JOURNAL OF CHEMICAL RESEARCH 2012 APRIL, 181–193 REVIEW 181

Micro reactors, flow reactors and continuous flow synthesis

Paul Wattsa* and Charlotte Wilesb
a
Department of Chemistry, University of Hull, Cottingham Road, Hull HU6 7RX, UK
b
Chemtrix BV, Burgemeester Lemmensstraat 358, 6163 JT, Geleen, The Netherlands

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 90 papers, and he regularly contributes to the field by way of invited book
chapters, review articles, and keynote lecturers on the subject of micro reaction technology in organic synthesis.
Dr Charlotte Wiles is the Chief Technology Officer at Chemtrix BV, and has been actively researching within the area
of micro reaction technology for 10 years, starting with a PhD entitled Micro reactors in organic chemistry, which she
obtained from The University of Hull in 2003. In the past decade, she has authored many scientific papers and review
articles, recently co-authoring a book on the subject of micro reaction technology in organic synthesis. More recently,
she has tailored her experience to the development and evaluation of commercially available continuous flow
reactors, systems and peripheral equipment.

1. Introduction 4. Flow processing in production

2. Micro reactors 5. Conclusions
3. Meso and flow reactors 6. References

This review article explains the advantages of micro reactors and flow reactors as tools for conducting organic
synthesis and describes how the technology may be used in research and development as well as production.
A selection of examples is taken from the literature to illustrate how micro reactors enables chemists to perform their
reactions more efficiently than when using batch processes.

Keywords: micro reactor, flow reactor, continuous synthesis, scale-up, photochemistry, electrochemistry, process chemistry

1. Introduction
Organic chemists have traditionally used batch reactors (test
tubes, round-bottomed flasks, stirred tanks, etc.) to conduct all
synthetic organic chemistry. Although automated equipment,
such as combinatorial synthesisers for example, has started to
be used in modern research laboratories, fundamentally the
reaction is still conducted in batch mode. However, from a
process chemistry perspective, a major problem observed
with conventional batch technology is the failure to scale-up
successful reactions; this is particularly problematic for
highly exothermic processes. In industry, this often means
redevelopment of synthetic routes on several occasions when
transferring from laboratory, to pilot scale and then finally
to production. This is a both a time consuming and costly
process.
More recently, the chemistry community has introduced
‘continuous flow’ synthesis as an alternative to batch process-
ing; however it should be noted that the petrochemical industry
has always manufactured using continuous flow, albeit on a
substantially larger scale. A key advantage of flow reactor
technology for the organic chemist is the ability to control
reaction parameters very accurately. For instance, the regula-
tion of temperature and concentration is crucial in maintaining
control over a reaction, not only to ensure selective product
formation, but also from a safety perspective. Due to the excel-
lent heat and mass transfer, and predictable flow properties
exhibited by flow reactors a high degree of reaction control is
attainable. For example, in traditional large-scale batch reactor
vessels, fluctuations in temperature are difficult to correct, as
any alterations made take time to have an effect on the reactor
as a whole; in comparison, changes are observed almost instan-
taneously within flow reactors. Along with increasing the rate
of mixing, decreasing the channel diameter of the reactor
results in an inherently high surface to volume ratio, allowing
rapid dissipation of any heat generated over the course of a
reaction.
* Correspondent. E-mail: P.Watts@hull.ac.uk
The original term used to describe this research field was
‘micro reactor technology’ (MRT). However, for newcomers
this does not clearly enable one to assess what type of equip-
ment is best suited for their application. Consequently this
review is split into sections on micro reactors, meso and flow
reactors and finally production systems, to illustrate how MRT
may be used in different applications ranging from small scale
synthesis as well as research and development, all the way to
production. In each case selected chemical examples are used
to illustrate the advantages of the technology; more detailed
information is cited in other review articles1–3 and books.4–6
2. Micro reactors
Micro reactors are most commonly regarded as planar devices
having channel dimensions in the range of a few hundred
microns and may be fabricated in a number of materials such
as silicon, quartz, glass, metals and polymers. They are often
termed ‘lab-on-a-chip’ devices and have volumes ranging from
nanolitres to microlitres. Consequently these are mostly used
in small scale synthesis and screening processes.
The most important consideration for synthetic applications
is chemical compatibility of the reagents and solvents with the
reactor material and consequently glass reactors are the most
widely reported. The second most common material for reac-
tors of this type is silicon, or a mixture of silicon and glass.1
Figure 1 shows a photograph of a micro reactor manufactured
by Chemtrix BV (Netherlands); other suppliers of similar glass
reactors include Future Chemistry (Netherlands), Mikroglas
(Germany) and Syrris (UK).
One advantage of these particular reactors is that very rapid
mixing occurs, due to the short diffusion distances within
such devices;7,8 as such it is often reported that high purity
products can be obtained because of suppression of side
reactions which occur due to poor mixing in batch reactors.9
The second advantage of micro reactors is the very efficient
thermal transfer, with heat transfer coefficients of the order
of 60,000 W m−2 K−1 compared with 100s W m−2 K−1 for batch
182 JOURNAL OF CHEMICAL RESEARCH 2012
Fig. 1 A glass micro reactor (2.2 x 4.5 cm) manufactured by
Chemtrix BV.
vessels.10 Consequently reaction exotherms can be readily dis-
sipated, enabling highly energetic materials to be synthesised
in a safe manner; examples of these are described later. The
third advantage is that the volume of these reactors is very
small; the reactor shown in Fig. 1 has a volume of 10 µL for
example. This means that a large number of reaction condi-
tions can be evaluated with very small reagent quantities.
As an example to illustrate this, Wiles and Watts performed
a study to investigate the reaction between diketone 1 and
hydrazine 2 to prepare a range of azoles 3 (Fig. 2) using a
10 µL glass reactor inserted within an automated micro reactor
platform (Fig. 3).11 The reaction was quenched in situ within
the reactor using acetone; this afforded accurate and robust
data.
In micro reactors, processes are optimised by sequentially
conducting a series of reactions at different residence times
(controlled by altering the flow rates of the input solutions)
and temperatures in order to optimise the reaction conditions.
It should also be emphasised that reactions are frequently
performed using back pressure control, enabling temperatures
above the boiling point of the reaction mixture to be
evaluated.
In the above example, the reaction was evaluated at eight
temperatures (25–195 °C) and five residence times (30 s to
5 min) using a variety of solvents. In this process, a total of
200 experiments were conducted in 27 h using less than 6 mL
of solvent and just 94 mg of the diketone. The optimum condi-
tions were found to be a reaction temperature of 125 °C and
residence time of 180 s using ethanol as the reaction solvent
(Fig. 4).
In another example, Sugimoto et al.12 reported an automated
system for the optimisation of a Sonogashira coupling reaction
Fig. 2 Micro reactor setup for the synthesis of azoles.
Fig. 3 Labtrix-S1® automated micro reactor system.
using a micro reactor. Performing the coupling of bromide 4
and acetylene 5 (Scheme 1) the authors screened reaction
temperature (70–110 °C) and time (20–60 min) to optimise
the synthesis of the metalloproteinase inhibitor (R)-3-(1H-
indol-3-yl)-2-(5-(p-tolylethynyl)thiophene-2-sulfonamido)-
propanoic acid 6. Performing the reaction screen, the authors
were able to identify a reaction time of 60 min and a tempera-
ture of 110 °C as being the optimal, affording the target in 88%
conversion. Repeating the study, this time varying the stoichi-
ometry of reagents, a residence time of 20 min, temperature
of 120 °C and 1.25 equiv. of acetylene 5 were found to be opti-
mal. Using this information, the authors subsequently operated
the reactor for 8 h affording 14 g of product 6 (84% isolated
yield). Further increases in scale were met by employing a
larger residence time unit, providing access to inhibitor 6 at a
throughput of 18.8 g h−1.
More recently Jensen and co-workers13 developed an
integrated process for the ‘self optimisation’ of reactions
performed within a micro reactor. Using the Nelder–Mead
Simplex computer method, the authors demonstrated the abil-
ity to integrate feedback control into the reaction optimisation
process, enabling a dramatic increase in speed compared
to conventional design of experiment (DoE) approaches.
Selecting the Heck reaction of 4-chlorobenzotrifluoride 7 and
2,3-dihydrofuran 8 as a reaction (Scheme 2), they identified
Pd(OAc)2 with tert-butyl-MePhos as the ligand and n-BuOH
as the best reagents and solvent mixture to form the coupled
product 9, reporting that the optimal conversion of 88% was
obtained using a residence time of 10 min at 90 °C.
Utilising a capillary-based micro reactor interfaced to an
ultra high performance liquid chromatography system, Fang
et al.14 demonstrated the development of a high-throughput

Fig. 4 Graph to illustrate effect of temperature and residence time on reaction.
Scheme 1 Sonogashira coupling reaction used to
demonstrate an automated micro reactor.
screening system for homogeneous catalysts, focussing on
the evaluation of catalyst efficacy towards the Friedel–Crafts
cyclisation of 10 to 11 (Scheme 3). Connecting the capillary
reactor to the auto injector of the chromatography system, they
were able to introduce the catalyst and reactant solutions into
Scheme 2 Heck reaction used to demonstrate the development of a self-optimising micro reactor.
JOURNAL OF CHEMICAL RESEARCH 2012 183
a continuous carrier stream affording small, discrete reaction
zones within the capillary. Using this approach, the authors
evaluated the effect of a series of Lewis and Bronsted acids
along with reaction temperature (0–40 °C) and molar ratio.
The authors were able to demonstrate the screening power of
their technique whereby 18 catalysts were assessed in 6 h for
each temperature; which enabled the identification of Er(OTf)3
as the most efficient catalyst. In addition to providing a rapid
technique for the screening of catalysts using low volumes of
reactants (ca 400 µg for each reaction), the methodology
proved to be reproducible.
As briefly outlined, micro reactors have attracted substantial
interest with regard to improving safety. A particularly prob-
lematic area of synthetic chemistry is that of diazonium chem-
istry, where hazards include light, heat and shock sensitivity,
which can all lead to uncontrollable decomposition of the
diazonium salts formed with the risk of explosion. Owing to
the fact that the technique provides a synthetically useful route
to an array of compounds such as, azo dyes, hydroxyarenes
and chloroarenes, rigorous conditions are required for the
large-scale application of diazonium salts. These hazards are
however amplified when isoamyl nitrite 12 is used in the prep-
aration of the diazonium salts, as it is prone to decomposition
even when refrigerated, limiting its use on an industrial scale.
Fortt et al.15 addressed these issues by investigating the
synthesis of chloroarenes in a glass micro reactor (channel
dimensions, 150 µm (wide) × 50 µm (deep) × 3.6 cm (length)).
As Scheme 4 illustrates, the first step of the reaction involved
treatment of the amine 13, with isoamyl nitrite 12 (2.4 equiv.),
at room temperature, to afford the diazonium salt 14, followed
by halogen abstraction, from copper chloride (1.3 equiv.), at
65 °C, to afford the respective chloroarene 15. Conducting the
184 JOURNAL OF CHEMICAL RESEARCH 2012

Scheme 3 Friedel–Crafts reaction for high-throughput catalyst screening in a micro reactor.

micro reaction in DMF, the authors found the reaction
proceeded in up to 71% conversion, observing that the reaction
was extremely efficient compared to traditional batch
approaches where typical conversions of 40% are reported.
The high surface to volume ratio not only improves heat
transfer, but is also advantageous when investigating biphasic
processes, as illustrated by Kobayashi and co-workers.16 As
Scheme 5 illustrates, the reaction selected involved the alkyla-
tion of ethyl 2-oxocyclopentanecarboxylate 16 with benzyl
bromide 17 in the presence of a phase transfer catalyst, tetra-
butylammonium bromide (TBAB). Employing a micro reactor
(channel dimensions, 100 µm (wide) × 100 µm (deep) × 45 cm
(length)), the authors investigated the effect of residence time
on the yield of the reaction. To perform a reaction, a solution
of substrate 16 and benzyl bromide 17 (0.30 and 0.45 M
respectively) in DCM was added from one inlet and an aque-
ous solution of sodium hydroxide (0.50 M) and TBAB (1.5 ×
10−2 M) from a second inlet. Maintaining the reactor at room
temperature, the authors investigated the effect of residence
time on the conversion to product 18. Using a residence time
of 2 min, the authors reported 75% yield of the desired product
18; in comparison to a stirred batch reactor, this represented an
increase of 26% over the same reaction time. Furthermore by
increasing the residence time to 10 min, a further increase in
yield was observed, affording ester 18 in 96% yield.
Micro reactor technology has also been used for reactions
catalysed by enzymes; for example using a β-galactosidase
enzyme, Kanno et al.17 reported quantitative hydrolysis of
p-nitrophenyl-β-D-galactopyranoside 19 to D-galactose 20
(Scheme 6) within a micro reactor (channel dimensions,
200 µm (wide) × 200 µm (deep) × 40 cm (length)). The authors
observed that by maintaining the micro reactor at 37 °C, the
reaction proceeded five times faster than in an analogous batch
reaction. This enhancement was attributed to the efficient
mixing obtained within the micro channel compared to a tradi-
tional batch set-up. Other examples of enzymatic processes
have been reported.18,19
It should also be emphasised that in addition to liquid phase
reactions, micro reactor technology is also highly suited to
reactions involving gases. Using a silicon-glass micro reactor
(reaction channel, 400 µm (wide) × 400 µm (deep) × 43.0 cm
(long)), Buchwald and co-workers20 evaluated a series of
Pd-catalysed Heck aminocarbonylations (Scheme 7). Employ-
ing reactor temperatures in the range of 116–160 °C, the
authors were able to convert efficiently a series of aryl halides
21 into the respective amides 22 in moderate to high yield
(32 to 83%). As the pressure was increased the synthesis of
α-keto amides 23 was observed.
The most application-driven area of micro reactors is that
of radiochemistry, where the short half lives of some of the

Scheme 4 Synthesis and reaction of diazonium salts in a micro reactor.

Scheme 5 Phase transfer alkylation of ethyl 2-oxocyclopentanecarboxylate.

Scheme 6 Biocatalytic hydrolysis in a micro reactor.

 JOURNAL OF CHEMICAL RESEARCH 2012 185

Scheme 7 Pd-catalysed Heck aminocarbonylation in a micro reactor.

isotopes impart severe time constraints on the reaction. With
this in mind, Lu and co-workers21 demonstrated the use of a
glass micro reactor (channel dimensions, 220 µm (wide) ×
60 µm (deep) × 1.4 cm (length)) for the rapid synthesis of a
series of radiolabelled compounds (Scheme 8). A pre-mixed
solution of 3-pyridin-3-ylpropionic acid 24 (0.01 M) and tetra-
n-butylammonium hydroxide (0.01 M in DMF) was introduced
from one inlet of the reactor and a solution of radioactive
11
CH3I 25 (0.01 M in DMF) was added from the other inlet B.
A residence time of 12 sec afforded the respective labelled
ester 26 (Scheme 8) with a radiochemical yield (RCY) of 88%.
This process provided an overall processing time of 10 min,
which is comparable to those reaction times currently employed
in PET tracer synthesis.
Among other examples, the authors also demonstrated the
synthesis of a peripheral benzodiazepine receptor (PBR) ligand
28 by the 11C-methylation of carboxylic acid 27 (Scheme 9),
obtaining the desired PBR ligand 28 in a RCY of 65%.21
The principle was further developed by Gillies and co-
workers;22,23 a glass micro reactor was employed for the incor-
poration of radiolabels (18F) into FDG 31. The micro reactor
was used to conduct the fluorination of mannose triflate 29,
followed by hydrolysis of the intermediate 30 to synthesise
[18F]fluorodeoxyglucose ([18F]FDG) 31 (Scheme 10), whereby
50% incorporation of the radiolabel was achieved with a
residence time of just 4 sec. Owing to the importance of this
PET tracer 31, Cheng-Lee et al.24 more recently demonstrated
the fabrication of an integrated micro fluidic system capable
of performing the multi-step synthesis and separation of
[18F]FDG 31.
Photochemistry provides an environmentally friendly and
green approach to the synthesis of complex molecules;

Scheme 8 Methylation of 3-pyridin-3-yl-propionic acid in a micro reactor.

Scheme 9 Synthesis of 11C-labelled peripheral benzodiazepine ligand in a micro reactor.

Scheme 10 Synthesis of the radiolabel 2-[18F]fluorodeoxyglucose ([18F]FDG) in a micro reactor.

186 JOURNAL OF CHEMICAL RESEARCH 2012
however, the ability to scale-up such reactions is marred with
problems that are largely associated with the power of light
sources. The fact that glass micro reactors are transparent is
ideal for investigating photochemical processes. Mizuno and
co-workers,25 reported an enhancement in reaction efficiency,
as well as regioselectivity, by conducting the photocycloaddi-
tion of a naphthalene derivative 32 (Scheme 11) in a transpar-
ent micro reactor. The authors found that in batch, irradiation
of a 1-cyanonaphthalene derivative 32, using a filtered Xenon
lamp (λ > 290 nm), afforded photocycloadducts 33 and 34
in 56% and 17% yield respectively. By comparison, when
conducting the reaction in a micro reactor employing an
irradiation time of just 3.4 min, the desired compound 33 was
obtained in an increased yield of 59%, while by-product 34
was reduced to 9%.
Similarly, Ueno et al.26 demonstrated the photocyanation of
pyrene 35 (Scheme 12) across an oil water interface within
a micro reactor (dimensions, 100 µm wide × 20 µm deep ×
3.5 cm length). To perform the reaction, an aqueous solution of
sodium cyanide and pyrene 35 was added from one inlet and
1,4-dicyanobenzene 36 in propylene carbonate (PC) was intro-
duced from the other inlet. Using a residence time of 3.5 min
while the whole reactor was irradiated using a high-pressure
Hg lamp (~330 nm) the authors reported an optimised 73%
conversion of pyrene 35 into 1-cyanopyrene 37.
Another photochemical transformation conducted in a micro
reactor involving a gaseous reagent was the photochemical
chlorination of toluene-2,4-diisocyanate 38 (Scheme 13).27
Employing a falling film micro reactor (channel dimensions,
600 µm (wide) × 300 µm (deep) × 6.6 cm (length)) consisting
of 32 parallel micro channels, the authors investigated the
irradiation of gaseous chlorine, through a quartz window,
generating chlorine radicals in the presence of toluene-2,4-
diisocyanate 38 in tetrachloropropane solvent. Using this
approach, the authors investigated the effect of varying the
flow rate of chlorine (14.0 to 56.0 mL min−1) and toluene-2,4-
diisocyanate 38 (0.1 to 0.6 mL min−1) on the proportion of
benzyl chloride-2,4-diisocyanate 39 produced. Maintaining
the reactor at 130 °C, the authors identified the optimal
residence time to be 9 sec, affording benzyl chloride-2,4-diiso-
cyanate 39 in 81% conversion.
Electroorganic synthesis also represents an efficient and
‘green’ tool for the formation of complex molecular structures.
The technique’s use has, however, been somewhat limited to
small scale syntheses due to the difficulties again associated
with successful scale-up. Using micro reactors, several authors
have begun the task of addressing the physical problems that
Scheme 11 Photocycloaddition of a naphthalene derivative in a micro reactor.
Scheme 12 Photocyanation of pyrene an oil/water interface in a micro reactor.
Scheme 13 Photochemical chlorination of
toluene-2,4-diisocyanate.
have limited application of this technology, namely an inho-
mogeneous electric field and energy loss due to Joule heating;
with the overall aim being to develop the technology to a stage
that it can be used for the production of chemicals. One of the
most important aspects of electochemical flow chemistry is
efficient incorporation of electrodes into the devices, an area
that numerous authors have investigated with techniques
ranging from plate electrodes28 to micro-imprinted electrodes29
or grooved electrodes.30
Nagaki et al.31 have demonstrated the ability to perform the
Friedel–Crafts alkylation of dimethoxy-substituted aromatics
and allylsilanes; observing that an improved product distribu-
tion could be obtained under flow with reduced polyalkylation.
The [4+2] cycloaddition of a series of electrochemically gen-
erated N-acyl iminium ions 40 was also demonstrated, with the
authors identifying the ability to react the N-acyl iminium
cations 40 with a series of styrene-based dienophiles 41
(Scheme 14) to form products 42 in high yield without the
formation of the polymeric products obtained under batch
conditions.
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 added electrolytes.32–34
One such example was the electrochemical reduction of
4-nitrobenzyl bromide 43 to afford the coupling product 1,2-
bis(4-nitrophenyl)ethane 44 (Scheme 15) in 92% conversion
with only 6% competing dehalogenation.35 In an extension to
this, the authors investigated the reductive coupling of benzyl
bromide with a series of olefins, to afford the C–C coupling
products in high yield and excellent selectivity.36
3. Meso and flow reactors
As discussed, one advantage of micro reactors is that heat
transfer is several orders of magnitude more efficient than that

Scheme 14 Synthesis of [4+2] adducts in an electrochemical micro reactor.
Scheme 15 Electrochemical reduction of 4-nitrobenzyl bromide in a micro reactor.
in batch reactors. Although this is clearly advantageous for
many reactions this level of process intensification is not
always necessary for every reaction and as a result a significant
number of companies are now marketing laboratory apparatus
containing tubular reactors having millimetre-sized reaction
channels with volumes typically ranging from 1-20 mL; exam-
ples include AM Technology (UK), Ehrfeld BTS (Germany),
ThalesNano (Hungary), Uniqsis (UK) and Vaportec (UK).
The reactors are most frequently made from either metal or
polymeric tubing; examples of reactions conducted in such
equipment are now presented.
Azides represent a synthetically useful functional group but
the hazards associated with their preparation have limited their
production and use. Kopach et al.37 reported the development
of a continuous flow reactor suitable for the synthesis of
azide 45 from the chloride 46, as illustrated in Scheme 16.
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.
The authors identified 90 °C as the optimal temperature at a
residence time of 20 min; affording azide 45 in 97% conver-
sion. Operating the reactor continuously for 2.8 h enabled the
authors to produce 25 g of the azide in 94% isolated yield after
extraction.
Owing to the biological uptake of fluorinated pharmaceuti-
cals, efficient synthetic methods are sought for the introduc-
tion of fluorine into small organic compounds. A recent
example reported by Gustafsson et al.38 demonstrated the
efficient synthesis of fluorinated alcohols, aldehydes and
carboxylic acids using diethylamino sulfur trifluoride 47
(DAST) in a PTFE tube reactor (volume, 16 mL). Employing
a reaction time of 16 min and a temperature of 70 °C, the
authors were able to isolate the target fluorinated compound in
yields ranging from 40 to 100% (Scheme 17). Subsequently,
Baumann et al.39 demonstrated the tolerance of their flow
methodology towards vinyl iodides, ethers and epoxides, with
electron deficient aldehydes readily fluorinated at 80 °C.
Scheme 16 Azide synthesis.
JOURNAL OF CHEMICAL RESEARCH 2012 187
Scheme 17 DAST-mediated fluorinations performed in a
PTFE flow reactor.
An alternative method for fluorination is the use of the very
toxic F2 gas. This is a highly exothermic and hazardous
process; however, the improved heat transfer and safety exhib-
ited within flow processing makes this process more realistic.
Chambers and Spink40 demonstrated the use of a nickel flow
reactor for the selective fluorination of a range of 1,3-dicar-
bonyl compounds, such as ethyl acetoacetate 48. Employing
10% elemental fluorine 49 in nitrogen carrier gas, the authors
demonstrated a route to the preparation of the monofluorinated
diketone, 2-fluoro-3-oxobutyric acid ethyl ester 50, with
only small quantities of the product undergoing further fluori-
nation to afford 2,2-difluoro-3-oxobutyric acid ethyl ester 51
(Scheme 18).
The group have subsequently reported the fluorination of
compounds such as nitrotoluene and ethyl 2-chloroacetoace-
tate, again demonstrating excellent conversion, product
selectivity and reaction control.41 In comparison to standard
batch fluorinations, performing such reactions in flow reactors
proves advantageous as the enhanced temperature control
leads to unprecedented reaction control and hence process
safety. Jensen et al.42 further demonstrated the direct fluorina-
tion of aromatic compounds within a silicon/Pyrex reactor,
with nickel-coated micro channels.
Employing a commercially available tubular reactor
(Vapourtec), Riva et al.43 demonstrated the reaction of a series
of carbonyl containing compounds with Grignard reagents as a
means of synthesising substituted alcohols. Using the devel-
oped methodology, the authors extended their investigation to
188 JOURNAL OF CHEMICAL RESEARCH 2012

Scheme 18 Selective fluorination in a nickel flow reactor.

evaluate the synthesis of (rac)-Tramadol 52 (Scheme 19).

Using the reactor, the authors reacted ketone 53 (0.25 M) with
Grignard reagent 54 (1.2 equiv.) at room temperature for a
period of 33 min. Under these conditions, the authors were
able to isolate the target compound in 96% yield as a diastereo-
isomeric mixture (8:2). The high degree of reaction control
obtained under flow conditions has been shown to be advanta-
geous in particular for the Grignard reaction, as a means of
suppressing side reactions and increasing product purity whilst Scheme 20 Diels–Alder reaction performed in a
decreasing reaction times. microcapillary flow disk reactor.
Employing a homemade microcapillary flow disk (MFD)
containing eight parallel reaction channels, each with a dimen-
sion of 180–220 µm, Mackley and co-workers44 investigated
the Diels–Alder reaction of maleic anhydride 55 and isoprene
56 to afford the cycloadduct 57 owing to its potential as a
pharmaceutically interesting scaffold (Scheme 20). Employing
MeCN as the reaction solvent, the authors introduced isoprene
56 (18.0 M) and maleic anhydride 55 (9.0 M) from separate Scheme 21 Diels–Alder cycloaddition at high temperatures
inlets and warmed the reactor to 60 °C using an immersion and pressures in a flow reactor.
bath. Varying the reaction time between 28 and 118 min, the
authors were able to perform the cycloaddition to afford yields
ranging from 85 to 98%. Under the optimal conditions, this
route enabled the authors to produce the cycloadduct 57 at a 10 to 30 min at room temperature. Through the application of
rate of 1.05 kg per day. ultrasound pulses, the authors were able to prevent the MnO2
Utilising a high temperature (300 °C) and pressure (200 bar) slurries from aggregating and blocking the device. In the
stainless steel tubular reactor, Kappe et al.45 were able to absence of ultrasound, fouling of the reactor was observed at
expand the processing window usually employed by research the point of mixing, retarding the continuous operation. In
chemists. Employing the cycloaddition of 2,3-dimethylbutadi- an extension to this, the authors investigated the potassium
ene 58 and acrylonitrile 59 as a suitable reaction (Scheme 21), permanganate Nef oxidation shown in Scheme 22. Employing
the authors were able to demonstrate dramatic reductions the nitroalkane 61 (0.25 M) and KOH (0.3 M) as a methanolic
in reaction time as a result of performing the reaction under solution as one reactant stream and aqueous KMnO4 (0.20 M)
continuous flow. Using toluene as the solvent, the authors as the second input, the authors were able to prepare the respec-
observed incomplete conversion to 3,4-dimethylcyclohex-3- tive carbonyl compound 62 in yields ranging from 58 to 95%
enecarbonitrile 60 with quantitative conversion obtained at with reaction times of 5 to 8 min at room temperature.
250 °C (200 bar) and a reaction time of 5 min. In a subsequent Transition metal catalysed C–C bond forming reactions
article, the authors reported exchange of toluene for solvents form one of the most widely studied classes of reaction that
such as MeCN and THF which enabled easier product have been performed under continuous flow conditions, with a
isolation.46 recent review by Singh et al.48 providing the background into
One of the biggest concerns about flow chemistry relates to the types of reactions investigated. As an example, Wilson
the ability to handle precipitates and slurries. Using KMnO4,
Sedelmeier et al.47 demonstrated the ability to perform oxida-
tions under continuous flow, with efficient downstream
processing of the MnO2 slurries. Reporting the oxidation of
alcohols and aldehydes to carboxylic acids in a FEP tubular
flow reactor (volume, 14 mL), the authors were able to develop
a scalable technique affording the target acids in high to
excellent yield (71–98%) with reaction times ranging from Scheme 22 Nef oxidation performed under continuous flow.

Scheme 19 Grignard reaction used in the synthesis of (rac)-Tramadol under flow conditions.

et al.49 demonstrated a Suzuki coupling reaction in a borosili-
cate glass coil reactor (volume, 10 mL). Using EtOH as the
reaction solvent and triethylamine as the base, the authors
investigated the synthesis of 4-(benzofuran-2-yl)benzaldehyde
63 by the PdCl2(PPh3)2-catalysed coupling of 4-bromobenzal-
dehyde 64 with benzofuran-2-yl boronic acid 65 (Scheme 23).
Optimal conditions were found to be a flow rate of 0.25 mL
min−1 (residence time of 8 min) and a reactor temperature of
140 °C, affording the coupling product 63 in 84% yield.
Using a PTFE tube reactor, Ahmed-Omer et al.50 evaluated
the efficacy of a series of catalysts (10 mol%) towards the
Heck reaction of iodobenzene 66 with methyl acrylate 67 in
the presence of triphenylphosphine (Scheme 24). Employing a
reactor temperature of 70 °C the authors were able to conclude
that Pd(PPh3)4 was the best catalyst under the flow conditions
investigated, affording methyl cinnamate 68 in 62% yield.
With the advent of flow equipment having wide operating
windows, the number of atom-efficient re-arrangement
reactions reported in the literature has increased dramatically.
One such example was reported by Kong et al.51 whereby a
stainless steel tube reactor [dimensions, 170 µm (i.d.) × 1.2 m
(long)] immersed in an oil bath afforded access reaction
temperatures of 220 °C and residence times of 8 to 24 min.
Employing a solution of 4-chlorophenyl ether 69, the authors
investigated the effect of time and temperature on the forma-
tion of 2-allyl-4-chlorophenol 70 (Scheme 25). Performing the
reaction at 220 °C, the authors were able to convert 82% of
69 into 70; representing a 68% increase when compared to a
batch reaction performed at reflux. Gratified by this result, the
authors evaluated a series of re-arrangements, obtaining the
target phenolic derivatives in moderate to high conversions.
Razzaq et al.52 also demonstrated the Claisen re-arrangement
under continuous flow conditions (240 °C), using the X-Cube
flashTM (ThalesNano) to investigate the effect of solvent,
pressure and additive on the conversion of 2-allylphenol into
(E)-2-(prop-1-enyl)phenol.
Kappe and co-workers53 have performed a significant
amount of research into the advantages associated with the
performance of synthetic reactions, under what are conven-
tionally termed ‘extreme’ reaction conditions. One such exam-
ple that demonstrates the novel conditions accessible within
flow reactors was the catalyst-free esterification (Scheme 26a)
and transesterification (Scheme 26b) reaction.54 Due to the
high ionic product of supercritical alcohols (TCEtOH = 268 °C,
PCEtOH = 61 bar; TCMeOH = 239 °C, PCMeOH = 81 bar), the solvent
acts as a catalyst, promoting the reaction. Ethyl benzoate 71
was synthesised in 87% yield from benzoic acid 72 at 300 °C
Scheme 23 Suzuki coupling performed using a glass coil reactor.
Scheme 24 Heck reaction used to screen the efficacy of catalysts under flow conditions.
JOURNAL OF CHEMICAL RESEARCH 2012 189
Scheme 25 Claisen re-arrangement under flow conditions.
(120 bar) and a residence time of 12 min. The authors
subsequently performed a transesterification reaction, isolat-
ing methyl 3-phenylpropanoate 73 in 85% yield from the
corresponding ethyl ester 74 when a reaction time of 8 min and
a temperature of 350 °C was employed.
The previous examples have been selected to illustrate how
important synthetic transformations have been transferred to
flow reactors. However, it needs to be emphasised that more
recently there has been an increased trend to couple directly
micro and flow reactors together in order to enable the efficient
multi-step synthesis of complex products. An early example of
a multi-step reaction performed under continuous flow condi-
tions was the Ciprofloxacin 75 synthesis reported by Schwalbe
et al. (Scheme 27).55
Expanding their investigations into the use of trimethylalu-
minium in the continuous synthesis of amides, Seeberger
et al.56 applied the technique in a key step of Efaproxiral 76
synthesis (Scheme 28), reporting that the use of a flow reactor
enabled the transformation to be performed in a residence time
of 2 min at 125 °C; such temperatures would not safely be used
in batch reactions.
During their research into the development of new reaction
pathways, McQuade et al. developed a continuous synthetic
route for the preparation of Ibuprofen 77 (Scheme 29). Using a
PFA tube reactor, the authors devised a pathway comprising
a Friedel–Crafts acylation, followed by a 1,2-aryl migration
and finally an ester hydrolysis to furnish the target compound
in 68% yield and 96% purity. Purification was subsequently
performed resulting in a 51% overall yield and 99% purity.57
Employing a series of polymer-supported reagents and cata-
lysts, Ley and co-workers have demonstrated the continuous
flow synthesis of a series of pharmaceutically relevant com-
pounds,1 with the synthesis of Imatinib 78 being one example
(Scheme 30). Performing three discrete reaction steps, the
authors were able to isolate the final active pharmaceutical
ingredient in an overall yield of 32% (95% purity).58
190 JOURNAL OF CHEMICAL RESEARCH 2012

Scheme 26 (a) Esterification and (b) transesterification reactions performed using supercritical solvents (sc)in flow reactors.

Scheme 27 Continuous flow synthesis of Ciprofloxacin.

4. Flow processing in production

As mentioned, a major problem observed with conventional
batch technology is the failure to scale-up successful reactions;
this is particularly problematic for highly exothermic
processes. In industry, this often means redevelopment of
synthetic routes on several occasions when transferring from
laboratory, to pilot scale and then finally to production. This is
a both a time consuming and costly process. This is where flow
processing has major advantages as the reactor length and
volume can be flexibly adjusted to enable production at the
relevant scale.
In an example illustrating the incredible processing safety
associated with flow reactor methodology, Loebbecke et al.59
reported the construction of a continuous flow plant for the
production of highly explosive nitrate esters (Fig. 5). Using
this approach, the authors were able to investigate safely previ-
ously unexplored reaction conditions. Once identified, the
optimal conditions were employed in conjunction with down- Scheme 28 Synthesis of Efaproxiral performed under flow
stream processing which included washing and extraction, to conditions.
afford the liquid explosives in pharmaceutical grade purity at
throughputs of 150 g min−1.
Similarly, using commercially available glass flow reactors 150 mL reactor was used to generate the target compound at a
(Corning Incorporated), Reintjens and co-workers demon- rate of 13 kg h−1, with intrinsic safely levels not attainable
strated selective nitration using neat nitric acid.60 Synthesising using conventional batch methodology. Operating eight reac-
a Naproxen derivative (Fig. 6), the researchers report that a tors in parallel enabled the scale to be increased to 100 kg h−1
 JOURNAL OF CHEMICAL RESEARCH 2012 191

Scheme 29 Continuous flow synthesis of Ibuprofen.

Scheme 30 Multiple solid-supported reagents and catalysts for the synthesis of Imatinib 78.

Fig. 5 Illustration of nitrate esters synthesised in an automated micro reactor.

which equates to a theoretical throughput of 800 tonnes

annum−1. The investigation illustrates the ease with which flow
processes can be scaled to achieve production-scale quantities
whilst retaining a relatively small system footprint.
With regard to high value materials, Tanaka et al.61 recently
demonstrated the application of methodology developed for
Fig. 6 Naproxen derivative. the dehydration of β-hydroxyketones to the synthesis of the
192 JOURNAL OF CHEMICAL RESEARCH 2012
natural product pristane 79. Employing p-TsOH as the acid
catalyst, the authors were able to synthesise the target
compound 79 at a rate of 5 kg a week, sufficient to meet
the current market demands for the immunoactivating agent
(Scheme 31).
An industrial application of a gas-liquid micro reactor was
described in a patent,62 whereby a falling film reactor was used
to investigate the selective chlorination of acetic acid 80 to
afford chloroacetic acid 81 (Scheme 32). Employing a series
of micro structured plates [channel dimensions, 1000 µm
(wide) × 300 µm (deep)] maintained at 170–190 °C, the authors
observed that the optimised gas/liquid contacting achieved
enabled acetic acid 80 to be efficiently converted into the
mono-chlorinated product 81. Operating at a flow rate of
50 g min−1, a yield of 90% chloroacetic acid 81 was obtained,
contaminated with 0.01% dichlorinated by-product 82.
Compared to conventional processing techniques (the use of
a bubble column), this represents a reduction of 3.5%, remov-
ing the need for the additional purification steps that are
commonly required.
5. Conclusion
It is now well established that flow reactors enable reactions to
be performed more rapidly, efficiently and selectively than
batch reactions. By optimising the residence time within the
reactor, chemists are able to perform reactions that are very
difficult to control under batch conditions. In addition, com-
pared with conventional reaction methodology, the inherent
safety associated with the use of small reactor volumes enables
users to employ reaction conditions previously thought to
Scheme 31 Illustration of the synthetic route employed for
the flow synthesis of Pristane.
Scheme 32 Selective chlorination of acetic acid to afford
chloroacetic acid.
be too hazardous for use within a production environment;
such as extreme reaction conditions or the use/generation of
‘hazardous’ compounds. Consequently, the types of reactions
available to the R&D chemist increases through the use of this
technology. Over the last 20 years, micro reaction technology
has progressed from proof of concept to the mainstream, where
continuous flow processing is now being implemented at
research, process and production stages by many pharmaceuti-
cal and fine chemical companies. With the advent of commer-
cially available micro and flow reactor equipment, there is now
the opportunity for researchers to investigate how the technol-
ogy can be implemented in a range of different applications.
Received 26 January 2012; accepted 5 February 2012
Paper 1201130 doi: 10.3184/174751912X13311365798808
Published online: 17 April 2012
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