A microchemical system with continuous recovery and recirculation of catalyst-immobilized magnetic particles

Article abstract of DOI:10.1002/anie.201002490

(Figure Presented) Keep on running: A microchemical system for continuous flow catalytic reactions with a magnetic catalyst is presented (see picture). It enables the automatic separation and recirculation of catalyst particles and is applicable to various catalytic reactions.

Full text of DOI:10.1002/anie.201002490

Angewandte
Chemie
DOI: 10.1002/anie.201002490
Microreactors
A Microchemical System with Continuous Recovery and Recirculation
of Catalyst-Immobilized Magnetic Particles**
Chan Pil Park and Dong-Pyo Kim*
Microfluidic systems have provided new concepts and chal-
lenging subjects for new chemical processes.[1] The advantages
offered are increased surface area to volume ratio, rapid
mass- and heat-transfer, enhanced process safety, simple
feasibility study for scaling up, and reduced waste. The
reaction variables in the confined microscale space can also
be controlled in easy and precise ways. Furthermore, it is a
challenge in the microfluidic community to develop sophis-
ticated continuous flow systems such as micro-TAS (total
analytical system) by integrating several consecutive process-
es of multistep reaction, separation/purification, and detec-
tion into a single-chip device.[2] For heterogeneous catalytic
reactions, efforts have been made to take advantage of
accelerated kinetics resulting from the shortened diffusion
path of the reagents, little or no product contamination, and
full resource utilization. Immobilizing catalysts on channel
surfaces[3] and packing solid catalysts including mesoporous
structures[4] have been attempted. However, the catalyst
immobilization on the channel surface is hampered by many
difficulties such as tricky immobilizing processes, the need for
precise quantitative control of immobilized catalysts, and an
inability to replace deactivated or poisoned catalysts. With
packed catalyst systems, additional difficulties arise such as
pressure drop control, low compatibility with a solid co-
catalyst or product (or reactant), and clogging of the flow,
which also applies to monolithic and porous silica capillary
tube type microreactors as recently reported.[5]
direction perpendicular to the solution flow.[7] Magnetic
particle supported catalysts have also been used extensively
for catalytic reactions. These supported catalysts particles are
typically reclaimed and reused in batch reactions. In micro-
reactors, these particles would be held on the microchannel
walls with the magnetic field applied externally. Furthermore,
an ideal microchemical system would be one in which the
catalyst-immobilized magnetic particles in flowing fluid are
continuously separated from the reacting stream in situ and
then put into the fresh feed stream so that the catalyst
particles can be recirculated and recycled continuously.
Herein, we present a microchemical system for continu-
ous flow catalytic reactions with catalyst-immobilized mag-
netic particles. The system consists of a microfluidic chip type
of microseparator and a capillary microtube reactor. In the
separator, the product stream carrying the catalyst-immobi-
lized magnetic particles flows coaxially along with the fresh
reactant feed stream that is introduced to the separator. As
shown in Figure 1b, the feed stream flows in the bottom half
Magnetic particles have recently been shown to be very
useful for rapid and facile separation. In particular, magnetic
particle embedded materials with various functions have been
used for wide application in bioseparation, drug delivery,
magnetic resonance imaging, and others.[6] Magnetic particles
labeled with cells or proteins can be recovered or sorted in a
microfluidic system by applying a magnetic field in the
Figure 1. a) Microchemical system consisting of a microseparator chip
and a capillary microtube reactor, where magnetic catalyst particles are
separated and recirculated. b) Magnetic particles in the product
stream in the laminar flow regime move toward the magnet and join
the feed stream.
of the microchannel and the magnetic particle carrying
product stream flows in the top half. Almost no mixing and
thus almost complete separation occurs as a result of laminar
flow when the two streams are each led to the reactor for
reaction and to the separator outlet to retrieve the product
stream. The magnetic field applied to the bottom wall of the
channel draws magnetic particles from the product stream to
the reactant feed stream, thereby completing the separation
of the catalyst particles from the product stream and the
placement of the particles in the feed stream for catalyst
recirculation and reuse. Although the concept is the same, a
two-stage separation scheme had to be devised for efficient
and complete separation of the particles (see movie in the
Supporting Information). In addition, the capillary microtube
facilitates a setup for microchemical reactions that require
[*] Prof. Dr. D.-P. Kim
National Creative Research Center of Applied Microfluidic Chemis-
try, Graduate School of Analytical Science and Technology
Chungnam National University, Daejeon, 305-764 (South Korea)
Fax: (+82)42-823-6665
E-mail: dpkim@cnu.ac.kr
Homepage: http://www.camc.re.kr
Dr. C. P. Park
National Creative Research Center of Applied Microfluidic Chemis-
try, Chungnam National University
Daejeon, 305-764 (South Korea)
[**] This work was supported by a National Research Foundation of
Korea (NRF) grant funded by the Korea government (MEST)
(20100000722).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201002490.
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high thermal and chemical resistance over an extended
period.
The continuous, self-regulated microchemical system
in the vicinal oxygenation of alkenes,[14] in connection with
Pd-catalyzed vicinal oxidation including diamination and
aminooxygenation based on the PdII/PdIV catalyst cycle.[15] In
this light, tridentate Pd catalyst 1 is expected to be a good
candidate for the oxidation with its inherent long-term
stability.
Testing for stable catalytic activity in the face of repeated
use of the catalyst was performed in a conventional batch
system with dioxygenation of alkene (Scheme 2). The Pd
allows investigation of catalytic reactions in a way that has
never been possible in microsystems. The automatic separa-
tion of catalyst particles and recirculation by the micro-
chemical system makes it possible to fully realize the
advantages a catalytic microreactor can offer. In addition, a
significant reduction in the amount of catalyst used for a
reaction can be realized. Furthermore, the microchemical
system can be used repeatedly for many different reactions.
In the preparation of magnetic particles 1 supporting
tridentate palladium complexes (Scheme 1),[8] commercially
available magnetic particles having silica surfaces functional-
Scheme 2. Stable catalytic activity of the Pd magnetic particles 1 in
batch dioxygenation reaction. Standard reaction conditions:
1.65 mol% Pd magnetic particles 1, DMF/AcOH (1:2), 508C, 5 h.
Yields were measured by NMR spectroscopy against an internal
standard.
magnetic particle 1 maintained 84–86% yield without degra-
dation of catalytic activity during three repeated dioxygena-
tion reactions. The dispersed magnetic particles in solution
were recovered by a NdFeB 35 permanent magnet (20 mm ꢀ
8 mm ꢀ 10 mm, magnetic field strength: 0.510 G at 1 mm
distance) after each reaction.[6] After the third reaction, the
amount of palladium on the magnetic particle measured with
ICP-AES was 1.97 mg in 230 mg of particles (0.081 mmolgÀ1),
which is quite close to the original concentration
(0.083 mmolgÀ1). No apparent shape deformation was
observed. This result demonstrates that the Pd magnetic
particle 1 is robust and reliable as a catalyst for repeated use.
Our initial microchemical system with Pd magnetic
particle 1 was a PDMS (poly(dimethylsiloxane)) microreactor
with a built-in separator for recovering the spent magnetic
particles with no recirculation of the recovered particles
(Figure 2). The reactor channel was 32 cm long, 300 mm wide,
and 50 mm high. The magnetic particles in the red DMF
Scheme 1. Immobilization of catalyst on silica surface of particles.
ized with primary amine group (average size: 1.99 mm,
AccuBead, bioneer, Korea) were used. The silica coating of
magnetic nanoparticle prevents direct contact of the magnetic
core with reagents, which can lead to unwanted interactions.
The molecular ligand was immobilized at the silica surface to
use the active metal as a catalyst. Typically, the magnetic
particles with amine groups were treated with pyridine-2,6-
dicarbonyl dichloride in methylene chloride under N2 atmos-
phere in the presence of excess triethylamine as a base at
408C. Subsequently, the terminal acyl group was blocked with
aniline. The three nitrogen donors from two amides and one
pyridine ring strongly bind the palladium center,[9] generating
a tridentate Pd complex immobilized on the silica surface of
the magnetic particle. The tridentate structure is intrinsically
more stable than mono- or bidentate structures, which leads
to a longer catalyst lifetime. There was no observable
difference in the shape of the catalyst immobilized particles
and the as-received particles, as seen in the SEM image
(Figure 1Sa in the Supporting Information). The amount of
palladium measured by inductively coupled plasma atomic
emission spectroscopy (ICP-AES) was 0.88 mg in a 100 mg
particle (0.083 mmolgÀ1). It should be noted that the same
approach leads to immobilization of various molecular metal
catalysts, including Cu, Ni, and Co.[10]
Dioxygenation of alkenes is an important reaction in
organic chemistry,[11] for which osmium catalysts have been
widely used.[12] The recent push for environmentally friendly
processes and highly efficient methods has led to efforts to
reduce the cost and to avoid toxicity of the catalysts.[13] Pd-
catalyzed dioxygenation has led to interesting developments
Figure 2. a) Initial microfluidic separator design for continuous recov-
ery of magnetic particle from product solution. b) Captured image at
part A: shaded solution is the product solution and black dots are
magnetic particles. Captured image at part B in the: c) absence and
d) presence of a magnetic field.
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solution moved with the laminar flow of the solution in the
absence of a permanent magnet (Figure 2c). When a mag-
netic field was applied, the particles drifted toward the
bottom wall (Figure 2d). The field strength was controlled by
varying the distance between the channel and the magnet.
Typically, 0.4 mol% of magnetic particles in the shaded
solution was completely recovered under an external mag-
netic field of 0.13 G at 10 mm distance at a combined injection
rate of the two inlet solutions of 4.5 mLminÀ1 (fluid velocity of
30 cmminÀ1 at the separation point). The yield of dioxygena-
tion of styrene (0.2 mmol) in DMF/AcOH (1:2) at room
temperature (3 equiv H2O, 1.2 equiv PhI(OAc)2) was only
21% owing to insufficient retention time (64 s). Furthermore,
a lower injection rate or a larger amount of magnetic particles
caused diffused mixing of two liquid flows or incomplete
separation of the particles from the product solution.
A few lessons were learned with initial design. First, it is
better to use a capillary microtube from PTFE (poly(tetra-
fluoroethylene)), rather than a microchannel engraved into
PDMS, because the length of the reactor can be easily
controlled with the PTFE tube and the material is much
better than PDMS in terms of resistance to swelling and high
temperature. Incomplete separation and recovery with the
first design taught us that a two-stage separation scheme is
needed and that building a recirculation system for the
catalyst particles would be better served by fabricating a
microfluidic chip type of separator on PDMS as shown in
Figure 3. The microchemical system thus designed and
of the flows. The solvent stream meets up with the reagent
stream to feed the reactor with the particles entrained in the
feed. Any particles not picked up by the solvent stream that
are contained in the product stream are separated at point A
in Figure 3a and collected into the feed stream at point B (see
Figure 3b,c). A peristaltic pump continuously circulates the
recovered catalyst particles (see movie in the Supporting
Information). Note that the way in which the solvent stream is
introduced to the separator ensures no mixing between the
product stream and the feed stream. Typical operating
conditions were a flow rate of 37 mLminÀ1, and a magnetic
field of 0.250 G created by placing a NdFeB 35 magnet
(20 mm ꢀ 8 mm ꢀ 10 mm) 5 mm away from the wall with a
total system volume of 525.0 mL (PTFE: 510.5 mL; pumping
system: 6.3 mL; chip: 8.3 mL). The retention time can be
controlled either by the length of the capillary tube or by the
amount of catalyst particles.
Three intermolecular and one intramolecular dioxygena-
tion reactions were carried out in the microchemical system
(Table 1). The catalyst loading was 0.0037 mmol (3.5 mol%,
Table 1: Dioxygenation of alkenes in a microchemical system with
continuous recirculation of Pd magnetic particles 1.[a]
Entry
Substrate
Product
T
Yield
83%
89%
1
2
RT
408C
3
4
508C
508C
85%[b]
84%
[a] Standard reaction conditions: 3.5 mol% Pd magnetic particles 1,
DMF/AcOH (1:2), 1.2 equiv PhI(OAc)2. Yields were measured by NMR
spectroscopy against an internal standard. [b] 3.81 mmol product was
formed after 10 h and was analyzed by NMR spectroscopy.
Figure 3. a) Design for continuous recirculation of magnetic particles
in the separator part of the microchemical system. Captured image at
b) position A, and c) position B.
45 mg of Pd magnetic particles 1), the total olefin in the
microreactor was 0.105 mmol (0.2m solution in 525 mL), and
1.2 equiv PhI(OAc)2 was used. The performance of the
microchemical system as revealed in Table 1 is excellent.
Styrene (Table 1, entry 1) and but-3-enenitrile (Table 1,
entry 2) converted into the corresponding dioxygenated
products with yields (measured by NMR spectroscopy) of
83% and 89%, respectively, with 14 min retention time.
Cyclohex-1-enyl-benzene (Table 1, entry 3) showed an 85%
yield with syn-addition selectivity for an identical retention
time (14 min) at 508C, which is comparable to that of bulk
reaction that could be realized in 5 h of reaction or retention
time. In addition, we also tried internal cyclization of but-3-
fabricated consists of a capillary microreactor and a micro-
separator (see Figure 2S in the Supporting Information). The
microreactor was a 260 cm long PTFE tube with an inside
diameter of 500 mm. In the separator part (300 mm ꢀ 50 mm ꢀ
20 mm), the product stream entraining the catalytic magnetic
particles merges with the solvent stream, and the particles in
the product stream move into the solvent stream as a result of
the external magnetic field. Note that little if any mixing
occurs between the two streams owing to the laminar nature
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Communications
enoic acid to construct the lactone ring, which is an important
particles for them to be recirculated. The continuous, self-
regulated microchemical system allows one to investigate
catalytic reactions in a way that has never been possible in
microsystems. The automatic separation of catalyst particles
and recirculation by the microchemical system makes it
possible to realize fully the advantages a catalytic micro-
reactor can offer. In addition, a significant reduction in the
amount of catalyst used for a reaction can be realized. As
illustrated with dioxygenation reactions, only 10% of the
catalyst needed for batch reaction is required for the micro-
chemical system. Furthermore, the microchemical system can
be used repeatedly for many different reactions with subse-
quent solvent cleaning. The microchemical system could be
applied to various well-known organic chemical processes,
and new chemistry could also be tried with the aid of already
reported or new magnetic catalyst.
building block for several natural products. The reaction gave
an 84% yield at 508C (Table 1, entry 4). The microchemical
system with catalyst recirculation provides many advantages.
It allows one to carry out different reactions in the same
system by simply replacing the reagents after washing with
fresh solvent for 30 min. No contamination problems were
encountered. More importantly, it is also possible to replace
the catalyst with fresh catalyst in this case, which is impossible
with heterogeneous catalytic system.[3]
To test the robustness and stability of the catalyst activity
and the separation efficiency of the magnetic particles over an
extended period of time, two reactions (Table 1, entries 1 and
2) were carried out continuously for up to 10 h. It is satisfying
that little deviation of the product yield was observed
(Figure 4), indicating the excellent durability of catalyst. In
addition, the product solution did not contain any black dots
Experimental Section
General description of the dioxygenation in the batch system: To the
solution of olefin (0.5 mmol) and Pd magnetic particles 1 (100 mg;
1.65 mol%) in 2.5 mL AcOH/DMF (2:1 by weight), H2O (1.5 mmol)
and PhI(OAc)2 (1.2 equiv; 177 mg) were added. The resulting mixture
was stirred for 5 h, and the Pd magnetic particles 1 was separated by a
NdFeB 35 permanent magnet. Ac2O (2 equiv) was added to the
solution, and the resultant mixture was stirred overnight at room
temperature. After the solvent was removed under reduced pressure,
the yield was measured by 1H NMR spectroscopy against an internal
standard.
General description of the dioxygenation in microfluidic system
using the circulation of Pd magnetic particles 1: The slurry of Pd
magnetic particles 1 was introduced into the microreactor by the refill
operation of a syringe pump. The total amount of loaded magnetic
particle was 45 mg. A peristaltic pump with marprene tube (inside
diamter: 250 mm, Watson-Marlow) was used to circulate the solution
in the microreactor at a flow rate of 37 mLminÀ1. The fresh solvent
and reagents (0.3m) were introduced at an injection rate of
23.5 mLminÀ1. The total retention time in the microreactor was
14 min. The product separated from the system and was collected.
Ac2O (2 equiv) was added to the collected solution, and the resultant
mixture was stirred overnight at room temperature. After the solvent
was removed under reduced pressure, the yield was measured by
NMR spectroscopy against an internal standard.
Figure 4. Variation of product yields with reaction time; &: but-3-
*
enenitrile; : styrene.
during the 10 h reaction, and no palladium was detected in the
solution by ICP-AES. Although 3.5 mol% catalyst was used
in the microchemical system as opposed to the 1.65 mol%
used in the batch reactor, continuous recycling over 10 h
corresponds to 42.9 {10 h ꢀ 60 (minhÀ1)/14 min (retention
time)} times the batch reaction and therefore the catalyst used
per cycle is only 3.5/42.9 (= 0.08) mol%. The productivity
comparison between the batch system and the microchemical
system can also be made on the basis of the ratio mol-
(product)mol(Pd)À1 unit timeÀ1. In the dioxygenation of
cyclohex-1-enyl-benzene (Table 1, entry 3), the three
repeated batch systems for 15 h (time for a catalyst recovery
was not included) gave 10.27 mmol(product)mmol(Pd)À1 hÀ1
{0.5 mmol ꢀ (0.86 + 0.84 + 0.84)/(0.5 mmolꢀ1.65 ꢀ 10À2)/15 h}.
However, the microchemical system for 10 h continuous
running generated 102.97 mmol(product)mmol(Pd)À1 hÀ1
Received: April 26, 2010
Revised: May 27, 2010
Published online: August 16, 2010
Keywords: heterogeneous catalysis · magnetic particles ·
.
microreactors · oxygenation
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which
is
In conclusion, we have developed a microchemical system
for continuous flow catalytic reactions with catalyst-immobi-
lized magnetic particles. The system consists of a microfluidic
chip type of microseparator and a capillary microtube reactor.
The separator cleanly separates the product stream from the
fresh feed stream and completely recovers spent catalyst
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