bromobutane 98 to 1-methylimidazole 99 was varied along with reactor temperature. Using this approach, the authors were able to determine that the reaction proceeds via 2nd order kinetics with respect to [1-bromobutane 98] and [1-methylimidazole 99] and has an activation energy of 78.4 kJ mol 1. Compared with conventional techniques, the authors found the use of a microflow system to be advantageous as the exothermic reaction could be controlled without the need for reactant dilution or the dropwise addition of either component. From a production perspective, this is advantageous as it reduces the waste generated and costs associated with the production of ionic liquids.159 In an example illustrating incredible processing safety associated with flow reactor methodology, Loebbecke et al.160 reported the construction of an automated micro reaction plant for the production of nitrate esters (Fig. 4). Using this 6530

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approach, the authors were able to safely investigate previously unexplored reaction conditions. Once identified, the optimal conditions were employed in conjunction with downstream processing which included washing and extraction, to afford the liquid explosives in pharmaceutical grade purity at throughputs of 150 g min 1. Utilising a StarLam 3000 micro reactor (IMM, Germany), Kirchneck and Tekautz161 incorporated micro reaction technology into an existing production plant, with the aim of doubling current production capacity of a two-step process. Implementing the technology for the first reaction step, the authors reported the successful development of a process capable of producing the undisclosed material at a throughput of 3.6 tonne h 1. After 10 months in operation, the system was inspected for corrosion and found to be unaffected by continuous chemical contact. Ebrahimi and co-workers162 investigated the use of micro structured reactors as a tool for the on-site production of peracetic acid, comparing factors such as transportation, handling and storage of the material. Basing their investigation on the production of peracetic acid via the H2SO4 (3–9 wt%) catalysed reaction of acetic acid and hydrogen peroxide, the authors identified an optimum reaction time of 300 s afforded efficient production of peracetic acid at a throughput of 10 kg h 1. Looking to the fire and explosion index, the risk was rated at 112 (intermediate) whereas the conventional batchwise process was rated at 226 (severe). The downtime associated with catastrophic failure of the micro reactor was also reduced to 35 days from 75 days for the batch process. Employing these metrics enabled comparison of the batch and flow processes in greater detail than conventional studies where focus has been on product purity and system throughput.

9.0.

Continuous flow purifications

Whilst from the examples provided it can be seen that there are obvious advantages associated with the performance of reactions under continuous flow, the synthetic step is only one of numerous unit operations used to prepare compounds on an industrial scale. It is therefore imperative to consider how the flow synthesis will be combined with other steps such as aqueous extraction, distillation, crystallisation and drying when proposing that such technology be applied to production scenarios. With one of the most widely employed purification techniques being liquid–liquid extraction (LLE), numerous authors have reported the performance of LLEs under continuous flow utilising co-flowing or counter-flow immiscible phases.163–165 A recent example of this was reported by Aljbour, Yamada and Tagawa166 who demonstrated sequential reaction and separation in a micro reactor. Employing the phase transfer This journal is

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Scheme 56 Illustration of the model reaction used to demonstrate phase transfer catalysis and the physical separation of aqueous and organic streams under flow conditions.

catalysis of benzyl chloride 100 with sodium sulfide 101 as a model reaction (Scheme 56), the authors demonstrated the use of a Pyrex micro reactor for the transformation. Introducing benzyl chloride 100 and tetrahexylammonium bromide 102 (0.4 M and 0.04 M in toluene) and sodium sulfide 101 (1.0 M) in DI H2O, the authors were able to react the benzyl chloride 100 and subsequently separate the aqueous and organic phases at a Y-shaped junction. Silanisation of the channel used to carry the aqueous reactant stream was found to increase separation efficiency of the phases upon exiting the reactor; removing the need for post reactor phase separation. In addition to two-phase extractions, researchers have also demonstrated the ability to perform back extractions under continuous flow. In this arrangement, it is possible to extract the analyte from the aqueous phase (feed) into an organic phase (transport) and then into a second aqueous phase (acceptor).167 A synthetic application of this technique was reported by van Beek et al.168 who reported the back extraction of the alkaloids Strychnine and Brucine extracted from Strychnos seeds. Using a model system, Fries and co-workers169 compared the liquid–liquid extraction efficiencies of various contacting types for the extraction of vanillin in order to benchmark the technology against conventional techniques. von Rohr et al.170 later published findings that the addition of an inert gas phase further increases separation efficiencies, with large capacity reactors able to process 10 000 metric ton y 1 of material. In addition to the use of co-flowing or counter-current flow streams, authors have also demonstrated the efficient extraction of ions using droplet-based flow.171,172 Jensen and co-workers173 subsequently reported the fabrication of LLE modules based on membrane technology which enables the rapid separation of immiscible phases exhibiting segmented flow by varying the wetting properties of the membrane. Using this technology as part of a continuous flow process, in which a series of Curtius rearrangements were performed, the authors were able to perform a phase separation to remove water formed during the initial azidation reaction, which enabled the authors to synthesise a series of carbamates from acyl chlorides in a continuous, un-interrupted process. The technology has also been demonstrated for the continuous separation of miscible and immiscible gas–liquid streams.174 Fluorous solvents and tags have also been exploited within flow systems as a means of rapidly isolating and recycling catalytic material. An example of the former is the aqueous Suzuki–Miyaura reaction performed by Theberge et al.175 and the latter was used by Goto and Mizuno et al.176 to synthesise and extract carbohydrates. This journal is

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Scheme 57 Illustration of the two-step strategy used for the synthesis of N-Boc-3,4-dehydro-L-proline methyl ester 103 using in-line scavengers.

9.1 Solid-assisted in-line purifications An area that has grown rapidly over the past 3 years is that of solid-assisted purifications whereby solid-supported scavenger resins are packed into columns, positioned strategically throughout the flow process to sequester any un-reacted starting materials,177 by-products178 or trace metals179,180 from within the reaction mixture. A recent example of continuous flow synthesis with in-line purification was reported by Tamborini and co-workers181 during an investigation into the synthesis of N-Boc-3,4dehydro-L-proline methyl ester 103 (Scheme 57). Using DCM as the solvent and pyridine as the base, the authors introduced a solution of Boc-methylester 104 (0.25 M) and py (0.25 M) into the tube reactor from one inlet and a solution of Tf2O 105 (0.25 M) from a second. Upon mixing at a T-piece, the reaction mixture was warmed to 40 1C with a residence time of 10 min prior to passing through a packed-column containing PS-DBU 106 (5 min at 100 1C) enabling the elimination reaction to proceed. In order to scavenge any un-reacted starting material 104, the flow stream was then diverted through a scavenger column containing Amberlyst-15 107 and QuadraPure benzylamine which afforded the target N-Boc-3,4-dehydro-L-proline methyl ester 103 as the sole product in an overall yield of 87% with a purity of 97% and an ee of >98%. Employing larger columns, and a 10 ml tube reactor, the authors were able to synthesise 9 g of 103 in a 12 h period. In addition to continuous scavenging, researchers have also developed continuous ‘catch and release’ methodology for the synthesis and purification of a-ketoesters,182 and peptides.183,184 There remains however some scepticism in the field as to the synthetic utility of scavengers when looking towards the use of continuous flow methodology as a tool for process intensification; however on a lab-scale the technique demonstrates a facile method for the purification of materials on the gram-scale. 9.2 Re-crystallisation and precipitation In the final stages of a synthesis, one of the most efficient methods of product purification is recrystallisation or precipitation of the material from a solution; with this in mind, several research groups have successfully developed continuous flow crystallisation techniques. Using liquid antisolvent precipitation, Chen et al.185 demonstrated the ability to tune the chemical composition and particle size of pharmaceutical nanoparticles within 300 mm2 micro channels. Through the technique developed, the authors propose that continuous flow crystallisations have a key role to play in pharmaceutical production as the ease with which Chem. Commun., 2011, 47, 6512–6535

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particle size can be adjusted means that sparingly soluble materials can be readily processed to increase bioavailability. Ni et al.186 subsequently demonstrated the use of a continuous oscillatory baffled crystalliser (COBC) reactor for the performance of both nucleation and crystal growth. Harnessing the excellent heat transfer capacity of flow reactors, the authors were able to crystallise an unnamed API, provided by AstraZeneca, reducing the processing time dramatically from 9 h 40 min to 12 min. Owing to the narrow particle size distribution, the flow process also removed the need for subsequent processing steps such as milling; reducing the costs associated with post synthetic production. The reactor has also been used for the synthesis of the industrially interesting compounds aspirin and vanisyl sodium.187 Exploiting the control obtained from the formation of droplets and micro emulsions, researchers have also developed tools for the microencapsulation of active pharmaceuticals affording novel vehicles for drug delivery.188 9.3

Continuous flow detection techniques

An important part of the ongoing efforts towards the implementation of continuous flow chemical processing into production is the integration of process analytical tools for the continuous, real-time monitoring of synthetic reactions. With this in mind, several research groups have probed both the contents of micro reaction channels and the outlet streams of flow reactors using conventional spectroscopic tools such as IR,193,194 Raman195 and NMR.196 In addition, several groups have acknowledged the need for the development of low cost sensors that could be employed in production units to monitor an array of chemical and physical changes.197,198 An excellent review summarising the application of in-line monitoring within continuous flow process is presented by McMullen and Jensen.199 When looking at the implementation of device arrays in production units, researchers have acknowledged the need for in situ real-time monitoring, with two Japanese groups developing strategies for the diagnosis of channel blockages, a useful diagnostic tool for process monitoring.200,201 6532

Over the past decade, micro reaction technology has progressed from an academic curiosity, through the proof of concept stage and is now moving into the mainstream; where continuous flow processing is being implemented at research, process and production stages by many pharmaceutical and fine chemical companies. With the advent of commercially available flow reactor equipment, there is now the opportunity for researchers to push the boundaries of the technology and start to identify novel reaction conditions and processes. It is clear from early adoptors of the technology that modularisation of equipment is required to enable the construction of re-configurable processing plants, stepping away from the ‘dedicated reactor’ mindset that dominated technological developments made during the fields infancy. Where the technology will go in the next decade remains to be seen however it is clear that this enabling technology has a lot to offer the chemist at all stages of research, development and production.

Micro-distillation

Owing to the industrial reliance on distillations for the purification of raw materials and final products, researchers have started to evaluate the possibility of developing microscale distillation units capable of being incorporated into continuous flow processes. An early example was a device reported by Wootton and de Mello189 that relied on the use of a He carrier gas to induce evaporative transport. Employing a 50 : 50 mixture of MeCN and DMF, the authors were able to demonstrate a nine-fold enrichment of MeCN from a single pass. Subsequently, Hibara and co-workers190 developed a fused-silica device in which 9% aqueous EtOH was concentrated to 19 wt% EtOH. More recently, Jensen et al.191 and Kato et al.192 have separately reported the use of membranes in their distillation devices, with Kato et al. achieving a theoretical plate number of 1.8 (out of 2.0) for the rectification of water and MeOH mixtures. 9.4

10.0. Outlook

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Notes and references 1 (a) Micro Process Engineering: A Comprehensive Handbook Volume 2: Devices, Reactions and Applications, ed. V. Hessel, A. Renken, J. C. Schouten and J. Yoshida, Wiley-VCH, Germany; (b) C. Wiles and P. Watts, Chem. Commun., 2007, 443–467; (c) C. Wiles and P. Watts, Micro Reaction Technology in Organic Synthesis, CRC Press Inc., 2011. 2 R. Gorges, T. Taubert, W. Klemm, P. Scholz and B. Ondruscka, Chem. Eng. Technol., 2005, 28(3), 376–379. 3 N.-T. Nguyen and Z. Wu, J. Micromech. Microeng., 2005, 15, R1–R16. 4 V. Hessel, H. Lowe and F. Schonfeld, Chem. Eng. Sci., 2005, 60, 2479–2501. 5 C. H. Hornung and M. R. Mackley, Chem. Eng. Sci., 2009, 64, 3889–3902. 6 G. Luca Morini, Int. J. Therm. Sci., 2004, 43, 631–651. 7 M. K. Patel and B. G. Davies, Org. Biomol. Chem., 2010, 8, 4232–4235. 8 F. E. Valera, M. Quaranta, A. Moran, J. Blacker, A. Armstrong, J. T. Cabral and D. G. Blackmond, Angew. Chem., Int. Ed., 2010, 49, 2478–2485. 9 J. Chun, S. Lu, Y. Lee and V. W. Pike, J. Org. Chem., 2010, 75, 3332–3338. 10 V. Hessel, Chem. Eng. Technol., 2009, 32(11), 1655–1681. 11 J. Fraga-Dubreuil, G. Comak, A. W. Taylor and M. Poliakoff, Green Chem., 2007, 9, 1067–1072. 12 Q. Yang, J. Wang, L. Shao, Q. Wang, F. Guo, J. Chen, L. Gu and Y. An, Ind. Eng. Chem. Res., 2010, 49, 140–147. 13 D. Lensen, K. Van Brekelen, D. M. Vriezema and J. C. M. van Hest, Macromol. Biosci., 2010, 10, 475–480. 14 K. Jasch, N. Barth, S. Fehr, H. Bunjes, W. Augustin and S. Scholl, Chem. Eng. Technol., 2009, 32(11), 1806–1814. 15 J. R. Burns and C. Ramshaw, Chem. Eng. Commun., 2002, 189, 1611–1628. 16 W. Ferstl, S. Loebbeck, J. Antes, H. Krause, M. Haeberl, D. Smalz, H. Muntermann, M. Grund, A. Steckenborn, A. Lohf, J. Hassel, T. Bayer, M. Kinzl and I. Leipprand, Chem. Eng. J., 2004, 101, 431–438. 17 J. Shen, Y. Zhao, G. Chen and Q. Yuan, Chin. J. Chem. Eng., 2009, 17, 412–418. 18 S. Braune, P. Po¨chlauer, R. Reintjens, S. Steinhofer, M. Winter, O. Lobet, R. Guidat, P. Woehl and C. Guermeur, Chem. Today, 2008, 26, 1–4. 19 M. E. Kopach, M. M. Murray, T. M. Braden, M. E. Kobierski and O. L. Williams, Org. Process Res. Dev., 2009, 13, 152–160.

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View Online 20 P. J. Nieuwland, B. Hanssen, K. Koch, P. Janssen, M. Delville and F. P. J. T. Rutjes, Proceedings of 11th Conference on Microreaction Technology, Kyoto,Japan, 2010, pp. 208–209. 21 J. C. Brandt and T. Wirth, Beilstein J. Org. Chem., 2009, 5, No. 30. 22 T. Gustafsson, R. Gilmour and P. H. Seeberger, Chem. Commun., 2008, 3022–3024. 23 M. Baumann, I. R. Baxendale, L. J. Martin and S. V. Ley, Tetrahedron, 2009, 65, 6611–6625. 24 E. Riva, S. Gagliardi, M. Martinelli, D. Passeralla, D. Vigo and A. Rencurosi, Tetrahedron, 2010, 66, 3242–3247. 25 M. Baumann, I. R. Baxendale and S. V. Ley, Synlett, 2010, 749–752. 26 B. Hallmark, M. R. Mackley and F. Gadala-Maria, Adv. Eng. Mater., 2005, 7(6), 545–547. 27 T. Razzaq, T. N. Glasnov and C. O. Kappe, Eur. J. Org. Chem., 2009, 1321–1325. 28 M. Damm, T. N. Glasnov and C. O. Kappe, Org. Process Res. Dev., 2010, 14, 215–224. 29 O. C. Okafor, S. Tadepalli, C. Tampy and A. Lawal, Ind. Eng. Chem. Res., 2010, 49, 5549–5560. 30 J. M. R. Monbaliu, A. Cukalovic, J. Marchand-Brynaert and C. V. Stevens, Tetrahedron Lett., 2010, 51, 5830–5833. 31 T. Kawaguchi, H. Minuata, K. Ataka, K. Mae and J. Yoshida, Angew. Chem., Int. Ed., 2005, 44, 2413–2416. 32 J. J. M. Van der Linden, P. W. Holberink, C. M. P. Kronenburg and G. J. Kemperman, Org. Process Res. Dev., 2008, 12, 911–920. 33 J. R. McConnell, J. E. Hitt, E. D. Daugs and t. A. Rey, Org. Process Res. Dev., 2008, 12, 940–945. 34 J. Sedelmeier, S. V. Ley, I. R. Baxendale and M. Baumann, Org. Lett., 2010, 12(16), 3618–3621. 35 E. Fritz-Langhals, Org. Process Res. Dev., 2005, 9, 577–582. 36 A. Bogdan and D. T. McQuade, Beilstein J. Org. Chem., 2009, 5, No. 17. 37 Y. M. A. Yamada, K. Torii and Y. Uozumi, Beilstein J. Org. Chem., 2009, 5, No. 18. 38 R. J. J. Jachuck, D. K. Selvaraj and R. S. Varma, Green Chem., 2006, 8, 29–33. 39 K. Koch, B. J. A. van Weerdenburg, J. M. M. Verkade, P. J. Nieuwland, F. P. J. T. Rutjes and J. C. M. Van Hest, Org. Process Res. Dev., 2009, 13, 1003–1006. 40 L. Ducry and D. M. Roberge, Org. Process Res. Dev., 2008, 12, 163–167. 41 J. Sedelmeier, S. V. Ley and I. R. Baxendale, Green Chem., 2009, 11, 683–685. 42 B. K. Singh, N. Kaval, S. Tomar, E. Van der Eycken and V. S. Parmar, Org. Process Res. Dev., 2008, 12, 468–474. 43 N. S. Wilson, C. R. Sarko and G. P. Roth, Org. Process Res. Dev., 2004, 8, 535–538. 44 B. Ahmed-Omer, D. A. Barrow and T. Wirth, Tetrahedron Lett., 2009, 50, 3352–3355. 45 L. R. Odell, J. Lindh, T. Gustafsson and M. Larhed, Eur. J. Org. Chem., 2010, 2210–2274. 46 A. Sugimoto, T. Fukuyama, M. Rahman and I. Ryu, Tetrahedron Lett., 2009, 50, 6364–6367. 47 A. Nagaki, A. Kenmoku, Y. Moriwaki, A. Hayashi and J. Yoshida, Angew. Chem., Int. Ed., 2010, 49, 7543–7547. 48 G. Shi, F. Hong, Q. Liang, H. Fang, S. Nelson and S. G. Weber, Anal. Chem., 2006, 78, 1972–1979. 49 C. Mauger, O. Buisine, S. Caravieihes and G. Mignani, J. Organomet. Chem., 2005, 690, 3627–3629. 50 M. Damm, T. N. Glasnov and C. O. Kappe, Org. Process Res. Dev., 2010, 14, 215–224. 51 M. Struempel, B. Ondruschka, R. Daute and A. Stark, Green Chem., 2008, 10, 41–43. 52 T. Tuercke, S. Panic and S. Loebbecke, Chem. Eng. Technol., 2009, 32(11), 1815–1822. 53 M. C. Bagley, V. Fusillo, R. L. Jenkins, M. C. Lubinu and C. Mason, Org. Biomol. Chem., 2010, 8, 2245–2251. 54 V. A. Soloshonok, H. T. Catt and T. Ono, J. Fluorine Chem., 2010, 131, 261–265. 55 L. Kong, Q. Lin, X. Lu, Y. Yang, Y. Jia and Y. Zhou, Green Chem., 2009, 11, 1108–1111. 56 T. Razzaq, T. N. Glasnov and C. O. Kappe, Chem. Eng. Technol., 2009, 32(11), 1702–1716.

This journal is

c

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57 S. Ceylan, C. Friese, C. Lammel, K. Mazac and A. Kirschning, Angew. Chem., Int. Ed., 2008, 47, 8950–8953. 58 K. Ulbrich, P. Kreitmeier and O. Reiser, Synlett, 2010, 13, 2037–2040. 59 B. Wahab, G. Ellames, S. Passey and P. Watts, Tetrahedron, 2010, 66, 3861–3865. 60 M. C. Bagley, R. L. Jenkins, M. Caterina Lubinu, C. Mason and R. Wood, J. Org. Chem., 2005, 70, 7003–7006. 61 A. Palmieri, S. V. Ley, K. Hammond, A. Polyzos and I. R. Baxendale, Tetrahedron Lett., 2009, 50, 3287–3289. 62 T. N. Glasnov, D. J. Vugts, M. M. Konigstein, B. Desai, W. M. F. Fabian, R. V. A. Orru and C. O. Kappe, QSAR Comb. Sci., 2006, 25, 509–518. 63 M. Brasholz, B. A. Johnson, J. M. Macdonald, A. Polyzos, J. Tsanaktsidis, S. Saubern, A. B. Holmes and J. H. Ryan, Tetrahedron, 2010, 66, 6445–6449. 64 H. Lu, M. A. Schmidt and K. F. Jensen, Lab Chip, 2001, 1, 22–28. 65 B. A. Hook, W. Dohle, P. R. Hirst, M. Pickworth, M. B. Berry and K. I. Booker-Milburn, J. Org. Chem., 2005, 70, 7558–7564. 66 K. Sakeda, K. Wakabayashi, Y. Matsushita, T. Ichimura, T. Suzuki, T. Wada and Y. Inuoe, J. Photochem. Photobiol., A, 2007, 192, 166–171. 67 V. Belluau, P. Noeureuil, E. Ratzke, A. Skvortsov, S. Gallagher, C. A. Motti and M. Oelgemo¨ller, Tetrahedron Lett., 2010, 51, 4738–4741. 68 H. Mukae, H. Maeda, S. Nashihara and K. Mizuno, Bull. Chem. Soc. Jpn., 2007, 80, 1157–1161. 69 T. Fukuyama, Y. Hino, N. Kamata and I. Ryu, Chem. Lett., 2004, 33, 1430–1431. 70 H. Matsubara, Y. Hino and I. Ryu, Proceedings of the 11th International Conference on Microreaction Technology, Kyoto, Japan, 2010, pp. 44–45. 71 A. Freitag, T. R. Dietrich and R. Scholz, Proceedings of the 11th International Conference on Microreaction Technology, Kyoto, Japan, 2010, pp. 25–26. 72 Y. Matsushita, S. Kumad, K. Wakabayashi, K. Sakeda and K. Ichimura, Chem. Lett., 2006, 35, 410–411. 73 Y. Matsushita, M. Iwasawa, T. Suzuki and T. Ichimura, Chem. Lett., 2009, 38, 846–847. 74 Y. Matsushita, N. Ohba, T. Suzuki and T. Ichimura, Catal. Today, 2008, 132, 153–158. 75 G. Takei, T. Kitamori and H. B. Kim, Catal. Commun., 2005, 6, 357–360. 76 J. Yoshida, K. Kataoka, R. Horcajada and A. Nagaki, Chem. Rev., 2008, 108, 2265–2299. 77 V. Mengeaud, O. Bagel, R. Ferrigno, H. H. Girault and A. Haider, Lab Chip, 2002, 2, 39–44. 78 H. Lowe and W. Ehrfeld, Electrochim. Acta, 1999, 44, 3679–3689. 79 K. Ueno, H. Kim and N. Kitamura, Anal. Chem., 2003, 75, 2086–2091. 80 M. Tsujimoto, O. Tonomura, M. Kano, S. Hasebe and T. Hinouchi, Proceedings of the 11th International Conference on Microreaction Technology, Kyoto, Japan, 2010, pp. 320–321. 81 S. Suga, M. Okajima, K. Fujiwara and J. Yoshida, J. Am. Chem. Soc., 2001, 123, 7941–7942. 82 D. Horii, T. Fuchigami and M. Atobe, J. Am. Chem. Soc., 2007, 129, 11692–11693. 83 A. Nagaki, M. Togai, S. Suga, N. Aoki, K. Mae and Y. Yoshida, J. Am. Chem. Soc., 2005, 127, 11666–11675. 84 K. Midorikawa, S. Suga and J. Yoshida, Chem. Commun., 2006, 3794–3796. 85 D. Horii, M. Atobe, T. Fuchigama and F. Marken, Electrochem. Commun., 2005, 7, 35–39. 86 C. A. Paddon, G. J. Pritchard, T. Thiemann and F. Marken, Electrochem. Commun., 2002, 4, 825–831. 87 R. Horcajada, M. Okajima, S. Suga and J. Yoshida, Chem. Commun., 2005, 1303–1305. 88 P. He, P. Watts, F. Marken and S. J. Haswell, Electrochem. Commun., 2005, 7, 918–924. 89 P. He, P. Watts, F. Markem and S. J. Haswell, Angew. Chem., Int. Ed., 2006, 45, 4146–4149. 90 G. Chen, J. Yue and Q. Yuan, Chin. J. Chem. Eng., 2008, 16(5), 663–669. 91 L. Poe, M. A. Cummings, M. P. Haaf and D. T. McQuade, Angew. Chem., Int. Ed., 2006, 45, 1544–1548.

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View Online 92 A. B. Theberge, G. Whyte, M. Frenzel, L. M. Fidalgo, R. C. R. Wootton and W. T. Huck, Chem. Commun., 2009, 6225–6227. 93 M. Fuchs, W. Goessler, C. Pilger and C. O. Kappe, Adv. Synth. Catal., 2010, 352, 323–328. 94 A. R. Bogdan and K. James, Chem.–Eur. J., 2010, 16, 14506–14512. 95 G. Shore, M. Tsimerman and M. G. Organ, Beilstein J. Org. Chem., 2009, 5, No. 35. 96 G. Shore, S. Morin and M. G. Organ, Angew. Chem., Int. Ed., 2006, 45, 2761–2766. 97 C. P. Park and D.-P. Kim, Angew. Chem., Int. Ed., 2010, 49, 6825–6829. 98 A. R. Bogdan, B. P. Mason, K. T. Sylvester and D. T. McQuade, Angew. Chem., Int. Ed., 2007, 46, 1698–1701. 99 C. Wiles, P. Watts and S. J. Haswell, Chem. Commun., 2007, 966–968. 100 F. Constantini, W. P. Bula, R. Salvio, J. Huskens, H. J. G. E. Gardiniers, D. N. Reinhoudt and W. Verboom, J. Am. Chem. Soc., 2009, 131, 1650–1651. 101 W. Lau, K. L. Yeung and R. Martin-Aranda, Microporous Mesoporous Mater., 2008, 115, 156–163. 102 A. El Kadib, R. Chimenton, A. Sachse, F. Fajula and B. Coq, Angew. Chem., Int. Ed., 2009, 48, 4969–4972. 103 S. Cserenyi, G. Szollosi, K. Szori, F. Fulop and M. Bartok, Catal. Commun., 2010, 12, 14–19. 104 D. K. Whelligan, S. Solanki, D. Taylor, D. W. Thomson, K. J. Cheung, K. Boxall, C. Mas-Droux, C. Barillari, S. Burns, C. G. Grummitt, I. Collins, R. L. M. van Montfort, G. W. Aherne, R. Bayliss and S. Hoelder, J. Med. Chem., 2010, 53, 7682–7698. 105 L. L. Woodcock, C. Wiles, G. M. Greenway, P. Watts, A. Wells and S. Eyley, Biocatal. Biotransform., 2008, 26, 501–507. 106 S. M. Mugo and K. Ayton, J. Mol. Catal. B: Enzym., 2010, 67, 202–207. 107 C. Wiles, M. J. Hammond and P. Watts, Beilstein J. Org. Chem., 2009, 5, No. 27. 108 W. Bonrath, R. Karge and T. Netscher, J. Mol. Catal. B: Enzym., 2002, 19–20, 67–72. 109 B. Ngamsom, A. M. Hickey, G. M. Greenway, J. A. Littlechild, P. Watts and C. Wiles, J. Mol. Catal. B: Enzym., 2010, 63, 81–86. 110 Y. Gao, R. Zhong, J. Qin and B. Lin, Chem. Lett., 2009, 38, 262–263. 111 T. Honda, M. Miyazaki, Y. Yamaguchi, H. Nakamura and H. Maeda, Lab Chip, 2007, 7, 366–372. 112 C. Csajagi, G. Szatzker, E. R. Toke, L. Urge, F. Darvas and L. Poppe, Tetrahedron: Asymmetry, 2008, 19, 237–246. 113 H. R. Luckarift, L. J. Nadeau and J. C. Spain, Chem. Commun., 2005, 383–384. 114 F. Venturoni, N. Nikbin, S. V. Ley and I. R. Baxendale, Org. Biomol. Chem., 2010, 8, 1798–1806. 115 C. Wiles, P. Watts and S. J. Haswell, Tetrahedron Lett., 2006, 47, 5261–5264. 116 T. Schwalbe, D. Kadzimirsz and G. Jas, QSAR Comb. Sci., 2005, 24, 758–768. 117 T. Gustafsson, F. Ponten and P. H. Seeberger, Chem. Commun., 2008, 1100–1102. 118 A. R. Bogdan, S. L. Poe, D. C. Kubis, S. J. Broadwater and D. T. McQuade, Angew. Chem., Int. Ed., 2009, 48, 8547–8550. 119 M. D. Hopkin, I. R. Baxendale and S. V. Ley, Chem. Commun., 2010, 46, 2450–2452. 120 T. Nisisako and T. Hatsuzawa, Microfluid. Nanofluid., 2009, 9, 427–437. 121 C. Tonhauser, D. Wilms, F. Wurm, E. Berger-Nicoletti, M. Maskos, H. Lo¨we and H. Frey, Macromolecules, 2010, 43, 5582–5588. 122 D. Webb and T. F. Jamison, Chem. Sci., 2010, 1, 675–680. 123 A. Cukalovic, J. M. R. Monbaliu and C. V. Stevens, Top. Heterocycl. Chem., 2010, 23, 161–198. 124 P. J. Nieuwland, K. Koch, N. van Harskamp, R. Wehrens, J. C. M. van Hest and F. P. J. T. Rutjes, Chem.–Asian J., 2010, 5, 799–805. 125 J. P. McMullen, M. T. Stone, S. L. Buchwald and K. F. Jensen, Angew. Chem., Int. Ed., 2010, 49, 7076–7080. 126 H. Fang, Q. Xiao, F. Wu, P. E. Floreancig and S. G. Weber, J. Org. Chem., 2010, 75(16), 5619–5626.

6534

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127 M. Zagnoni and J. M. Cooper, Lab Chip, 2010, 10, 3069–3073. 128 A. B. Theberge, F. Courtois, Y. Schaerli, M. Fischlechner, C. Abell, F. Hollfelder and W. T. S. Huck, Angew. Chem., Int. Ed., 2010, 49, 5846–5868. 129 W. Liu, D. Chen, W. Du, K. P. Nichols and R. F. Ismagilov, Anal. Chem., 2010, 82, 4606–4612. 130 D. Belder, Angew. Chem., Int. Ed., 2010, 49, 6484–6486. 131 G. Chen, J. Yue and Q. Yuan, Chin. J. Chem. Eng., 2008, 16(5), 663–669. 132 M. O’Brien, I. R. Baxendale and S. V. Ley, Org. Lett., 2010, 12(7), 1596–1598. 133 N. Steinfeldt, R. Abdallah, U. Dingerdissen and K. Jahnisch, Org. Process Res. Dev., 2007, 11, 1025–1031. 134 S. Hubner, U. Bentrup, U. Budde, K. Lovis, T. Dietrich, A. Freitag, L. Kupper and K. Jahnisch, Org. Process Res. Dev., 2009, 13, 952–960. 135 E. R. Murphy, J. R. Martinelli, N. Zaborenko, S. L. Buchwald and K. F. Jensen, Angew. Chem., Int. Ed., 2007, 46, 1734–1737. 136 Y. Takebayashi, K. Sue, S. Yoda, T. Furuya and K. Mae, Proceedings of 11th International Conference on Microreaction Technology, Kyoto, Japan, 2010, pp. 188–189. 137 D. Wehle, M. Dejmek, J. Rosenthal, H. Ernst, D. Kampmann, S. Trautschold and R. PechatschekVerfahren zur herstellung von monochloressihaure in mikroreaktoren, DE10036603 A1. 138 R. D. Chambers, G. Sandford, J. Trmcic and T. Okazoe, Org. Process Res. Dev., 2008, 12, 339–344. 139 C. de Bellefon, T. Lamouille, N. Pestre, F. Bornette, H. Pennemann, F. Neumann and V. Hessel, Catal. Today, 2005, 110, 179–187. 140 S. K. Ajmera, M. W. Losey, K. F. Jensen and M. A. Schmidt, AIChE J., 2001, 47, 1639–1647. 141 E. V. Rebrov, E. A. Klinger, A. Berenguer-Murcia, E. S. Sulman and J. C. Schouten, Org. Process Res. Dev., 2009, 13, 991–998. 142 A. Abou-Hassan, O. Sandre and V. Cabuil, Angew. Chem., Int. Ed., 2010, 49, 6268–6286. 143 J. Wagner, T. R. Tshikhudo and J. M. Kohler, Chem. Eng. J., 2008, 135, S104–S109. 144 A. Toyota, H. Nakamura, H. Ozono, K. Yamashita, M. Uehara and H. Maeda, J. Phys. Chem. C, 2010, 114, 7527–7534. 145 H. L. Hung, K. M. Choi, W. Y. Tseng, Y. C. Tan, K. J. Shea and A. P. Lee, Lab Chip, 2006, 6, 174–178. 146 S. A. Khan, A. Gunther, M. A. Schmidt and K. F. Jensen, Langmuir, 2004, 20, 8604–8611. 147 H. Wang, H. Nakamura, M. Uehara, M. Miyazaki and H. Maeda, Chem. Commun., 2002, 1462–1463. 148 S. F. Chin, K. S. Iyer, C. L. Raston and M. Saunders, Adv. Funct. Mater., 2008, 18, 922–927. 149 F. Bondioli, A. B. Corradi, A. M. Ferrari and C. Leonelli, J. Am. Ceram. Soc., 2008, 91, 3746–3748. 150 T. Laird, Chem. Ind. Dig., 2010, 51–56. 151 M. N. Kashid, A. Gupta, A. Renken and L. Kiwi-Minsker, Chem. Eng. J., 2010, 158, 233–240. 152 A. Weilier, G. Wille, P. Kaiser and F. Wahl, Chem. Today, 2009, 27, 38–39. 153 S. Togashi, T. Miyamoto, Y. Asano and Y. Endo, J. Chem. Eng. Jpn., 2009, 42, 512–519. 154 T. Schwalbe, V. Autze and G. Wille, Chimia, 2002, 56, 636–646. 155 F. P. J. T. Rutjes, R. Segers, P. Nieuwland, K. Koch, H. G. Lelivelt, J. F. van den Berg and J. C. M. van Hest, Proceedings of 11th International Conference on Microreaction Technology, Kyoto, Japan, 2010, pp. 104–105. 156 K. Tanaka, S. Motomatsu, K. Koyana, S. Tanaka and K. Fukase, Org. Lett., 2007, 9, 299–302. 157 H. Lowe, R. D. Axinte, D. Breuch and C. Hofmann, Chem. Eng. J., 2009, 155, 548–550. 158 S. Hu, A. Wang, H. Lo¨we, X. Li, C. Li and O. Yang, Chem. Eng. J., 2010, 162, 350–354. 159 M. N. Kashid, A. Renken and L. Kiwi-Minsker, Chem. Eng. Sci., 2011, 66, 1480–1489. 160 S. Loebbecke, D. Boskovic, T. Tuercke, A. Mendl and J. Antes, Proceedings of 11th International Conference on Microreaction Technology, Kyoto, Japan, 2010, pp. 82–83. 161 D. Kirchneck and G. Tekautz, Chem. Eng. Technol., 2007, 30, 305–308.

This journal is

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View Online 162 F. Ebrahimi, E. Kolehmainen and I. Turnen, Org. Process Res. Dev., 2009, 13, 965–969. 163 M. Tokeshi, T. Minagawa and T. Kitamori, J. Chromatogr., A, 2000, 894, 19–23. 164 A. Smirnova, K. Shimura, A. Hibara, M. A. Proskurnin and T. Kitamori, Anal. Sci., 2007, 23, 103–107. 165 M. Ueno, H. Hisamoto, T. Kitamori and S. Kobayashi, Chem. Commun., 2003, 936–937. 166 S. Aljbour, H. Yamada and T. Tagawa, Top. Catal., 2010, 53, 694–699. 167 A. Hibara, M. Tokeshi, K. Uchiyama, H. Hisamoto and T. Kitamori, Anal. Sci., 2001, 17, 89–93. 168 K. K. R. Tetala, J. W. Swarts, B. Chen, A. E. M. Janssen and T. A. van Beek, Lab Chip, 2009, 9, 2085–2092. 169 D. M. Fries, T. Voitl and P. R. von Rohr, Chem. Eng. Technol., 2008, 31, 1182–1187. 170 N. Assmann, S. Desportes and P. R. von Rohr, Proceedings of 11th International Conference on Microreaction Technology, Kyoto, Japan, 2010, pp. 336–337. 171 M. Kumemura and T. Korenaga, Anal. Chim. Acta, 2006, 558, 75–79. 172 H. Shen, Q. Fang and Z.-L. Fang, Lab Chip, 2006, 6, 1387–1389. 173 J. G. Kralj, H. R. Sahoo and K. F. Jensen, Lab Chip, 2007, 7, 256–263. 174 R. L. Hartman, H. R. Sahoo, B. C. Yen and K. F. Jensen, Lab Chip, 2009, 9, 1843–1849. 175 A. B. Theberge, G. Whyte, M. Frenzzel, L. M. Fidalgo, R. C. R. Wootton and W. T. Huck, Chem. Commun., 2009, 6225–6227. 176 H. Kawakami, K. Goto and M. Mizuno, Proceedings of 11th International Conference on Microreaction Technology, Kyoto, Japan, 2010, pp. 172–173. 177 I. R. Baxendale, S. C. Schou, J. Sedlemeier and S. V. Ley, Chem.–Eur. J., 2010, 16, 89–94. 178 M. Baumann, I. R. Baxendale, L. J. Martin and S. V. Ley, Tetrahedron, 2009, 65, 6611–6625. 179 A. Hinchcliffe, C. Hughes, D. A. Pears and M. R. Pitts, Org. Process Res. Dev., 2007, 11, 477–481. 180 C. D. Smith, I. R. Baxendale, S. Lanners, J. J. Hayward, S. C. Smith and S. V. Ley, Org. Biomol. Chem., 2007, 5, 1559–1561. 181 L. Tamborini, P. Conti, A. Pinto and C. De Micheli, Tetrahedron: Asymmetry, 2010, 21, 222–225. 182 A. Palmieri, S. V. Ley, A. Polyzos, M. Ladlow and I. R. Baxendale, Beilstein J. Org. Chem., 2009, 5, No. 23.

This journal is

c

The Royal Society of Chemistry 2011

183 G. P. Wild, C. Wiles, P. Watts and S. J. Haswell, Tetrahedron, 2009, 65, 1618–1629. 184 I. R. Baxendale, S. V. Ley, C. D. Smith and G. K. Tranmer, Chem. Commun., 2006, 4835–4837. 185 H. Zhao, J. X. Wang, Q. A. Wang, J. F. Chen and J. Yun, Ind. Eng. Chem. Res., 2007, 46, 8229–8235. 186 S. Lawton, G. Steel, P. Shering, L. Zhao, I. Laird and X. W. Ni, Org. Process Res. Dev., 2009, 13, 1357–1363. 187 C. Ricardo and N. Xiongwei, Org. Process Res. Dev., 2009, 13, 1080–1087. 188 R. Karnik, F. Gu, P. Basto, C. Cannizzaro, L. Dean, W. Kyei-Manu, R. Langer and O. C. Farokhzad, Nano Lett., 2008, 8, 2906–2912. 189 R. C. R. Wootton and A. J. de Mello, Chem. Commun., 2004, 266–267. 190 A. Hibara, K. Toshin, T. Tsukahara, K. Mawatari and T. Kitamori, Chem. Lett., 2008, 37, 1064–1065. 191 R. L. Hartman, H. R. Sahoo, B. C. Yen and K. F. Jensen, Lab Chip, 2009, 9, 1843–1849. 192 Y. Zhang, S. Kato and T. Anazawa, Lab Chip, 2010, 10, 899–908. 193 S. Hubner, U. Bentrup, U. Budde, K. Lovis, T. Dietrich, A. Freitag, L. Kupper and K. Jahnisch, Org. Process Res. Dev., 2009, 13, 952–960. 194 C. F. Carter, H. Lange, S. V. Ley, I. R. Baxendale, B. Wittkamp, J. G. Goode and N. L. Gaunt, Org. Process Res. Dev., 2010, 14, 393–404. 195 S. Mechtilde, S. Eduard and F. Andreas, J. Phys. Conf. Ser., 2006, 28, 115–118. 196 J. Bart, A. J. Kolkman, A. J. Oosthoek-de Vries, K. Koch, P. J. Nieuwland, H. J. W. G. Janssen, J. P. J. M. van Bentum, K. A. M. Ampt, F. P. J. T. Rutjes, S. S. Wijmenga, H. J. G. E. Gardeniers and A. P. M. Kentgens, J. Am. Chem. Soc., 2009, 131, 5014–5015. 197 T. Jacobs, C. Kutzzner, M. Kropp, G. Brockmann, W. Lang, A. Steinke, A. Kienle and P. Hauptmann, Procedia Chem., 2009, 1, 1127–1130. 198 W. Ferstl, S. Loebbecke, J. Antes, H. Krause, M. Haeberl, D. Schmalz and H. Muntermann, Chem. Eng. J., 2004, 101, 431–438. 199 J. P. McMullen and K. F. Jensen, Annu. Rev. Anal. Chem., 2010, 3, 19–42. 200 Y. Tanaka, O. Tonomura, K. Isozaki and S. Hasebe, Chem. Eng. J., 2011, 167, 483–489. 201 Y. Kaburagi, M. Noda and H. Nishitani, Comput.-Aided Chem. Eng., 2009, 27, 1239–1244.

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