The Claisen-Schmidt reaction carried out in microfluidic chips

Article abstract of DOI:10.1055/s-2005-922763

The Claisen-Schmidt reaction of benzaldehyde in a microfluidic chip has been found to be more efficient than that in a round-bottom flask with vigorous stirring. Slug flow was formed when the organic and aqueous phases were introduced through the microchannel with a width of 300 μm, which provides faster mass transfer than laminar flow. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-922763

LETTER
3163
The Claisen–Schmidt Reaction Carried Out in Microfluidic Chips
T
he Claise
i
n–Schm
n
idt Reactio
-
n
in Mic
X
rofluidic
C
hips ia Mu, Xue-Feng Yin,* Yan-Guang Wang
Department of Chemistry, Zhejiang University, Hangzhou, 310027, P. R. of China
Fax +86(571)87952070; E-mail: yinxf@zju.edu.cn
Received 2 August 2005
(4.0 M) and benzaldehyde (1.0 M), and an aqueous sodi-
um hydroxide solution (0.5 M) through the two inlets of
the Y-shaped microfluidic chip with two syringe pumps
under continuous flow conditions at ambient temperature.
Abstract: The Claisen–Schmidt reaction of benzaldehyde in a mi-
crofluidic chip has been found to be more efficient than that in a
round-bottom flask with vigorous stirring. Slug flow was formed
when the organic and aqueous phases were introduced through the
microchannel with a width of 300 mm, which provides faster mass The residence time of the reactants in the microchannel
transfer than laminar flow.
was controlled by varying the total length of the micro-
channels, while keeping constant the linear flow rate of
the organic and aqueous phases. Microfluidic chips with
different dimensions were fabricated on soda-lime glass
using a photolithographic and wet chemical etching pro-
cedure described elsewhere.4 The channels were etched to
a depth of 80 mm with different width of 300 mm and 500
mm, and length of 12, 16, 24, 32, 40, 48, 72, 96 cm. The
dependence of the conversion of benzaldehyde to benzyl-
idineacetone on the residence time in microchannels was
examined by introducing the reactants into microchannels
at the same linear flow rate of 12.0 cm/min and collecting
the products from the outlets of the microfluidic chips.
The conversions were determined by GCMS. The results,
compared with the standard batch system,5,6 are shown in
Figure 2. The conversion increases, as the residence time
prolongs. Conversions of 93% and 80% were obtained af-
ter an eight-minute reaction in microchannels with the
width of 300 mm and 500 mm, respectively. In comparison,
60% conversion was obtained using the standard batch
system with vigorous stirring of 1250 rpm. Doubling the
reaction time to 16 minutes only increased the conversion
to 73%. The outputs obtained from microfluidic chips at
the conversion of 93% and from standard batch system at
the conversion of 73% were 11 mg/h and 100 mg per run,
respectively.
Key words: microfluidic chips, phase-transfer catalysts, Claisen–
Schmidt reaction, benzaldehyde, acetone
Combinatorial chemistry as a high-throughput synthetic
technology has became a powerful tool for the discovery
of new drugs and materials.1 Increasing interests have
been drawn onto the application of microfluidic chips in
this field.2 Unlike the standard batch systems, the utmost
attributes of microfluidic chips include short molecular
diffusion distance, large specific interfacial area and small
heat capacity, which make chemical reactions carried out
in microfluidic chips to be highly effective. In addition,
the reagents used and wastes generated in microfluidic
chips are much less than that in standard batch systems.
The phase-transfer catalysts (PTCs) have been widely
applied in organic synthesis. In the case of phase-transfer
reaction, rapid mass transfer of starting material and the
produced chemical species across the liquid–liquid inter-
face plays an important role to realize fast chemical reac-
tions with high conversion. Vigorous stirring is the
prerequisite for a successful phase-transfer reaction in a
round-bottomed flask, which increases the interfacial area
and reduces molecular diffusion distance. The microchan-
nel dimensions of microfluidic chips are ideally suited for
the phase-transfer reaction. In microchannel, a large inter-
facial area and short molecular diffusion distance could be
obtained without any stirring. It was reported that the
phase-transfer diazo-coupling and alkylation reactions in
microfluidic chips gave higher yields than that using the
standard batch systems even with vigorous stirring.3 The
PTC-catalyzed Claisen–Schmidt reaction of ketones with
aldehydes is an important reaction in both academia and
industry. In this paper, we report the Claisen–Schmidt
reaction of acetone with benzaldehyde performed in
microfluidic chips.
Figure 1 Schematic structure of the microfluidic chip.
The mechanism for Claisen–Schmidt reaction of benzal-
dehyde with acetone is shown in Figure 3. By carrying out
the reaction in microchannels, larger interfacial area and
short diffusion distance provide effective molecular diffu-
sion conditions. The distribution of the reactants and the
product between the phase–interface in microchannels is
faster than in a bulk reaction with vigorous stirring, which
allows the product to be transferred into the organic phase
from contacting with the base in the aqueous phase.
The structure of our microfluidic chip is illustrated in
Figure 1. The microscale reaction was performed by
introducing an ethanol solution containing both acetone
SYNLETT 2005, No. 20, pp 3163–3165
1
9
.1
2
.2
0
0
5
Advanced online publication: 28.11.2005
DOI: 10.1055/s-2005-922763; Art ID: W00505ST
© Georg Thieme Verlag Stuttgart · New York

3164
J.-X. Mu et al.
LETTER
In order to examine the effect of flow rate on the rate of
mass transfer between the two phases, the conversions
were determined after introducing the reactants at differ-
ent flow rates through the microchannels with a width of
300 mm. Microfluidic chips with different lengths were
used to fix the reaction time at four minutes. In all the flow
rates tested, slug flow can be observed. The effect of flow
rate on conversion is shown in Figure 5. With the increase
of flow rate, the conversion also increased. The higher
rate of mass transfer may result from the internal circula-
tion within the slugs, which could be stimulated by the
shear between the stationary water at the microchannel
wall and the moving organic slugs.
Figure 2 Conversions in microchannels and standard batch system
a. 300 mm; b. 500 mm; c. standard batch system.
Therefore, the reaction speed and conversion of Claisen–
Schmidt reaction in microfluidic chips were higher than in
standard batch systems.
Recently, the formation of plugs in the two-phase flow in
microfluidic channels has been studied by the Ismagilov
group7 and also applied in synthesis.8,3b Capillary number
(Ca) was used to characterize the flow pattern inside the
microchannel. Ca is defined as Um/g, where U [m s–1] is
the velocity of the flow, m [kg m–1 s–1] is the viscosity of
the flow, g [kg s–2] is the surface tension at the interface
between the aqueous and organic phases. In our experi-
ments, although the capillary numbers in both channels
were the same, which is ca. 1.5 × 10–4, slug flow was
formed reproducibly in the 300-mm wide microchannel
(Figure 4, a) and laminar flow was formed in the 500-mm
wide microchannel (Figure 4, b). The reason remains to
be investigated further.
Figure 4 Charge-coupled device (CCD) images of flow type in
microchannels with different diameters.
In the laminar flow, two streams flow in the channel side
by side. The concentration gradient exists in the radial di-
rection and the mass transfer occurs across an area corre-
sponding to the cross-section of the channel and over a
path length equal to half of the channel diameter. In the
slug flow, larger interfacial area was formed not only at
both ends of the segments but also around the whole
droplets, which is generally larger than the channel’s
cross-sectional area. Therefore, the conversions in the
narrower microchannel (Figure 2, curve a) is higher than
in the relatively wider microchannel (Figure 2, curve b).
In the standard batch system, N2 is usually bubbled in
order to protect benzyaldehyde from air oxidation. In
microfluidic chips, however, the reaction is performed in
closed microchannels, the oxidation of benzaldehyde was
thus hindered even without N2.
O
O
CH
starting
material
C CH3
CH
CH
org.
aq.
O
starting
material
CH
O
_
+ H2O + OH
Figure 5 The effect of flow rate on conversion.
+
O
C
CH3
CH
CH
H3C C CH3
In conclusion, herein we report the Claisen–Schmidt reac-
tion carried out in microfluidic chips. Compared with the
traditional round-bottom flask, the Claisen–Schmidt reac-
tion of benzaldehyde with acetone in the microfluidic chip
was more rapid and efficient due to the fast distribution of
+
OH
Figure 3 Phase-transfer in the Claisen–Schmidt reaction of
benzaldehyde with acetone.
Synlett 2005, No. 20, 3163–3165 © Thieme Stuttgart · New York

LETTER
The Claisen–Schmidt Reaction in Microfluidic Chips
3165
(4) Gao, J.; Yin, X. F.; Fang, Z. L. Lab Chip 2004, 4, 47.
(5) (a) Chaphekar, S. S.; Samant, S. D. J. Chem. Technol.
Biotechnol. 2004, 79, 769. (b) Bell, R. P. J. Chem. Soc.
1937, 1637.
(6) General Procedure.
the reactants and the product between the phase-interface
in microchannels. Furthermore, the smaller (300 mm in
width) microchannels gave higher conversions than larger
(500 mm in width) microchannels.
Benzaldehyde (1 mmol), acetone (4 mmol), EtOH (1.0 mL)
and aqueous NaOH (0.5 M, 1.0 mL) were placed in a 10-mL
round-bottomed flask and stirred at ambient temperature
under a N2 atmosphere. After stirring for period indicated in
Figure 2, the reaction was quenched with HCl (0.5 M, 1 mL).
The organic layer was separated and the aqueous layer was
extracted with Et2O (3 × 2 mL). The combined organic
layers were washed with H2O (5 mL) and dried with Na2SO4.
The solvent was removed to give benzylidineacetone. The
conversion of each period is cited in Figure 2.
Acknowledgment
This work was supported by the National Natural Science Founda-
tion of China (No. 0299030).
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Synlett 2005, No. 20, 3163–3165 © Thieme Stuttgart · New York