The use of electroosmotic flow as a pumping mechanism for semi-preparative scale continuous flow synthesis

Article abstract of DOI:10.1039/b614559k

By employing a series of reactions we demonstrate the use of electroosmotic flow as a continuous pumping mechanism suitable for semi-preparative scale synthesis, affording an array of small organic compounds, of analytical purity, with yields ranging from 0.57-1.71 g h^-1. The Royal Society of Chemistry.

Full text of DOI:10.1039/b614559k

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
The use of electroosmotic flow as a pumping mechanism for
semi-preparative scale continuous flow synthesis
Charlotte Wiles, Paul Watts* and Stephen J. Haswell
Received (in Cambridge, UK) 6th October 2006, Accepted 24th November 2006
First published as an Advance Article on the web 11th December 2006
DOI: 10.1039/b614559k
materials. Although this technique illustrated advantages asso-
By employing a series of reactions we demonstrate the use of
electroosmotic flow as a continuous pumping mechanism
suitable for semi-preparative scale synthesis, affording an array
of small organic compounds, of analytical purity, with yields
ciated with continuous flow syntheses, namely the ease of product
isolation and catalyst recycle, the technique employed large
volumes of solvent (30 ml mmol21) and provided no control over
flow rate. This inability to readily alter a reagent’s residence time
led to incomplete product conversions when less reactive analogues
were employed, resulting in the need for additional off-line
purification. To address this shortfall, continuous flow techniques
have evolved to employ pressure-driven flow (in the form of
HPLC or displacement pumps), enabling the rate at which
reagents pass through the packed beds to be controlled.5 Using this
approach, an array of synthetic transformations have been
demonstrated including hydrogenations,6 oxidations,7 reductions,8
Diels–Alder reactions,9 Suzuki couplings10 and Michael addi-
tions,11 culminating in the ability to perform automated multi-
step syntheses, as illustrated by Ley and co-workers12 for the
synthesis of (¡)-oxomaritidine. Whilst the aforementioned
examples serve to illustrate the versatility of continuous flow
systems, in order for the technique to become more widely adopted
problems such as irreproducible flow (especially at low flow rates),
back-pressure generation and cumbersome operating systems,
need to be addressed.
ranging from 0.57–1.71 g h21
.
One of the slowest steps associated with lead compound generation
is the efficient synthesis and purification of small organic
compounds, in particular those used to introduce diversity into
combinatorial libraries. At present, the majority of synthetic
transformations performed in research laboratories employ
techniques, and glassware, that has remained largely unchanged
for decades. Furthermore, the use of long standing protocols can
mean that such reactions are performed using un-optimised
reaction conditions, the outcome of which is largely operator
dependent. Consequently, when target compounds are identified
and prepared for transfer to production, the synthetic route
frequently requires re-optimization, not only to address changes in
scale, but also to enable the process to be operated under a more
efficient continuous flow regime.
Owing to the pharmaceutical importance of a,b-unsaturated
compounds, we were interested in developing a simple synthetic
technique that would enable the rapid production of gram
quantities of analytically pure material, using continuous flow
methodology. Whilst a range of green approaches have been
investigated for the synthesis of such analogues, the use of water1
or ionic liquids2 as reaction media demands that a formal work-up
be performed in order to isolate, and where possible recycle, the
catalyst. To circumvent this problem, numerous authors have
reported the use of solid-supported bases, which can simply be
filtered from the reaction mixture.3 However, difficulties with the
technique arise due to mechanical degradation of the support
upon prolonged stirring, or shaking, of the reaction mixture in a
batch mode.
In the late 1980s, Venturello and co-workers4 reported the
Knoevenagel condensation under continuous flow, using a vertical,
double jacketed glass column packed with aminopropyl function-
alised silica gel. Reactions were performed by simply placing a
solution of aldehyde and activated methylene at the top of the
column, where it passed through the catalyst under gravity (as in
a liquid chromatographic process). Collection of the reaction
mixture at the outlet, followed by evaporation of the solvent
system, afforded the desired product and any unreacted starting
Having recently demonstrated the ability to synthesise milligram
quantities of analytically pure compounds in
a series of
miniaturised electroosmotic flow (EOF) based reactors,13 we were
interested in exploring methodologies capable of increasing the
throughput of the system. One option was to scale-out the
technique, i.e., increase the number of optimised micro-reactor
units employed, while an alternative approach was to simply
increase the size of the catalyst bed.
To date, EOF has largely found use as a pumping mechanism
for the manipulation of nl to ml quantities of material within
micron-sized capillaries and channel networks.14 However, as the
volumetric flow rate is largely dependent upon the cross-sectional
area of a channel, increasing the size of the channel enables the
flow rate to be readily increased. As such reactions are diffusion
limited, increasing the size of a reaction channel can be detrimental
to reaction efficiency as it leads to inefficient mixing. This is,
however, not the case when employing packed catalyst beds, as
the diffusion distance between the liquid phase and the solid-
supported catalyst, or reagent, remains the same irrespective of
the overall bed size. Unlike simple pressure-driven systems where
packed-bed size is limited by a reactor’s tolerance to pressure,
electroosmotic systems generate minimal back-pressure and
therefore have the potential to be scaled-up with ease. In addition,
the absence of mechanical pump drivers greatly reduces the
footprint of the reaction set-up, which simply consists of a power
supply (16 cm (w) 6 6 cm (d) 6 27 cm (l)) and a flow reactor
Department of Chemistry, Faculty of Science and the Environment, The
University of Hull, Cottingham Road, Hull, HU6 7RX, UK.
E-mail: P.Watts@hull.ac.uk.; Fax: +44 (0)1482 466410;
Tel: +44 (0)1482 465471
966 | Chem. Commun., 2007, 966–968
This journal is ß The Royal Society of Chemistry 2007

View Article Online
(6 cm (w) 6 1 cm (d) 6 6 cm (l)). Automation of the system also
enables the reactors to be operated remotely from a safe working
distance, reducing the amount of valuable fume cupboard space
required. Using this approach, we investigated the ability to scale-
up our previously optimised reaction set-up which employed a
0.5 mm (id) capillary to a 3.0 mm (id) capillary, the results of
which are reported herein.
Table 1 Summary of the results obtained for the synthesis of
a,b-unsaturated compounds in an EOF-based continuous flow reactor
(unless stated otherwise, all reactions were conducted for 1 h)
As Fig. 1 illustrates, the reaction set-up employed consists of a
borosilicate glass capillary (3.0 mm (id), 3.0 cm (length)), fritted at
both ends to retain the solid-supported reagent, attached to two
borosilicate glass reagent reservoirs via rubber stoppers (No. 9,
Suba Seal). To perform a reaction, the packed-bed is primed with
anhydrous acetonitrile (MeCN) (to form a complete electrical
circuit) and platinum electrodes (0.25 mm (od) 6 2.5 cm (length))
are then placed in reservoirs A and B, respectively. A solution of
starting material is then placed in reservoir A and an aliquot of
solvent placed in reservoir B. The reaction mixture is subsequently
passed through the packed-bed by application of a positive voltage
to reservoir A (167 to 300 V cm21) and the reaction products
collected in reservoir B (0 V cm21). Unless otherwise stated,
reactions are carried out for 10 min, after which the contents of
reservoir B are removed and analysed, off-line, by GC-MS. Once
optimised, the reactors are operated continuously for a period of
1 h (2.5 h in some instances), the reaction products collected,
concentrated in vacuo and the crude product dissolved in CDCl3
prior to purity evaluation by NMR spectroscopy.
R1
R2
R3
R4
Flow rate21 Conv. Yield
/ml min
(%)a
99.9
100.0
99.9
99.9
99.9
99.9
99.9
100.0
99.9
100.0
/g
H
H
H
H
CO2Et 62.0
CO2Et 56.1
0.75
(99.7)b
0.87
(99.8)
0.78
H
CO2Me
H
OMe
H
OMe CO2Et 50.1
(99.9)
0.94
OBn
Br
H
H
H
H
CO2Et 51.1
CO2Et 55.1
(99.7)
2.30c
(99.4)
0.57
(99.4)
0.76
(98.8)
0.71
(99.2)
0.75
H
H
H
CN
CN
62.1
60.4
55.7
48.4
48.3
H
CO2Me
H
OMe
H
OMe CN
OBn
Br
H
H
CN
CN
(99.4)
1.70c
(99.8)
To assess the reactor’s performance, we firstly investigated
the incorporation of silica-supported piperazine (0.100 g,
H
1.70 mmol g21
) into the packed-bed, demonstrating the
a
b
c
n = 15. Number in parentheses represents % yield. Reaction
conducted for 2.5 h.
Knoevenagel condensation of two activated methylenes with a
series of aldehydes (Table 1). Employing an applied field of
200 V cm21, a pre-mixed solution of aldehyde and activated
methylene (both 1.0 M in anhydrous MeCN) was placed in
reservoir A and passed through the packed-bed at flow rates in the
range from 48.3 to 62.1 ml min21, depending on the aldehyde
employed. In all cases, optimised reaction conditions afforded the
desired a,b-unsaturated product (trans-isomer only) in excellent
product purity (.99.9%) and yield (.98.8%), demonstrating
reactor stability over ¢15 runs. To further demonstrate the
feasibility of operating such reactors continuously, the syntheses of
3-(4-bromophenyl)-2-cyanoacrylic acid ethyl ester and 2-(4-brom-
benzylidene)malononitrile were investigated over an extended 2.5 h
period, affording 2.30 g (99.4%) and 1.70 g (99.8%) of analytically
pure material, respectively.
product purity but also to a dramatic reduction in reaction time,
affording near quantitative yields with residence times in the
range of 0.15–0.19 min.{ The generality of the technique was
subsequently evaluated by incorporating polymer supported
diazabicyclo[2.2.2]octane (1.45 mmol N g21), 3-(dimethylamino)-
propyl (1.50 mmol N g21), 3-aminopropyl (1.70 mmol N g21
)
and 3-(1,3,4,6,7,8-hexahydro-2H-pyrimido[1.2.1]-pyrimidino)pro-
pyl (2.40 mmol N g21) functionalised silica gels into the flow
reactor, whereby 3-(4-bromophenyl)-2-cyano-3-phenylacrylic acid
ethyl ester was obtained in excellent yield and purity (.99.0%).
Compared with the gravity-based system reported by Venturello
and co-workers,4 the approach described here is also advantageous
as it represents a significant reduction in solvent usage, requiring
only 1 ml mmol21 of product, cf. 30 ml mmol21. In addition, as
the products synthesised are obtained in excellent purity, no
subsequent off-line chromatographic purification is needed, further
reducing the environmental burden associated with the technique.
In addition to the base-catalysed syntheses discussed, the study
also investigated the feasibility of performing acid catalysed
reactions in such continuous flow systems. Based on our previous
experience of solid-supported acid catalysts, the synthesis of
dimethyl acetals was selected as a model reaction. In brief,
reactions were performed by mobilising a pre-mixed solution of
aldehyde and trimethylorthoformate (1.0 M and 2.5 M, respec-
tively, in MeCN) through a packed bed, containing Amberlyst-15
(0.075 g, 0.315 mmol), upon application of 300 and 0 V cm21, to
reservoirs A and B respectively. Again, the reaction products were
Based on the results presented in Table 1, it can be seen that the
use of continuous flow reactors not only leads to enhanced
Fig. 1 Schematic illustrating the reaction set-up used for the continuous
flow synthesis of small organic compounds by EOF.
This journal is ß The Royal Society of Chemistry 2007
Chem. Commun., 2007, 966–968 | 967

View Article Online
Table 2 Synthesis of dimethylacetals in a wide bore, EOF-based,
continuous flow reactor (unless stated otherwise, all reactions were
conducted for 1 h)
Flow rate/ Conv.
ml min21
Fig. 2 Schematic illustrating the multi-step synthesis of 3-(4-bromophe-
Starting material
(%)a
Yield/g
nyl)-2-cyanoacrylic acid ethyl ester in an EOF based, continuous flow
reactor.
Benzaldehyde
139.0
124.0
120.0
111.0
112.0
126.0
121.0
100.0 1.26 (99.2)b
99.8 1.31 (99.2)
99.9 1.33 (99.5)
99.9 1.71 (99.7)
99.9 1.42 (99.4)
99.9 1.52 (99.8)
99.9 1.52 (99.4)
99.9 1.50 (99.8)
99.9 1.20 (99.4)
99.6 3.64 (99.7)c
c
4-Cyanobenzaldehyde
4-Chlorobenzaldehyde
4-Benzyloxybenzaldehyde
3,5-Dimethoxybenzaldehyde
2-Naphthaldehyde
ethylcyanoacetate, to afford 3-(4-bromophenyl)-2-cyanoacrylic
acid ethyl ester. To perform a reaction, a pre-mixed solution of
1-bromo-4-dimethoxymethylbenzene and ethylcyano acetate
(1.00 M in MeCN) was placed in reservoir A and pumped
Methyl-4-formylbenzoate
5-Nitro-2-thiophenecarboxaldehyde 123.0
113.0
105.0
through
a packed-bed containing Amberlyst-15 (0.036 g,
trans-Cinnamaldehyde
4-Bromobenzaldehyde
0.151 mmol) and silica-supported piperazine (0.050 g,
0.085 mmol). By ensuring that each step of the reaction proceeds
to completion, multiple reaction steps can be performed in
series, without the need to purify the reaction intermediates.
Consequently, operation of the reactor at an optimised flow rate of
54.9 ml min21 afforded 3-(4-bromophenyl)-2-cyanoacrylic acid
ethyl ester in excellent purity (100.0% by GC-MS) with a system
a
b
n = 15. Number in parentheses represents % yield. Reaction
conducted for 2.5 h.
Table 3 Evaluation of the catalytic activity of an acid and a base
catalyst employed within the EOF-based flow reactor
Catalyst/
mmol
Product/
mmol
Turnover
number
throughput of 0.926 g h21
.
From the examples presented, it can be seen that EOF is a
versatile pumping technique that affords accurate, pulse-free
reagent delivery, enabling reactions to be readily optimised.
Furthermore, the ease with which the supported reagents are
recycled provides reaction reproducibility and catalyst lifetimes
unobtainable in traditional agitated reaction systems.
Silica-supported piperazine
Amberlyst-15
0.17
0.32
42.00
80.71
247
256
a
Based on the data presented herein (catalysts remain active).
collected at 10 min intervals and analysed off-line by GC-MS.
Once optimised, reactions were operated continuously for 1 h and
the products isolated by evaporation of the reaction solvent: the
purity of the ‘crude’ material was subsequently evaluated by NMR
spectroscopy. Employing flow rates in the range of 111.0–
139.0 ml min21 resulted in optimal conversion of an array of
aldehydes to their respective dimethylacetal (Table 2), obtaining
greater product purity compared with analogous batch reactions.
This observation is attributed to the unique reaction conditions
attained within continuous flow reactors, which enable reaction
products to be removed from the reactor prior to, in this
case, competing acid-catalysed deprotection occurring. Again,
extended operation was demonstrated for the synthesis of
Full financial support provided by the EPSRC (C.W.) (Grant
No. GR/S34106/01) is gratefully acknowledged.
Notes and references
{ The total volume of the flow reactor was found to be 9.0 ml, therefore
when operating at 50.0 ml min21 a residence time of 0.18 min is obtained.
1 A. Pande, K. Ganesan, A. K. Jain, P. K. Gupta and R. M. Malhotra,
Org. Process Res. Dev., 2005, 9, 133.
2 D. W. Morrison, D. C. Forbes and J. H. Davis, Tetrahedron Lett., 2001,
42, 6053.
3 (a) J. Simpson, D. L. Rathbone and D. C. Billington, Tetrahedron Lett.,
1999, 40, 7031; (b) F. Texier-Boulett and A. Foucod, Tetrahedron Lett.,
1982, 23, 4927.
4 (a) E. Angelletti, C. Canepa, G. Martinetti and P. Venturello, Tetra-
hedron Lett., 1988, 29, 2261; (b) E. Angelletti, C. Canepa, G. Martinetti
and P. Venturello, J. Chem. Soc., Perkin Trans. 1, 1989, 105.
5 A. Kirschning, W. Solodenko and K. Mennecke, Chem.–Eur. J., 2006,
12, 5972.
6 (a) R. V. Jones, L. Godorhazy, N. Varga, D. Szalay, L. Urge and
F. Darvas, J. Comb. Chem., 2006, 8(1), 110; (b) N. Yoswathananont,
K. Nitta, Y. Nishiuchi and M. Sato, Chem. Commun., 2005, 40.
7 C. Wiles, P. Watts and S. J. Haswell, Tetrahedron Lett., 2006, 47, 5261.
8 S. Itsuno, K. Ito, T. Maruyama, N. Kanda, A. Hirao and S. Nakahama,
Bull. Chem. Soc. Jpn., 1986, 59, 3329.
1-bromo-4-dimethoxymethylbenzene, affording
h21
a space time
yield of 1.46 g . Furthermore, system generality was
demonstrated via the incorporation of additional solid-supported
Lewis acid catalysts, including silica-supported sulfonic acid
(1.50 mmol g21), polymer supported para-toluene sulfonic acid
(2.00 to 3.50 mmol g21), ytterbium polystyryl sulfonate(III)
(0.80 mmol g21), whereby excellent yields and purities were
obtained in all cases.
Based on the data presented herein it can be concluded that the
catalysts remain active over prolonged periods of time, enabling
catalytic turnovers in excess of 247 times to be attained (Table 3).
The scope of the technique was subsequently extended to
evaluate the feasibility of performing continuous flow, multi-step
syntheses. As Fig. 2 illustrates, the model reaction selected
involved an acid-catalysed acetal deprotection, followed by a
base-catalysed condensation, of the in situ generated aldehyde with
9 K. Kamahori, K. Ito and S. Itsuno, J. Org. Chem., 1996, 61, 8321.
10 I. R. Baxendale, C. M. Griffiths-Jones, S. V. Ley and G. K. Tranmer,
Chem.–Eur. J., 2006, 72, 4407.
11 F. Bonfils, I. Cazaux, P. Hodge and C. Caze, Org. Biomol. Chem., 2006,
4, 493.
12 I. R. Baxendale, J. Deeley, C. M. Griffiths-Jones, S. V. Ley, S. Saaby
and G. K. Tranmer, Chem. Commun., 2005, 2566.
13 (a) C. Wiles, P. Watts and S. J. Haswell, Tetrahedron, 2005, 61, 5209; (b)
C. Wiles, P. Watts and S. J. Haswell, Tetrahedron, 2004, 60, 8421.
14 S. J. Haswell, Analyst, 1997, 112, 1R.
968 | Chem. Commun., 2007, 966–968
This journal is ß The Royal Society of Chemistry 2007