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Simple and Versatile Laboratory Scale CSTR for MultiphasicContinuous-Flow Chemistry and Long Residence Times
Michael R. Chapman,†,§ Maria H. T. Kwan,§ Georgina King,§ Katherine E. Jolley,§ Mariam Hussain,†
Shahed Hussain,∥ Ibrahim E. Salama,†,§ Carlos González Niño,‡ Lisa A. Thompson,§ Mary E. Bayana,†,§Adam D. Clayton,§ Bao N. Nguyen,†,§ Nicholas J. Turner,∥ Nikil Kapur,*,‡,§ and A. John Blacker*,†,§
School of Chemical and Process Engineering, ‡School of Mechanical Engineering, and §Institute of Process Research andDevelopment, School of Chemistry, University of Leeds, Leeds LS2 9JT, U.K.
∥
School of Chemistry, Manchester Institute of Biotechnology, University of Manchester, Manchester M1 7DN, U.K.
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†

S Supporting Information*

ABSTRACT: A universal multistage cascade CSTR has been developed that is suitable for a wide range of continuous-ﬂow
processes. Coined by our group the “Freactor” (free-to-access reactor), the new reactor integrates the eﬃciency of pipe-ﬂow
processing with the advanced mixing of a CSTR, delivering a general “plug-and-play” reactor platform which is well-suited tomultiphasic continuous-ﬂow chemistry. Importantly, the reactor geometry is easily customized to accommodate reactions
requiring long residence times (≥3 h tested).

■

INTRODUCTION
The past two decades have seen far-reaching progress in thedevelopment of microﬂuidic systems for use in chemical
synthesis, with the ﬁeld continuing to mature exponentially.1−7
On account of their low chemical inventory, continuous-ﬂow
systems are highly suited to implement many of the Twelve
Principles of Green Chemistry, often producing safer process
operating conditions and higher eﬃciency than can be obtainedwith traditional batch processing.8,9 Moreover, the integrationof real-time analysis and automation with low-volume ﬂow
reactors enables chemists to explore incredibly wide regions ofoperational parameter space over relatively short periods oftime.10 This paradigm shift from conventional batch chemistry
has been employed to eﬃciently produce numerous pharmaceutical compounds with unmatched environmental footprints,
such as Ibuprofen by McQuade,11 Zyprexa by Kirschning,12 andTamoxifen by Ley.13 In a well-argued publication by Jensen andMcMullen, the defacto conditions under which ﬂow chemistry“makes sense” have been condensed to those whereby the rateof chemical reaction surpasses the associated mass transfer of asystem.14 Unfortunately, this regime excludes many multiphasic
reaction systems, in which a combination of gas, liquid, or solid
comprises the reactants, reagents, catalysts, or (by)products as
the reaction proceeds. Frequently met multiphasic examples
include enzymatic reactions (organic−aqueous phases), slurries(solid−liquid), or hydrogenation (solid−liquid−gas)each
requiring eﬀective mixing and long residence times. Static
mixers built within tubular reactors can oﬀer these conditions,though they require high volumetric ﬂow rates which may not
be feasible for slow reactions (e.g., >5 min) (Figure 1).15
In 2011, Greiner and colleagues made some headway toward
slow continuous-ﬂow processing through use of a nested-pipe
reactor.16 During a 14 day test campaign, the authors
demonstrated the potential of this reactor geometry by
producing 20 kg of product per day. However, the bespoke© 2017 American Chemical Society

Figure 1. Top: Impact of biphasic ﬂow performance on mixing regime
in tubular/static mixed reactors. Middle: Coﬂore reactor developed by
AMTech. Bottom: Well-mixed cascade CSTR reactor reported here.

reactor is not trivial to assemble nor appropriate for small scale
processing. Taylor-Couette reactors, in which a rotating
cylinder provides mixing, have been employed in slow
continuous biological and polymerization processes, though
they rely on product extraction against gravity which may
become challenging in cases where solid products areformed.17,18 Consecutive or cascade continuous stirred tankreactors (CSTRs) provide a solution to these problems.
However, conventional cascade CSTRs are convoluted,
expensive, and oversized where material availability is lowatechnological gap which places limitation on the accessibility
Received: May 11, 2017
Published: June 28, 2017
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Organic Process Research & Development

Articlethe surroundings with no additional insulation. Conventional
machining of a plastic stock rather than 3D printing thereactors24 (which is entirely feasible for this geometry) brings
advantages of high structural integrity of the reactors and the
ﬂexibility to change materials (e.g., PTFE to metal). Where 3D
printing may become more appropriate, albeit currently at theexpense of structural performance, is building additional
functionality or ﬂexibility in evaluating designs. The basecomponent of each reactor unit comprises a cylindricalreservoir (2 mL volume) containing a magnetic stir bar forenhanced, low-volume, and uniform mixing (Figure 2, top left).

and development of continuous-ﬂow chemistry in academia
and industry.19 Thus, miniaturization of CSTRs for synthetic
research laboratories represents a signiﬁcant step toward
broadening the range of chemical transformation suitable forcontinuous mode. AMTech has produced a laboratory andlarge scale multistage CSTR, the Coﬂore reactor, consisting of aseries of loose-ﬁtting polymer inserts that provide mixing as theentire unit is shaken (Figure 1, middle).20 Equally, the Jensengroup has recently reported a miniature consecutive CSTR
which performed comparably to its standard size counterpart intwo solid-forming reactions.21 Likewise, Lapkin and Meadowshave also recently published a reactor which closely resembles asequence of CSTRs linked in a single compact block,comprising no unmixed connections between adjacentchambers, and is suitable for solid-forming processes.22 Herein,
we report our own independent successes in CSTR
miniaturization, based on the principles of open-source,
inexpensive, and modular reactor design (Figure 1, bottom).
The freely accessible cascade CSTRs described here are simple
to assemble and modify and provide chemists with a generalplatform to explore continuous-ﬂow processing with little
expertise required. As with other cascade CSTR systems, as thenumber of reactors in series is increased, the overall
performance tends toward that of a well-mixed plug-ﬂow
reactor, which ensures uniformity of processing conditions. For
example, ﬁve 2 mL cascade CSTRs provide greater uniformityof residence time than a single 10 mL CSTRin general, thegreater the number of CSTRs, the closer to ideality the system
becomes. The CSTRs have been evaluated against their batchcounterparts for a variety of important and challenging
multiphasic processes, including enzymatic imine reduction,
cycloisomerization, N-chloroamine synthesis, classical resolution of chiral amines, and heterogeneous Pd-catalyzed hydrogenation. Through these examples, we tackle many of thediﬃculties associated with scale-up of multiphasic phenomena
and demonstrate the tunability of our reactor to facilitate
reactions requiring long residence times (τr, covering a tested
range of 2 min to 3 h).

Figure 2. Top left: individual components of the reactor (10 pence forscale). Top right: assembled single reactor unit. Bottom: three-stage
cascade of reactors in series.

A convex glass lens is clamped, convex side down, onto a PTFE
gasket above the volume element via a triangular lid component
with three bolts to provide a robust and simple ﬂow-reactor
assembly (Figure 2, top right). The glass window allows
physical reaction monitoring and could enable real-time
spectroscopic analysis of ﬂow systems or the use of photochemistry by careful choice of glass type and volume depth. Up
to ﬁve (but generally three) ports are drilled perpendicular to
the reaction chamber to allow modular combinations of inlets
and outlets. Standard HPLC 1/8 in. o.d. ferrules and tube
ﬁttings are suﬃcient to allow continuous ﬂow of gases, liquids,
and solids. The reactor units have been tested up to 6.9 bar
using a sequential BPR method (see Supporting Information),with some evidence of leaking beyond this pressure.
Importantly, the reactors are stirred magnetically, which ismuch simpler than use of mechanical agitators or shaker beds
(Figure 2, bottom).25 Both straight and cross-bar PTFE-coatedmagnetic stir bars (diameter 8−10 mm) were selected toprovide a close ﬁt to the walls of the reactor vessel. The
rotation rate of the stir bar was assessed using a stroboscope(16 rs−1), comparing favorably with commercial stirrer platesalso used within our study (18 rs−1).
Reactor Characterization. Heat transfer capability, residence time distribution (RTD) analysis, and gas−liquid masstransfer eﬃciency (kLa) were evaluated and are supplied in the
Supporting Information.
Enzymatic Biotransformation. Imine Reductase (IRED).
Imine reductase enzymes are highly eﬃcient biocatalytic■

RESULTS AND DISCUSSION
Reactor Design. Practicality, simplicity, and versatility toaccommodate diﬀerent reactions were identiﬁed as importantdesign principles from the outset. Other key features sought
were general chemical resistance, an observation window,
simple cleaning, cost eﬀectiveness, and mass production
capability. An early decision was made by our team to provide
the reactor as an open-source piece of equipment and develop
an online user community to share experiences. (The CSTR
“Freactors” and stirrer motors were made to the design
described in the Supporting Information, with plans to become
available from both www.iprd.leeds.ac.uk/Freactors and Asynt
Ltd.) The CSTRs and ancillaries are mobile and able to sit
alongside standard laboratory equipment (e.g., syringe/
peristaltic pumps, glassware, in-line ﬁlters, back-pressure
regulators, separators, on- or at-line analysis). The reactor
reported here is composed of polyacetal plastic, which is
inexpensive, compatible with most solvents/reagents (withexception of strong acids/bases), and easily fabricated.23 Thisacetal plastic performs well as an insulator, allowing hightemperature reactions to be conducted through feeding hot
starting materials directly into the reactor. Over a single CSTR,
a ﬂow of water (1 mL min−1) at 50 °C gave a 3.9 °C
temperature drop (0.35 W) over the reactor, due to heat loss to1295

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Articlealternatives to chemical (transfer) hydrogenation catalysts inthe asymmetric reduction of imines to aﬀord enantioenrichedamines.26,27 The purpose of our study was to evaluate the use of
our reactor in improving the productivity of IREDs for imine
reduction. A ﬁve-stage assembly was connected to two syringe
pumps. Feed 1 contained the (R)-IRED and glucose
dehydrogenase in aqueous phosphate buﬀer (pH 7.0). Feed 2
contained a mixture of glucose, NADPH cofactor, and 0.1 M 2propyl-3,4,5,6-tetrahydropiperidinium hydrochloride (Scheme
1).28 At an overall ﬂow rate of 0.52 mL min−1 (τr = 19 min),Table 1. Continuous Liquid Biphase Reaction of NaOCl
with Amine in Toluene/Water

entry

no. of CSTRs(n)reactor volume
(mL)

τres
(min)

conversiona
(%)

1b
2b
3b
4b
5b
6b
7d
8d

static mixer
1
2
3
5
5
1
5

6 (1.6 mixed)
50
4
6
10
10
50
10

20
25
20
10
10
5
50
30

89c
94c
100
83
93
94
40c
42

Scheme 1. Continuous-Flow Biotransformation of
Propyliminium with (R)-IRED in Five-Stage CSTRaaAnalyzed by 1H NMR spectroscopy. bProduct N-chloro-N-methylbenzylamine. cFrom ref 31. dProduct N-chlorodibenzylamine.

phase transfer catalyst even slower and unsuitable for poorly
mixed tubular reactors. In the single-stage 50 mL CSTR fromprevious studies, dibenzylamine chlorinated with 40% conversion in 50 min residence time (entry 7). Pleasingly, using
our reactor at 1/5 scale, a comparable conversion was realized
in a residence time of 30 min (entry 8), indicating improved
mass transfer.
Electrocyclization. Our group recently reported a rapid,
NaOH-promoted cycloisomerization reaction of several Nalkynylated 2-aminopyridinium bromides under aqueousconditions.32 The pyridinium halides are cyclized instantaneously upon contact with base, producing the imidazopyridine
products as water-insoluble oils during reaction. While thissimpliﬁes product recovery in batch, we speculated that such a
rapid reaction would naturally suit a continuous-ﬂow mode toboost space-time-yield. Although the reaction itself appears
under diﬀusive control (i.e., does not require additional mixing
nor long residence times), preliminary results have shown thedispersion of product to resist ﬂow through a tubular pipe,
complicating process translation. Two options became available
to us upon consideration of our reactor for this system: (i)exploit the additional turbulent mixing of the reactor tomaintain product dispersion out of the pipe or (ii) input anorganic solvent feed to extract the product in situ. To
demonstrate the modularity of our design, the latter was
selected. Using a four-stage CSTR, aqueous solutions of Npropargyl-2-aminopyridinium bromide (1 M) and NaOH (1.25
M) were fed at equal ﬂow rate into chamber 1. Prior to themixing zone, a constant stream of DCM solvent was fed at amatched overall ﬂow rate to immediately extract the desired
product in continuous ﬂow. At this point, the beneﬁts of ourplug-and-play design became evident as the ﬁnal chamber was
linked to a liquid−liquid membrane separator via standard
HPLC ﬁxtures, allowing simple in-line puriﬁcation of theheterocyclic product (Scheme 2).
Following 2 RVs, the desired product was formed andseparated in 97% yield with a residence time of 2 min (Figure3), generating a steady-state space-time-yield of 32 g L−1
min−1triple the value obtained in batch (10.9 g L−1 min−1).
N-Acetylation of Ethylene Diamine. Selective monofunctionalization of symmetrical materials, such as diamines, isimportant due to their widespread use as linkers in thepharmaceutical industry. However, two key challenges exist foraConversion (%) and ee (%) determined by chiral GC. V = reactor
volume, QF = ﬁnal volumetric ﬂow rate.

the process reached steady state after 2.5 reactor volumes(RVs)noting that the RV is based on the total volume of thecascade.
At this point, 89% conversion of substrate was achieved to
produce (R)-amine with 98% ee. The space-time-yield of 17 g
L−1 h−1 compares favorably with the batch reaction (6.4 g L−1h−1), and the improvement is likely due to lack of productaccumulation within the system, known to inhibit the catalyst.
It is anticipated that this productivity value could be optimized
through operating at the optimal temperature of the enzyme,
though this is beyond the scope of this version of the reactor.
Chemical Reactions. Synthesis of N-Chloroamines.
Chlorinated amines represent an electrophilic aminating tool
and are useful for a wide number of synthetic reactions.29 The
biphasic liquid synthesis of N-chloroamines from NaOCl andsecondary amine in organic solvent may be considered a green
reaction, generating only NaCl and NaOH byproducts withhigh atom eﬃciency.30 We have previously reported acontinuous-ﬂow synthesis of various N,N-dialkyl-N-chloroamines using either a bespoke mesoscale tubular reactor withstatic mixers or a 50 mL single-stage CSTR (Table 1, entries 1
and 2, respectively).31 Taking N-chloro-N-methylbenzylamine
as an example, we decided to compare these reactor types to
our CSTR (see subsequent entries of Table 1).
Using a two-stage CSTR construct, N-methylbenzylamine(1.0 M in toluene) and NaOCl (1.1 M in water) were fed
independently into the reactor at room temperature. Adopting
a residence time of 20 min, the chlorinated product was formedin quantitative conversion (entry 3). More productively, a ﬁvestage reactor and residence time of 5 min delivered the productin 94% conversion, leading to a productivity of 0.88 kg L−1 h−1
at steady state (entry 6). Comparing these with previous
studies, a tubular static mixed system produced the N-chloro-Nmethylbenzylamine in 89% conversion and a single-stage CSTR
in 94% conversion (τr = 20 and 25 min, respectively, entries 1
and 2). Interestingly, dibenzylamine substrate partitions
preferably into the organic phase, making reactions without a
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ArticleScheme 2. Continuous-Flow Electrocyclization with In-Line
Membrane Separation of ProductaaTable 2. Batch versus Continuous Liquid Biphase
Monoacetylation Reaction

Yield (%) is isolated. Qorg = exit ﬂow rate of organic stream.

entry

no. of
CSTRs (n)

τres
(min)

conversiona (%)/
selectivitya,b (%)

productivity(g L−1 h−1)

1
2
3
4
5

batch
2
4
6
5

20
20
20
20
30

69/87
53/88
83/80
85/80
83/84

51
112
163
163
173

a

Analyzed by 1H NMR spectroscopy at steady state. bSelectivity formonoacetylated amine.

Continuous Crystallization. Solid-forming reactions arenotoriously challenging to process in continuous ﬂow due toreactor fouling and blockage, often at small gauge tubing
connectors or sharp turns in reactor channeling. These
problems have been tackled by (i) introduction of a solubilizing
agent, (ii) use of ultrasonication/pulsed agitation, or (iii) use of
speciﬁcally engineered reactors to facilitate the transport of aslurry.35−39 With these in mind, we became interested in theability to manage the ﬂow of particulate suspensions, as a
general alternative to those listed above. The classical resolutionof rac-salsolidine 1, via diastereomeric crystallization with (S)mandelic acid 2(S), was investigated (Scheme 3). Employing a
Scheme 3. Slurry-Flow Diastereomeric Crystallization of
Salsolidine and (S)-Mandelic Acid in a Five-Stage Reactora

Figure 3. Representative plot of isolated yield (red)/cumulative mass
yield (blue) of imidazo[1,2-a]pyridine as a function of reactor volume.

these reactions: (i) suppression of overfunctionalization and(ii) control of phase partitioning, which often leads to lowyielding processes. Maurya and Wille have independently
shown the use of continuous plug-ﬂow and microreactor
technology to provide high selectivity in making monoprotected diamines.33,34 Throughout the reaction, diﬀerent
species partition into separate solvent phasesmaking mixing
crucial to this type of system. Our miniaturized CSTR oﬀers a
simple platform to optimize an experimental design (i.e., DOE)
for this reaction, allowing for a continuously well-mixed biphaseto both minimize difunctionalization and maximize productpartitioning. To test this hypothesis, an aqueous feed ofethylene diamine was met with an equimolar toluene solutionof acetic anhydride in chamber 1 of the reactor andsubsequently ﬂowed through n CSTR stages (Table 2, column
2).
In comparison to batch (entry 1), a six-stage CSTR allowed a
16% increase in conversion of ethylene diamine, with a 7% dropin selectivity to form the desired product (entry 4). Selectivity
could be improved by reducing the number of stages in thereactor geometry while maintaining a residence time of 20 min,though this was shown to compromise conversion (entry 2).
Employing a ﬁve-stage CSTR, with a residence time of 30 min
delivered the desired diamine in 83% conversion with 84%
selectivity, leading to a productivity value 3.4-fold higher thanthat obtained in batch mode (entry 5).

aWeight of crystals are dry, and de (%) is determined by 1H NMR
spectroscopy. V = reactor volume, QF = ﬁnal volumetric ﬂow rate.

ﬁve-stage CSTR, EtOAc/MeOH (7:1) solutions of each werepumped into chamber 1immediately producing a crystalline
slurry upon contact (0.7 wt % at steady state). Following a
residence time of 20 min, crystals of 1(R)·2(S) from the output
stream were collected by ﬁltration and analyzed by 1H NMR
spectroscopy to show a de of 91% at steady state.
Each RV consistently delivered crystals of 1(R)·2(S) in 1.8%
isolated yield, which, albeit relatively low, produced acumulative yield of 24% over 13 RVs (Figure 4). Theseﬁndings compare favorably with the analogous batch system,
aﬀording lower quality crystals in 30% yield with 83% de (seethe Supporting Information). Ongoing research from our grouphas shown semibatch recirculation of the mother liquor throughthe reactor to be a useful method of achieving full resolution(i.e., 50% yield).
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ArticleFigure 4. Representative plot of cumulative yield (red)/diastereomeric
excess (blue) of 1(R)·2(S) as a function of reactor volume. Cumulative
yield is calculated based on 1.8% yield per RV, ceasing at a maximum
value of 50%.

Figure 5. Top: Experimental conﬁguration, centered around amultiposition stirrer hot plate at 80 °C. Bottom: Well-mixed triphasic
reaction mixtures in cascade CSTRs.

Three-Phase Catalytic Hydrogenation. Hydrogenation oforganic compounds in the presence of a suitable heterogeneous
metal catalyst is of great importance to both academic andindustrial laboratories. Small scale batch hydrogenations posean operational hazard in the use of hydrogen gas, requiring
dedicated high-pressure resistant reactors and autoclave
conditions.40 Moreover, small batch vessels at the industrial
scale become impractical, as reduced plant size incurs thepenalty of multiple ﬁll/empty cycles. Our low-volume reactor
oﬀers a combination of better heat transfer and mixing thantypical batch reactorsideal for S/L/G-phase reactions such ashydrogenation which are both exothermic and mass transfer
limited (for heat capacity studies, see the Supporting
Information). A benchmark reduction reaction comprising asolid catalyst (Pd/C), liquid reagent feed (nitrobenzene), andhydrogen gas was employed to assess the feasibility of this idea.
A methanolic slurry of 5% Pd/C and nitrobenzene (500 mM)
was fed into chamber 1 of a four-stage CSTR, meeting three
separate streams of hydrogen gas in the mixing zones ofchambers 1, 2, and 3 (Scheme 4 and Figure 5).

Figure 6. Representative plot of conversion of nitrobenzene to aniline
over 4 RVs, as determined by GC analysis.

This ﬁnal study demonstrates the (i) modularity, (ii)enhanced mixing over long residence time, and (iii) simple
heating capability of the reactor, opening up a broad array ofcontinuous-ﬂow chemistry to this reactor type.

Scheme 4. Triphasic Hydrogenation of Nitrobenzene in a
Four-Stage Heated Reactor■

CONCLUSIONS
A new, free-to-access multistage continuous stirred tank reactor
has been designed, constructed, and implemented in a variety
of multiphasic chemical processes. The reactor has been
conceived to enable chemists to explore continuous-ﬂow
methodology with little to no expertise required. The design
is simple, versatile, and inexpensive to produce, with 60 reactors
and stirrer motors currently in operation from our laboratory.
The small volume of each reactor is well-suited to laboratory
scale experiments where materials are typically precious and notcommercially available. Moreover, these plug-and-play units areequipped with universal HPLC ﬁxtures and ﬁttingsideal for
deployment among common laboratory equipment (asdemonstrated within). Through this report, we have provided
examples of processes involving combinations of solid, liquid,and gas reagents/products and the potential for our reactor

The full, noninsulated reactor was simply heated using a
multiposition stirrer hot plate, generating a reaction mixture
temperature of 60 °C after 2 min heating time (Figure 5). Aftera long residence time of 3 h was employed and following 1 RV,
the aromatic nitro group was reduced to aﬀord aniline in 84%
conversion at steady state (Figure 6). In our hands, theanalogous batch protocol required 16 h to reach 92%
conversion (see the Supporting Information).
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Articlegenase CDX-901 Codexis (2 mgmL−1) in 50 mL of NaPi buﬀer(100 mM, pH 7.0). Syringe 2: 2-propyl-3,4,5,6-tetrahydropiperidinium hydrochloride (100 mM), NADPH (10 mM),
glucose (50 mM) in 50 mL of NaPi buﬀer (100 mM, pH 7.0).
Each syringe was fed at 0.26 mL min−1 (τres = 19 min), and thereactor eluent was collected in RV fractions containing NaOH
(10 M, aqueous) to immediately quench the output phase.
Under steady-state conditions, the reaction achieved 89%
conversion and 98% ee, as determined by the same chiral GC
method above.
Synthesis of N-Chloroamines. Two syringe pumps
equipped with 50 mL syringes were connected to a reactor ofn chambers in series. Syringe 1: N-methylbenzylamine/N,Ndibenzylamine (1 M in toluene). Syringe 2: NaOCl (1.1 M inwater). Each syringe was fed at equal ﬂow rate to provide thedesired τres over n CSTRs (see Table 1). The reactor eluent wascollected in RV fractions and the organic phase separated
immediately to prevent further reaction. The organic phase wasconcentrated in vacuo and analyzed by 1H NMR spectroscopy
to determine crude conversion (see below).
N-Chloro-N-methylbenzylamine. Two-stage CSTR, τres =20 min, quantitative conversion. 1H NMR (CDCl3, 400 MHz)δH (ppm) 7.35−7.31 (m, 5H, CHAr), 4.05 (s, 2H, CH2), 2.94
(s, 3H, CH3).
N-Chloro-N,N-dibenzylamine. Five-stage CSTR, τres = 30
min, 42% conversion. 1H NMR (CDCl3, 300 MHz) δH (ppm)
7.39−7.30 (m, 20H, CHAr amine and chloramine), 4.14 (s, 4H,
2 × NClCH2 chloramine), 3.81 (s, 4H, 2 × NHCH2 amine). Alldata are consistent with those reported in the literature.31
Electrocyclization Reaction. A four-stage CSTR wasconnected to two input feeds. Feed 1: a biphasic (binary)
mixture of aqueous NaOH (1.25 M) and DCM (blank). Feed
2: aqueous N-propargylpyridinium bromide (1 M). Each feed
was pumped at 2.0 mL min−1 (τres = 2 min) through thereactor, and a commercially available membrane-based liquid/
liquid separator (Zaiput) was utilized to segment the organic
and aqueous phases in continuous ﬂow.41 The organic partition
was collected in reactor volume fractions (4 mL, based on fullL−L separation) and the solvent allowed to evaporate. The
residue was analyzed by 1H NMR spectroscopy to assess purity
and weighed to determine isolated yield. Under steady-state
conditions, the imidazopyridine product was formed in 97%
isolated yield.
2-Methylimidazo[1,2-a]pyridine. 1H NMR (300 MHz,CDCl3) δH (ppm) 8.24 (dt, J = 6.6, 2.1, 0.9 Hz, 1H, pyH),
7.58 (d, J = 9.0 Hz, 1H, pyH), 7.49 (s, 1H, imH), 7.20 (m, 1H,
pyH), 6.80 (td, J = 9.0, 6.6, 0.9 Hz, 1H, pyH), 2.41 (d, J = 0.9
Hz, 3H, CH3). 13C{1H} NMR (75 MHz, CDCl3) δC (ppm)
143.2, 140.2, 126.5, 126.1, 115.2, 113.3, 110.2, 13.1. All data areconsistent with those reported in the literature.32
Amine Monoacetylation Reaction. Batch procedure:
ethylene diamine (60 mg, 1 mmol) and DI water (0.63 mL)
were added to a round-bottomed ﬂask. Acetic anhydride (102
mg, 1 mmol) in toluene (0.63 mL) was added dropwise, andthe reaction continued for 20 min. The aqueous phase wasseparated, and water was removed to leave a crude productresidue. The oil composition was analyzed by 1H NMR
spectroscopy.
Flow procedure: two syringe pumps equipped with 50 mL
syringes were connected to a reactor of n chambers in series.
Syringe 1: ethylene diamine (1.6M) in NaOAc/AcOH (2M,
buﬀered to pH 5). Syringe 2: acetic anhydride (1.6M) intoluene. Each syringe was fed at equal ﬂow rate to provide thedesign to accommodate each (see Table 3 for a summary). In
all but one of the cases, productivities were improved by
Table 3. Summary of Multiphasic Reactions Evaluatedwithin This Study
productivity(g L−1 h−1)
entrytype of reaction

phase (G, L, S)

τres (min)

batch

ﬂow

1
2
3
4
5
6

IRED
N-chloroamine
monoacetylation
heterocyclization
crystallizationhydrogenation

L
L/L
L/L
L → L/L
L → L/S
G/L/S

19
5−50
30
2
20
180

6.4
198a
51
660c
8.2
3.5d

17
826b
173
1920
31
0.12

Using static mixer; see ref 31. bτres = 5 min. cSee ref 32. d92% yield at
16 h.

a

process translation from batch to ﬂow. The current modelshows some limitation where solid−liquid reactions areconcerned (0.7 wt % demonstrated here), though a recent
study from our group (not reported here) has shown a slurry of
Cs2CO3 in DMF to ﬂow comfortably through the reactor
without blockage; research remains ongoing to improve thesesystems. Nevertheless, our straightforward design requires only
removal of one bolt to fully disassemble the reactor for easyclean-out of reaction debris. The ability to join low-volume
CSTR units in cascade provides a means of tailoring reactor
volume, and therefore residence time, to suit markedly diﬀerent
reaction types. On each end of this spectrum, we have
performed a rapid, room temperature heterocyclization reaction(τr = 120 s) alongside a much slower, high-temperature
triphasic catalytic hydrogenation (τr = 3 h)both being
feasible with the same reactor geometry, which is unprecedented. It is anticipated that these simple yet robust, freely
accessible reactors will open new avenues for ﬂow chemistry
and help lift the current barriers associated with processtranslation for the modern chemist.

■

EXPERIMENTAL SECTION
General Remarks. Standard 1/8 or 1/6 in. o.d. PTFE
tubing and ﬁttings were used as purchased from commercial
HPLC suppliers. PTFE-coated magnetic cross (10 mm dia.)and straight stir bars (8 × 3 mm) were obtained from VWRLtd. All reactor cascades were linked using 1/8 in. PTFE
tubing. All reactions were carried out under an atmosphere of
air. Propargylpyridinium bromide was prepared as previously
reported.32 Deuterated CDCl3 and D2O were used as supplied.
1
H and 13C NMR spectra were recorded on either a Bruker
DPX300 (300/75 MHz) spectrometer or a Bruker AV3-400(400/100 MHz) spectrometer using the residual solvent as aninternal standard. The values of chemical shifts are reported inparts per million (ppm) with the multiplicities of the spectra
reported as follows: singlet (s), doublet (d), triplet (t), quartet(q), multiplet (m), and broad (br); values for coupling
constants (J) are assigned in hertz.
Imine Reductase Bioreaction. Batch procedure: apreviously reported protocol (Turner et al.) was followed toobtain (R)-2-propylpiperidine with >98% conversion and >98%
ee after 24 h.27 Product analyzed by chiral GC: tR(imine) = 14.92,
tR(S)‑amine = 15.57, tR(R)‑amine = 15.80 min. Flow procedure: a ﬁvestage CSTR was connected to two 50 mL automated syringes.
Syringe 1: (R)-IRED enzyme (2 mgmL−1), glucose dehydro1299

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Org. Process Res. Dev. 2017, 21, 1294−1301

Organic Process Research & Development

Articlestirrer hot plate maintained at 80 °C, generating an internalsolvent temperature of 60 °C. The output of stage 4 was ﬂowed
directly into a sealed container housing a back-pressure
regulator (20 psi) exit valve to provide controlled multiphasic
ﬂow. The reactor eluent was collected in RV fractions (4 × RVs
over 12 h process time), ﬁltered over Celite, diluted with aninternal standard, and analyzed by gas chromatography toassess conversion: tR(ArNO2) = 3.10, tR(ArNH2) = 1.81, tR(ISTD) =11.10 min. Under steady-state conditions, the reaction achieved
84% conversion.

desired τres over n CSTRs (see Table 2). The biphasic reactor
eluent was collected in RV fractions, and the aqueous phase wasseparated immediately to prevent further reaction. Water was
removed in vacuo to leave the crude product mixture as an oily
residue, which was analyzed by 1H NMR spectroscopy todetermine crude composition (see below).
Monoacetylated Amine. 1H NMR (500 MHz, D2O) δH
3.42 (t, J = 5.8 Hz, 2H, AcHNCH2), 3.07 (t, J = 5.8 Hz, 2H,
H2NCH2) 1.95 (s, 3H, CH3). All data are consistent with thosereported in the literature.42
Diacetylated Amine. 1H NMR (500 MHz, D2O) δH 3.22 (s,4H, 2 × CH2), 1.90 (s, 6H, 2 × CH3). All data are consistent
with those reported in the literature.43
Continuous Crystallization Reaction. A ﬁve-stage CSTR
was connected to two syringe pumps equipped with 60 mL
syringes. Syringe 1: rac-salsolidine (0.35 g, 16.8 mmol, 0.28M)
in EtOAc/MeOH (7:1) (60 mL). Syringe 2: (S)-mandelic acid
(1.3 g, 8.4 mmol, 0.14M) in uniform solvent. Each syringe was
fed at 0.25 mL min−1 (τres = 20 min), and the reactor output
was collected in RV fractions. Each fraction was ﬁltered, dried,
and weighed to assess isolated yield (the sum of which provides
cumulative yield). The de of each RV was determined by 1H
NMR spectroscopy, relative to each pure diastereoisomeric salt(see below).

■

ASSOCIATED CONTENT* Supporting InformationS

The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.oprd.7b00173.
Reactor design and characterization information andsupplementary reaction information (PDF)■

AUTHOR INFORMATION

Corresponding Authors*E-mail: n.kapur@leeds.ac.uk.
*E-mail: j.blacker@leeds.ac.uk.
ORCID

Adam D. Clayton: 0000-0002-4634-8008
Nicholas J. Turner: 0000-0002-8708-0781
A. John Blacker: 0000-0003-4898-2712
Author Contributions

The manuscript was written through contributions from A.J.B.,
N.K., M.B., and M.R.C. All authors have given approval to theﬁnal version of the manuscript.

11(S)·2(S). [α]23D = +39.6 (c 1.10, CHCl3). H NMR (CDCl3,
500 MHz) δH (ppm) 7.31 (d, J = 7.0 Hz, 2H, H14 and H18),
7.19 (m, 3H, H15, H16 and H17), 6.53 (s, 1H, H8), 6.47 (s, 1H,
H5), 4.77 (s, 1H, H12), 3.98 (q, J = 6.6 Hz, 1H, H1), 3.87 (s, 3H,
OCH3), 3.86 (s, 3H, OCH3), 3.16 (m, 1H, H3), 2.98 (m, 1H,
H3), 2.72 (m, 2H, H3 and H4), 1.45 (d, J = 6.6 Hz, 3H, CH3).
13
C{1H} NMR (125 MHz, CDCl3) δC (ppm) 178.8 (C11),
148.6 (C7), 148.3 (C6), 142.2 (C13), 128.0 (C15 and C17),127.0 (C16), 126.5 (C14 and C18), 125.6 (C9), 123.6 (C10),
111.3 (C8), 108.7 (C5), 74.4 (C12), 56.1 (OCH3), 55.9
(OCH3), 50.3 (C1), 39.0 (C3), 25.2 (C4), 19.8 (CH3).
1
1(R)·2(S). [α]23D = +66.3 (c 1.10, CHCl3). H NMR (CDCl3,
14500 MHz) δH (ppm) 7.27 (m, 2H, H and H18), 7.15 (m, 3H,
H15, H16 and H17), 6.55 (s, 1H, H8), 6.48 (s, 1H, H5), 4.74 (s,1H, H12), 4.17 (q, J = 6.6 Hz, 1H, H1), 3.87 (s, 3H, OCH3),
3.86 (s, 3H, OCH3), 3.19 (m, 1H, H3), 2.89 (m, 2H, H3 andH4), 2.74 (m, 1H, H4), 1.41 (d, J = 6.6 Hz, 3H, CH3). 13C{1H}
NMR (125 MHz, CDCl3) δC (ppm) 178.8 (C11), 148.6 (C7),148.3 (C6), 142.1 (C13), 127.9 (C15 and C17), 127.0 (C16),
126.4 (C14 and C18), 125.7 (C9), 123.6 (C10), 111.3 (C8),108.7 (C5), 74.4 (C12), 56.1 (OCH3), 56.0 (OCH3), 50.3
(C1), 38.9 (C3), 25.3 (C4), 19.6 (CH3).
Catalytic Hydrogenation Reaction. Stage 1 of a fourstage CSTR was connected to two input feeds. Feed 1: a 50 mL
glass syringe containing a microstir bar charged with nitrobenzene (500 mM), 5% Pd/C (4 mgmL−1), and methanol (50mL). The syringe contents were stirred throughout the reaction
to allow pumping of a uniform suspension, at 0.04 mL min−1.
Feed 2: a gastight glass syringe containing hydrogen gas (100mL), fed at 0.2 mL min−1. Stages 2 and 3 were each linked tohydrogen gas feeds in an analogous manner. The entire reactor
was placed directly onto a commercially available multiposition

Notes

The authors declare no competing ﬁnancial interest.

■

ACKNOWLEDGMENTS
The authors would like to thank AstraZeneca and EPSRC for
the CASE award studentship (M.K. and L.T.). They would also
like to thank BBSRC for the BioCatNet NIBB Grant and ACS
GCI Pharmaceutical Roundtable for Green Chemistry Award(M.R.C., N.J.T., N.K., A.J.B., and I.E.S.). N.K. thanks GSK and
RAEng for his Research Chair. The research leading to theseresults has received funding from the Innovative Medicines
Initiative Joint Undertaking under Grant Agreement No.
115360, resources of which are composed of ﬁnancial
contribution from the European Union’s Seventh Framework
Programme (FP7/2007-2013) and EFPIA companies in kind
contribution (to K.E.J.).

■

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