Enhancement of reaction rates by segmented fluid flow in capillary scale reactors

Article abstract of DOI:10.1002/adsc.200505480

For a simple biphasic hydrolysis, we show that the application of various reaction conditions in microreactors using segmented flow can dramatically increase the reaction rate. A tandem diazotation/ Heck reaction served as an example that even homogeneous reactions can be accelerated by segmentation in microreactors.

Full text of DOI:10.1002/adsc.200505480

FULL PAPERS
DOI: 10.1002/adsc.200505480
Enhancement of Reaction Rates by Segmented Fluid Flow in
Capillary Scale Reactors
a, b
b,
a,
Batoul Ahmed, David Barrow, * and Thomas Wirth *
a
Cardiff School of Chemistry, Cardiff University, Cardiff, CF103AT, U.K.
Fax : (+44)-29-2087-6968; e-mail: wirth@cf.ac.uk
Laboratory for Applied Microsystems, Cardiff School of Engineering, Cardiff University, Cardiff, CF24 3AA, U.K.
b
Fax : (+44)-29-2087-4716; e-mail: barrow@cf.ac.uk
Received: December 16, 2005; Accepted: April 6, 2006
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: For a simple biphasic hydrolysis, we show geneous reactions can be accelerated by segmenta-
that the application of various reaction conditions in tion in microreactors.
microreactors using segmented flow can dramatically
increase the reaction rate. A tandem diazotation/ Keywords: biphasic reactions; Heck reaction; hydrol-
Heck reaction served as an example that even homo- ysis; microreactors; segmented flow
Introduction
common mode of multiphase interface is known as
parallel flow in which the respective fluid phases align
The miniaturisation of chemical processes using chip- side-by-side and mixing between them occurs princi-
based microreactors can exhibit significant advantages pally via diffusion. Another multiphase mode, seg-
over existing conventional techniques. The properties mented flow, can be created in a microchannel when
and reaction conditions in such microreactors are dif- two (or more) fluid phases form serial trains of fluid
ferent to large-scale systems. A high surface-to- packets, each phase being separated by the other.
volume ratio, short diffusion distances, fast and effi- Once these fluid packets or segments are formed, an
cient heat dissipation and mass transfer enable novel internal fluid vortex is generated which causes rapid
and diverse applications.[ These properties have mixing within a given segment by continuously re-
1]
[
2]
been advantageously used in organic synthesis.
freshing the diffusion interface as shown in Figure 1.
The area of this interface is approximately propor-
tional to the cross-sectional area of the microchannel.
The cross-section must be smaller than the length of
the segments, otherwise emulsions are formed.[ Fur-
Results and Discussion
4]
A microchip system applied in synthetic chemistry thermore, the constructional material of the micro-
usually consists of an arrangement of microstructures
such as capillary scale ducts, sensors and actuators. A
combination of such microcomponents and a chip-to-
world interface of fluidic, electrical, optical and other
interconnects may form a microreactor which can be
fabricated in different geometries and from a variety
of materials. The majority of chemical reactions in so-
lution carried out in microreactors involve homogene-
ous reactions at room temperature. Recently, an inter-
est in applying microreactors utilising multiphase flow
(
gas/liquid or liquid/liquid biphasic systems) has
[
3]
emerged. In a microchannel, the contact interface
between immiscible liquids can follow various flow
patterns, due to the forces at the interface generated
Figure 1. Schematic representation of segmented flow in a
microchannel: Rapid mixing within a given fluid segment is
caused by the internal vortex fluid flow; mass transfer be-
from the different physical properties of both phases tween contiguous fluid segments is enhanced by the continu-
such as viscosity and surface tension. The most ously refreshing interface.
Adv. Synth. Catal. 2006, 348, 1043 – 1048
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Batoul Ahmed et al.
FULL PAPERS
channel plays a significant role in the formation of
segments and influences their shape due to the effects
[5]
of interfacial tension and surface energies. The com-
parison of microreactors with conventional processing
has become of interest recently as exploitation of
their industrial usage is increasing.[
6]
Scheme 1. Hydrolysis of p-nitrophenyl acetate (1).
Herein we report the effect of internal vortex circu-
lation in segmented flow systems and compare these
data with results obtained using conventional flasks.
We investigated the hydrolysis of p-nitrophenyl ace-
Firstly, we performed biphasic reactions in which a tate (1), dissolved in toluene, with aqueous sodium
mass-transfer between two phases is necessary in hydroxide as a biphasic reaction (Scheme 1). The re-
order for a reaction to proceed. Secondly, we describe action progress was monitored by the UV absorption
the acceleration of homogeneous reactions taking of phenolate 2 at lmax =400 nm. The reaction was per-
place only in one phase, which is rapidly mixed by an formed in a microreactor as described in the Experi-
immiscible, second inert phase.
mental Section (300 mm ” 300 mm microchannel,
For the generation of segmented flow, a microreac- 400 mm length) or in a PTFE tube (300 mm internal
tor or PTFE (polytetrafluoroethylene) tube with a T- diameter, 400 mm length). The yield of the reaction is
junction geometry was used. One fluid phase moves dependent upon reaction time which is inversely pro-
into the channel whilst the other phase is forced into portional to the flow rate. Additionally, the size of the
the junction, thus cutting the flow of the first phase segments will also have an effect on the reaction rate
due to the high interfacial forces between the phases. as the ratio of volume:interfacial area increases with
Pressure build up then reverses the configuration, and increasing size of the segments (Figure 3).
as these events are repeated a regular segmented flow
A solution of substrate 1 in toluene (0.05M) and an
stream is formed (Figure 2). The lengths of segments aqueous solution of sodium hydroxide (0.5M) were
are dependent on flow velocities and surface proper- passed through the two inlets of the microreactor or
ties. Additionally, a material with a high surface into a T-junction of PTFE tubes using a dual syringe
energy with respect to one phase (i.e., larger contact pump.
angle) will lead to more rounded fluid segments. For
The hydrolysis of p-nitrophenyl acetate (1) was car-
example, in the case of an organic/aqueous system in ried out under different reaction conditions in differ-
a channel made of perfluoro polymeric material, the ent reactors. It is possible to deduce a number of
aqueous phase will have a larger contact angle and trends from the results shown in Figure 3. A compari-
hence a higher surface energy compared to the organ-
ic phase, leading to the formation of “rounder” aque-
ous segments and expanded organic ones.
Figure 3. Hydrolysis of 1 using different flow types and reac-
tion times: (a) Short segmented flow (approx. 2 mm) under
microwave irradiation at 508C. (b) Long segmented flow
(
approx. 10mm) under microwave irradiation at 50 8C. (c)
Segmented flow in PTFE tubing heated in an oil bath at
08C. (d) Segmented flow at room temperature in a PMMA
5
Figure 2. Photo image of segmented flow during biphasic hy-
drolysis reaction in PMMA microreactor with T-junction;
Phase A is the aqueous layer and Phase B is the organic
layer.
reactor. (e) Segmented flow at room temperature in PTFE
tubing. (f) Hydrolysis reaction at 508C in a flask with stir-
ring. (g) Hydrolysis reaction at room temperature in flask
with stirring.
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Enhancement of Reaction Rates by Segmented Fluid Flow in Capillary Scale Reactors
FULL PAPERS
son of the results of reactions labelled (f) and (g) in segment length for a given system with defined geom-
Figure 3 with the other results is obvious. The reac- etry and used this approximation for the estimation of
[
4a,10]
tion rate of the hydrolysis using a conventional flask mass transfer coefficients.
This numerical model
is much lower than using microreactors and the differ- suggests that with increasing segment length and de-
ence between hydrolysis at room temperature (g) and creasing flow rate, the mass transfer time increases.
at 508C (f) is not significant at that timescale.
As homogeneous reactions are as important as bi-
Reactions labelled (d) and (e) were both carried phasic reactions, we successfully attempted their ac-
out under similar reaction conditions, but in different celeration by using the segmented flow technique.
reactors. These results show that the reaction in the The hydrolysis of the acetate 1 was now performed
PMMA (polymethyl methacrylate) microreactor (d) using acetonitrile as a solvent together with aqueous
performs slightly better than in the PTFE tubing (e). sodium hydroxide to create a homogeneous system of
The better performance in the PMMA microreactor laminar flow in the microchannel (Figure 4). This ace-
is probably due to the visually slightly shorter seg- tonitrile/water phase was then combined with an inert
ments and their higher regularity. The different T- immiscible solvent (hexane) to divide the reaction so-
junctions for creating the segmented flow might also lution into segments and to achieve intense mixing in
play a role. As the PMMA microreactor with its the microchannel as described above. In this homoge-
metal housing cannot be inserted in the microwave, neous reaction with a second immiscible organic sol-
the experiments at elevated temperature (a, b, c) vent there will be almost no mass transfer occurring
have been performed using PTFE tubing.
at the interface; only rapid internal vortex fluid flow
An increase of the reaction rate by heating can be is achieved. The rate constant calculated for the ho-
À1
seen by comparison of (e) and (c). A further increase mogeneous segmented flow (k=0.2031 s ) is larger
is observed by microwave irradiation of the micro- than the rate for homogeneous laminar flow (k=
À1
reactor in a water bath (b) instead of heating with a 0.129 s ) (for details see Supporting Information).
conventional oil bath (c). By microwave irradiation of The rate constants have been calculated under the as-
the microreactor without a surrounding fluid, insuffi- sumption of pseudo-first order kinetics.
cient energy is absorbed to cause significant heating.
This is due to the low loss microwave materials mogeneous reactions by introducing an immiscible
PMMA, PTFE) used in construction and the low ab- solvent such as hexane to generate segmented flow.
sorption characteristics of the fluidic duct geometry. As an example, we performed tandem diazotation/
Finally, we enabled the enhancement of other ho-
(
[
11]
Those are known properties and microwave heating Heck reaction sequences (Scheme 2).
of microreactors with outside deposition of gold
Heck reac-
[
7]
metal to increase microwave absorbance is known.
Macroscale flow reactors suitable for microwave irra-
[8]
diation have also recently been reported.
The reactions labelled (a) and (b) in Figure 3 have
both been carried out under microwave irradiation,
but the segment size in (a) is smaller than in (b). The
reaction rate is further increased by the generation of
shorter segments, which was achieved by applying a
higher flow rate (1.5 times higher) of the aqueous
phase compared to the organic phase using two differ-
ent sized syringes in the syringe pump.
The effect of the channel size on the segmented
flow system was also studied. In microchannels of
smaller diameter (either PMMA microreactor or
PTFE tubing), higher reaction rates were observed as
detailed in the Supporting Information, which sug-
gests the influence of a relatively larger interfacial
Figure 4. Homogeneous hydrolysis of 1 (at room tempera-
ture): (a) homogeneous segmented flow and (b) homogene-
ous laminar flow.
[
9]
area to volume ratio in the smaller microchannels.
As flow rate increases, mass transfer increases and
leads to a larger conversion rate, but for a given
length of the microchannel, the reaction time (resi-
dence time) will be smaller and the overall reaction
may be less efficient. However, the length of individu-
al fluid segments will also have an effect on the con-
version rate. Ramshaw has expressed the relationship Scheme 2. Heck reactions using homogeneous segmented
between the mass transfer time, the flow rate and the flow conditions.
Adv. Synth. Catal. 2006, 348, 1043 – 1048
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www.asc.wiley-vch.de
1045

Batoul Ahmed et al.
FULL PAPERS
tions have already been investigated in microreactors ExperimentalSection
[
12]
using a different set-up and reaction conditions.
This palladium(II)-catalysed arylation reaction of Device Microfabrication
aniline (3) with styrene (4a) was performed via the di-
azonium intermediate. When the reaction was carried PMMA (polymethylmethyl acrylate) and PTFE (polytetra-
fluoroethylene) were the chosen material for the microchan-
out in a conventional manner using a flask, stilbene
nel used for the study. LPKF milling machine was used to
(
5a) was isolated in 83% yield after 20h reaction
microfabricate the PMMA microdevices. Microchannels
were fabricated using a 250 mm 2FM double edge cutter
milling tool to produce 300 mm channels size of uniform
depth and width. The microchannels were enclosed with a
PMMA cover plate consisting of z-axis inlet and outlet ports
that will enable access from the chemical reservoirs into the
time. Initially we compared homogeneous laminar
flow with homogeneous segmented flow using the
substrates 4a and 4b.[ GC analysis using an internal
standard (decane) showed that the yields were im-
proved when switching from laminar flow to segment-
13]
ed flow conditions. With homogeneous laminar flow microreactor channels. Inlet and outlet ports, with an inter-
5
a was obtained in 52% yield (5b: 68%). Introduc- nal diameter of 1.6 mm, were fabricated using a 1 mm 4FM
tion of hexane using an additional feeding line into double edge cutter milling tool, to form a tight fit for the
connection tubings. The two plates were fused by thermal
the microreactor resulted in segmentation and under
these homogeneous segmented flow conditions 5a was
obtained in 66% yield (5b: 77%). The product dis-
solves also in the hexane segments which could have
an effect on the reaction rate as the product concen-
tration in the acetonitrile segments decreases. The in-
bonding at 1278C. Successful fusion of the two polymer sub-
strates required each surface to be scrupulously cleaned by
washing several times with methanol and 2-propanol to
remove contaminants, followed by drying with nitrogen gas
and heating for 48 h at 958C prior to fusion (see Figure S2
in the Supporting Information).
ternal standard can dissolve in the hexane segments,
but after the reaction all solvents were removed with-
out separation, and the residue analysed. Further op-
timisation of the segmented reaction conditions led to ExperimentalSet-Up
even higher conversions in the microreactor (300 mm
”
30 0mm microchannel, 900 mm length). This was ob- A stainless steel housing was designed to hold the fabricated
microdevice which was then connected to the chemical res-
served after 20min reaction time and stilbene ( 5a)
was isolated in 79% yield. The reaction with methyl
acrylate (4b) led to methyl cinnamate (5b) in 54%
isolated yield using the homogeneous segmented flow
ervoirs using PEEK tubings (1/16’ꢁ ” 5 cm, i.d. 0.030’’) fitted
with tight seal connections using flangeless nut and ferrule
(
M6, Sigma–Aldrich Supelco) to the chemical reservoirs
which are air-tight glass syringes (10mL, Sigma–Aldrich Su-
pelco). Stock solutions of the chemical reagents were loaded
into the syringe and delivered to the microreactor using a
syringe pump (KD Scientific Inc).
[
14]
conditions.
Conclusions
In conclusion, by utilizing the large specific interfacial
area provided by a microreactor, the hydrolysis reac- GeneralRemarks
tion of p-nitrophenyl acetate (1) was found to be
much more efficient than applying conventional Reactions at room temperature were performed in a
PMMA microreactor (300 mm ” 400 mm), with a T-junction
to create segmented flow, using the stainless steel housing.
PTFE microchannel tube (300 mm ” 400 mm) was used for
raised temperature reactions with a KEL-F Tee connector
methods. This is particularly the case when the tech-
nologies of segmented flow microreactor and micro-
wave irradiation were used. Even homogeneous reac-
tions could be enhanced by using the segmented flow
technique. In the hydrolysis of 1 mentioned above but
also in transition metal-catalysed processes like the
Heck reaction higher reaction rates were found than
(
Sigma–Aldrich Supelco). The hydrolysis reaction transfor-
mation was monitored and analysed quantitatively using
UV (Jasco, V-570, UV/Vis/NIR). For the Heck reaction
quantitative analysis using GC was carried out on Varian
using conventional reaction flasks. Application of this 3900 gas chromatography equipped with a flame ionisation
microreactor system towards other synthetically detector (FID) using a Varian Factorfour capillary column
useful methods are in progress.
(VF-1 ms, 15 m ” 0.25 mm). All reaction products were ana-
lysed by H and C NMR in CDCl3.
1
13
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Adv. Synth. Catal. 2006, 348, 1043 – 1048

Enhancement of Reaction Rates by Segmented Fluid Flow in Capillary Scale Reactors
FULL PAPERS
Method for the Biphasic/Homogeneous Laminar flow
Hydrolysis of p-NitrophenylAcetate (1) in a PMMA
Microreactor at Room Temperature:
Method for the Homogeneous Segmented Flow
Hydrolysis of p-NitrophenylAcetate (1) in a PMMA
Microreactor at Room Temperature
A solution of p-nitrophenyl acetate (1) in toluene/acetoni-
trile (10 mL, 0.05M) was loaded into syringe A and an
aqueous solution of sodium hydroxide (10mL, 0. 5M) was
loaded in syringe B. Syringes A and B were attached to a sy-
ringe pump (KD Scientific) and connected to the microreac-
tor housing through PEEK tubings. The reagents were deliv-
ered in controlled flow rates. The reacted mixture was col-
lected in a small vial immersed in an ice container. The re-
action product was analysed quantitatively using UV and
NMR.
A solution of p-nitrophenyl acetate (1) in acetonitrile (10m,
0.05M) was loaded in syringe A and an aqueous solution of
sodium hydroxide (10mL, 0.5M) was loaded in syringe B.
An extra syringe, loaded with hexane, was introduced (C).
Syringes A, B and C were fitted on a syringe pump (KD Sci-
entific) and connected to the microreactor housing through
PEEK tubings. Syringes A and C were joined first using a
three-way connector then connected to one of the inlet
ports of the microdevice. The reagents were delivered in
controlled flow rates. The reacted mixture was collected in a
small vial immersed in an ice container. The reaction prod-
uct was analysed quantitatively using UV.
Method for the Biphasic Hydrolysis of p-Nitrophenyl
Acetate (1) in a PTFE Microreactor at 508C using an
OilBath
Method for the Homogeneous Laminar Flow
Diazonium-Heck reaction in a PMMA Microreactor
A solution of p-nitrophenyl acetate (1) in toluene (10mL,
0.05M) was loaded in syringe A and an aqueous solution of
sodium hydroxide (10mL, 0.5M) was loaded in syringe B.
Syringes A and B were fitted on a syringe pump (KD Scien-
tific) and connected to the PTFE microchannel through
PEEK tubings using a KEL-F Tee connector. The micro-
channel was submerged in oil bath maintained at 508C. The
reagents were delivered in controlled flow rates. The reacted
mixture was collected in a small vial immersed in an ice con-
tainer. The reaction product was analysed quantitatively
using UV.
A solution of aniline (30mg, 0. 322 mmol) and the alkene
4
(
0.322 mmol) in acetonitrile (5 mL) was loaded in syringe A.
In syringe B, a prepared solution mixture of palladium ace-
tate catalyst (5 mol%) in acetonitrile (5 mL) was loaded. A
neat mixture (total of 2.2 mL) of tert-butyl nitrite
(
2.80 mmol) and acetic acid (0.1 mL/0.129 mmol of aniline)
was loaded in syringe C. Syringes A, B and C were fitted on
syringe pumps (KD Scientific) and connected to the micro-
reactor housing through PEEK tubings. Syringes A and C
were joined first using a three-way connector then connect-
ed to one of the inlet ports of the microdevice, while syringe
B was connected to the other port. The reagents were deliv-
ered in controlled flow rates using the pump. The reacted
mixture was collected in a small vial immersed in an ice con-
tainer. The reaction product was analysed quantitatively
using GC and NMR.
Method for the Biphasic Hydrolysis of p-Nitrophenyl
Acetate (1) in a PTFE Microreactor at 508C using
Microwave Irradiation
Same as the hydrolysis reaction at 508C except that the mi-
crochannel was irradiated with CEM focused microwave at
508C (50watts). The reagents were delivered in controlled
flow rates. The reacted mixture was collected in a small vial
immersed in an ice container. The reaction product was ana-
lysed quantitatively using UV.
Method for the Homogeneous Segmented Flow Heck
Reaction in a PMMA Microreactor
A solution mixture of aniline (30mg, 0. 322 mmol) and the
alkene 4 (0.322 mmol) in acetonitrile (5 mL) was loaded in
syringe A. In syringe B, a prepared solution mixture of pal-
ladium acetate catalyst (5 mol%) in acetonitrile (5 mL) was
loaded. A neat mixture (total of 2.2 mL) of tert-butyl nitrite
Adv. Synth. Catal. 2006, 348, 1043 – 1048
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www.asc.wiley-vch.de
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Batoul Ahmed et al.
FULL PAPERS
(
2.80 mmol) and acetic acid (0.1 mL/0.129 mmol of aniline)
Roth, K. Martin, J. Metze, Chem. Eng. J. 2004, 101,
201–216; d) A. Günther, S. A. Khan, M. Thalmann, F.
Trachsel, K. F. Jensen, Lab Chip 2004, 4, 278–286;
e) D. Belder, Angew. Chem. 2005, 117, 3587–3588;
Angew. Chem. Int. Ed. 2005, 44, 3521–3522; f) B.
Zheng, R. F. Ismagilov, Angew. Chem. 2005, 117, 2576–
was loaded in syringe C. An extra syringe (D), loaded with
hexane (5 mL) was introduced. Syringes A, B C and D were
fitted on KD Scientific syringe pumps and connected to the
microreactor housing through PEEK tubings. Syringes A
and C were joined first using a three-way connector and
then connected to one of the inlet ports of the microdevice.
Syringes B and D were joined first using also a three-way
connector then connected to the other inlet port of the mi-
crodevice . The reagents were delivered in controlled flow
rates using the pump. The reacted mixture was collected in
a small vial immersed in an ice container. The reaction
product was analysed quantitatively using GC and NMR.
2
579; Angew. Chem. Int. Ed. 2005, 44, 2520–2523;
g) B. K. H. Yen, A. Günther, M. A. Schmidt, K. F.
Jensen, M. G. Bawendi, Angew. Chem. 2005, 117,
5
583–5587; Angew. Chem. Int. Ed. 2005, 44, 5447–
5
451.
[
4] a) J. R. Burns, C. Ramshaw, Lab Chip 2001, 1, 10–15;
b) T. Thorsen, R. W. Roberts, F. H. Arnold, S. R.
Quake, Phys. Rev. Lett. 2001, 86, 4163–4166; c) T. Nisi-
sako, T. Torii, T. Higuchi, Lab Chip 2002, 2, 24–26;
d) S. Sugiura, M. Nakajima, M. Seki, Langmuir 2002,
Acknowledgements
1
8, 5708–5712; e) J. D. Tice, H. Song, A. D. Lyon, R. F.
We thank EPSRC for support of this work and the National
Mass Spectrometry Service Centre, Swansea, for mass spec-
trometric data.
Ismagilov, Langmuir 2003, 19, 9127–9133; f) S. Okushi-
ma, T. Nisisako, T. Torii, T. Higuchi, Langmuir 2004,
20, 9905–9908.
[
5] a) A. Serizawa, Z. Feng, Z. Kawara, Experimental
Thermal and Fluid Science 2002, 26, 703–714; b) G. M.
Greenway, S. J. Haswell, D. O. Morgan, V. Skelton, P.
Styring, Sensors and Actuators B 2000, 63, 153–158;
c) N. Harries, J. R. Burns, D. A. Barrow, C. Ramshaw,
Int. J. Heat Mass Transfer 2003, 46, 3313–3322; d) G.
Dummann, U. Quittmann, L. Gtoschel, D. W. Agar, O.
Worz, K. Morgenschweis, Cat. Today 2003, 79–80, 433–
439; e) T. J. Jonson, D. Ross, L. E. Locascio, Anal.
Chem. 2002, 74, 45–51.
References
[1] a) W. Ehrfeld, V. Hessel, H. Lçwe, Microreactors, New
Technology for Modern Chemistry, Wiley, New York,
2
000; b) M. Matlosz, W. Ehrfeld, J. P. Baselt, (Eds.),
Microreaction Technology - IMRET 5: Proceedings of
the Fifth International Conference on Microreaction
Technology, Springer, Berlin, 2001; c) S. J. Haswell,
R. J. Middleton, B. OꢁSullivan, V. Skelton, P. Watts, P.
Styring, Chem. Commun. 2001, 391–398; d) P. D. I.
Fletcher, S. J. Haswell, E. Pombo-Villar, B. H. Warring-
ton, P. Watts, S. Y. F. Wong, X. Zhang, Tetrahedron
[6] H. Pennemenn, P. Watts, S. J. Haswell, V. Hessel, H.
Lçwe, Org. Proc. Res. Develop. 2004, 8, 422–439.
[
[
[
7] P. He, S. J. Haswell, P. D. I. Fletcher, Sensors Act. B
2
005, 105, 516–520.
2
002, 58, 4735–4757; e) K. Jähnisch, V. Hessel, H.
8] M. C. Bagley, R. L. Jenkins, M. C. Lubinu, C. Mason,
R. Wood, J. Org. Chem. 2005, 70, 7003–7006.
9] M. Ueno, H. Hisamoto, S. Kabayashi, T. Kitamori,
Chem. Commun. 2003, 936–937.
Lçwe, M. Baerns, Angew. Chem. 2004, 116, 410–451;
Angew. Chem. Int. Ed. 2004, 43, 406–446.
[
2] a) P. Watts, S. J. Haswell, Chem. Eng. Technol. 2005, 28,
2
90–301; b) P. He, P. Watts, F. Marken, S. J. Haswell,
[
10] a) J. R. Burns, C. Ramshaw, Chem. Eng. Res. Des. 1999,
7, 206–211; b) J. R. Burns, C. Ramshaw, Chem. Eng.
Electrochem. Commun. 2005, 7, 918–924; c) T. Kawa-
guchi, H. Miyata, K. Ataka, K. Mae, J. Yoshida,
Angew. Chem. 2005, 117, 2465–2468; Angew. Chem.
Int. Ed. 2005, 44, 2413–2416; d) T. Honda, M. Miyaza-
ki, H. Nakamura, H. Maeda, Lab Chip 2005, 5, 812–
7
Commun. 2002, 189, 1611–1628.
[
[
11] M. Beller, H. Fischer, K. Kühlein, Tetrahedron Lett.
1
994, 35, 8773–8776.
12] a) S. Liu, T. Fukuyama, M. Sato, I. Ryu, Org. Process
Res. Dev. 2004, 8, 477–481; b) T. Fukuyama, M. Shin-
men, S. Nishitani, M. Sato, I. Ryu, Org. Lett. 2002, 4,
8
18.
[
3] a) V. Hessel, W. Ehrfeld, T. Herweck, V. Havercamp,
H. Lowe, J. Sechiewe, C. Wille, Gas/liquid Microreac-
tors; Hydrodynamics and mass transfer, Proceedings of
the Fourth International Conference on Micoreaction
Technology, 2000; b) B. Zheng, L. S. Roach, R. F. Isma-
gilov, J. Am. Chem. Soc. 2003, 125, 11170–11171;
c) J. M. Kohler, T. Henkel, A. Grodrian, T. Kirner, M.
1
691–1694.
À1
[
[
13] Reagents in DMF: 2.5 mLmin ; substrates in DMF:
À1
À1
.
2
.5 mLmin ; hexane: 16.5 mLmin
14] 5a: 85% conversion; 5b: 68% conversion (determined
by GC).
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Adv. Synth. Catal. 2006, 348, 1043 – 1048