Simple and Versatile Laboratory Scale CSTR for Multiphasic Continuous-Flow Chemistry and Long Residence Times

Article abstract of DOI:10.1021/acs.oprd.7b00173

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 to multiphasic continuous-flow chemistry. Importantly, the reactor geometry is easily customized to accommodate reactions requiring long residence times (≥3 h tested).

Full text of DOI:10.1021/acs.oprd.7b00173

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Full Paper
A Simple and Versatile Laboratory Scale CSTR for Multiphasic
Continuous-Flow Chemistry and Long Residence Times
Michael R Chapman, Maria H. Kwan, Georgina King, Katherine E Jolley, Mariam Hussain,
Shahed Hussain, Ibrahim E Salama, Carlos González Nino, Lisa A Thompson, Mary E
Bayana, Adam Clayton, Bao N. Nguyen, Nicholas J Turner, Nikil Kapur, and A. John Blacker
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.7b00173 • Publication Date (Web): 28 Jun 2017
Downloaded from http://pubs.acs.org on June 28, 2017
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A Simple and Versatile Laboratory Scale CSTR for
Multiphasic ContinuousꢀFlow Chemistry and Long
Residence Times
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Michael R. Chapman,a,c Maria H. T. Kwan,c Georgina King,c Katherine E. Jolley,c Mariam
Hussain,a Shahed Hussain,d Ibrahim E. Salama,a,c Carlos González Niño,b Lisa A. Thompson,c
Mary E. Bayana,a,c Adam D. Clayton,c Bao N. Nguyen,a,c Nicholas J. Turner,d Nikil Kapur,*b,c
and A. John Blacker*a,c
a School of Chemical and Process Engineering, University of Leeds, Clarendon Road, Leeds,
LS2 9JT, UK.
b School of Mechanical Engineering, University of Leeds, Woodhouse Lane, Leeds, LS2 9JT,
UK.
c Institute of Process Research and Development, School of Chemistry, University of Leeds,
Woodhouse Lane, Leeds, LS2 9JT, UK.
d School of Chemistry, University of Manchester, Manchester Institute of Biotechnology, 131
Princess Street, Manchester, M1 7DN, UK.
*Corresponding authors. Eꢀmails: j.blacker@leeds.ac.uk, n.kapur@leeds.ac.uk
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ABSTRACT: A universal multiꢀstage cascade CSTR has been developed which is suitable for a
wide range of continuousꢀflow processes. Coined by our group the ‘Freactor’ (freeꢀtoꢀaccess
reactor), the new reactor integrates the efficiency of pipeꢀflow processing with the advanced
mixing of a CSTR, delivering a general ‘plugꢀandꢀplay’ reactor platform which is wellꢀsuited to
multiphasic continuousꢀflow chemistry. Importantly, the reactor geometry is easily customized to
accommodate reactions requiring long residence times (≥ 3 hours tested).
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KEYWORDS: continuous flow; small continuous stirred tank reactor; multiphase; gas liquid
solid; productivity; residence time.
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INTRODUCTION
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The past two decades have seen farꢀreaching progress in the development of microfluidic
systems for use in chemical synthesis, with the field continuing to mature exponentially.1–7 On
account of their low chemical inventory, continuousꢀflow 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 obtained with traditional batch processing.8,9
Moreover, the integration of realꢀtime analysis and automation with lowꢀvolume flow reactors
enables chemists to explore incredibly wide regions of operational parameter space over
relatively short periods of time.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 Kirschning12 and
Tamoxifen by Ley.13 In a wellꢀargued publication by Jensen and McMullen, the de-facto
conditions under which flow chemistry ‘makes sense’ have been condensed to those whereby the
rate of chemical reaction surpasses the associated mass transfer of a system.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 (organicꢀaqueous phases),
slurries (solidꢀliquid) or hydrogenation (solidꢀliquidꢀgas) – each requiring effective mixing and
long residence times. Static mixers built within tubular reactors can offer these conditions,
though require high volumetric flow rates which may not be feasible for slow reactions (e.g. > 5
minutes) (Figure 1).15
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Figure 1. Top: impact of biphasic flow performance on mixing regime in tubular/static mixed
reactors. Middle: CofloreTM reactor developed by AMTech. Bottom: wellꢀmixed cascade CSTR
reactor reported here.
In 2011, Greiner and colleagues made some headway towards slow continuousꢀflow
processing through use of a nestedꢀpipe reactor.16 During a 14ꢀday test campaign, the authors
demonstrated the potential of this reactor geometry by producing 20 kg of product per day.
However, the bespoke reactor is not trivial to assemble nor appropriate for small scale
processing. TaylorꢀCouette reactors, in which a rotating cylinder provides mixing, have been
employed in slow continuous biological and polymerization processes, though rely on product
extraction against gravity which may become challenging in cases where solid products are
formed.17,18 Consecutive or cascade continuous stirred tank reactors (CSTRs) provide a solution
to these problems. However, conventional cascade CSTRs are convoluted, expensive and
oversized where material availability is low – a technological gap which places limitation on the
accessibility and development of continuousꢀflow chemistry in academia and industry.19 Thus,
miniaturization of CSTRs for synthetic research laboratories represents a significant step towards
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broadening the range of chemical transformation suitable for continuous mode. AMTech have
produced a laboratory and large scale multistage CSTR, the CofloreTM reactor, consisting of a
series of looseꢀfitting polymer inserts that provide mixing as the entire unit is shaken (Figure 1,
middle).20 Equally, the Jensen group have recently reported a miniature consecutive CSTR which
performed comparably to its standard size counterpart in two solidꢀforming reactions.21
Likewise, Lapkin and Meadows have also recently published a reactor which closely resembles a
sequence of CSTRs linked in a single compact block, comprising no unmixed connections
between adjacent chambers and is suitable for solidꢀforming processes.22 Herein, we report our
own independent successes in CSTR miniaturization, based on the principles of openꢀsource,
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 general platform
to explore continuousꢀflow processing with little expertise required. As with other cascade CSTR
systems, as the number of reactors in series is increased, the overall performance tends towards
that of a wellꢀmixed plugꢀflow reactor, which ensures uniformity of processing conditions. For
example, five 2 mL cascade CSTRs provide greater uniformity of residence time than a single 10
mL CSTR – in general, the greater the number of CSTRs the closer to ideality the system
becomes. The CSTRs have been evaluated against their batch counterparts for a variety of
important and challenging multiphasic processes, including enzymatic imine reduction,
cycloisomerization, Nꢀchloroamine synthesis, classical resolution of chiral amines and
heterogenous Pdꢀcatalyzed hydrogenation. Through these examples, we tackle many of the
difficulties associated with scaleꢀup of multiphasic phenomena and demonstrate the tunability of
our reactor to facilitate reactions requiring long residence times (τr, covering a tested range of 2
minutes to 3 hours).
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RESULTS AND DISCUSSION
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Reactor design. Practicality, simplicity and versatility to accommodate different reactions
were identified as important design 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
openꢀsource piece of equipment, and develop an online userꢀcommunity to share experiences.†
The CSTRs and ancillaries are mobile and able to sit alongside standard laboratory equipment
(e.g. syringe/peristaltic pumps, glassware, inꢀline filters, backꢀpressure regulators, separators, onꢀ
or atꢀline analysis). The reactor reported here is composed of polyacetal plastic, which is
inexpensive, compatible with most solvents/reagents (with exception of strong acids/bases) and
is easily fabricated.23 This acetal plastic performs well as an insulator, allowing high temperature
reactions to be conducted through feeding hot starting materials directly into the reactor. Over a
single CSTR, a flow of water (1 mLminꢀ1) at 50°C gave a 3.9°C temperature drop (0.35 W) over
the reactor, due to heat loss to the surroundings with no additional insulation. Conventional
machining of a plastic stock rather than 3D printing the reactors24 (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 the expense of structural performance, is building additional functionality or
flexibility in evaluating designs. The base component of each reactor unit comprises a cylindrical
reservoir (2 mL volume) containing a magnetic stir bar for enhanced, lowꢀvolume and uniform
mixing (Figure 2, top left). 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
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robust and simple flowꢀreactor assembly (Figure 2, top right). The glass window allows physical
reaction monitoring, and could enable realꢀtime spectroscopic analysis of flow systems, or the
use of photochemistry by careful choice of glassꢀtype and volume depth. Up to five (but
generally three) ports are drilled perpendicular to the reaction chamber to allow modular
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combinations of inlets and outlets. Standard HPLC /8” 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 ESI), with some evidence of leaking
beyond this pressure. Importantly, the reactors are stirred magnetically which is much simpler
than use of mechanical agitators or shakerꢀbeds (Figure 2, bottom).25 Both straight and crossꢀbar
PTFEꢀcoated magnetic stir bars (dia. 8ꢀ10 mm) were selected to provide a close fit to the walls of
the reactor vessel. The rotation rate of the stir bar was assessed using a stroboscope (16 rsꢀ1),
comparing favorably with commercial stirrer plates also used within our study (18 rsꢀ1).
Figure 2. Top left: individual components of the reactor (10 pence for scale). Top right:
assembled single reactor unit. Bottom: 3ꢀstage cascade of reactors in series.
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Reactor characterization. Heat transfer capability, residence time distribution (RTD) analysis
and gasꢀliquid mass transfer efficiency (kLa) were evaluated and are supplied in the ESI.
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Enzymatic Biotransformation
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Imine reductase (IRED). Imine reductase enzymes are highly efficient biocatalytic
alternatives to chemical (transfer) hydrogenation catalysts in the asymmetric reduction of imines
to afford enantioenriched amines.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 5ꢀstage 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
0.1M 2ꢀpropylꢀ3,4,5,6ꢀtetrahydro piperidinium hydrochloride (Scheme 1).28 At an overall flowꢀ
rate of 0.52 mLminꢀ1 (τr = 19 min), the process reached steadyꢀstate after 2.5 reactor volumes
(RVs) – noting that the RV is based on the total volume of the cascade.
Scheme 1. Continuousꢀflow biotransformation of propyl iminium with (R)ꢀIRED in 5ꢀstage
CSTR.
Conversion (%) and e.e. (%) determined by chiral GC. V = reactor volume, QF = final
volumetric flowꢀrate.
At this point, 89% conversion of substrate was achieved to produce (R)ꢀamine with 98% e.e..
The spaceꢀtimeꢀyield of 17 gLꢀ1hꢀ1 compares favorably with the batch reaction (6.4 gLꢀ1hꢀ1), the
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improvement is likely due to lack of product accumulation 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.
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Chemical Reactions
Synthesis of N-chloroamines. Chlorinated amines represent an electrophilic aminating tool
which are useful for a wide number of synthetic reactions.29 The biphasic liquid synthesis of
Nꢀchloroamines from NaOCl and secondary amine in organic solvent may be considered a green
reaction, generating only NaCl and NaOH byproducts with high atom efficiency.30 We have
previously reported a continuousꢀflow synthesis of various N,NꢀdialkylꢀNꢀchloroamines using
either a bespoke mesoꢀscale tubular reactor with static mixers, or a 50 mL singleꢀstage CSTR
(Table 1, entries 1 and 2, respectively).31 Taking NꢀchloroꢀNꢀmethylbenzylamine as an example,
it was decided to compare these reactor types to our CSTR (see subsequent entries of Table 1).
Table 1. Continuous liquid biphase reaction of NaOCl with amine in toluene/water.
Entry No. CSTRs (n) Reactor Volume (mL) τres (min) Conversion (%)a
1b
2b
3b
4b
5b
6b
Static mixer
6 (1.6 mixed)
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25
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10
10
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89c
94c
100
83
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5
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50
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6
10
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aAnalyzed by 1H NMR spectroscopy, bproduct NꢀchloroꢀNꢀmethylbenzylamine, cref.31,
dproduct Nꢀchlorodibenzylamine.
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Using a 2ꢀstage CSTR construct, Nꢀmethylbenzylamine (1.0M in toluene) and NaOCl (1.1M in
water) were fed independently into the reactor at room temperature. Adopting a residence time of
20 minutes, the chlorinated product was formed in quantitative conversion (entry 3).
More productively, a 5ꢀstage reactor and residence time of 5 minutes delivered the product in
94% conversion, leading to a productivity of 0.88 kgLꢀ1hꢀ1 at steadyꢀstate (entry 6). Comparing
these with previous studies, a tubular static mixed system produced the NꢀchloroꢀNꢀ
methylbenzylamine in 89% conversion, and a singleꢀstage CSTR in 94% conversion (τr = 20 and
25 minutes, respectively – entries 1 and 2). Interestingly, dibenzylamine substrate partitions
preferably into the organic phase, making reactions without a phase transfer catalyst even slower
and unsuitable for poorly mixed tubular reactors. In the singleꢀstage 50 mL CSTR from previous
studies, dibenzylamine chlorinated with 40% conversion in 50 minutes’ residence time (entry 7).
1
th
Pleasingly, using our reactor at /5 the scale, a comparable conversion was realized in a
residence time of 30 minutes (entry 8), indicating improved mass transfer.
Electrocyclization. Our group recently reported a rapid, NaOHꢀpromoted cycloisomerization
reaction of several Nꢀalkynylated 2ꢀaminopyridinium bromides under aqueous conditions.32
The pyridinium halides are cyclized instantaneously upon contact with base, producing the
imidazopyridine products as waterꢀinsoluble oils during reaction. Whilst this simplifies product
recovery in batch, we speculated that such a rapid reaction would naturally suit a continuousꢀ
flow mode to boost spaceꢀtimeꢀyield. Although the reaction itself appears under diffusive control
(i.e. does not require additional mixing nor long residence times), preliminary results have shown
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the dispersion 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 to maintain product dispersion out of the pipe, or
(ii) input an organic solvent feed to extract the product in situ. To demonstrate the modularity of
our design, the latter was selected. Using a 4ꢀstage CSTR, aqueous solutions of Nꢀpropargylꢀ2ꢀ
aminopyridinium bromide (1M) and NaOH (1.25M) were fed at equal flowꢀrate into chamber 1.
Prior to the mixing zone, a constant stream of DCM solvent was fed at a matched overall flowꢀ
rate to immediately extract the desired product in continuousꢀflow. At this point, the benefits of
our plugꢀandꢀplay design became evident as the final chamber was linked to a liquidꢀliquid
membrane separator via standard HPLC fixtures, allowing simple inꢀline purification of the
heterocyclic product (Scheme 2).
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Scheme 2. Continuousꢀflow electrocyclization, with inꢀline membrane separation of product.
In-line
membrane
separator
Br
(1M in H2O)
N
NH2
DCM feed
Organic
N
N
NaOH(aq)
(2.5M)
Qorg
2.0 mLmin-1
4
97%
V = 8 mL
τr = 2 min
Aqueous
NaBr, H2O
Yield (%) is isolated. Qorg = exit flowꢀrate of organic stream.
Following 2 RVs, the desired product was formed and separated in 97% yield with a residence
time of 2 minutes (Figure 3), generating a steadyꢀstate spaceꢀtimeꢀyield of 32 gLꢀ1minꢀ1 – triple
the value obtained in batch (10.9 gLꢀ1minꢀ1).
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Figure 3. Representative plot of isolated yield (red)/cumulative mass yield (blue) of
imidazo[1,2ꢀa]pyridine as a function of reactor volume.
N-Acetylation of ethylene diamine. Selective monoꢀfunctionalization of symmetrical
materials, such as diamines, is important due to their widespread use as linkers in the
pharmaceutical industry. However, two key challenges exist for these reactions: (i) suppression
of overꢀfunctionalization, and (ii) control of phase partitioning, which often leads to low yielding
processes. Maurya and Wille have independently shown the use of continuous plugꢀflow and
microreactor technology to provide high selectivity in making monoꢀprotected 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 wellꢀmixed biphase
to both minimize diꢀfunctionalization and maximize product partitioning. To test this hypothesis,
an aqueous feed of ethylene diamine was met with an equimolar toluene solution of acetic
anhydride in chamber 1 of the reactor, and subsequently flowed through n CSTR stages (Table 2,
column 2).
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Table 2. Batch versus continuous liquid biphase monoꢀacetylation reaction.
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Entry No. CSTRs τres Conversion (%)a/ Productivity
(n)
(min) Selectivity (%)a,b
(gLꢀ1hꢀ1)
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Batch
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aAnalyzed by 1H NMR spectroscopy at steadyꢀstate, bselectivity for monoꢀacetylated amine.
In comparison to batch (entry 1), a 6ꢀstage CSTR allowed a 16% increase in conversion of
ethylene diamine, with 7% drop in selectivity to form the desired product (entry 4).
Selectivity could be improved by reducing the number of stages in the reactor geometry whilst
maintaining a residence time of 20 minutes, though this was shown to compromise conversion
(entry 2). Employing a 5ꢀstage CSTR, with a residence time of 30 minutes delivered the desired
diamine in 83% conversion with 84% selectivity, leading to a 3.4ꢀfold higher productivity value
than obtained in batch mode (entry 5).
Continuous crystallization. Solidꢀforming reactions are notoriously challenging to process in
continuousꢀflow due to reactor 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
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engineered reactors to facilitate the transport of a slurry.35–39 With these in mind, we became
interested in the ability to manage the flow of particulate suspensions, as a general alternative to
those listed above. The classical resolution of racꢀsalsolidine 1, via diastereomeric crystallization
with (S)ꢀmandelic acid 2(S) was investigated (Scheme 3). Employing a 5ꢀstage CSTR,
EtOAc/MeOH (7:1) solutions of each were pumped into chamber 1 – immediately producing a
crystalline slurry upon contact (0.7 wt.% at steadyꢀstate). Following a residence time of 20
minutes, crystals of 1(R).2(S) from the output stream were collected by filtration and analyzed by
1H NMR spectroscopy to show a d.e. of 91% at steadyꢀstate.
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Scheme 3. Slurryꢀflow diastereomeric crystallization of salsolidine and (S)ꢀmandelic acid in a 5ꢀ
stage reactor.
1
Weight of crystals are dry, and d.e. (%) is determined by H NMR spectroscopy. V = reactor
volume, QF = final volumetric flowꢀrate.
Each RV consistently delivered crystals of 1(R).2(S) in 1.8% isolated yield, which albeit
relatively low, produced a cumulative yield of 24% over 13 RVs (Figure 4). These findings
compare favorably with the analogous batch system, affording lower quality crystals in 30%
yield with 83% d.e. (see ESI). Ongoing research from our group has shown semiꢀbatch
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recirculation of the mother liquor through the reactor to be a useful method of achieving full
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resolution (i.e. 50% yield).
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Figure 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%.
Three-phase catalytic hydrogenation. Hydrogenation of organic compounds in the presence
of a suitable heterogenous metal catalyst is of great importance to both academic and industrial
laboratories. Small scale batch hydrogenations pose an operational hazard in the use of hydrogen
gas, requiring dedicated highꢀpressure resistant reactors and autoclave conditions.40 Moreover,
small batch vessels at the industrial scale become impractical, as reduced plant size incurs the
penalty of multiple fill/empty cycles. Our lowꢀvolume reactor offers a combination of better heat
transfer and mixing than typical batch reactors – ideal for S/L/Gꢀphase reactions such as
hydrogenation which are both exothermic and mass transfer limited (for heat capacity studies,
see ESI). A benchmark reduction reaction comprising a solid catalyst (Pd/C), liquid reagent feed
(nitrobenzene) and hydrogen gas was employed to assess the feasibility of this idea. A
methanolic slurry of 5% Pd/C and nitrobenzene (500 mM) were fed into chamber 1 of a 4ꢀstage
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CSTR, meeting 3 separate streams of hydrogen gas in the mixing zones of chambers 1, 2 and 3
(Scheme 4 and Figure 5).
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Scheme 4. Triphasic hydrogenation of nitrobenzene in a 4ꢀstage heated reactor.
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H2(g)
H2(g)
NO2
BPR
500 mM
NH2
2
5% Pd/C (4 mgmL-1)
MeOH slurry
84%
Freactor directly heated
to 60°C
Figure 5. Top: experimental configuration, centered around a multiꢀposition stirrer hotplate at
80°C. Bottom: wellꢀmixed triphasic reaction mixtures in cascade CSTRs.
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The full, nonꢀinsulated reactor was simply heated using a multiꢀposition stirrer hotplate,
generating a reaction mixture temperature of 60°C after 2 minutes heating time (Figure 5).
Employing a long residence time of 3 hours and following 1 RV, the aromatic nitro group was
reduced to afford aniline in 84% conversion at steadyꢀstate (Figure 6). In our hands, the
analogous batch protocol required 16 hours to reach 92% conversion (see ESI).
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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 of continuousꢀflow
chemistry to this reactor type.
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CONCLUSIONS
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A new, freeꢀtoꢀaccess multiꢀstage 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 continuousꢀflow methodology with littleꢀtoꢀno
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 not
commercially available. Moreover, these plugꢀandꢀplay units are equipped with universal HPLC
fixtures and fittings – ideal for deployment amongst common laboratory equipment (as
demonstrated 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 design
to accommodate each (see Table 3 for a summary). In all but one cases, productivities were
improved by process translation from batch to flow. The current model shows some limitation
where solidꢀliquid reactions are concerned (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 these systems.
Nevertheless, our straightforward design requires only removal of one bolt to fully disassemble
the reactor for easy cleanꢀout of reaction debris. The ability to join lowꢀvolume 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 heterocyclisation reaction (τr = 120 seconds) alongside a much slower, high
temperature triphasic catalytic hydrogenation (τr = 3 hours) – both being feasible with the same
reactor geometry, which is unprecedented. It is anticipated that these simple yet robust, freely
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accessible reactors will open new avenues for flow chemistry, and help lift the current barriers
associated with process translation for the modern chemist.
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Table 3. Summary of multiphasic reactions evaluated within this study.
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Entry Type of Reaction
Phase
(G, L, S) (min)
τres Productivity (gLꢀ1hꢀ1)
Batch
Flow
1
2
3
4
5
6
IRED
L
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5ꢀ50
30
6.4
17
NꢀChloroamine
Monoꢀacetylation
L/L
L/L
198a
51
826b
173
1920
31
Heterocyclization L → L/L
2
660c
Crystallization
Hydrogenation
L → L/S
G/L/S
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8.2
180
3.5d
0.12
aUsing static mixer, see ref. 31. bτres = 5 minutes. cSee ref. 32. d92% yield at 16 hours.
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EXPERIMENTAL
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General remarks. Standard /8” or /16” O.D. PTFE tubing and fittings were used as purchased
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from commercial HPLC suppliers. PTFE coated magnetic cross (10 mm dia.) and straight stir
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bars (8 × 3 mm) were obtained from VWR Ltd.. All reactor cascades were linked using /8”
PTFE tubing. All reactions were carried out under an atmosphere of air. Propargyl pyridinium
bromide was prepared as previously reported.32 Deuterated CDCl3 and D2O were used as
supplied. H and 13C NMR spectra were recorded on either a Bruker DPX300 (300/75 MHz)
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spectrometer or a Bruker AV3ꢀ400 (400/100 MHz) spectrometer using the residual solvent as an
internal standard. The values of chemical shifts are reported in parts 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 Hz.
Imine reductase bioreaction. Batch procedure: a previously reported protocol (Turner et al.)
was followed to obtain (R)ꢀ2ꢀpropylpiperidine with >98% conversion and >98% e.e. after
24 hours.27 Product analyzed by chiral GC: tR(imine) = 14.92, tR(S)ꢀamine = 15.57, tR(R)ꢀamine = 15.80
minutes. Flow procedure: a 5ꢀstage CSTR was connected to two 50 mL automated syringes.
Syringe 1: (R)ꢀIRED enzyme (2 mgmLꢀ1), glucose dehydrogenase CDXꢀ901 Codexis (2 mgmLꢀ1)
in 50 mL of NaPi buffer (100 mM, pH 7.0). Syringe 2: 2ꢀpropylꢀ3,4,5,6ꢀtetrahydropiperidinium
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 mLminꢀ1 (τres = 19 minutes), and the reactor eluent
was collected in RV fractions containing NaOH (10M, aqueous) to immediately quench the
output phase. Under steadyꢀstate conditions, the reaction achieved 89% conversion and 98% e.e.,
as determined by the same chiral GC method above.
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Synthesis of N-chloroamines. Two syringe pumps equipped with 50 mL syringes were
connected to a reactor of n chambers in series. Syringe 1: Nꢀmethylbenzylamine/N,Nꢀ
dibenzylamine (1M in toluene). Syringe 2: NaOCl (1.1M in water). Each syringe was fed at
equal flowꢀrate to provide the desired τres over n CSTRs (see Table 1). The reactor eluent was
collected in RV fractions and the organic phase separated immediately to prevent further
reaction. The organic phase was concentrated in vacuo and analyzed by 1H NMR spectroscopy to
determine crude conversion (see below).
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N-Chloro-N-methylbenzylamine. 2ꢀStage CSTR, τres = 20 min, quantitative conversion. H NMR
(CDCl3, 400 MHz) δH (ppm) 7.35ꢀ7.31 (m, 5H, CHAr), 4.05 (s, 2H, CH2), 2.94 (s, 3H, CH3).
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N-Chloro-N,N-dibenzylamine. 5ꢀStage CSTR, τres = 30 min, 42% conversion. H NMR (CDCl3,
300 MHz) δH (ppm) 7.39ꢀ7.30 (m, 20H, CHAr amine and chloramine), 4.14 (s, 4H, 2 × NClCH2
chloramine), 3.81 (s, 4H, 2 × NHCH2 amine). All data are consistent with those reported in the
literature.31
Electrocyclization reaction. A 4ꢀstage CSTR was connected to two input feeds. Feed 1: a
biphasic (binary) mixture of aqueous NaOH (1.25M) and DCM (blank). Feed 2: aqueous Nꢀ
propargyl pyridinium bromide (1M). Each feed was pumped at 2.0 mLminꢀ1 (τres = 2 minutes)
through the reactor, and a commercially available membraneꢀbased liquid/liquid separator
(Zaiput) was utilised to segment the organic and aqueous phases in continuousꢀflow.41 The
organic partition was collected in reactor volume fractions (4 mL, based on full LꢀL separation)
1
and the solvent allowed to evaporate. The residue was analysed by H NMR spectroscopy to
assess purity, and weighed to determine isolated yield. Under steadyꢀstate conditions, the
imidazopyridine product was formed in 97% isolated yield.
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2-Methylimidazo[1,2-a]pyridine. H NMR (300 MHz, CDCl3) δH (ppm) 8.24 (dt, J = 6.6, 2.1,
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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 are consistent
with those reported in the literature.32
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Amine mono-acetylation reaction. Batch procedure: ethylene diamine (60 mg, 1 mmol) and
D.I. water (0.63 mL) were added to a roundꢀbottomed flask. Acetic anhydride (102 mg, 1 mmol)
in toluene (0.63 mL) was added dropwise, and the reaction continued for 20 minutes. The
aqueous phase was separated, and water removed to leave a crude product residue. 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) in toluene. Each syringe was fed at equal flowꢀrate to
provide the desired τres over n CSTRs (see Table 2). The biphasic reactor eluent was collected in
RV fractions and the aqueous phase separated 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 to determine crude composition (see below).
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Mono-acetylated amine. H 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 those reported in the
literature.42
Di-acetylated 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
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Continuous crystallization reaction. A 5ꢀstage CSTR was connected to two syringe pumps
equipped with 60 mL syringes. Syringe 1: racꢀsalsolidine (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 mLminꢀ1 (τres = 20 minutes) and the reactor output
collected in RV fractions. Each fraction was filtered, dried and weighed to assess isolated yield
(the sum of which provides cumulative yield). The d.e. of each RV was determined by 1H NMR
spectroscopy, relative to each pure diastereoisomeric salt (see below).
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1(S).2(S). [ꢀ]ꢂꢁꢃ = +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,
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1H, H3), 2.98 (m, 1H, H3), 2.72 (m, 2H, H3 and H4), 1.45 (d, J = 6.6 Hz, 3H, CH3). 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).
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1(R).2(S). [ꢀ]ꢂꢁꢃ = +66.3° (c 1.10, CHCl3). H NMR (CDCl3, 500 MHz) δH (ppm) 7.27 (m, 2H,
H14 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,
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2H, H3 and H4), 2.74 (m, 1H, H4), 1.41 (d, J = 6.6 Hz, 3H, CH3). C{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
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(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).
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Catalytic hydrogenation reaction. Stage 1 of a 4ꢀstage 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 mgmLꢀ1) and methanol (50 mL). The syringe contents were stirred
throughout the reaction to allow pumping of a uniform suspension, at 0.04 mLminꢀ1. Feed 2: a
gasꢀtight glass syringe containing hydrogen gas (100 mL), fed at 0.2 mLminꢀ1. Stages 2 and 3
were each linked to hydrogen gas feeds in an analogous manner. The entire reactor was placed
directly onto a commercially available multiꢀposition stirrer hotplate maintained at 80°C,
generating an internal solvent temperature of 60°C. The output of stage 4 was flowed directly
into a sealed container housing a backꢀpressure regulator (20 psi) exit valve, to provide
controlled multiphasic flow. The reactor eluent was collected in RV fractions (4 × RVs over 12
hours’ process time), filtered over Celite, diluted with an internal standard and analyzed by gas
chromatography to assess conversion: tR(ArNO2) = 3.10, tR(ArNH2) = 1.81, tR(ISTD) = 11.10 minutes.
Under steadyꢀstate conditions, the reaction achieved 84% conversion.
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ASSOCIATED CONTENT
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Supporting Information
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The Supporting Information document provides reactor design and characterization information
and supplementary reaction information. This file (.PDF) is available free of charge.
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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 the final version of the manuscript.
Notes
† The CSTR ‘Freactors’ and stirrer motors were made to the design described in the ESI, with
plans to become available from both www.iprd.leeds.ac.uk/Freactors and Asynt Ltd..
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 these
results 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 (FP7/2007ꢀ2013) and EFPIA companies’ in
kind contribution (to K.E.J.).
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