Design of a capillary-microreactor for efficient Suzuki coupling reactions

Article abstract of DOI:10.1016/j.tetlet.2004.08.017

A Pyrex glass capillary (0.4 mm internal diameter) microreactor was developed and used for Suzuki coupling reactions. Capillary-microreactors are more attractive than photolithographic microfluidic devices in terms of simplicity, low cost and ease of handling. Compared with the conventional synthesis procedure, our approach of using a capillary-microreactor offers a convenient and highly efficient means to optimize reaction conditions and the performance of catalysts. The procedure exhibits good precision, reproducibility and high reaction yield for a range of reactants investigated.

Full text of DOI:10.1016/j.tetlet.2004.08.017

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 7297–7300
Design of a capillary-microreactor for efficient Suzuki
coupling reactions
*
Chanbasha Basheer, Fathima Shahitha Jahir Hussain, Hian Kee Lee and
*
Suresh Valiyaveettil
Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 117543, Republic of Singapore
Received 4 June 2004;revised 29 July 2004;accepted 3 August 2004
Available online 20 August 2004
Abstract—A Pyrex glass capillary (0.4 mm internal diameter) microreactor was developed and used for Suzuki coupling reactions.
Capillary-microreactors are more attractive than photolithographic microfluidic devices in terms of simplicity, low cost and ease of
handling. Compared with the conventional synthesis procedure, our approach of using a capillary-microreactor offers a convenient
and highly efficient means to optimize reaction conditions and the performance of catalysts. The procedure exhibits good precision,
reproducibility and high reaction yield for a range of reactants investigated.
Ó 2004 Elsevier Ltd. All rights reserved.
1
. Introduction
ever, design and fabrication of even simple fluidic
systems require clean room facilities and expensive
instrumentation. To overcome these problems, we
describe here a simple, inexpensive and disposable capil-
lary-microreactor in combination with HPLC analysis.
Recently, capillary-microreactors have been utilized in
various fields including peptide analysis and oxidation
Microfluidic technology offers many benefits in various
1
fields including chemistry, biology and medicine. Over
the past decade, the trend towards miniaturization
has been driven by the need for rapid, simple and
on-line measurements in chemical synthesis, pharmaceu-
tical screening, medical diagnostics and environmental
analysis. A few reports have demonstrated the funda-
mental advantages of miniaturized systems, as com-
pared to conventional large-scale synthesis.
1
5,16
reactions.
the Suzuki coupling reaction
However, the present study discusses
17,18
2
–6
in a capillary-micro-
reactor involving a single reactant, or a mixture of
reactants.
7
–11
Owing
to their large surface area, microfluidic devices have
excellent mass and heat transfer properties.
Microreactors represent a promising way to reduce
time and costs of chemical processes with increased
selectivity and safety for chemical synthesis and bio-
In our approach, the reaction device is a glass capillary
(0.4 mm internal diameter) connected to a power
supply (Fig. 1). Within the capillary, the palladium
nanoparticles interact with the reactants under an
applied potential and enhance the efficiency of the
12,13
chemical reactions.
In synthesis, a large number of
applications have demonstrated the fundamental advan-
tages of miniaturized systems such as lab-on-a-chip
devices compared with a conventional, large-scale
1
4
set-up.
Photolithographic microfabrication is a useful method-
ology for the fabrication of miniaturized devices. How-
Keywords: Microreactors;Reaction engineering;Suzuki coupling;
Microfluidics.
*
Corresponding authors. Tel.: +65 6874 2995;fax: +65 6779 1691;
e-mail addresses: chmleehk@nus.edu.sg;chmsv@nus.edu.sg
Figure 1. Schematic diagram of the capillary-microreactor.
0
040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.08.017

7298
C. Basheer et al. / Tetrahedron Letters 45 (2004) 7297–7300
coupling reaction. Compared with conventional synthe-
sis, a higher yield is expected under optimized reaction
conditions.
4. Suzuki coupling reaction in a capillary-microreactor
The basic arrangement of the capillary-microreactor is
depicted in Figure 1. Polypropylene pipette tips were
inserted at the end of the capillary tube to serve as res-
ervoirs. The capillary (5cm length) and reservoirs A
and B were filled with 50mmol of phosphate buffer solu-
tion (pH12) mixed with 5% of palladium catalyst.
Extreme care was taken to ensure that air bubbles were
absent inside the capillary tube (by measuring a constant
current). For reactions, a 5lL of reactant mixture (i.e.,
2
. Synthesis of palladium nanoparticles
The palladium nanoparticles were prepared from palla-
1
9–21
dium acetate.
was added to a solution of poly(N-vinyl-2-pyrrolidone)
2.5g) in 150mL methanol and the mixture was refluxed
Briefly, 50mg of palladium acetate
(
for 2h. The resulting brown colloidal solution was
filtered using a 0.2-lm Teflon filter and concentrated
to 25mL. A drop of the colloidal solution was spotted
onto Formvar stabilized copper grids, and a JEOL
3
mmol of phenylboronic acid, 4.8mg in 10mL);1mmol
of 4-bromophenol (1.7mg in 10mL);1mmol of chloro-
benzene (1.1mg in 10mL) and 1mmol of 4-bromo-
benzonitrile (1.8mg in 10mL) were introduced in the
reservoir. A stoichiometry of 1:1 between the boronic
acid and the halo compound was maintained. For indi-
vidual reactions, 5lL of reaction mixture containing
(Tokyo, Japan) TEM system was used to characterize
the size of the nanoparticles.
1
mmol of phenylboronic acid with 1mmol 4-bromophe-
3
. Suzuki coupling reaction by conventional method
nol or 4-bromobenzonitrile or chlorobenzene was intro-
duced. A reaction potential of 5kV and 100lA current
were applied to reservoir A, and reservoir B was con-
nected to ground. Platinum wires were used as elec-
trodes. The direction of the applied potential was
switched alternately (i.e., initially A+ve and Bꢀve, then
Aꢀve and B+ve and so on) after every 5min at constant
current and the reaction was monitored for 40min at
room temperature. The reaction yields were quantified
by HPLC.
The Suzuki coupling reactions between phenylboronic
acid and halobenzenes were carried out using palladium
nanoparticles, as described previously. For conven-
tional route Suzuki coupling, sodium acetate (0.49g,
2
2
6
mmol), phenylboronic acid (0.37g, 3mmol) and a
mixture (0.20g, 1mmol) of each reactant (i.e., chloro-
benzene, 4-bromobenzonitrile and 4-bromophenol) was
added to 150mL of a 3:1 mixture of acetonitrile:water
(
see the reaction, Scheme 1). The solution was
heated to 80°C, followed by the addition of 5mL
of the palladium nanoparticle solution to start the
reaction. The reaction mixture was refluxed for a total
of 12h and the reaction yields were quantified by HPLC
5. Optimization of Suzuki coupling reaction in the
capillary-microreactor
(
Table 1).
In order to optimize the Suzuki coupling reactions in the
capillary-microreactor, analytical factors such as sample
pH, length of the capillary, applied potential and reac-
tion time were studied. Temperature was kept constant
at room temperature throughout the reactions. Initially,
individual reactions (Scheme 1) were carried out sepa-
rately. The results were then compared with those
involving a mixture of all three halo compounds and
the boronic acid. However a 1:1 stoichiometry between
the boronic acid and halo compound was maintained
in both routes. To our surprise, no significant difference
in the yield was observed. Therefore, the conditions of
the respective coupling reactions were optimized based
on a mixture of reactants.
OH
Br
OH
4
Br
-hydroxybiphenyl
4
-bromophenol
4
-bromobenzonitrile
CN
CN
B(OH)2
phenylboronic acid
4-cyanobiphenyl
Cl
chlorophenol
biphenyl
Quantitative yields were determined by separate calibra-
tion curves. The analytical factors were evaluated in
Scheme 1. Coupling reactions tested with the microreactor.
Table 1. Comparison of reaction efficiency in capillary-microreactor with conventional synthesis via Scheme 1
Reactants
Products
Yield % in conventional
b
procedure
Yield % in capillary-microreactor
a
a
Individual reactions
Mix reactions
Phenylboronic acid and 4-bromophenol
Phenylboronic acid and 4-bromobenzonitrile
Phenylboronic acid and chlorobenzene
4-Hydroxybiphenyl
4-Cyanobiphenyl
Biphenyl
17
23
11
78
89
83
82
88
95
a
Reaction was performed in a 5cm capillary-microreactor for 40min at 5kV applied potential, 100lA current, rt and pH12, individual reaction
involves only one bromo compound whereas the mix reactions involve all three bromo compounds.
The boronic acid was reacted with a mixture of bromo compounds in a stoichiometry of 3:1:1:1.
b

C. Basheer et al. / Tetrahedron Letters 45 (2004) 7297–7300
100
7299
triplicate. There was an increase in the size of the cata-
lyst particles after 30min reaction, causing coagulation
in the microreactor. This is attributed to Ostwald ripen-
ing, which has been reported previously for such parti-
cles. However, we did not attempt to measure the
palladium nanoparticle size distribution in this study.
Due to the precipitation of the catalyst, the particles
could be easily removed by filtration before HPLC
analysis.
7
5
0
20
5
4-cyanobiphenyl
4-hydroxybiphenyl
biphenyl
25
0
6
. Reaction time
0
1
2
3
4
5
applied potential (kV)
Reaction time is one of the most important parameters
in the Suzuki coupling reactions. It was varied between
Figure 3. Effect of different applied potentials on the product yield in
the capillary-microreactor (at pH12 and reaction time 40min, rt).
1
0 and 60min and the reaction yield with respect to
times shown in Figure 2. In general, the reaction yield
increases with increase in reaction time, up to 40min,
which appears to be an optimum period.
0
.016
7
3
5
AU
7
. Applied potential
2
4
1
In the capillary microreactor, the analytes mobility has
been driven by electro osmatic flow and the flow could
be controlled by the applied potential. Additionally,
the higher applied potential increases the analyte inter-
action with the nanoparticles and enhances the reaction
yield. The necessary applied potential to achieve a high
yield was obtained by applying various applied poten-
tials in the range of 1–5kV at a constant current of
6
0
.000
44.00
1
0.00
20.00
Retention time (min)
Figure 4. Liquid chromatogram of product mixture after Suzuki
coupling reactions in the capillary-microreactor at pH8. Peaks were
identified as 4-bromophenol 1, 4-bromobenzonitrile 2, phenylboronic
acid 3, 4-hydroxybiphenyl 4, 4-cyanobiphenyl 5, chlorobenzene 6 and
biphenyl 7 using standard samples.
100lA. Figure 3 shows the influence of the applied
potential on the yield. As can be seen, a maximum prod-
uct yield was obtained by using 5kV.
4-cyanobiphenyl
4-cydroxybiphenyl
biphenyl
1
00
75
8
. Reaction pH
The influence of pH ranging from 2 to 12 on the yield of
the coupling reaction in the capillary-microreactor was
investigated. Figure 4 shows the liquid chromatogram
of the product mixture after each reaction involving dif-
ferent starting materials (Scheme 1) for 40min at a pH8.
The results are summarized in Figure 5.
5
0
25
0
1
00
pH 2
pH 4
pH 6
pH 8
pH 10
pH 12
4
4
-cyanobiphenyl
-hydroxybiphenyl
Reaction pH
biphenyl
7
5
2
5
0
5
0
Figure 5. Effect of reaction pH on the product yield in the capillary-
microreactor (at 40min reaction time and applied potential 5kV).
9. Lengthof t he capillary-microreactor
An interesting problem in microdevices is the scaling
factor that results when miniaturizing the volume of
microreactors. It has been shown that for microdevices
using an electrophoretic separation at constant field, res-
olution is proportional to the square of the channel
0
20
40
60
Reaction time
2
3
length. However, in our study no significant improve-
ment in the reaction yield was obtained when the length
of the capillary was increased from 3 to 7cm.
Figure 2. Effect of different reaction times on the product yield in the
capillary-microreactor (at pH12 and applied potential 3kV, rt).

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C. Basheer et al. / Tetrahedron Letters 45 (2004) 7297–7300
1
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1. Mechanism of the reaction
The oxidative addition of bromoarenes to the surface of
the Pd nanoparticle is believed to be the first step in the
coupling reactions.
enhanced by the incorporation of electron withdrawing
0
2
4
Rate of the reaction can be
2
5
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2
6
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We have demonstrated the design and feasibility of per-
forming Suzuki coupling reactions using a glass capil-
lary-microreactor with high yields (82–95% in
comparison with 11–23% for the conventional method).
Either individual or a mixture of reactants can be used
in the reactor without compromising the identity or
yield of the reaction product(s). The reaction protocol
is rapid and could be useful for the qualitative and quan-
titative determination of novel catalytic reactions.
Unlike photolithographic microreactors, our ordinary
glass capillary reactors are easily available, affordable,
easier to use and the progress of the reaction can be
monitored through a variety of techniques, including
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