Phase-transfer alkylation reactions using microreactors

Article abstract of DOI:10.1039/b301638b

Phase-transfer alkylation in a microreactor proceeds smoothly, and the reaction has been found to be more efficient than that in a round-bottomed flask with vigorous stirring; we have observed by an optical microscope study that an interfacial area provid

Full text of DOI:10.1039/b301638b

Phase-transfer alkylation reactions using microreactors
a
b
b
a
Masaharu Ueno, Hideaki Hisamoto, Takehiko Kitamori and Sh u¯ Kobayashi*
a
Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo,
13-0033, Japan. E-mail: skobayas@mol.f.u-tokyo.ac.jp; Fax: +81 3 5684 0634; Tel: +81 3 5841 4790
Department of Applied Chemistry, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo,
Bunkyo-ku, Tokyo, 113-8656, Japan
1
b
Received (in Cambridge, UK) 12th February 2003, Accepted 5th March 2003
First published as an Advance Article on the web 27th March 2003
Phase-transfer alkylation in
a
microreactor proceeds
was performed by introducing a dichloromethane solution
containing 1a (0.30 M), 2a (0.45 M), and resorcinol dimethyl
ether as an internal standard, and an aqueous solution containing
sodium hydroxide (0.50 N) and TBAB (0.015 M) through the
two-inlets of the microchip under continuous flow conditions at
ambient temperature. Mean residence time of the starting
materials in the microreactor was determined by total volume of
the microchannel and volume flow rates of the organic and
aqueous phases. Yields were determined by collecting the
definite volume of the product from the output of the
microreactor, while the flow rate was kept constant. We
measured yields of the product at several points of mean
residence time by HPLC analysis.
The profile of the alkylation of 1a with 2a in the microreactor
is shown in Fig. 2 (a). The reaction proceeded smoothly, and the
desired alkylation product 3a was obtained in 57% yield in the
microreactor at 60 seconds. The yield increased to over 90%
after 300 seconds. We also conducted macroscale experiments
using normal batch systems for comparison. In the cases of the
macroscale reactions, 2.0 ml each of the reagent solutions was
poured into a round-bottomed flask and stirred. Reaction rates
of the benzylation were dependent on the stirring conditions
(Fig. 2). Product 3a was obtained in 37% yield after vigorous
stirring (1350 rpm) for 60 seconds, while lower yields of the
product were obtained with slower stirring rate (400 rpm) or
without stirring. It is noted that a much higher yield was
obtained using a microreactor than that using standard batch
systems even with vigorous stirring. In this phase-transfer
benzylation, larger interfacial areas are expected to increase
yields of the product, and it has been demonstrated that the
microreactor system is superior to normal batch systems to
create such reaction conditions.
smoothly, and the reaction has been found to be more
efficient than that in a round-bottomed flask with vigorous
stirring; we have observed by an optical microscope study
that an interfacial area provided by organic and aqueous
phases is more extended in a microreactor.
Recent microchip technology has enabled versatile applications
in chemistry. In particular, applications in the field of analytical
chemistry have been established as one of the promising
1
research fields. On the other hand, increasing interest has also
been paid to applications in synthetic organic chemistry.2
–7
A
liquid microspace such as a microchannel on a glass microchip
provides interesting characteristics such as short molecular
diffusion distance, large specific interfacial area, and small heat
capacity, all of which would be expected to promote highly
effective chemical reactions in the microchip.
When organic and aqueous phases are introduced through
two inlets of a microchannel, a large specific interfacial area
would be obtained without any stirring. By utilizing the large
specific interfacial area provided by organic and aqueous
phases, it is expected that efficient phase transfer processes can
8
be performed with high yields. Based on this idea, we planned
to perform several fundamental carbon–carbon bond-forming
reactions in microreactors. In this paper, we report phase-
transfer alkylation reactions of b-keto esters in microreactors.
Alkylation reactions of b-keto esters are among the most
important carbon–carbon bond-forming reactions in organic
synthesis.9 First, we tested the benzylation reaction of ethyl
–11
2
-oxocyclopentanecarboxylate (1a) with benzyl bromide (2a)
in the presence of 5 mol % of tetrabutylammoniun bromide
TBAB) as a phase transfer catalyst (Scheme 1). The experi-
(
ment system of a microreactor is illustrated in Fig. 1. A teflon
tube (ø200 µm 3 10 cm) was connected at the end of the
microchip (the channels were 200 µm in width, 100 µm in
depth, and 45 cm in length) and the calculated total volume of
the microchannel contained the volume of the tube. The reaction
Scheme 1 The phase-transfer benzylation reaction of ethyl 2-oxocyclo-
pentanecarboxylate (1a) with benzyl bromide (2a).
Fig. 2 The profile of the alkylation of 1a with 2a in a microreactor and
standard batch systems.
Next, we examined the effect of the width of the micro-
channels for reactors (Fig. 3). In microchip reactors with thinner
channel width, higher reaction rates of the benzylation were
observed. In all cases shown in Fig. 3, segment states, which
were formed by continuous flow of organic and aqueous layers
in the microchannel, were observed. These results suggested
that smaller particles formed by the thinner channel width in the
microreactors provided larger interfacial area. The shape of the
1
2
Fig. 1 An experiment system of a microreactor.
segment using an optical microscope is shown in Fig. 4. It was
9
36
CHEM. COMMUN., 2003, 936–937
This journal is © The Royal Society of Chemistry 2003

Table 1 Phase-transfer alkylation of other substratesa
Product 2 min
10 min
96%
7
7
5% (49%)
3% (48%)
85%
87%
92%
97%
4
3
9
5% (18%)
5% (18%)
1% (87%)
Fig. 3 The effect of the width of the reactors.
6
4
5% (20%)
4% (17%)
71%
90%
Fig. 4 The shape of the segment (optical microscope). The length of the
segment is ca. two to five times of the channel width.
a
Isolate yield. In the parentheses, macroscale reactions for 2 min. See
text.
shown that the organic phases were divided into small droplets
and flowed inside the aqueous tube. These segments were
formed presumably due to the difference in affinity of the
organic and aqueous layers with the glass wall of the
microchannels. It is noteworthy that a larger interfacial area was
formed not only in both ends of the segments but also around the
organic droplets.
This work was partially supported a Grant-in-Aid for
Scientific Research from Japan Society of the Promotion of
Science.
Notes and references
1 W. Ehrfeld, V. Hessel and H. Löwe, in Microreactors, Wiley-VCH,
Weinheim, 2000.
2 S. J. Haswell, R. J. Middleton, B. O’Sullivan, V. Skelton, P. Watts and
P. Styring, Chem. Commun., 2001, 391.
We examined phase-transfer alkylation reactions using
several other substrates in a microchip reactor (Table 1). Under
the microscale conditions, the flow rate was kept constant for
2
1
the mean residence time of 2 or 10 min (5.9 µl min for 2 min
2
1
and 1.2 µl min for 10 min), and the yield was determined by
collecting 0.2 mmol of the substrates (0.67 ml of 0.3 M solution)
and isolation by the usual methods. In all cases, the reactions
proceeded smoothly to afford the desired alkylated adducts in
high yields. As comparison, we performed macroscale reac-
tions; the same volume of organic and aqueous layers (0.67 ml
each) was mixed under vigorous stirring, and after 2 min, the
reaction mixture was quenched with aqueous saturated ammo-
nium chloride, and the product was isolated by the usual
methods. In the reactions using not only benzyl bromide but
also various alkyl bromides as alkylation reagents, and an a-
cyano ketone13 as a substrate, the phase-transfer alkylation in
microreactor gave higher yields than those in a round-bottomed
flask with vigorous stirring at the same residence time.
In conclusion, we have revealed that phase-transfer alkyla-
tion in a microchip reactor was more reactive than that in a
round-bottomed flask with vigorous stirring. To the best of our
knowledge, this is the first example of synthetically useful
phase-transfer carbon–carbon bond-forming reactions in a
microchip reactor. By optical microscope study, we observed
that the interfacial area provided by organic and aqueous phases
was more extended in the microchannel for reactors. Further
investigation to develop other synthetic reactions in a microchip
reactor is now in progress.
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