Recent Advances in Micro Reaction Technology: Chem. Commun

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FEATURE ARTICLE
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Recent advances in micro reaction technology

Charlotte Wiles*a and Paul Watts*ab
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 briey
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 fteen 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 ow reactors.
The scale that reactions are performed on is key to the
advantages of this technology, aording access to a series of
unique properties which are unattainable through the use of
conventional batch reactors. The rst of these advantages is
the rapid mixing that occurs due to the short diusion
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 ecient thermal transfer, with heat transfer
a
Chemtrix BV, Burgemeester Lemmensstraat 358, 6163 JT, Geleen,

The Netherlands. E-mail: c.wiles@chemtrix.com;
Tel: +44 (0)1482 466459
b
The Department of Chemistry, The University of Hull,
Cottingham Road, HU6 7RX, UK. E-mail: p.watts@hull.ac.uk;
Tel: +44 (0)1482 465471
Dr Charlotte Wiles is the Chief Technology Ocer 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 scientic 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 ow reactors, systems and peripheral equipment.
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Chem. Commun., 2011, 47, 65126535
coecients 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 eects 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 ow 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 intensied due to rapid mixing and ecient thermal
management and slow reactions can be improved by employing
higher temperatures and pressures when compared to batch
processes.9 Opening up the processing window10,11 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 eld 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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The Royal Society of Chemistry 2011
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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 exible enough to respond
to changes in the market or supply chain, examples of which
will be given later.
For those new to the eld one of the most frequently ask
questions about micro reactors is dont 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 solutionthis 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,
purications 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 ow conditions as a means of increasing
the process safety associated with this transformation.15,16
Investigating the exothermic nitration of 2-ethylhexanol to
aord 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 oine 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
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Scheme 1 Synthesis of a pharmaceutically interesting intermediate

via continuous ow 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 ow 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 ow reactor suitable for the
synthesis of 1-(azidomethyl)-3,5-bis(triuoromethyl)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 identied 90 1C as the optimal temperature
at a residence time of 20 min; aording 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(triuoromethyl)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 eect of reaction time (530 s) and
temperature (6080 1C) on the azidation of alkyl halides, using
HCl in EtOAc/acetone as a quench solvent. Using this
approach, the authors identied 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 ow synthesis of

carbamoyl azides.
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whereby subsequent thermal rearrangement of the isocyanate 4

in the presence of IN3 3 aorded 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, aording the target products in isolated
yields of 21 to 44%.
1.3
Fluorinations
Owing to the increased biological uptake of pharmaceutical

agents containing uorine substituents, ecient synthetic
methods are sought for the introduction of uorine into small
organic compounds. A recent example reported by Seeberger
et al.22 demonstrated the ecient synthesis of uorinated
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
uorinated compound in yields ranging from 40 to 100%
(Scheme 3). Subsequently, Baumann et al.23 demonstrated
the tolerance of their ow methodology towards vinyl iodides,
ethers and epoxides, with electron decient aldehydes readily
uorinated 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 ow
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 ow conditions.
1.5 Cycloadditions
Due to the ease with which complex scaolds can be prepared,
and diversity introduced, cycloadditions have been widely studied
under ow conditions. Using a combination of ow reactors and
the H-cubes system, Baumann and co-workers25 demonstrated
the generation of azomethine ylides and their dipolar cycloaddition reaction to aord a series of 3-nitropyrrolidines 10
(60120 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 ow disk (MFD) containing
eight parallel reaction channels, each with a dimension of
180220 mm, Mackley and co-workers26 investigated the
DielsAlder reaction of maleic anhydride 11 and isoprene 12
to aord the cycloadduct 3a,5,7a-trimethyl-3a,4,7,7a-tetrahydro-isobenzofuran-1,3-dione 13 owing to its potential as a
pharmaceutically interesting scaold (Scheme 6).
Scheme 5 Illustration of the continuous ow synthesis of

3-nitropyrrolidines and their subsequent hydrogenation.
Scheme 3 Illustration of the

performed in a PTFE ow reactor.
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DAST-mediated
Chem. Commun., 2011, 47, 65126535
uorinations
Scheme 6 Illustration of the DielsAlder reaction performed in a

MFD reactor.
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Scheme 7 Model reaction used to demonstrate the DielsAlder

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 aord 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 ow.
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 aord
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 identied 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 aorded ecient mixing of
the biphasic reactant streams and represents a scalable technique
for the production of such cyclic intermediates.
Focusing on the hetero DielsAlder reaction of nitrosodienophiles to aord 3,6-dihydro-1,2-oxazine scaolds,
Stevens and co-workers30 investigated the advantages associated
with performing the reaction under continuous ow conditions.
Using the reaction of 2-nitrosotoluene 17 and cyclohexadiene 18,
the authors rstly investigated the eect 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 aord the respective cycloadduct in high yield;
without the need for additives or metal catalysts (Scheme 8b).
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Scheme 8 Schematic illustrating (a) the hetero DielsAlder 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 SwernMoatt 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 ow 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 ow, with ecient downstream
processing of MnO2 slurries. Reporting the oxidation of
alcohols and aldehydes to carboxylic acids in a FEP tubular
ow reactor (volume = 14 ml), the authors were able to
develop a scalable technique aording the target acids in high
to excellent yield (7198%) 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 ow.
Scheme 13 Schematic illustrating a homogeneous Suzuki coupling

performed using a glass coil reactor.
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
ow 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 ow 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 (0.30.4 M) and 10 mol% LiOtBu 23
through a tube reactor at 180 1C (160 bar), for a xed period
of time, prior to passing the reaction mixture through a
scavenger cartridge containing a tosyl-functionalised resin.
Using this approach, the authors identied 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 CC bond forming reactions form

one of the most widely studied classes of reaction that have
been performed under continuous ow conditions, with
Scheme 12 Illustration of the transition metal free reduction of

ketones performed under continuous ow conditions.
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SuzukiMiyaura 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 ow rate of 0.25 ml min 1 (residence time = 8 min) and a
reactor temperature of 140 1C, aording the coupling product
25 in 84% yield. Repeating the reaction using conventional
heating, analogous results were obtained conrming that this
was not a microwave eect.
Heck coupling. Using a PTFE tube reactor, Wirth et al.44
evaluated the ecacy 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
ow conditions investigated, aording methyl cinnamate 31 in
62% yield. The authors subsequently investigated the eect of
inserting peruorodecalin into the reaction stream, aording a
biphasic droplet system, which resulted in a 29% increase in
yield; attributed to an increase in mixing eciency 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 ow 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 4286% for thirteen vinyl derivatives
depending on the boronic acid under investigation.
Scheme 14 Illustration of the Heck reaction used to probe the

ecacy of catalysts under ow conditions.
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Scheme 15 General reaction scheme illustrating the vinylation of aryl

boronic acids under ow 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 ow
reactions. Using the Sonogashira coupling reaction as a model
(Scheme 16) the authors screened reaction temperature
(70110 1C) and time (2060 min), using oine 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, aord 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
aording 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 ow conditions,
Yoshida and co-workers47 recently extended their investigations
to incorporate lithiation and Murahasi couplings in a single
uidic 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 ow reactors, the authors were able to rapidly
develop a ow process for the cross-coupling reaction illustrated
in Scheme 17. The reactor comprised of three micromixers,
Scheme 17 Illustration of the HLi exchange and subsequent

Murahasi coupling reactions performed under ow conditions.
connected to a series of tube reactors (internal diameter =

1000 mm) maintained at dierent temperatures using
thermostatted baths.
In the rst 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 ArLi
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 eect 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 puried using
a combination of ash 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; aording 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 HLi 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 ow conditions include the Stille
coupling48 and the BuchwaldHartwig reaction,49 both
of which have shown increased purity proles as a result of
employing ow reactor technology.
1.9 Esterications
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

signicant 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 identied that it is possible to
perform reactions in the absence of catalysts and/or promoters.
One such example that demonstrates the novel conditions
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Scheme 20 Schematic illustrating the reaction pathway used for the

synthesis of 5-hydroxymethylfurfural 48 under ow conditions.
Scheme 18 Illustration of the (a) esterication and (b) transesterication

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 ow conditions.
accessible within ow reactors was the catalyst-free esterication

(Scheme 18a)/transesterication (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 transesterication, 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 eect of reactor temperature
(085 1C) with a xed 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 eorts towards increasing the cleanliness and eciency 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
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Chem. Commun., 2011, 47, 65126535
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 7681% selectivity;
depending on the wt% of fructose 49 employed (1050%).
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 ow cyclodehydrations, Bagley
and co-workers53 reported the ability to take reactions from
commercial micro reactors to mesoscale production using a
microwave ow reactor. Using the BohlmannRahtz 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 solventsnding a
mixture of toluene and AcOH (5 : 1) aorded 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, lled 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 aorded
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 ow reactor for the biomimetic
reductive amination of uorinated 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 uorinated 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
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Scheme 24 Thermal rearrangement of substituted furfuryl alcohols

performed under ow 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
(8795%)
however
increases in ee were obtained using the ow protocol
(9095% cf. 7797%), an observation attributed to the ease
of base removal and product isolation.
1.12
Rearrangements
With the advent of commercially available ow equipment

with wide operating windows, the number of atom ecient
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 aorded 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 eect 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
reux. To conrm 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. Gratied 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 ow conditions (240 1C),
using the X-Cube ashTM (ThalesNano) to investigate the
eect 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 ow

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 ow 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 ow 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).
NewmanKwart. Using the NewmanKwart rearrangement,
researchers at Eli Lilly reported the ability to synthesise an
O-thiocarbamate 55, from a bisaryl-phenol 56 under ow
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 7077 bar of pressure at 300 1C, the authors
employed a residence time of 7.6 min (ow rate = 7.5 ml min 1)
which aorded 99.1% conversion of 56 to 55 with 0.6%
residual phenol 56 and 0.3% of an unknown impurity. Distilling
o the DME and addition of heptane as an antisolvent was
found to initiate crystallisation aording 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 ow radiosyntheses, Wahab and co-workers59
evaluated the Fischer indolisation under ow 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 1.92.3 mg h 1.
Using a continuous ow microwave reactor, Bagley and
co-workers60 were able to indolise phenyl hydrazine 58 and
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Scheme 27 Illustration of the key steps employed in the synthesis of

6,6,5-congured spiropiperidines.
Scheme 25 Schematic illustrating the NewmanKwart rearrangement performed under ow 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
aord 6,6,5-congured 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 ow processes, the

number of photochemical transformations performed under
ow 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 diastereodierentiation.66
Employing standard commercially available light sources,
Oelgemoller 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

ow conditions.
cyclohexanone 59 to aord 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 ow 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 ow
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Scheme 28 Schematic illustrating the addition of phenylacetates to

phthalimide 62 and dehydration to aord 3-arylmethyleneisoindolin1-ones 63.
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conventional photochemistry, including the formation of the

product as a potassium salt and signicant 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 buer, 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, aording high selectivity towards the
E-isomer.
Employing a Xenon lamp (500 W, 280 nm) and an in-house
fabricated glass : ionomer lm 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 aorded 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 oer 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 eciency
compared to the PaternoBuchi 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 aord 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
eciency 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, aording an array of substituted
cyclohexanone derivatives.
Other examples from the group include the black light
promoted selective halogenation of cycloalkenes, reporting
the ecient 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 ow
photochemistry, Freitag and co-workers71 have reported the
construction of multipass ow reactors as a means of increasing
photochemical eciency 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 PaternoBuchi 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 ow 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 ecient tool

for the formation of complex molecular architectures. The
techniques use has however been somewhat limited to small
scale syntheses due to the diculties associated with successful
scale-up. Using ow cells, several authors have begun the
task of addressing the physical problems that have limited
application of this technology, namely an inhomogeneous
electric eld 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 ow chemistry is ecient
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
ow for the formation of CC bonds (Fig. 1).
Subsequently, Atobe and co-workers82 developed a ow
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
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In an extension to this, the authors investigated the

reductive coupling of benzyl bromide with a series of olens,
to aord the CC 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
signicantly transform how synthetic reactions are performed;
opening up, for the rst time, the ability to apply electrochemistry in production scenarios.
Fig. 1 Illustration of the reactor conguration used for the electrochemical generation of cations under continuous ow.
streams. This approach was found to be particularly successful

as oxidation of the nucleophile was not observed. Selecting
2,2,2-triuoroethanol as the solvent, the authors were able to
oxidise methyl pyrrolidinecarboxylate and subsequently react
the cation with allyltrimethylsilane to aord 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 FriedelCrafts alkylation
of dimethoxy-substituted aromatics and allylsilanes; observing
that an improved product distribution could be obtained
under ow 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 ow 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.8587 One such example was the electrochemical
reduction of 4-nitrobenzyl bromide 67 to aord 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 ow.
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 benet from continuous processing is that of multi-phase
reactions. Be it liquidliquid (ll), gasliquid (gl) (Section 6.1),
liquidsolid (ls) (Sections 4.14.3) or gasliquidsolid (gls)
(Section 6.2), numerous permutations have been demonstrated
under continuous ow 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 ow
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 purication will still be
required to isolate the target compound.
In addition to those examples of click chemistry using
homogeneous catalysts under ow conditions, examples have
also been performed using copper-in-charcoal in packed-bed
reactors and even copper tube reactors. Employing a CuC as
a catalyst, Fuchs and Kappe et al.93 were able to gain
mechanistic insight into copper(I)-catalysed azidealkyne
cycloadditions by performing reactions within a continuous
ow reactor (X-Cubes, ThalesNano). Using the reaction
between benzyl azide and phenyl acetylene as a model, the
Scheme 33 Indigo 69 synthesis under continuous ow.
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authors investigated the eect of reaction time and temperature

on the triazole synthesis, nding that a 12 s residence time
within the packed bed and a temperature of 170 1C aorded
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 quantied, 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 ow 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 cycloadditionsshowing
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-lm
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 lm
which upon coating with Au, aord 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 ow rate of 25 ml min 1. Under
microwave irradiation, the authors observed 90% conversion
Scheme 34 Illustration of a typical ow 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 aord comparable
conversions. To identify if this was a microwave or ow eect,
the reaction was repeated using an oil bath (190 1C), whereby
only 14% conversion was obtained. The authors postulate that
this eect 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 eect on
the yield of the reaction (4078%). Performing the reactions on
700 ml slugs of reactants, the authors were able to generate
7080 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 SuzukiMiyaura 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 eld
(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 ow. Using a working
solution comprising of the olen 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 eect 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 eective 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 ow reactors is the Knoevenagel condensation
(Scheme 37), with authors demonstrating the use of packed-beds
with pressure-driven ow98 and electroosmotic ow,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 ow conditions.
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Scheme 38 Continuous ow 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 lled cartridges, the H-cubes has
been widely reported throughout the scientic literature for
continuous ow 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 ecient exploration of immobilised biocatalysts. Using
commercially available Novozyme 435 immobilised lipase
biocatalyst, Woodcock et al.105 reported the ow 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 modied
surface was measured spectrophotometrically using the
hydrolysis of p-nitrophenyl butyrate which conrmed 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 ow rate
of 1 ml min 1, aording a residence time of 38 s. The reaction
products were collected and periodically analysed oine using
GC-MS. Investigating the eect of acid to alcohol ratio,
the authors identied 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 ureahydrogen peroxide
78 or H2O2 as the oxidant. When compared to a batch process
the ow 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 ow 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 aord 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 ow 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 ow conditions.
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Scheme 42 Biocatalytic enantioselective hydrolysis performed under

continuous ow 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 eective 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 ow 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 solidliquid 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 aord imidazopyridazines as
Scheme 43 General synthetic protocol employed for the synthesis of

the imidazopyridazine scaold under ow 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 ecient
oxidising agent which readily converts alcohols to their
respective carboxylic acid. Employing the reagent under ow
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 ow reactor.
Using this approach, fteen 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 ow reactions
An early example of multi-step reactions performed under

continuous ow conditions was the Ciprooxacin 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 ow 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
FriedelCrafts acylation, followed by a 1,2-aryl migration and
nally an ester hydrolysis to furnish the target compound 86 in
68% yield and 96% purity. Purication 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 ow synthesis of Ciprooxacin 84 and its analogues.
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Scheme 45 Illustration of the synthesis of Efaproxiral 85 performed

under ow 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 ow synthesis of Ibuprofen 86.
continuous ow 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 ow reactions in series,
Venturoni and co-workers114 were able to demonstrate the
synthesis of Casein Kinase I inhibitors. To achieve this,
the authors rstly performed the arylation of a picoline
derivative using n-BuLi 38 and a series of esters. With this
material in hand, the second ow 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
aord an imidazo[1,2-b]pyridazine (5282% yield). The
nal step of the reaction displacement of the chlorine to
introduce structural diversity was achieved by reaction of the
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Chem. Commun., 2011, 47, 65126535
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 ne chemical or
pharmaceutical industries, the technology has also been
applied to polymerisations120 giving rise to well-dened
organic polymers. Frey et al.121 reported the use of a
microstructured reactor to perform living anionic polymerisation
to aord 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, aording an array of end
functionalised polystyrenes.
By varying the mixer temperature (2560 1C) and the
residence time (6 to 12 s), the authors were able to evaluate
Fig. 2 Illustration of the Casein Kinase I inhibitor scaold

synthesised under ow conditions.
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Scheme 49 Illustration of the model reaction used to demonstrate the

high-throughput screening of catalysts using online UHPLC.
Fig. 3 Illustration of the termination agents used in the ow synthesis

of end functionalised polystyrenes.
the eect on molecular weight and the molecular weight

distribution, enabling the realisation of customised polystyrenes
with pre-dened 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 ow 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
SwernMoatt oxidation. Investigating the eect 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 identied optimal conditions, the authors were able to
synthesise the oxidation product in 96% yield.
Selecting the Heck reaction of 4-chlorobenzotriuoride 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 NelderMead 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-chlorobenzouoride 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 lled

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
eciency 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
catalystsfocussing on the evaluation of catalyst ecacy
towards the FriedelCrafts 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 aording 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 eect 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 identication of Er(OTf)3 as the most
ecient 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 eective 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 uorophilic modication 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, aording 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 articial lipid bilayers and study diusion processes.
In addition, the strategic positioning of reagent containing
droplets has the potential to aord a method for the controlled
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performance of discrete chemical reactions further increasing

the number and type of addressable reactions screened under
ow 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 uidic
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

Gasliquid reactions
In addition to enabling access to less conventional operating

conditions, the use of continuous ow reactor technology has
also opened up the availability of gasliquid reactions to the
synthetic chemist.131 In a recent communication, OBrien
et al.132 reported the construction of a gasliquid reactor for
the ozonolysis of alkenes comprising of a semi-permeable tube
(Teon 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 ow rate equivalent to a 1 h reaction
time, and the vessel lled with ozone 91. Upon exiting the
reactor, the reaction mixture was quenched using polymersupported triphenylphosphine in MeOH and the target
compounds isolated by ltration and solvent evaporation
after testing with peroxide strips. The crude materials were
subsequently puried by silica gel chromatography to aord
the target ketones in moderate to high yield (57 to 95%).
Using a falling-lm 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 siliconglass 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 eciently 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 ecient method for the synthesis of isocyanates.
Using pressures of o1 MPa, the authors were able to exploit the
ecient mass transfer obtained at the gasliquid interface to
perform the reductive carbonylation. Other examples of gas
liquid reactions include chlorinations,137 selective uorinations138
and hydrogenations.139
6.2 Gasliquidsolid reactions
As observed for liquidsolid reactions, gasliquidsolid
reactions can also be performed under ow conditions
employing the solid reagent or catalyst in a packed-bed,140
as a monolith (solgels) or as a wall-coat141 expanding the
processing conditions available to the researcher.
7.0.
Scheme 50 Illustration of the continuous ow synthesis of a Vitamin

D precursor.
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Chem. Commun., 2011, 47, 65126535
Inorganic chemistry
In addition to the dramatic uptake of the technology in the

area of synthetic chemistry, the past ve years has seen
growth in the area of inorganic chemistry142 with researchers
focussing on the preparation of metals,143 metal oxides and
semiconductors.
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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 aect
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 480510 nm (bluegreen) and by increasing the reactor
temperature (300 1C), time (60 s) and additive proportion
(20 wt%) the wavelength could be tuned to 570600 nm
(orange). By embedding a series of replicate within their
study, the authors were able to conrm that the system
was reproducible for the same stock solution; with slight
variations observed when dierent raw material batches
were used.
Employing droplet based ow, 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
ow conditions, a large proportion of work has been undertaken into the continuous ow preparation of metal oxide
nanoparticles. In an early example, Jensen and co-workers146
evaluated the eect of reactor design, ow velocity, reaction
time and ow type on the formation of SiO2 particles using the
Stober process. Comparing segmented ow with laminar ow,
the authors were able to conclude that segmented ow oered
a facile means of obtaining narrow particle size distributions
when compared with laminar ow; whereby axial dispersion
led to a large size variation.
The ow synthesis of TiO2 nanoparticles was also studied by
Wang and co-workers147 via the hydrolysis and condensation
of titanium tetraisopropoxide. By varying the ow rate of two
reactant solutions, the authors were able to generate a stable
laminar interface at which particle growth occurred. Collecting the nanoparticles oine 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 ow, 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 510 nm
particles with a narrow particle size distribution and a high
saturation magnetisation. Employing a microwave ow
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 ow
chemistry also has processing advantages to oer the inorganic
chemist.
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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 ecient 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 eciencies.151 With continuous ow 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 rst time has the
ability to generate synthetic methodology that can be directly
applied to production should the material need to be taken
forward within industryopening 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 ow 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
ve. Devising a manifold with accurate ow 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
PaalKnorr synthesis under continuous ow (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,
sucient to meet the current market demands for the immunoactivating agent (Scheme 54).
Scheme 53 Illustration of the PaalKnorr 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 ow

synthesis of Pristane 95.
Scheme 55 Illustration of the model reaction used to probe reaction

kinetics under ow conditions.
Lowe 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 triate. 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,
tted 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 Lowe
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 oine 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 microow 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 ow 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
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Chem. Commun., 2011, 47, 65126535
approach, the authors were able to safely investigate previously

unexplored reaction conditions. Once identied, the optimal
conditions were employed in conjunction with downstream
processing which included washing and extraction, to aord
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 rst 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 unaected 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 (39 wt%)
catalysed reaction of acetic acid and hydrogen peroxide, the
authors identied an optimum reaction time of 300 s aorded
ecient production of peracetic acid at a throughput of 10 kg h 1.
Looking to the re 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 ow processes in
greater detail than conventional studies where focus has been
on product purity and system throughput.
9.0.
Continuous ow purications
Whilst from the examples provided it can be seen that there are
obvious advantages associated with the performance of
reactions under continuous ow, 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 ow 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 purication techniques
being liquidliquid extraction (LLE), numerous authors have
reported the performance of LLEs under continuous ow
utilising co-owing or counter-ow immiscible phases.163165
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
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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 ow conditions.
catalysis of benzyl chloride 100 with sodium sulde 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 sulde 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 eciency 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 ow. 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 liquidliquid extraction eciencies 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 ndings that the addition of an inert gas phase
further increases separation eciencies, with large capacity
reactors able to process 10 000 metric ton y 1 of material.
In addition to the use of co-owing or counter-current
ow streams, authors have also demonstrated the ecient
extraction of ions using droplet-based ow.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
ow by varying the wetting properties of the membrane.
Using this technology as part of a continuous ow 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 gasliquid
streams.174
Fluorous solvents and tags have also been exploited within
ow systems as a means of rapidly isolating and recycling
catalytic material. An example of the former is the aqueous
SuzukiMiyaura reaction performed by Theberge et al.175 and
the latter was used by Goto and Mizuno et al.176 to synthesise
and extract carbohydrates.
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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 purications

An area that has grown rapidly over the past 3 years is that of
solid-assisted purications whereby solid-supported scavenger
resins are packed into columns, positioned strategically
throughout the ow 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 ow synthesis with in-line
purication 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 ow stream was then
diverted through a scavenger column containing Amberlyst-15
107 and QuadraPure benzylamine which aorded 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 purication of a-ketoesters,182 and
peptides.183,184
There remains however some scepticism in the eld as to the
synthetic utility of scavengers when looking towards the use of
continuous ow methodology as a tool for process intensication;
however on a lab-scale the technique demonstrates a facile
method for the purication of materials on the gram-scale.
9.2 Re-crystallisation and precipitation
In the nal stages of a synthesis, one of the most ecient
methods of product purication is recrystallisation or
precipitation of the material from a solution; with this in
mind, several research groups have successfully developed
continuous ow 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 ow crystallisations have a key role
to play in pharmaceutical production as the ease with which
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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 baed crystalliser (COBC) reactor for
the performance of both nucleation and crystal growth.
Harnessing the excellent heat transfer capacity of ow
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 ow 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
aording novel vehicles for drug delivery.188
9.3
Continuous ow detection techniques
An important part of the ongoing eorts towards the

implementation of continuous ow 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
ow 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 ow 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
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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 ow
processing is being implemented at research, process and
production stages by many pharmaceutical and ne chemical
companies. With the advent of commercially available ow
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-congurable
processing plants, stepping away from the dedicated reactor
mindset that dominated technological developments made
during the elds 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 oer the chemist at all stages of research, development
and production.
Micro-distillation
Owing to the industrial reliance on distillations for the

purication of raw materials and nal products, researchers
have started to evaluate the possibility of developing microscale distillation units capable of being incorporated into
continuous ow 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 rectication
of water and MeOH mixtures.
9.4
10.0. Outlook
Chem. Commun., 2011, 47, 65126535
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Chem. Commun., 2011, 47, 65126535
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Recent Advances in Micro Reaction Technology: Chem. Commun

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Cite this: Chem. Commun., 2011, 47, 65126535

Recent advances in micro reaction technology

Chemtrix BV, Burgemeester Lemmensstraat 358, 6163 JT, Geleen,

Dr Charlotte Wiles is the Chief Technology Ocer at Chemtrix

Chem. Commun., 2011, 47, 65126535

coecients of the order of 6 104 W m 2 K 1 compared with

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Whilst the low system volumes can be perceived as a

The exothermic and corrosive nature of nitration reactions

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Scheme 1 Synthesis of a pharmaceutically interesting intermediate

methodology. Operating eight reactors in parallel enabled the

Scheme 2 Illustration of the protocol used for the ow synthesis of

Chem. Commun., 2011, 47, 65126535

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whereby subsequent thermal rearrangement of the isocyanate 4

Owing to the increased biological uptake of pharmaceutical

Employing a commercially available tubular reactor (Vapourtec),

Scheme 4 Synthetic approach used in the synthesis of (rac)-Tramadol

Scheme 5 Illustration of the continuous ow synthesis of

Scheme 3 Illustration of the

Chem. Commun., 2011, 47, 65126535

Scheme 6 Illustration of the DielsAlder reaction performed in a

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Scheme 7 Model reaction used to demonstrate the DielsAlder

Employing MeCN as the reaction solvent, the authors

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Scheme 8 Schematic illustrating (a) the hetero DielsAlder reaction

Schematic illustrating the oxidation of testosterone 19.

Chem. Commun., 2011, 47, 65126535

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Scheme 10 Illustration of the KMnO4 20 promoted Nef oxidation

Scheme 13 Schematic illustrating a homogeneous Suzuki coupling

a recent review by Parmar and co-workers42 providing

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

Where more selective oxidations are required, oxidants such

Unlike oxidations, until recently few reductions had been

Transition metal catalysed CC bond forming reactions form

Scheme 12 Illustration of the transition metal free reduction of

Chem. Commun., 2011, 47, 65126535

SuzukiMiyaura coupling. Employing microwave heating,

Scheme 14 Illustration of the Heck reaction used to probe the

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Scheme 15 General reaction scheme illustrating the vinylation of aryl

Sonogashira coupling. In a recent example, Fukuyama

Scheme 17 Illustration of the HLi exchange and subsequent

connected to a series of tube reactors (internal diameter =

Scheme 16 Schematic of the Sonogashira coupling reaction used to

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Kappe and co-workers50 have over the years performed a

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Scheme 20 Schematic illustrating the reaction pathway used for the

Scheme 18 Illustration of the (a) esterication and (b) transesterication

Scheme 19 Illustration of the in situ preparation of diazomethane 46

accessible within ow reactors was the catalyst-free esterication

In eorts towards increasing the cleanliness and eciency of

Chem. Commun., 2011, 47, 65126535

of a glass micro reactor (dimensions = 1200 mm 300 cm)