Tutorial Review: Continuous Ow Reactors: A Perspective

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Cite this: Green Chem., 2012, 14, 38
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Continuous flow reactors: a perspective
Charlotte Wiles*a and Paul Wattsb
Received 18th August 2011, Accepted 4th October 2011
Published on 10 November 2011 on http://pubs.rsc.org | doi:10.1039/C1GC16022B
DOI: 10.1039/c1gc16022b
With aspects of continuous processing featuring heavily in efforts towards increasing the ‘green’
prospects of pharmaceutical and fine chemical manufacturing, this article focuses on the
developments made into the application of continuous flow reactors for sustainable chemical
research and production.
Introduction tors have significant processing advantages including improved

thermal management, mixing control and the application of
The chemical sector has long been viewed by wider society extreme reaction conditions.6 Consequently, synthetic processes
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as being ‘dirty’; however, in the past two decades significant can be intensified by reducing the volume of solvent employed
amounts of research have been conducted into the development whilst maintaining control of reaction temperature.7 With this
of ‘green’ techniques for chemical synthesis, with the goal being in mind, this article focuses on identifying which of the twelve
to reduce the waste generated by the chemical industry.1 principles of green chemistry, as outlined by Anastas et al.,8 have
In 2007, the Green Chemistry Institute (GCI), part of the the potential to benefit from flow reactor technology (*discussed
American Chemical Society (ACS), set up a roundtable in con- herein);
junction with a series of global pharmaceutical companies. The 1. Prevention: It is better to prevent waste than to treat or
roundtable listed several key areas where research was required clean up after creation.*
to facilitate the development of sustainable manufacturing, the 2. Atom economy: Synthetic methods should be designed
details of which can be found in a recent publication by Jiménez- to maximise the incorporation of all materials into the final
González et al.2 The importance of continuous processing was product.*
acknowledged, with the panel ranking continuous processing as 3. Less hazardous chemical syntheses: Synthetic methods
the primary key area for research activities. should be designed to use and generate substances that possess
With the pharmaceutical industry in particular still domi- little or no toxicity to humans and the environment.
nated by flexible batch processes and segmented unit opera- 4. Designing safer chemicals: Chemical products should be
tions, there is a lot to be learnt from the petrochemical and designed to effect their desired function while minimizing their
food industries where continuous processing features widely toxicity.
as a means of keeping productivity high and costs low. With 5. Safer solvents and auxiliaries: The use of auxiliary sub-
these factors in mind, there has been renewed interest in the stances should be avoided and where necessary be innocuous.*
development of sustainable processes, with many of the ‘big 6. Design for energy efficiency: Energy requirements of chem-
pharma’ looking towards new techniques for both research and ical processes should be recognised for their environmental and
production.3,4 For this to be a success however, techniques are economic impacts and should be minimised.*
required that compliment the way that early stage researchers 7. Use of renewable feedstocks: A raw material or feedstock
and process chemists work, therefore advantages associated with should be renewable whenever technically and economically
its use must span both disciplines; continuous flow technology practical.*
has the potential to do this. 8. Reduce derivatives: Unnecessary derivatisation should be
Unlike batch reactor technology, which has changed little over avoided because such steps can generate waste.*
the past Century, continuous flow reactors form part of a rapidly 9. Catalysis: Catalytic processes (as selective as possible) are
growing research area which has the opportunity to change the superior to stoichiometric reagents.*
way synthetic chemistry is performed both at a research and 10. Design for degradation: Chemical products should be
industrial level.5 Compared to stirred tank reactors, flow reac- designed so that at the end of their function they break down
into innocuous products that do not persist in the environment.
11. Real-time analysis for pollution prevention: In-process
a
Chemtrix BV, Burgemeester Lemmensstraat 358, 6163JT, Geleen, The monitoring and control to minimise the formation of hazardous
Netherlands. E-mail: c.wiles@chemtrix.com; Tel: +44 (0)1482 466459 substances.*
b
The Department of Chemistry, The University of Hull, Cottingham
Road, Hull, HU6 7RX. E-mail: p.watts@hull.ac.uk; Tel: +44 (0) 1482
12. Inherently safer chemistry for accident prevention: Sub-
465471 stances used in a chemical process should be chosen to minimise
38 | Green Chem., 2012, 14, 38–54 This journal is © The Royal Society of Chemistry 2012
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the potential for chemical accidents, such as releases, explosions, In the second example, Löwe and co-workers12 performed the
and fires.* addition of secondary amines to a,b-unsaturated compounds
whereby reaction times of 17 to 25 h were typically required
Principle 1. Prevention of waste in order to maintain thermal control over the batch process.
Utilising a micro mixer with dimensions of 40 mm (wide) ¥
Historically, the focus of reaction development has been on
200 mm (deep) and a tube reactor, the authors were able to access
increasing the production yield of high value target compounds.
reaction times in the range of 0.8 to 5.0 ms, without the need for
More recently, due to changes in legislation and rising material
additional cooling; owing to the high heat transfer capacity of
costs, objectives have changed to also consider the green profile
the microstructured device (4000 W (m2 K)-1 ).
of a reaction/process.9 This can be seen in Principle 1 which
A niche product area that has the potential to benefit
focuses on the development of synthetic methods that prevent
from solvent-free continuous processing is that of ionic liquid
waste generation; rather than treating or cleaning-up the waste
synthesis, whereby conventional synthetic procedures rely on

once it has been created.
lengthy purification steps in order to access these solvents in
Solvent-free. With reaction solvents contributing greatly sufficient purities. Batch techniques are limited due to the rapid
towards the waste generated by a synthetic process, considerable and exothermic nature of the reactions, which give rise to
research has been undertaken to identify if more conventional impurities-characterised by a yellow colouration. Renken et al.13
solvents can be substituted with environmentally benign or investigated the use of a microstructured reactor as a means
recyclable analogues (see Principle 5, for a detailed discussion of of increasing reaction control and product purity. Using the
published examples utilising safer solvents and auxiliaries under synthesis of [EMIM][EtSO4 ] as a model reaction, the authors
flow conditions). Whilst the use of ‘green solvents’ can be viewed investigated the solvent-free alkylation under flow conditions.
as a step in the right direction, the most desirable approach Using a catepillar static mixer, the authors were able to increase
remains to perform reactions in the absence of a solvent. In
the production efficiency by three orders of magnitude obtaining

batch, this is undesirable as it can lead to uncontrollable reaction the ionic liquid at a throughput of 0.5 kg h-1 .
exotherms due to insufficient thermal management of reactor Employing a polysilane-supported palladium/alumina hy-
vessels; consequently, relatively few solvent-free reactions are brid catalyst, Kobayashi and co-workers14 recently reported
employed on a production scale.10 In comparison, the excellent the development of a gas-liquid-solid reactor suitable for the
thermal management obtained within continuous flow reactors, hydrogenation of unsaturated C–C bonds 4 and deprotection
and in particular microstructured reactors, means that it is now of carbobenzyloxy functional groups under solvent-free condi-
possible to safely and efficiently manage such reactions in the tions. Using this approach, the authors were able to perform
absence of a diluting solvent. Two early examples of this mode of selective hydrogenations without the need for dilute substrate
operation were the Paal–Knorr and Michael addition reactions concentrations, affording high turnover numbers (8700) and no
reported by Schwalbe et al.11 (Scheme 1a) and Hessel et al.12 Pd-leaching (ICP-MS analysis) (Scheme 2). In the case of solid
(Scheme 1b) respectively. substrates, small quantities of solvent were required however
substrate concentrations in the range of 0.33 to 1.0 M were
typically employed.
Scheme 2 Hydrogenation of ethylcinnamate 4 under solvent-free

conditions.
When considering the removal of a reaction solvent for use

under flow conditions, it is essential that the reactants and
Scheme 1 Illustration of solvent-free reactions performed under con- products remain in the liquid phase, under the processing
tinuous flow conditions. conditions employed, otherwise fouling of the reactor will
result. It is for this reason that continuous flow reactions are
In the former case, the synthesis of 2-(2,5-dimethylpyrrol-1- more often performed at higher concentrations than their batch
yl)ethanol 1 was used as a model reaction, enabling Schwalbe counterparts, but few allow the complete exclusion of solvent.
and co-workers11 to demonstrate the ability to dramatically To overcome this issue, additional research is required into
reduce the reaction time required for the Paal–Knorr reaction by improving post reaction separation of solvents in order to
efficiently controlling the reactor temperature. Using a stainless further develop solvent recyclers for use with continuous flow
steel microstructured reactor, the authors were able to increase reactors.
thermal control of the reaction identifying a reaction time of
5.1 min and a reactor temperature of 65 ◦ C as being optimal Minimal reagent consumption. In further efforts towards
for the target pyrrole 1 (91% yield); obtaining a throughput minimising waste formation, micro reactors have a key role to
of 260 g h-1 . Compared to batch, the main time saving was play in reaction screening and optimisation. When performed
achieved via the ability to constantly add neat ethanolamine 2 in batch, scouting experiments can be conducted on small
to acetonylacetone 3 whilst controlling the reactor temperature. scales utilising typically mg of reactants and ml of solvents;
This journal is © The Royal Society of Chemistry 2012 Green Chem., 2012, 14, 38–54 | 39
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with the number of reactions performed dependant on reaction To address this, Kappe and co-workers18 evaluated the use of a
time and available material. In flow, ten’s to hundred’s of high temperature and pressure tubular reactor to enable access
reactions can be performed using these quantities of materials, to Claisen re-arrangement products without the need for long
leading to reduced reagent consumption and waste production. reaction times.
In addition, the ability to rapidly change reaction conditions Examining the synthesis of 2-allylphenol 5 from allyl phenyl
enables reactions to be probed in a more detailed way, increasing ether 6 (Scheme 3), the authors employed toluene as the reaction
user understanding ahead of scaling reactions to prepare and solvent and examined the effect of reactor temperature and
isolate target compounds. This approach was demonstrated in a pressure on the reaction. Focussing on the use of a stainless
recent publication by van Hest, Rutjes and co-workers15 whereby steel reactor (volume = 4 ml), the authors identified that a
the Moffatt-Swern oxidation was evaluated using an automated reactor temperature of 240 ◦ C and system pressure of 100 bar
reaction platform. afforded the target phenol 5 in 95% yield, with a reaction time
Using a borosilicate glass micro reactor (Channel dimen- of 4 min. Using inductive heating, Kirschning et al.19 have also
sions = 120 mm (wide) ¥ 55 mm (deep) ¥ 0.26 or 13.20 cm (long); demonstrated the Claisen re-arrangement where increases in
Volume = 0.14 or 7.02 ml) the authors were able to conduct a product yield (~23%) were obtained when utilising a flow reactor.
detailed optimisation study which enabled a 32 s mixing time and
a reaction temperature of 70 ◦ C to be identified as being the best
conditions for obtaining the target compound whilst minimising
competing side reactions. By employing a flow reactor, many
more reaction conditions could be evaluated than would be prac-
Scheme 3 Illustration of a Claisen re-arrangement reaction performed
tical in batch whilst having the added advantage that minimal
under high temperature and pressure flow conditions.
reagent volumes are consumed and higher reactor temperatures
can be readily evaluated. Once identified, the optimised reaction

Exploiting the ability to access extreme combinations of
conditions were used to produce the oxidation product, which
temperature and pressure, researchers at Lilly also demonstrated
was obtained in 96% yield.
the use of a re-arrangement reaction as a key synthetic step in
In the same year, Buchwald and Jensen16 reported the
the preparation of a thiol required for an early stage develop-
combination of micro reactors and feedback control for the
ment project.20 Employing a Newman-Kwart re-arrangement
development of a self-optimising platform. Using the Heck
(Scheme 4), the authors were able to screen the effect of temper-
reaction as a model, the authors were able to rapidly optimise the
ature (250–320 ◦ C) on the reaction, reporting the conversion of
process using minimal quantities of reagent and then scale those
O-thiocarbamate 7 to the respective S-thiocarbamate 8 in high
optimised conditions by a factor of fifty to produce the coupling
yield and purity. Optimal thermal conditions were found to be
product in comparable yield. The ability to tune a reaction using
300 ◦ C, affording the target product 8 in 99.1% conversion and
small quantities of reactants therefore not only minimises the
93% isolated yield after recrystallisation.
waste generated during early stage reaction screening, but also
has the potential to simplify downstream processing and hence
decrease the volume of waste generated at the clean-up step(s).
Further waste prevention can also come about through the use
of catalysts in place of stoichiometric reagents, for examples of
the use of catalysts under flow, please refer to Principle 9.
Principle 2. Atom economy

The atom economy of a reaction is a measure of the percentage
of the mass of reactants that are incorporated into the product
and is often used as a measure of waste generation.17 Whilst
this approach describes the theoretical economy of a synthetic
route, reactions can still be low yielding and require purification
to isolate the target compound. When looking towards contin-
uous flow reactors, researchers have shown that by stringently
controlling reaction conditions, the purity profile of reaction
products can be improved, therefore reducing the complexity of
subsequent purification steps or even removing the need for them
altogether. Focussing on those reactions conventionally termed
atom economic, the following section describes the additional
synthetic advantages that can be accessed by their performance Scheme 4 Conversion of an O-thiocarbamate 7 to an S-thiocarbamate
under flow conditions. 8 under high temperature flow conditions.
Re-arrangement reactions. When looking at employing atom
economic reactions, intramolecular re-arrangements represent Addition reactions. Several researchers have investigated the
some of the most synthetically useful; reaction conditions Diels–Alder cycloaddition under continuous flow using stainless
required to promote them can however be viewed as extreme. steel reactors.21,22 Using a polymeric microflow disk reactor,
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containing eight parallel channels (~200 mm i.d.), Hallmark batch reactions, the authors comment that flow reactors provide
and co-workers23 reported the reaction of isoprene 9 with a significantly safer method for the large scale synthesis of
maleic anhydride 10 to afford 3a,5,7a-trimethyl-3a,4,7,7a- tetrazoles as the liquid filled reactor has no headspace. In one
tetrahydroisobenzofuran-1,3-dione 11 (Scheme 5). Immersing example, 18.9 g of a tetrazole (89% yield) was synthesised in
the reactor in an oil bath, the reaction was investigated at a 1 h continuous experiment. The authors have subsequently
60 ◦ C, whereby the authors obtained isolated yields of 85 utilised a flow reactor to investigate the decomposition of
to 98% depending on the residence time employed (28 to 5-benzhydryl-1H-tetrazole to diphenylmethane, employing a
113 min). Under optimal reaction conditions, the authors were reaction temperature of 220 ◦ C and a residence time of 10 min.26
able to produce the pharmaceutically relevant core-motif at a Jensen and Zaborenko27 concurrently reported the use of a
throughput of 1.05 kg day-1 . silicon micro mixer (volume = 4.1 ml) for the two-step synthesis
of the highly energetic sodium nitrotetrazole, gaining access to
the material at an impressive throughput of 4.4 g h-1 .
Improved atom economy has also been demonstrated for

polymer synthesis in flow. Using a process of reversible
addition-fragmentation chain transfer, Hornung and co-
workers28 demonstrated the ability to perform the controlled
radical polymerisation of a series of monomers including n-
Scheme 5 A Diels–Alder reaction performed under flow conditions isopropylacrylamide and n-butyl acrylate. Performing the reac-
within a MFD reactor. tions under flow conditions, the authors were able to obtain
narrow molecular weight distributions, when compared to
Using a chiral organocatalyst 12, Odedra and Seeberger24 batch techniques, representing a more efficient incorporation of
reported the performance of the Mannich reaction in a glass
precursors into the target products. To obtain high conversions

micro reactor. Employing DMSO as the reaction solvent, the (80–100%), the authors found it necessary to minimise the
reaction of a-iminoglyoxylate 13 and cyclohexanone 14 was proportion of oxygen in the solvent system and reactor, thus
investigated to afford b-aminoketone 15 (Scheme 6). Using preventing quenching of the radicals generated. The reaction
5 mol% of catalyst 12 and a reactor temperature of 60 ◦ C, the sensitivity to O2 was also highlighted when a gas permeable
authors obtained the target compound in 91% yield (>95% de). PFA tube reactor was compared with a steel system, resulting in
significantly lower product conversions.
Asymmetric synthesis. Another way of increasing the effi-

ciency of a synthetic process is to increase the enantiomeric
excess of the target compound thus reducing the proportion of
substrate that is consumed in the formation of the undesirable
enantiomer.
Forming part of a continuous strategy for the synthesis of
Scheme 6 Continuous flow Mannich reaction performed using an (±)-fluoxetine 16 Sanderson and Ahmed-Omer29 reported the
organocatalyst 12. development of an enantioselective reduction, used for the
preparation of a key (S)-alcohol 17 (Scheme 8). Employing
Looking to capitalise on the growing synthetic interest in the Corey–Bakshi–Shibata conditions, the authors investigated the
synthesis of substituted tetrazoles from medicinal, coordination reduction of ketone 18 with borane-N,N-diethylaniline 19 in
and materials chemists, Roberge and Kappe25 recently disclosed the presence of a chiral oxazaborolidine catalyst 20. Perform-
details of a continuous flow process for the atom efficient synthe- ing the reaction at 0.24–0.40 M, no reaction was observed;
sis of tetrazoles. Using the addition of hydrazoic acid to organic however, increasing the concentration to 0.70 M resulted in
nitriles, the authors were able to exploit the increased process
safety associated with flow reactors to efficiently synthesise a
series of 5-substituted 1H-tetrazoles (Scheme 7).
Scheme 7 General schematic illustrating the conditions used for the

continuous synthesis of 5-substituted 1H-tetrazoles.
Employing a two feed Sulfinert tube reactor, the authors

reacted a solution of nitrile in NMP/AcOH with a solution of
aqueous sodium azide (2.5 eq.). Heating the system to 220 ◦ C,
the authors were able to safely generate HN3 in situ, obtaining
the target tetrazoles in isolated yields ranging from 75 to 98% Scheme 8 Enantioselective synthesis of a secondary alcohol 17 used in
with reaction times of 5 to 15 min. Compared to analogous the synthesis of (±)-fluoxetine 16.
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quantitative reduction to afford (S)-3-chloro-1-phenyl-propanol

17 in 72% ee. Reducing the reactor temperature to -7 ◦ C
afforded the desired increase in ee, delivering the alcohol 17
in 88% yield and 92% ee. The alcohol 17 was subsequently
converted to the iodo derivative in batch, followed by amination
under biphasic flow conditions. The final step, a Mitsunobu
reaction, enabled the nucleophilic substitution of alcohol 17
with 4-hydroxybenzotrifluoride to afford (±)-fluoxetine 16; at Scheme 10 Illustration of a polymer-supported cinchonidine derivative
a throughput of 4.8 mmol h-1 . 22 used to promote the enantioselective Michael addition in a packed-
To further increase the efficiency of asymmetric syntheses, bed reactor.
Moberg and co-workers30 developed a solid-supported Lewis
for use in the aldol reaction. As Scheme 11 illustrates, the model
acid catalyst, affording a means of efficiently recycling the

reaction involved the reaction of a silyl derivative 26 and alde-
catalyst and simultaneously simplifying the post reaction pro-
hyde 27 (2 : 1) in the presence of scandium bis(perfluorooctane-
cessing required to isolate the target compounds. Using the
sulfonyl)amide 28 (0.06 mol%); with quantification performed
enantioselective synthesis of TMS-cyanohydrins (Scheme 9), the
offline using GC-FID analysis of the toluene phase. Applying
authors evaluated the Lanthanide-Pybox catalyst 21 illustrating
a reaction time of 10.8 s, the authors obtained 92% conversion
ease of reaction screening compared to batch techniques.
of the silyl enol ether 26 (1.5 : 1 29:30) compared to 11% in a
stirred batch reactor (2 h); an observation that is attributed to
the high interfacial area obtained in the micro reactor. Under
the aforementioned conditions, the catalyst 28 remained in the
perfluorinated solvent and the authors isolated the reaction
products from the toluene phase; enabling the catalyst solution

Scheme 9 Use of a solid-supported catalyst 21 for the enantioselective to be re-used without the need for post reaction processing.
synthesis of TMS-cyanohydrins.
Hodge et al.31 demonstrated the use of a polymer-supported

cinchonidine derivative 22 (Fig. 1) and evaluated it towards
the enantioselective Michael addition depicted in Scheme 10.
Employing a glass tubular reactor containing 15 g of PS-
cinchonidine 22, the authors investigated the addition reaction
between 1-oxoindan-2-carboxylate 23 and methyl vinyl ketone
24 to afford the Michael adduct as the (S)-enantiomer 25. Using Scheme 11 Illustration of the aldol reaction used to demonstrate the
1.06 eq. of MVK 24 and toluene as the reaction solvent the advantages of fluorous solvents in flow reactors.
reaction mixture was pumped through the reactor which was
maintained at 50 ◦ C. Under the aforementioned conditions, the In addition to fluorinated solvents, ionic liquids have also been
authors obtained the Michael adduct in 97% yield and 52% ee employed as a reaction media for flow reactions. Using 1-butyl-
at a throughput of 10 g day-1 , using a simple reaction set-up. 3-methylimidazolium bis(trifluoromethylsulfonyl)imide, Ryu
et al.34 evaluated the continuous flow Heck reaction (Scheme
12) and subsequent recycling of the reaction solvent.
Fig. 1 Polymer-supported cinchonidine derivative 22 shown to pro-

mote enantioselective addition reactions. Scheme 12 Illustration of the Heck reaction performed in a recyclable
ionic liquid.
Principle 5. Safer solvents and auxilliaries

Biphasic reactions. Biphasic reaction conditions represent
When looking to improve the environmental performance of a a largely under utilised area of synthetic chemistry, namely
chemical process, solvents play a large role in the defining process because of the poor mixing that occurs between the two liquid
costs and safety; consequently, the use and definition of ‘green phases; particularly when reactions are performed at scale. When
solvents’ has attracted significant interest.32 such transformations are conducted in micro flow reactors, be
Employing a biphasic solvent system comprising of co- they etched channel networks or microbore tubes, the high
flowing perfluoromethylcyclohexane/toluene, Mikami et al.33 interfacial surface area that results can have a dramatic increase
demonstrated the ability to readily recycle a Lewis acid catalyst in reaction rate compared to flask based reactions.35,36 A recent
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example exploiting this phenomenon was a biphasic Wittig frequencies of 4.3 ¥ 106 h-1 for the coupling of iodobenzene
reaction reported by Krajnc and Šinkovec.37 Using a simple and phenylacetylene performed in the environmentally benign
FEP tube reactor (0.25 mm i.d. ¥ 90 cm or 17 m), the authors solvent-water. Product isolation was also easy, with the precip-
investigated the reaction of benzyltriphenyl-phosphonium salt itated Pd0 filtered under vacuum and the product isolated via
and methoxybenzaldehyde in DCM, with an aqueous solution phase separation from the aqueous reaction solvent.
of sodium hydroxide as the base. In this case, the advantages An interesting area that has received attention from re-
of a biphasic system were two-fold, firstly the slug flow regime searchers is the development of continuous methodology for the
obtained in a tube reactor afforded a reproducible method for preparation of well defined semiconductor materials. Applying
increasing the interfacial area between the two phases, resulting continuous flow processing to the synthesis of quantum dots,
in an increase in reaction rate and secondly, the presence of H2 O Jensen et al.45 reported the development and use of a high
prevented the precipitation of Ph3 PO within the small reaction temperature and high pressure micro reactor suitable for the
channels. For additional examples of precipitate manipulation synthesis of nanocrystalline quantum dots. In addition to
under flow conditions, please see McQuade et al.,38 Dolman demonstrating an increase in the optical characteristics of the
et al.39 and Jensen et al.40,41 CdSe quantum dots, the authors were also able to replace
Whilst authors have demonstrated rate acceleration as a conventional solvents such as squalane and octadecane with
result of utilising segmented flow,42 Buchwald and Nager43 reduced toxicity solvents such as hexane, toluene and octane.
recently reported the need for additional mixing of the im-
miscible toluene : water phases when performing a C–N cross Principle 3: Less hazardous chemical syntheses
coupling reaction (Scheme 13). Packing an FEP tube reactor
with stainless steel spheres (60–125 mm), the authors ob- Whilst the toxicity and hazards associated with a specific final
served 60% conversion of 2-chloroanisole 31 to ethyl 2-((2- product do not alter with the production method employed,
the fact that flow reactor technology has routinely been shown
methoxyphenyl)amino)benzoate 32 compared with 10% in an

open tube reactor; rising to 98% conversion at a residence time to generate products in higher yield and selectivities, it can
of 6 min. Evaluating the effect of packed-bed size, the authors be envisaged that the implementation of this technology at a
observed increased substrate conversion with increasing bed size, production level has the potential to reduce the number and
concluding that the higher fluid velocity resulted in increased type of by-products generated and hence reduce the generation
mixing efficiency. of hazardous products realised via side reactions.
Principle 6: Design for energy efficiency
Over the past decade it has become widely accepted in academic

circles that flow reactors offer the user the potential to intensify
processes and thus reduce the energy impact of transformations
employed at a production scale; with industrial researchers more
recently reporting its application.
In an early disclosure by industry, researchers at Degussa
AG described the ability to boost production capacity of
an existing tubular reactor plant by installing a wall-coated
microstructured reactor upfront.46 Focussing on the synthesis of
acrolein via a gas-phase partial oxidation reaction, the authors
determined that the process would afford a temperature rise
of 133 ◦ C when performed in a 10 mm (i.d.) tubular reactor,
Scheme 13 Model reaction used to demonstrate the C–N cross reducing to only 1.3 ◦ C in a 1 mm tube. With this in mind,
coupling under flow conditions. a wall-coated microstructured device was fabricated where the
increased process control led to a reduction in operational costs
previously associated with thermal management. Using this
Supercritical solvents. By developing customised reactor approach, the researchers calculated that for a highly exothermic
solutions, it is now possible for the research chemist to access reaction the use of such a system would enable a 20% increase
reaction conditions previously termed ‘extreme’ within con- in production capacity by exploiting micro process technology
ventional synthetic laboratories, opening up new opportunities for the modification of existing plant infrastructure.
for the synthetic chemist. Using this approach, Kappe and
co-workers22 have reported the utility of supercritical solvents Microwave heating. The coupling between continuous flow
for the catalyst free esterification and transesterification of and microwave heating has received a significant amount of in-
simple carboxylic acids. In a second example, the dramatic terest as a means of efficiently producing synthetically interesting
rate accelerations possible when performing reactions in flow chemicals at the small scale. In a critical assessment, Moseley and
under high temperature and pressure was also reported by Kappe47 however appraised the energy efficiency of microwave
Kawanami and Sato44 who demonstrated the PdCl2 catalysed assisted organic synthesis, concluding that on a small scale
Sonogashira coupling with reaction times of the order of 0.1 to (1 to 50 ml) any energy savings made are due to the reduction
4.0 s. Employing the rapid collision of super-heated reagents and in reaction time, accessed through the use of sealed vessels, and
water, the authors were able to access unprecedented turnover not because microwave irradiation is a more energy efficient
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method of heating. When considering large scale reactors,

multi-mode microwave reactors have been found to be more
energy efficient than small single mode systems, but not more
efficient than conventional heating; due to minimal penetration
depth.48 Coupled with the fact that microwave heating is 8
times more expensive than conventional heating,49 techniques
for efficient heat transfer are required if costs are to be reduced,
particularly at the production level. One way of achieving this is
to use small volume continuous flow reactors, with the authors
demonstrating a reduction in energy usage mol-1 . Kappe has also
shown that heating to the same temperature in a flow reactor
by conventional means affords the same product therefore flow

reactors have the ability to scale reactions screened in microwave
reactors without a loss in performance with an increase in
heating efficiency.50 Scheme 14 illustrates a scalable two-step
process developed for the continuous synthesis of Nabumetone
33 capable of producing the target compound in 75% yield at a
throughput of 0.35 kg h-1 .51 Scheme 15 Illustration of a multi-component flow reaction promoted
using inductive heating.
complex architectures from relatively simple precursors, the

lack of commercially available equipment and the stigma of

being a difficult technique to scale means that photochemical
routes are often not even considered. If we think that micro
reactors, generally speaking, have a small liquid depth, it stands
to reason that increases in reaction efficiency and selectivity
could be possible due to homogeneous light penetration. With
photochemical routes including isomerisations, cycloadditions,
bond cleavages reported, this is something that researchers in the
flow community hope to exploit by the development of reactors
that could make high volume photochemical syntheses a reality.
An early example of photochemistry under flow was reported
by Lu, Schmidt and Jensen,53 whereby the conversion of ben-
zophenone to benzopinacol under UV irradiation (l = 366 nm)
was investigated in a silicon/quartz micro reactor (Channel
dimensions = 500 mm2 ).
Maeda et al.54 subsequently investigated the intramolecular
Scheme 14 Two-step synthesis of Nabumetone 33 developed using [2+2] and [2+3] photocycloaddition of 2-(2-alkenyloxymethyl)-
microwave reactors and scaled using flow reactors. naphthalene-1-carbonitriles, comparing the efficiency of reac-
tions performed under standard and flow conditions (Channel
dimensions = 2.5 mm (wide) ¥ 60 mm (long)); employing a
Radiofrequency heating. Using tube reactors filled with
Xenon lamp (500 W, l = 280 nm) (Scheme 16). Performing
functionalised superparamagnetic nanoparticles or steel beads,
the reaction under flow conditions the authors were able to
Kirschning et al.52 demonstrated the ability to efficiently heat
uniformly irradiate the reaction mixture, which not only reduced
continuous flow reagent streams by placing the reactor in an
the irradiation time from 240 min to 1 min, but also minimised
electromagnetic field; affording the temperatures of 350 ◦ C to
the proportion of photocycloreversion observed. Using this ap-
be achieved. With this technique in hand, the authors compared
proach, the authors were able to selectively perform the desired
the use of an oil bath, microwave and inductive heating for a
[2+2] photocycloaddition, affording the 1,2-adduct in excellent
Claisen re-arrangement, reporting 17% for the oil bath, 38%
selectivity (96%); demonstrating that when fast reversible reac-
for the microwave and 39% for the inductively heated system.
tions and slow irreversible reactions co-exist, micro reactors offer
Based on these results, the authors have subsequently explored
an efficient method for the synthesis of materials via the former
the utility of this technique reporting a range of transformations
reaction pathway. The generality of the technique developed was
including condensations, hydrogenations, oxidations and multi-
then investigated for a series of substituted carbonitriles whereby
component reactions. Scheme 15 illustrates an example of a
excellent selectivities were obtained when benchmarked against
multi-component reaction whereby the target compound was
comparable photochemical batch reactions.
obtained in 87% yield representing a 17% increase compared to
Shvydkiv, Nolan and Oelgemöller,55 recently described the
the batch process.
development of 4,4¢-dimethoxybenzophenone 34 mediated mi-
Photochemistry. Whilst the synthetic power of photochem- crophotochemical transformations of phthalimides. Employing
istry is widely recognised as a means of preparing structurally a FoturanTM micro reactor (Volume = 1.6 ml) and five 8 W UVA
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ated and reacted under flow conditions at temperatures greater

than those conventionally required in batch. In an extension
to this investigation, the authors have also demonstrated an
additional advantage of flow reactors over batch vessels, that
being the ability to readily perform reaction steps for precise
times at different temperatures (Scheme 18).59
Scheme 16 Illustration of the intramolecular [2+2] and [2+3] pho-

tocycloaddition reactions of 2-(2-alkenyloxymethyl)-naphthalene-1-
carbonitriles performed under flow conditions.
lamps (l = 350 nm) as a light source, the authors investigated

a series of photodecarboxylation addition (Scheme 17a) and
cyclisation reactions (Scheme 17b).
Scheme 18 Sequential lithiation and Murashasi couplings performed

at different temperatures under flow conditions.
Under batch conditions, the authors formed the organo-

lithium intermediate 35 at -78 ◦ C, warming the reaction mixture
to 30 ◦ C to perform the Murahasi coupling, affording 53%
4-methoxybiphenyl 36, 7% 4-butylmethoxybenzene and 3%
butylbenzene. In comparison, generation of the organolithium
intermediate at 0 ◦ C (Residence time = 2.6 s) in a flow reactor,
followed by the coupling reaction at 30 ◦ C (Residence time = 16 s)
the authors were able to increase the yield of 4-methoxybiphenyl
36 to 80%. Further increasing the second reactor temperature
to 50 ◦ C enabled isolation of the biphenyl derivative 36 in 93%
yield at a semi-preparative throughput of 15.6 g h-1 . In other
Scheme 17 Illustration of photochemical (a) addition and (b) cyclisa- work the authors have also demonstrated the safe manipulation
tion reactions performed using a FoturanTM flow reactor. of sec-BuLi at -48 ◦ C, representing a 30 ◦ C increase compared
to batch60 and the homocoupling of aryl halides using FeCl3 .61
Compared to conventional cylindrical Schlenk apparatus, The manipulation of moisture sensitive reagents and their
the authors calculated that the irradiated area of the micro introduction into flow reactors can prove challenging, refer to
reactor was 5 to 8 times larger than a 50–100 ml batch ‘Challenges of flow reactor technology’ for details.
vessel and demonstrated larger energy efficiencies. Furthermore, In addition to lithiations, other transformations have been
decomposition processes were also avoided through the use of a shown to benefit from increased reactor temperature include
flow reactor as ‘over-irradiation’ could be minimised. With these the Swern-Moffatt oxidation15 (see Principle 1. Prevention of
observations in mind, the researchers are currently exploring the waste). In some cases reactor temperatures have been increased
development of a solid-supported mediator to aid with product by 80 ◦ C whilst having no detrimental effect on the reaction
purification. yield and product selectivity-giving access to a wide range of
Devices for the photochemical degradation of waste materials chemistries that may otherwise not be employed at a production-
have also been developed as a means of reducing the impact of scale due to the need for cryogenic conditions. Looking towards
chemical production and waste treatment.56 production environments, this approach has potential to sub-
stantially reduce energy requirements and simultaneously the
Active cooling. In addition to increasing the efficiency with
costs associated with the use of such synthetic pathways.
which energy can be put into reactions, the excellent thermal
management within micro reactors means that cryogenic condi-
Principle 7. Use of renewable feedstocks
tions are often no longer required. An observation initially made
by Schwalbe et al.57 for the halogen-lithium exchange reaction The use of renewable feedstocks in synthetic research is a
between an organolithium derivative and 3-bromoanisole. relatively new area, examples of their application under flow
In recent years Yoshida and co-workers58 have extensively conditions are however starting to appear in the literature.
explored this area of flow chemistry, concluding that a series of Using biphasic flow, Brasholz and Tsanaktsidis62 demonstrated
short living organolithium intermediates can be readily gener- the ability to synthesise value-added furan derivatives, such as
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5-(chloromethyl)furfural 37 from renewable feedstocks (Scheme

19). Employing aqueous HCl at 130 ◦ C, the authors reported the
efficient dehydration of sucrose 38 to 5-(chloromethyl)furfural
37 at a throughput of 18.0 g min-1 .
Scheme 19 Use of renewable feedstocks for the synthesis of value-

added furan derivatives.
As an extension, the authors also reported the ability to

synthesise levulinic acid 39 from D-fructose 40 using 2.0 M
HCl and MeOH as the reaction solvent. Employing a reactor
temperature of 140 ◦ C for 80 min, the target compound was
obtained in 72% yield with 11% 5-(hydroxymethyl)furfural 41
(Scheme 20).
Scheme 20 Synthesis of levulinic acid 39 from D-fructose 40 under flow

conditions.
Scheme 21 Schematic illustrating the reaction protocol used for the
non-covelent protection of amines under flow conditions.
Looking towards the renewability of feedstocks, the gen-
eration of hydrogen from water and its subsequent use in
hydrogenation reactions represent an area that has received research level techniques such as ‘catch and release’ are shown
significant interest from the flow chemistry community; see to afford facile access to high purity materials, at a production
Principle 12 for examples using water as the H2 source. level the procedures used to prepare and regenerate the solid-
supported material must also be considered when assessing the
Principle 8. Reduce derivatives environmental impact of a process.
More recently, Kim, Nagaki and Yoshida64 reported a
One approach to reducing the environmental burden of synthetic flow reactor approach for the protecting group free synthesis
chemistry is to develop methodology that requires minimal or and reaction of organolithium derivatives (Scheme 22). In
no protecting group steps. conventional batch reactors, treatment of a ketone with an
Whilst protecting group chemistry is by its very nature not organolithium reagent would result in reaction. By carefully
atom efficient, Wild and co-workers63 were able to develop controlling the reaction time in a micro mixer (<0.003 s), the
a novel, re-usable non-covalent N-protecting group strategy; authors found it possible to generate aryllithium intermediates
which coupled with continuous flow enabled the synthesis of O- from substrates possessing a ketonic moiety without the need
tyramine acetate 42 in high yield and selectivity. In comparison, for formal protection; which was not possible using a stirred
when the reaction was performed in the absence of the protecting reactor. The synthetic utility of the methodology developed was
group, a mixture of tyramine acetate 42 (23%), tyramine N- subsequently demonstrated for the preparation of derivative 44,
acetate (12%), tyramine diacetate (20%) and residual starting an intermediate used in the synthesis of the natural product
material (45%) was obtained. Pauciflorol F 45 (Fig. 2). Using the micro reaction strategy
With a strategy based on the non-covalent N-protection described, the authors were able to synthesise compound 45
via an immobilised crown ether, the authors were able to N- in 81% yield at a throughput of 12.7 g h-1 .
protect bifunctional compounds, which upon reaction could be The increased control micro reactors afford enables the user
released to afford the derivatised amine. Using the O-acetylation to exploit subtle differences in reaction rate in order to select the
of tyramine 42 as a model reaction, the authors evaluated desired synthetic pathway over a competing one. This approach
the synthetic strategy outlined in Scheme 21, obtaining the therefore has great potential for the modern synthetic chemist,
target compound 42 in quantitative yield and selectivity. In enabling the realisation of protecting group free synthesis.
addition, using an organic base 43 as a releasing agent left
the crown ether cavity free for subsequent use. Whilst the
Principle 9. Catalysis
solid-supported reagent could be utilised in a stirred vessel,
mechanical degradation occurs making efficient recovery after Catalysis is a powerful synthetic tool used to increase the
each step problematic. In addition, large volumes of solvent efficiency and selectivity of reactions; however identification
and reagents are required in order to perform each step when of suitable reaction conditions, catalyst loadings and type
compared to the use of a packed-bed reactor. Whilst at a can be both laborious and consume significant quantities of
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Scheme 23 Decarboxylative biaryl synthesis and the accompanying

protodecarboxylation by-product 46.
channel devices, opening up the possibility to design and

evaluate novel, selective catalyst types. For additional examples
please see the tutorial review by Frost and Mutton72 and the
references cited therein.
Scheme 22 Illustration of the protecting group free synthesis of Biocatalysis. Whilst biocatalysts are extremely efficient, par-
derivative 44, a key component in the synthesis of Pauciflorol F 45. ticularly with regards to stereoselective reactions, the costs as-
sociated with their use have somewhat limited industrial uptake.
Researchers have however shown that by employing continuous

flow reactors, small quantities of precious biocatalytic material73
can be used to obtained detailed information regarding re-
action kinetics, substrate specificity and operational stability.
Furthermore, researchers have demonstrated the screening of
biocatalytic flow processes at the bench-scale allows facile
translation of synthetic methodology to production-scale.
Using previously developed polymer brushes as a surface
for functionalisation, Vancso and Verboom74 demonstrated the
ability to efficiently incorporate a lipase biocatalyst (Candidia
Fig. 2 Natural product Pauciflorol F 45. Rugosa type VII) onto the walls of silicon-glass micro reactors.
Assessment of the devices using the BCA assay confirmed the
precious material. With this in mind, micro flow reactors immobilisation of 3.25–4.25 ¥ 10-8 mg mm-2 of biocatalyst,
are advantageous as they enable rapid screening of catalysts depending on the coating time used and the thickness of the
towards and array of substrates whilst minimising the volume of resulting catalytic layer; as with all immobilised biocatalysts,
catalysts required. Strategic examples are selected to illustrate reduction in activity was observed compared to the free
the advantages associated with performing catalysed processes biocatalyst. Using the modified micro channel reactor, the
conducted under flow conditions. authors were able to determine that the hydrolysis of nitrophenyl
Utilising a Cu/Pd catalyst system, Underwood and Gooßen65 acetate was first order and extracted a rate constant of 22 ¥
described the development of a new synthetic strategy for the 10-3 s-1 . More recently He, Greenway and Haswell75 combined
decarboxylative biaryl synthesis performed under flow condi- biphasic flow with an immobilised lipase (C. antarctica lipase
tions (Scheme 23). When attempted under batch conditions, A) demonstrating the ability to biocatalytically hydrolyse 4-
minimal C–C bond formation was observed (6%), with pro- nitrophenyl butyrate at 80 ◦ C without loss of activity over
todecarboxylation dominating to afford nitrobenzene 46 as the 480 h.
major product (Scheme 23). In comparison, when the reaction An early example of scaling a biocatalytic flow process was
was performed under the same reaction conditions in a tubular the lipase catalysed synthesis of (E)-retinyl acetate 48, an
flow reactor 4¢-methyl-2-nitro-1,1¢-biphenyl 47 was isolated in intermediate in the preparation of Vitamin A (Scheme 24),
71% yield, with no nitrobenzene 46 formation observed. The reported by Orsat, Wirz and Bischof.76 Starting from a 1,6-diol
origin of this impressive C–C selectivity is currently the subject 49, the authors employed an immobilised Chirazyme L2-C2 50
of further investigations by the authors. as the biocatalyst and vinyl acetate 51 in acetone as the acylating
In addition to employing homogeneous catalysts, several agent. Employing a small packed-bed reactor, containing 5.0 g
authors have described the used of heterogeneous catalysts of Chirazyme L2-C2 50, the authors were able to synthesise (E)-
within flow reactors as a means of increasing the ease and retinyl acetate 48 in 99% yield and >97% selectivity affording a
efficiency of catalyst recovery and recycle. Several methods have throughput of 49 g day-1 . Scaling the technique to the mini-plant,
been employed to incorporate the catalyst into the reactors the authors employed 120 g of biocatalyst 50 and evaluated the
including packed-beds,65 monoliths66,67 and wall-coated systems reactor for long-term stability. After a few days they observed
(Au-films,68 polymer brushes,69 zeolites70 and Pd nanoparticles71 ) a decrease in production efficiency, identifying deactivation as a
to exploit the high surface to volume areas obtained in micro result of feedstock impurities. Adding a protective pre-column,
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issues and divert out of specification process streams before

significant batches of material are spoiled. In addition to offering
product quality management, process analytical tools (PAT)
are also an important safety measure within the production
environment. Whilst PAT such as on-line Raman and IR
spectrometry find frequent application in the monitoring of in-
dustrial processes, the techniques are not yet widely exploited in
synthetic research laboratories; however they have the potential
to greatly increase the understanding of process at the research
level.
Raman spectrsocopy. To demonstrate the synthetic utility of

the Raman spectroscopy, Nordon and Mozharov78 coupled a

micro reactor to a Raman spectrometer as a means of gathering
Scheme 24 Biocatalytic synthesis of a key intermediate of Vitamin A. real-time reaction information from which they were able to
determine reaction order and rate. Using the base-catalysed
it was possible to operate the system at a throughput of 10 g Knoevenagel condensation reaction between ethylcyanoacetate
min-1 (1.6 kg day-1 ) over a period of 100 days without needing and benzaldehyde 27 as a model reaction, the authors were
to replace the pre-column. Isolation of the target product 48 able to readily determine the observed reaction rate k =
was achieved via distillation of acetaldehyde and rectification of 0.24 mol-0.1 dm0.3 s-1 was obtained at 40 ◦ C.
residual vinyl acetate 51 allowed re-use.
Whilst considerable research has been performed into the Infra-red spectroscopy. Jensen and co-workers79 reported an
development of chiral organocatalysts, biocatalysts afford the early example of online FTIR by mounting a micro reactor into
ultimate atom efficient route enantiomerically pure products. the sample holder of a standard bench-top instrument. More
Using crude enzyme lysates, containing hydroxynitrile lysate, recently online flow cells have been reported, with researchers
Rutjes et al.77 evaluated the synthesis of a series of (S)- coupling them to the outlet of continuous flow reactors to
cyanohydrins in a glass microstructured reactor. Employing an perform real-time analysis of process streams. The ReactIRTM
organic phase containing the aldehyde (plus internal standard) (Mettler Toledo) system has been widely employed in the
and an aqueous solution containing potassium cyanide and labs of Baxendale for the monitoring of short-lived reactive
the enzyme lysate, the effect of a fixed reaction time (12.5 intermediates; illustrating in one example the instruments use
min) on substrate reactivity was investigated under biphasic in the synthesis of butane-2,3-tartrates.80
laminar flow. Using this approach, the authors obtained the
target (S)-cyanohydrins in moderate to high yields, as illustrated Mass spectrometry. Coupling a micro reactor directly to
in Scheme 25, with > 95% ee for aromatic substrates and the spray capillary of a mass spectrometer, Santos and co-
~85% for aliphatic aldehydes. Employing (R)-P. amygdalus, workers81 were able to identify and characterise intermediates
the authors also investigated the synthesis of (R)-cyanohydrins of the Sandmeyer reaction; confirming the mechanism of this
using an automated screening platform to reduce biocatalyst controversial reaction (Scheme 26). Reacting isonitroacetanilide
consumption, an important consideration when selecting an 52 with sulfuric acid 53 in a T-mixer, connected directly with the
appropriate biocatalyst for a specific transformation. ESI-MS instruments source, the authors were able to sample
the reactor effluent allowing samples to be analysed < 2.0 s.
Under these conditions, the authors confirmed that the reaction
proceeded through a previously unidentified cationic species.
In addition to analytical instrumentation, examples of spe-
cialised sensors have been reported within flow reactors as a
means of monitoring changing in conduction which can be
related to chemical conversion.82 Due to the specific nature
of these sensors, they are relatively inexpensive and therefore
demonstrate great potential for the monitoring of continuous
Scheme 25 Biocatalytic synthesis of cyanohydrins, developed under
flow processes.
biphasic flow conditions.
Principle 11. Real time analysis for pollution prevention
A key element of a production process is validation of product

quality. Should part of a process deviate from the set condition
i.e. dosing rate, temperature, it is imperative that the change Scheme 26 Model reaction used to demonstrate the identification of
be picked up and the effect on the process as a whole known. short-lived intermediates using online ESI-MS detection.
With this in mind, process analytics offer the ability to monitor
a process in real-time, readily identifying deviations from the For those that are interested in additional reading on this
production target-allowing operators to more rapidly resolve subject, an excellent review summarising the application of
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in-line monitoring within continuous flow process was recently

published by McMullen and Jensen.83
Principle 12. Inherently safer chemistry for accident prevention

One of the potentially most interesting aspects of flow chemistry
is ability to increase the safety profile of synthetic transforma-
tions through reactor engineering.
Ebrahimi et al.84 investigated the production of unstable
percarboxylic acids which find application as oxidisers in Scheme 27 Illustration of the over-oxidation product obtained for the
bleaches and disinfectants; comparing the safety rating with a hydrogenation of 3-methyl-1-penten-3-ol 54 in batch.
batch process. In addition, the authors explored the possibility
within the laboratory, further increasing operator safety.88 Over

of developing micro processing systems to enable customers to
the past 5 years, the equipment has been used for an array
generate the compounds at the point of use, concluding that
of gas-liquid-solid reductions such as nitro, alkene, alkyne,
this mode of operation would reduce the hazards, costs and
oxime and nitrile, along with debenzylations and deuterations.
environmental burden associated with transportation of these
These examples have served to demonstrate not only increased
unstable materials.
process safety but also dramatic reductions in reaction time,
In addition to speciality chemical production, a niche area
enhanced catalytic lifetimes and increased product selectivity
that has benefited from increased process safety is that of gas-
accessible through flow.89 Scheme 28 illustrates a recent example
liquid reactions, for which access has previously been limited in
utilising the H-cubeTM in the synthesis of 2-phenyl-3-(1H-
the everyday synthetic laboratory.
pyrrol-2-yl)propan-1-amines by Tarleton and McCluskey.90 For
Hydrogenation. Whilst hydrogenations represent one of the a discussion of recent advances in this area of flow chemistry,
most synthetically useful transformations, the hazards asso- please refer to the review article of Kappe and co-workers.91
ciated with the manipulation of H2 gas, and the need to
employ pressure in order to drive reactions, means that stringent
safety precautions are required. To address this, researchers
at the University of Cambridge85 developed a prototype ‘tube
in tube’ reactor which employs a gas-permeable Teflon AF-
2400 tube housed within a PTFE tube. Using this approach,
the authors are able to deliver H2 through the outer tube,
making efficient contact with the fluid flowing through the
inner tube. Using Crabtree’s catalyst or Pd–C, the authors were
able to demonstrate the technique for both homogeneous and
heterogeneous hydrogenations, with the former taking typically
160 s cf . 110–250 min for the latter.
Again employing a capillary based system, this time derived
from a GC column, Kreutzer and co-workers86 demonstrated
the ability to eliminate axial dispersion, utilising gas-liquid
segmented flow to gain access to product selectivities cur- Scheme 28 Illustration of the key hydrogenation steps employed under
rently unobtainable using conventional techniques. Investigating flow conditions for the preparation of synthetically interesting pyrroles.
the hydrogenation of 3-methyl-1-penten-3-ol 54, the authors
employed a Pd impregnated g-Al2 O3 55 wall-coating as the Oxidations. Due to safety concerns associated with the use
catalyst (tunable Pd contents of 0.02–5.7 wt% Pd) and evaluated of gases such as oxygen on a production scale, the chemical
the effect of reaction time on the product distribution. Over industry have in the past missed the opportunity to implement
the course of 1 day, the authors were able to optimise their direct oxidation routes for the preparation of pharmaceutically
system to attain a maximum yield of 78 ± 2% 56, which is interesting materials. By applying the use of flow reactor tech-
in line with previous kinetic modelling studies (Scheme 27).87 nology, researchers are beginning to demonstrate the industrial
In a subsequent experiment, the technique was applied to the advantages associated with this new way of thinking.
hydrogenation of aliphatic azides, due to the pharmaceutical Using a commercially available tube reactor, Hii et al.92
relevance of the resulting amines. evaluated the Ru-catalysed oxidation of benzylic and allylic
When commercially available flow chemistry equipment is alcohols to aldehydes (and ketones) with >99% selectivity. Using
discussed, more often than not the piece of equipment that air (15 bar) as the oxidant in place of O2 57, the authors
comes to mind is the H-cubeTM (Thalesnano, Hungary), the demonstrated no change in reaction selectivity; illustrating a
primary reason for this being that it is an engineered solution tolerance to halides and heteroatoms (S and N). In an extended
to a long-standing laboratory problem. With laboratory safety application, the authors developed a tandem oxidation (90 ◦ C,
being at the forefront of the modern researchers mind, the 1 h) and olefination (3 h) which could be performed without a
development of a dedicated piece of equipment capable of solvent switch (Scheme 29).
performing hydrogenations via the in situ generation of hydrogen Concurrently, Johnson, Yates and Stahl93 reported the devel-
from water was inspired, removing the need for H2 cylinders opment of a continuous flow process for the aerobic oxidation
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developed a series of microstructured flow reactors in which they

are able to safely and efficiently perform direct fluorinations
using F2 .96
In a recent example, Sandford et al.97 reported for the
first time the ability to combine gas-liquid and liquid–liquid
reaction steps in the synthesis of 4-fluoropyrazole derivatives
(Scheme 31). Employing a stream of F2 in N2 59 (10%), the first
step of the reaction was performed in a nickel micro reactor,
enabling the selective fluorination of 2,4-pentanedione 60 to
afford 3-fluoropentane-2,4-dione 61 in quantitative conversion.
Scheme 29 An example of a tandem oxidation and olefination reaction
The output of the nickel reactor was then connected to a T-
performed in toluene. piece where a solution of hydrazine derivative (1.5 eq.) in MeCN,
EtOH or H2 O was mixed and the cyclisation reaction performed
of alcohols using a dilute oxygen source (8% O2 57 in N2 ), in a PTFE tube reactor. Using this approach, the authors were
taking inspiration from the commodity chemicals industry able to obtain the 4-fluoropyrazole derivatives in moderate to
where selective oxidations are performed on large scales. A high yields (66–83%), with product purities determined using
further advantage of the technique developed was that the offline 19 F NMR spectroscopic analysis.
authors operated outside the explosive regime which meant that
decomposition of the Pd catalyst, to Pd metal, was avoided
giving rise to potential recycle of the catalyst.
Ozonolysis. Another underutilised synthetic transformation
is that of ozonolysis whereby alkenes are readily converted into

aldehydes or carboxylic acids. The central reason for this is
the hazards associated with both the handling and disposal of
ozone, discouraging researchers from widely adopting this green
oxidant.
As observed with hydrogenations, laboratory flow equipment
is also commercially available for ozonolyses, with the ozonolysis
of 1-decene to nonanal at -10 ◦ C demonstrated by Gavriilidis
et al.94 Glasnov et al.95 recently demonstrated the high yielding
ozonolysis of styrenes and thioanisole, whereby the methods
developed were suitable for the preparation of up to 10 g of
oxidised material per day (Scheme 30). Scheme 31 Illustration of the selective fluorination step used to
synthesise 4-fluoropyrazoles.
In addition to gas-liquid fluorinations, several authors have

also reported the successful performance of liquid–liquid fluori-
nations employing reagents such as DAST (diethylaminosulfur
trifluoride) 62. The details of a comprehensive study was
reported by Seeberger and co-workers98 who identified that
fluorinations could be performed in a simple PTFE tubular
reactor (volume = 16 ml) by mixing the substrate with DAST
62 at a T-mixer, followed by quenching using NaHCO3 . Scheme
32 illustrates an example of the transformation performed on a
complex alcohol 63 whereby the target fluorinated analogue 64
was obtained in 61% yield as a 6 : 1 mixture of diastereomers.
Whilst from the examples provided it can be seen that there
Scheme 30 Illustration of the selective ozonolysis of thioanisole 58
are some obvious benefits associated with increasing the ease
achieved under flow conditions.
with which flammable gases are generated and manipulated,
the safety profile of liquid–liquid phase reactions has also
By performing such reactions under controlled gas handling
been shown to be increased through the use of flow reactor
and with a suitable quench agent such as triphenyl phosphine,
technology. The following section includes several a examples
ozonolyses have the potential to become another routine addi-
of the techniques applied to the large-scale production of fine
tion to the synthetic chemists toolbox. See section 2.0 for an
chemicals and pharmaceuticals.
example of an ozonloysis performed at the tonne scale.
Fluorinations. Due to the hazards associated with the use of
Production-scale processes
fluorine gas, the direct fluorination of small organic molecules
is not routinely performed in the research lab. Over the past 15 From the examples provided it is clear that flow processing has
years however, the research group at Durham University have the advantage of providing the researcher access to a series of
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Fig. 3 Illustration of Yellow-12 65 an azo-dye produced under flow

conditions.
processing for the production of Yellow-12 65 (Fig. 3); with

improved particle size distribution, glossiness and transparency
among the metrics reported.
Scheme 32 Fluorination of alcohols using DAST 62 under flow Looking towards the production of highly energetic materials,
conditions.
Loebbecke et al.105 described the construction of a micro reaction
previously forbidden transformations using either homemade or plant for the synthesis and downstream processing of nitrate
commercially available platforms. When it comes to production, esters. Owing to the thermallability of the materials, a remote
reactor safety is key and with the foundations of the technology controlled reactor was constructed and the optimisation of
being the facile up-scaling of bench process to production, an undisclosed material performed; enabling the evaluation
it comes as no surprise that a series of large-scale examples of process parameters that would have previously remained
have been reported by the fine chemical and pharmaceutical uninvestigated. Once identified, the optimal processing condi-
industries, with system engineers reporting the fabrication of tions were transferred an automated multi-purpose plant where
both dedicated and flexible installations.99 continuous synthesis of the explosive materials was performed;
incorporating downstream processes such as washing and ex-
Liquid–liquid phase traction. Using this approach the authors were able to synthesise
materials such as trinitroglycerin at a pharmaceutical grade with
In an early example of micro reaction engineering, Kirschneck throughputs of 9 kg h-1 .
and Tekautz,100 reported the installation of a StarLam 3000 Experiencing significant temperature rises (180 to 445 ◦ C)
static micro mixer and tube reactor for the performance of during a key synthetic step in the preparation of a drug candidate
a two-stage industrial reaction. Conventionally performed in 66, researchers at Bristol Myers Squibb proposed a safe process
a 10 m3 batch reactor at a throughput of 1800 kg h-1 , with could be developed through the application of continuous flow.
a reaction time of 4 h, the authors were able to double the Employing a stainless steel tube reactor, heated to 220 ◦ C,
system productivity to 3600 kg h-1 employing a reaction time the authors investigated the effect of reaction time (3.5–17.7
of 60 s and demonstrating significant energy savings. At the min) Claisen re-arrangement of propargyl ether 67 to 6-cyano-
point of reporting, the system had been installed for 18 months 2,2-dimethylchromene 68; observing >96% conversion under all
and had been operated with no operational problems reported. conditions explored (Scheme 33).106
After ten months in use, the mixer was dismantled from the
system and inspection revealed no corrosion; demonstrating
the applicability of micro-structured reactors to fine chemical
production.
de Mello and co-workers101 illustrated at the bench-scale, the
potential of micro reactors for the continuous flow synthesis
of azo-dyes, highlighting that operator safety was increased as
a result of performing the diazotisation in situ. The technique
was subsequently exploited for the transformation of anilines
to aryl chlorides under continuous flow conditions using the
Sandmeyer reaction.102 Building on this initial work, Wille
et al.103 employed a three-stage pilot plant for the synthesis of
an undisclosed azo-dye capable of operating at a throughput of Scheme 33 Illustration of the Claisen re-arrangement which forms a
30 L h-1 . Pennemann and co-workers104 subsequently described key step in the synthesis of the benzopyran-based potassium channel
improvements in pigment quality as a result of employing flow activator 66 of BMS.
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Increasing the reactor volume, the authors readily scaled the

process to afford the benzopyran 68 derivative in 91% yield at a
throughput of 7 kg h-1 . By controlling the exothermicity of the
reaction, the authors were also able to increase the quality of the
product generated, with purities > 96% obtained over four 40 g
batches.
Gas-liquid phase
In addition to the laboratory scale examples of ozonolysis

reactions, Roberge and Nobis107 recently published details
of a tonne-scale ozonolysis reaction performed under flow
conditions. Looking to the conversion of chrysanthemic ester

69, as illustrated in Scheme 34, the authors were able to develop
a safe method of synthesising the corresponding aldehyde 70-a
key intermediate of an insecticide. Utilising a 450 L loop reactor,
the ester was safely reacted with ozone 71 in a process that was
optimised to a production scale of 0.5 tonne day-1 ; with Lonza
demonstrating the manufacture of commercial quantities of the
material.
Scheme 35 Illustration of the synthetic route developed for the
continuous processing of 6-hydroxybuspirone 72.
flow process capable of rapidly preparing pinacol boronate esters

at a maximum product concentration of 0.2 M in moderate to
high yield and > 95% purity; after an offline aqueous extraction
(Scheme 36).
Scheme 34 Oxidation of chrysanthemic ester 69 to the aldehyde 70
which is a key intermediate in the synthesis of an insecticide.
With a view to reducing scaling issues associated with a key

oxidation step, which required 16–24 h at -70 ◦ C in batch,
LaPorte and co-workers108 developed a three-stage continuous
flow process for the synthesis of 6-hydroxybuspirone 72 (Scheme
35). Utilising a pre-formed enolate 73, the authors investigated
its reaction with oxygen 57 at a reactor temperature of -10 ◦ C
and addition of triethylphosphite 74 afforded the target product
72 in 65–70% conversion; which was readily increased to 85–
92% by the addition of a second stream of O2 57; affording a
throughput of 300 g day-1 . Compared to the previous process,
reaction times were reduced to 5 min and large cost savings
harnessed by increasing the reactor temperature by 60 ◦ C for
the oxidation step.
Scheme 36 Illustration of the synthetic route to pinacol boronate esters

Challenges of flow reactor technology
under segmented flow conditions.
Whilst it can be seen from the examples provided that flow
reactor technology is an emerging technique that will benefit Another significant aspect of flow reactor research that is
many synthetic researchers over the years to come, a recent often over-looked by those new to the field is the importance of
publication by Ley and co-workers109 succinctly combines a selecting the correct reactor for the process under investigation.
practical description of the advantages and disadvantages Of the wide number of reactors available, it is imperative that
of continuous flow processing.22 In this report, the authors the user select the correct one for the task at hand, this can
highlight on one hand the processing advantages associated include (but not exhaustively) wetted material type, pumping
with the performance of reactions under cryogenic conditions; mechanism, reactor size and mixer type. This is illustrated in an
without the need for liquid N2 or solid CO2 baths. On the example by Browne et al.110 where the manipulation of slurries
other hand, the authors detail the challenges associated with would be unsuitable in a tube reactor however the hydroiodide
the manipulation of highly corrosive reagents and the foresight salt of N-iodomorpholine 75 (Scheme 37) is efficiently prepared
required in order to prevent precipitation of intermediates and at a throughput of 3.9 kg week-1 ; even in this case however it
products within the reactor coil itself. Once time is spent to must be noted that homogeneous solutions were required to
overcome these technical challenges, the result is a segmented dose the reagents due to the pumping technology employed.
View Online
22 C. Wiles and P. Watts, Micro Reaction Technology in Organic

Synthesis, 2011, CRC-Press.
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Green Chemistry Dynamic Article Links

Cite this: Green Chem., 2012, 14, 38

www.rsc.org/greenchem TUTORIAL REVIEW

Introduction tors have signiﬁcant processing advantages including improved

synthesis, whereby conventional synthetic procedures rely on

the production efﬁciency by three orders of magnitude obtaining

Scheme 2 Hydrogenation of ethylcinnamate 4 under solvent-free

When considering the removal of a reaction solvent for use

can be readily evaluated. Once identiﬁed, the optimised reaction

Principle 2. Atom economy

Improved atom economy has also been demonstrated for

precursors into the target products. To obtain high conversions

Asymmetric synthesis. Another way of increasing the efﬁ-

Scheme 7 General schematic illustrating the conditions used for the

Employing a two feed Sulﬁnert tube reactor, the authors

quantitative reduction to afford (S)-3-chloro-1-phenyl-propanol

acid catalyst, affording a means of efﬁciently recycling the

products from the toluene phase; enabling the catalyst solution

Hodge et al.31 demonstrated the use of a polymer-supported

Fig. 1 Polymer-supported cinchonidine derivative 22 shown to pro-

Principle 5. Safer solvents and auxilliaries

methoxyphenyl)amino)benzoate 32 compared with 10% in an

Principle 6: Design for energy efﬁciency

Over the past decade it has become widely accepted in academic

method of heating. When considering large scale reactors,

by conventional means affords the same product therefore ﬂow

complex architectures from relatively simple precursors, the

lack of commercially available equipment and the stigma of

ated and reacted under ﬂow conditions at temperatures greater

Scheme 16 Illustration of the intramolecular [2+2] and [2+3] pho-

lamps (l = 350 nm) as a light source, the authors investigated

Scheme 18 Sequential lithiation and Murashasi couplings performed

at different temperatures under ﬂow conditions.

Under batch conditions, the authors formed the organo-

5-(chloromethyl)furfural 37 from renewable feedstocks (Scheme

Scheme 19 Use of renewable feedstocks for the synthesis of value-

As an extension, the authors also reported the ability to

Scheme 20 Synthesis of levulinic acid 39 from D-fructose 40 under ﬂow

Scheme 23 Decarboxylative biaryl synthesis and the accompanying

protodecarboxylation by-product 46.

channel devices, opening up the possibility to design and

Researchers have however shown that by employing continuous

issues and divert out of speciﬁcation process streams before

Raman spectrsocopy. To demonstrate the synthetic utility of

the Raman spectroscopy, Nordon and Mozharov78 coupled a

Principle 11. Real time analysis for pollution prevention

A key element of a production process is validation of product

in-line monitoring within continuous ﬂow process was recently

Principle 12. Inherently safer chemistry for accident prevention

within the laboratory, further increasing operator safety.88 Over

developed a series of microstructured ﬂow reactors in which they

is that of ozonolysis whereby alkenes are readily converted into

In addition to gas-liquid ﬂuorinations, several authors have

Fig. 3 Illustration of Yellow-12 65 an azo-dye produced under ﬂow

processing for the production of Yellow-12 65 (Fig. 3); with

Increasing the reactor volume, the authors readily scaled the

In addition to the laboratory scale examples of ozonolysis

conditions. Looking to the conversion of chrysanthemic ester