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Continuous process technology: a tool for

Cite this: Green Chem., 2014, 16, 55
sustainable production
Received 30th August 2013, Charlotte Wiles*a and Paul Wattsb
Accepted 25th October 2013
DOI: 10.1039/c3gc41797b Reviewing the open literature, the authors give their perspective on if continuous process technology has
a role to play in sustainable production within the chemical industry.
Published on 25 October 2013. Downloaded on 29/11/2017 17:59:30.

www.rsc.org/greenchem

What are continuous reactors? coined by Hessel et al.,5 but also the rapid reaction interrog-
ation and optimisation that results from the small reaction
Flow, micro or meso reactors are all names given to devices or volumes employed.6 Facilitating the rapid transfer of processes
modules that facilitate the continuous performance of syn- from R&D to production, the technology has been shown to be
thetic reactions or transformations. Emergence of this techno- time and cost efficient.
logy into the mainstream has resulted from the ability to Efficiency: Due to enhanced heat and mass transfer, flow
design reactors in order to execute the process of interest, reactors have the potential to reduce the energy costs associ-
rather than the restrictive historical batch approach of con- ated with performing reactions at a production-scale.7 In
straining the reaction to fit within the vessel(s) available.1 The addition, the modular nature of the technology enables pro-
technology therefore allows tailoring of the reactor size, and duction volumes to be flexibly increased or decreased in order
the features contained within in it, to the process and the goal to meet the current material demands. Modularity also lends
of the investigation. This can be viewed as a deviation from the itself to the construction of process specific plants whilst
early stage ‘Lab on a Chip’ research, where miniaturisation of maintaining the ability to re-purpose the modules at the end
the total reaction system was key2 – here size is determined by of the compounds lifecycle.
the required performance. As such, the technology offers Quality: Owing to the ability determine the effect of para-
broad spectrum applicability from small-scale feasibility meter changes, such as feed quality, reaction time, reagent
assessment through to large-scale industrial production – ratio’s and reaction temperature at the research level, Compa-
enabling users to capitalise on the benefits of making the nies are able to develop robust manufacturing protocols – QbD
switch from batch to continuous processing irrespective of the (Quality by Design).8 Furthermore, flow processes can be
project stage that it is implemented i.e. R&D or production. readily monitored through the use of in-line analytics9
affording process control which enables specification changes
to be identified and resolved, with the affected material segre-
gated – reducing the proportion of material rejected compared
Why use flow reactors? to batch technologies.
The past decade has seen this technology transfer3 from a
Types of continuous flow reactors
niche academic application to an accepted industrial tech-
nique with proven advantages including: A wide range of reactor materials have been reported, with the
Safety: The small hold-up volume in such systems affords selection being based on the intended application. The user
unprecedented control over highly exothermic processes. Fur- must therefore consider the required chemical compatibility,10
thermore, with no headspace in such reactors there is no thermal range, pressure requirements and method of acti-
accumulation of highly unstable intermediates.4 vation (i.e. thermal, microwave,11 ultrasound,12 radio fre-
Speed: Speed relates not only to the ability to intensify pro- quency,13 photochemical14 and electrochemical15) when
cesses through the access of ‘novel process windows’, as selecting a reactor type. With this in mind, reported materials
of construction include polymers,16 silicon,17 glass,18 metals19
and ceramics.20 Furthermore, reactor type is also dependent
a
Chemtrix BV, Chemelot Innovation Park, Geleen, The Netherlands.
upon the process of interest and the goal of the investigation.
E-mail: c.wiles@chemtrix.com; http://www.chemtrix.com; Tel: +44 (0)1482 466459
b
InnoVenton:NMMU Institute for Chemical Technology, Nelson Mandela
For example, with respect to a lab-based assessment it can be
Metropolitan University, PO Box 77 000, Port Elizabeth, 6031, South Africa. sufficient to execute reactions is a simple tubular system.
E-mail: paul.watts@nmmu.ac.za; Tel: +27 (0) 41 504 3694 However if the goal of the development is to take a compound

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to production, then a more strategic approach is required

whereby design of a reactor must consider maintenance of
reaction characteristics such as mass transfer, heat transfer,
reaction time and residence time distribution. Consequently a
micro/meso-structured approached is therefore often selected. Scheme 1 General schematic illustrating the conditions used for the
continuous synthesis of 5-substituted 1H-tetrazoles.
The technology therefore lays a clear pathway for processes to
follow from early stage development through to industrial
production.
able to exploit the increased process safety associated with
The role of continuous processing in sustainable chemical flow reactors to efficiently synthesise a series of 5-substituted
production 1H-tetrazoles (Scheme 1).
Process intensification (PI) is a key aspect in the development Employing a two feed Sulfinert tube reactor (Uniqsis, UK),
of increasingly sustainable synthetic processes and a key the authors reacted a solution of nitrile in NMP–AcOH with a
feature of continuous flow reactors is the ability to routinely solution of aqueous sodium azide (2.5 eq.). Heating the system
operate at pressure – which has the advantage of enabling the to 220 °C, the authors were able to safely generate HN3 in situ,
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use of low boiling solvents and reagents at elevated tempera- obtaining the target tetrazoles in isolated yields ranging from
tures – facilitating product isolation. Furthermore, the tight 75 to 98% with reaction times of 5 to 15 min. Compared to
parameter control accessible in such systems means that it can analogous batch reactions, the authors commented that flow
be possible to selectively run reactions in the absence of reactor provided a significantly safer method for the large
formal protecting groups thus reducing the number of re- scale synthesis of tetrazoles as the liquid filled reactor had no
actions steps and purifications required to access synthetically headspace. In one example, 18.9 g of a tetrazole (89% yield)
important compounds. Additionally there is less risk associ- was synthesised in a 1 h continuous experiment. The authors
ated with process scale-up. These observations have multiple have subsequently utilised a flow reactor to investigate the
resource benefits, including more efficient use of time, cost decomposition of 5-benzhydryl-1H-tetrazole to diphenyl-
and materials; together with a reduction in waste generated.21 methane, employing a reaction temperature of 220 °C and a
That said, in a recent survey of 50 European Companies residence time of 10 min.
(69% in France), Pichon22 of MEPI (la Maison Européenne des Looking further into the synthesis of hazardous reagents
Procédés Innovants) reported that the primary reason for and intermediates, several research groups have evaluated the
choosing to implement or investigate flow processing was formation and reaction of azides under flow conditions,26 with
safety, closely followed by competitiveness and product the group of Seeberger assessing the thermolysis27 or photo-
quality – this is not unsurprising as the cost benefits of these lysis28 of aryl azides as a means of accessing efficient and safe
metrics can be readily determined. Interestingly, the ecological techniques for utilising these energetic transformations. In
impact of processes was ranked as a ‘nice to have’ but not the former case, the authors employed a stainless steel tube
found to currently be a decision maker – a feature that is sure reactor (volume = 2 ml; Vapourtec R series) for the high temp-
to change over the coming years. erature (180 to 220 °C) synthesis of indoles from a series of
In our previous article in this series,23 we focused on asses- azidoacrylates. With heterocycles such as the DAAO inhibitor 1
sing which of the twelve principles of Green Chemistry, as out- precursor, used in the treatment of schizophrenia, synthesised
lined by Anastas et al.24 have the potential to benefit from flow in high yield (Throughput = 8.5 g in 21 min). Whilst these reac-
reactor technology. Herein we focus on the technologies appli- tions have found application at a research level, in particular
cation towards the development and execution of sustainable within natural product synthesis, the use of high boiling sol-
chemical processes25 at both the laboratory and production vents and sealed tube reactors has previously limited the reac-
scale through a series of literature examples. tions application at an industrial level (Scheme 2).

Safety
When considering intensification of a process reduction of
solvent is a common starting point. In batch this can however
be problematic and lead to increased dosing times in order to
thermally control the target synthetic process. In flow reactors
the characteristically high thermal management often means
that these dosing limitations can be overcome. Additionally
they can enable the performance of exothermic reactions at
elevated temperatures whilst maintaining process control. An
example of this was recently reported by Roberge and Kappe10
whereby the development of a continuous flow process for the
atom efficient synthesis of tetrazoles was disclosed. Using the Scheme 2 Synthetic route to a DAAO inhibitor 1 used in the treatment
addition of hydrazoic acid to organic nitriles, the authors were of schizophrenia.

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On-site production of unstable intermediates

Focusing on the development of a safe production process
for per-carboxylic acids, Kolehmainen and co-workers29 of
Lappeenranta University of Technology (Finland) assessed the use
of a slit-interdigital micromixer. Employing catalytic H2SO4
(6 wt%), the effect of reactor temperature was investigated over
the range −5 to 45 °C. Identifying 5 °C as the optimal the
authors proposed a design for a compact reaction unit that
would be suitable for the on-site production of per-acetic acid
at a rate of 20 kg h−1 (23 wt%) – removing the need to trans-
port this hazardous oxidising agent. This is an example where
in the future Companies will operate decentralised business
models, leading to a reduction in transportation costs and
increased safety.
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Rapid library generation

Looking to the use of alternative activation techniques, Organ
et al.30 have a proven track record for the development of
microwave-assisted continuous organic syntheses. In a recent
example his group explored diversity oriented synthesis (DOS)
utilising a multi-capillary reactor – enabling the preparation of
a 50-member library of 1,2,5-thiadiazepane 1,1-dioxide deri-
vatives via a one-pot elimination/double aza-Michael strategy.
Using this approach, the authors were able to generate the Scheme 3 Precise reaction time control obtained under flow conditions.
target sultans at the mg-level in yields ranging from 50 to 80%.
The materials of interest were then scaled by operating a
single capillary reactor for an extended period of time – provid-
ing access to 100–300 mg of each material. With the total
investigation performed in a period of 2 weeks.

Precise reaction control

Exploiting the short reaction times accessible in continuous
flow devices, Yoshida et al.31 recently demonstrated the syn- Scheme 4 A key iodide–lithium exchange reaction used in the syn-
thesis of a key intermediate used in the preparation of the thesis of a Pauciflorol F intermediate.
natural product Macbecin I 2. By precisely controlling the
reaction times employed for each step, the authors were able
to efficiently synthesise the target in 73% overall yield Reaction selectivity
(Scheme 3). Focusing on the synthesis of a fluorocyclobutane containing
H3 antagonist 4, researchers at Pfizer33 identified that the chemo-
selective addition of a Mg-complex to a keto-ester required
Novel synthetic routes tight stoichiometric control, short addition times and low re-
In a second demonstration of superior reaction time control, action temperatures – the combination of which pointed to the
Kim, Nagaki and Yoshida32 reported the ability to perform need for a flow process in order to reliably produce the syn-
organolithium reactions in the presence of carbonyl contain- thetic target (Scheme 5).
ing compounds without the need for protection. Using a micro Utilising a tubular reactor (Vapourtec, UK), the authors
reactor, the authors were able to perform an iodide-lithium employed a reaction temperature of −5 °C and successfully
exchange with reaction times <0.003 s, followed by reaction of performed the reaction on a 12 g scale (65% yield 5; 4 : 1 5 : by-
the organolithium derivatives with a range of electrophiles. product). Based on these positive results, whereby a time con-
The methodology was subsequently demonstrated for the syn- suming and costly 1 h addition time was removed, the authors
thesis of (Z)-3-(3,5-dimethoxyphenyl)-4,6-dimethoxy-1-(4-meth- constructed a kilo-lab apparatus based on a static mixer and
oxybenzylidene)-1,3-dihydroisobenzofuran 3 (81% yield; assessed the effect of reactor temperature (−25 to 0 °C) for a
212 mg min−1), a key intermediate used in the synthesis of the reaction time of 6–7 min observing excellent product 5 selecti-
natural product Pauciflorol F as illustrated in Scheme 4. vity in all cases. Owing to the fact that ∼5% starting material

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Scheme 7 Illustration of a key synthetic step in the synthesis performed

Scheme 5 Chemoselective reaction explored under flow conditions by under flow conditions.
researchers at Pfizer.
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inexpensive substrates and Pd–C (10%) in EtOH, the target

remained un-reacted at −25 °C, the authors concluded that
compound 6 could be prepared at a rate of >100 g day−1,
0 °C afforded the most optimal temperature – without detri-
affording facile access the required 300 g of isolated material
mental effect on product selectivity.
with an impressive 60% reduction in cost of goods compared
to previous batch methods.
Cost reduction With a view to increasing reaction control, Pontén and co-
In addition to increasing reaction temperature to reduce pro- workers38 demonstrated the advantages of using continuous
cessing time, several groups have demonstrated time and cost flow processing at the early stage scale-up of a reflux inhibitor
savings as a result of executing reactions under flow that intermediate 7 (Scheme 7), whereby reduced costs of goods
would previously have required the use of cryogenic con- and improved product quality were also reported as advantages
ditions. Performing what are termed dosing limited batch reac- of the process developed.
tions, researchers often find that cryogenic conditions Using a 20 ml tube reactor (Vapourtec, UK) and an initial
combined with dropwise addition of reagents is required in reaction time of 2 min, the authors processed 1.3 kg of 8
batch to maintain the target selectivity. Owing to the improved (3.4 mol) in 25 h. Isolation of the target compound 7 was
thermal performance that flow reactors can exhibit, it has however problematic due to the use of excess 9, with purifi-
been demonstrated that dosing limitations can be removed cation by chromatography resulting in a variable yield (24 and
and furthermore increased reaction temperatures can be 54%) of the labile compound. In order to address this
employed thus reducing operating costs. Examples include problem, the authors investigated the use of 1 equivalent of
ionic liquid synthesis,34 lithium-halide exchanges35 and oxi- the N-Boc-glycine methyl ester 9, and were gratified to find
dations such as the Swern reaction.36 that a yield of 58% 7 was obtained with a reaction time of only
In addition to savings on temperature control, using com- 90 s. Secondly, the authors observed that the product 7 could
mercially available hydrogenation apparatus, researchers at tolerate high reaction temperatures for short periods of time
Janssen Research and Development demonstrated the prepa- and consequently assessed the effect of increasing the reactor
ration of a benzylpiperazine substrate using a direct and scal- temperature from −78 to 35 °C. Using LDA 10 as the base
able reductive amination reaction (Scheme 6).37 Employing (3 eq.) 1.3 kg of phosphinate 8 was again processed at 35 °C
with a reaction time of 90 s affording the target reflux inhibitor
AZD6906 11 in 400 g (99% purity) after batch deprotection of 7
and treatment with charcoal.

Reduced operator exposure

With the dual goal of reducing worker exposure and achieving
commercial scale production within a laboratory fume cup-
board, researchers at Eli Lilly & Company assessed the develop-
ment of a continuous process for the synthesis of a cytotoxic
acyl sulfonamide, Tasisulam 12 (Scheme 8).39
Initial assessments centered on the development of a solu-
bilised batch process whereby triethylamine was replaced by
Scheme 6 Illustration of a development target produced in flow via a hunigs base; however, this approach was found to yield no
reductive amination step. advantages over the current batch process. With this in mind,

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Comparison of production costs

Buddoo et al.41 of CSIR Biosciences (South Africa) reported the
used of a static mixer for the transesterification of triglycerides
derived from vegetable oils to afford fatty acids methyl esters
(FAME). Table 1 compares the flow and batch production tech-
niques highlighting impressive potential savings on both
capital (24%) and manufacturing (11%) costs for production
volumes in the range of twenty thousand tonnes per annum.
Owing to the importance of alkyl nitrites as building blocks
and reagents in the chemical and pharmaceutical industries,
Scheme 8 Synthetic strategy employed by Eli Lilly & Company for the Monbaliu and co-workers42 assessed the use of glass
continuous production of a cytotoxic compound.
continuous flow reactors (Corning S.A.S.) for their synthesis
(Scheme 9).
Currently industrial processes employ the reaction of
the authors decided rather than operate within the constraints nitrous acid (aq.) or nitrogen oxides in the presence of nitric
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of the batch conditions, to design a process from the outset acid or oxygen, requiring long reactions times and labour
with flow in mind, consequently it was required that all intensive extractions/distillations in order to isolate the alkyl
reagents were solutions at room temperature. nitrites. With a view to developing an economically viable
Owing to the high solubility of the target 12 in water, the industrial process, Monbaliu et al. assessed the feasibility of
possibility of using Schotten Baumann conditions was performing such liquid phase reactions under flow, employing
assessed – earlier rejected in batch due to the formation of a HCl and sodium nitrite 13. Using a reaction temperature of
significant proportion of a benzoic acid derived by-product. 18 °C, with pre-cooled feeds, the authors performed a liquid
Assessing a series of solvents and bases, the authors revealed a phase separation at the outlet of the reactor in order to isolate
reaction temperature of 65 °C with IPA–H2O–toluene as the the organic fraction from the aqueous; which was treated with
solvent system afforded the target compound 12 in 99% con- urea to destroy any excess nitrous acid. With a reaction time of
version – without the need for a phase transfer catalyst. Sub- 4.8 s the authors were able to isolate isopropylnitrite in >98%
sequently, in-line counter-current extraction and continuous purity and >99% conversion cf. 90% for a standard batch pro-
crystallisation were explored which led to high levels of impur- cesses. Operating the reactor for 24 h illustrated the feasibility
ity rejection. For validation purposes, the production unit was of continuous organonitrite synthesis with production
operated at a throughput of 5.2 g h−1. capacities in the range of 10 tonnes annum−1.

Application to material production Continuous downstream processing

Although at the various stages of chemical development the Whilst the use of biphasic reaction systems can be viewed as a
goal and focus of particular functions change, for example a way to drive reversible reactions in the desired direction, fur-
medicinal chemist is charged with rapidly preparing NCE’s to thermore in the case of rapid and non-reversible reactions the
support toxicological evaluation, often using sub-optimal syn- same principle can be exploited as a means of extracting/
thetic routes, at the end point the process R&D chemist is
responsible for the smooth transfer of well developed, safe,
scalable, robust and economical chemical process to pro- Table 1 Comparison of batch and flow techniques for the production
of biodiesel
duction – across these stages, continuous flow processing has
been demonstrated to be applicable. With this in mind, Dach Parameter Batch Flow Comment
and Roschanger40 of Boehringer Ingelheim Pharma GmbH
Plant output (tons year−1) 20 000 20 000 —
and Boehringer Ingelheim Pharmaceuticals Inc. respectively
Reactor volume (m3) 10 2.4 × 10−3 4167× smaller
wrote an article entitled ‘The Eight Criteria Defining a Good Plant footprint (m2) 149 60 60%
Chemical Manufacturing Process’. Within the article the Surface to volume (m2 m−3) 14.9 2.5 × 10−4 1678× higher
Productivity (kg h−1 m−3) 250 10.4 × 10−5 4167× higher
authors discuss the fact that the past decade has seen API
Energy input (kJ kg−1) 7.1 0.4 18× lower
manufacturing costs rise by 20% and this has contributed to Capital cost (Rm) 8.6 6.5 24% saving
the innovation drive experienced by the industry and the target Manufacturing costs (R/L) 6.6 5.9 11% saving
to reduce the number of ‘out of spec’ batches. The goal being
to design more robust, viable, cost effective manufacturing
processes in early stage development then transferring these
processes with minimal change to production. From the
examples presented herein, it can be seen that continuous
flow processing is one such technology that has the potential
to deliver on these targets. Scheme 9 Esterification of alcohols with nitrous acid.

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separating the target analyte from any reaction by-products or process. Such an approach requires a high degree of process
catalytic species. data and whilst it is more conventionally applied after process
Jensen and co-workers43 recently reported the fabrication of development, this could be viewed as being too late as critical
a membrane based liquid-liquid separator with integrated decisions have already been taken and criteria fixed. With this
pressure control as a means of improving the commonly in mind, the authors propose that the technique be applied at
encountered failure modes for membrane based separators; the R&D stage, via a process known as vertical LCA, to screen
1. Breakthrough of retained phase the effect of decisions taken at this early stage. An example was
2. Retention of the permeate phase given for the Kolbe–Schmidt reaction focusing on the reaction
Employing pressure control, the authors were able to only – however in the future downstream processing should
demonstrate the separation of hexane–water or ethyl acetate– also be considered.48
water mixtures (1 to 10 ml min−1) and comment on the use of
such a module to facilitate solvent ‘swaps’ which can be New areas for application
required when executing multi-step continuous flow processes In addition to the synthesis of small organic molecules, flow
whereby telescoping is not applicable.44 Additionally, further reactors are also emerging as tools for the preparation of
research efforts are required into the area of reactive sepa- highly defined nanomaterials. An example of this was reported
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rations, as outlined by Zimmerman et al.45 by Abou-Hassan and co-workers49 who generated high quality
CoFe2O4 nanoparticles in only 16 min by connecting two flow
How to select the right reactor reactors together in series. In the first reactor they rapidly
With clear processing benefits to be gained from the homogenised Fe3+ and Co2+ at room temperature to afford pre-
implementation of continuous process technology, several cipitates of the respective hydroxides, this was followed by
groups have begun to develop methodologies for determining heating to 98 °C upon which aging and evolution of amor-
which is the best reactor type for a given process, so called phous hydroxides into crystalline CoFe2O4 was observed. Com-
‘best available technology’ (BAT). One such group is that of de pared to batch processes whereby 10–20 nm particles were
Bellefon,46 who have focused on hydrogenation reactions, with prepared, the two-stage flow approach generated particles with
a view to assisting the pharmaceutical industry. Basing their an average size of only 5 nm.
assessment on eight criteria – rate, thermicity, deactivation, Employing a Coflore Agitated Cell Reactor (AM Technology),
solubility, conversion, selectivity, viscosity and catalyst, the Maggini et al.50 reported the ability to functionalise carbon
model reaction illustrated in Scheme 10 was executed in a nanotubes with a diazonium moiety – tailoring the degree of
stirred batch reactor, CSTR, fixed bed reactor and a falling film functionalisation as a result of reaction time. Most impressive
reactor. Whilst the approach is in its infancy, comparison of was the ability to reduce the reaction time from batch of 15 h
the metrics presented for given reactors does represent an to 30 min.
interesting technique for ranking equipment suitability for a In a recent publication, Wong and co-workers51 reported
given process. the ability to obtain a series of conjugated polymers in narrow
When considering process suitability, Hessel et al.47 molecular weight distribution and reduced reaction times as a
comment on the fact that the ‘Twelve Principles of Green result of performing the transformation in a 10 ml tube
Chemistry’ allow for qualitative assessment of a processes reactor (Vapourtec, UK). Using the Suzuki-coupling reaction to
‘Green Credentials’ however for a comprehensive assessment it construct the polymers, the authors reported the dosing of
is proposed that Life Cycle Assessment (LCA) is required as a monomer solutions, Pd-catalyst and an aqueous base into a
means of determining the environmental burden of a given heated and pressurised (8 bar) system. Employing reaction
times of 0.5 to 2 h, the authors were able to obtain the target
polymers in 70 to 90% yield with comparable or improved
molecular weight distributions. Scheme 11 illustrates a gene-
ralised protocol implemented for the synthesis of conjugated
polymers – which find application as organic photovoltaics.
In another synthesis utilising thiophenes, Seyler and co-
workers52 reported the development of a continuous flow
process for the synthesis of organo-electronic dyes affording
access, for the first time, to the compounds on a gram-scale.

Outlook & perspective on continuous flow technology for

sustainable production
Looking to the fundamental aspects of Green Chemistry, con-
tinuous flow technology has been shown to facilitate process
intensification,53 provide access to novel synthetic routes,54
Scheme 10 Model reaction used to develop a tool for ‘best available lead to improved reaction selectivity,55 reduce downstream pro-
technology’ assessment. cessing costs and afford increased process safety.56 However,

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Notes and references

1 S. Hickling and P. Poechlauer, Spectrochim. Chem., 2012,
22–23.
2 R. Daw and J. Finkelstein, Nature, 2006, 442, 367.
3 (a) D. T. McQuade and P. H. Seeberger, J. Org. Chem., 2013,
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B. Gregertsen and M. Ridemark, Org. Process Res. Dev.,
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4 N. Kockmann and D. M. Roberge, Chem. Eng. Technol.,
2009, 32, 1682–1694.
5 V. Hessel, D. Kralisch, N. Kockmann, T. Noel and Q. Wang,
ChemSusChem, 2013, 6, 746–789.
6 (a) R. C. Wheeler, E. Baxter, I. B. Campbell and
S. J. F. Macdonald, Org. Process Res. Dev., 2011, 15, 565–569;
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Scheme 11 Illustration of a generalised protocol used for the synthesis

of conjugated polymers under flow conditions. (b) D. Breuch and H. Löwe, Green Process. Synth., 2012, 1,
261–267.
7 A. Salic and B. Zelic, Goriva i Maziva, 2011, 50, 98–110.
whilst flow processing is an established technique used in 8 (a) J. M. Juran, Juran on Quality by Design, Free Press,
other manufacturing industries such as food and petrochem- 1992; (b) N. Mantos and M. Gil, Spectrochim. Chem., 2013,
ical, a perceived barrier within the chemical industry, and in 10–13.
particular the pharmaceutical industry, is regarding the 9 (a) J. Goode and D. Hebrault, Chem. Today, 2012, 30(60),
technologies disruptive effect on regulatory approval. In a 20–24; (b) T. Brodmann, P. Koos, A. Metzger, P. Knochel
recent article, Gonzalez57 of the US Environmental Protection and S. V. Ley, Org. Process Res. Dev., 2012, 16, 1102–
Agency – Sustainable Technology Division reported positively 1113.
the advantages that enable the development of sustainable 10 B. Gutman, T. N. Glasnov, T. Razzaq, W. Goeddler,
continuous processes are a direct result of the ability to D. M. Roberge and C. O. Kappe, Beilstein J. Org. Chem.,
‘impart a high degree of control on several key reactor and 2011, 7, 503–517.
reaction parameters’ and as has been discussed previously this 11 (a) D. Obermayer, T. N. Glasnov and C. O. Kappe, J. Org.
facilities the ability to follow a QbD approach.58 Chem., 2011, 76, 6657–6669; (b) E. Gjuraj, R. Kongoli
Whilst the number of industrial examples utilising flow is and G. Shore, Chem. Biochem. Eng. Q., 2012, 26(3), 285–
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and purification stages of material production, more examples 2008, S280–S283; (b) J. Sedelmeier, S. V. Ley, I. R. Baxendale
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