Alternating magnetic field mediated micro reaction system for palladium-catalyzed coupling reactions

Article abstract of DOI:10.1039/c7ra07324k

A continuous flow reaction system in which a palladium magnetic catalyst was immobilized and vibrated by an alternating induced magnetic field was developed. The alternating electromagnetic field improved the mixing efficiency and catalytic activity for the palladium-catalyzed coupling reactions. This flow reaction system showed good product yields for various reactions such as Sonogashira, Heck, Suzuki, Stille, Hiyama and decarboxylative coupling reactions.

Full text of DOI:10.1039/c7ra07324k

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Alternating magnetic field mediated micro reaction
system for palladium-catalyzed coupling
reactions†
Cite this: RSC Adv., 2017, 7, 37181
Hee Jae Kim, Jinseop Choi, Jaehoon Choe, Kwang Ho Song *a
a
b
c
b
and Sunwoo Lee
*
A continuous flow reaction system in which a palladium magnetic catalyst was immobilized and vibrated by
an alternating induced magnetic field was developed. The alternating electromagnetic field improved the
mixing efficiency and catalytic activity for the palladium-catalyzed coupling reactions. This flow reaction
system showed good product yields for various reactions such as Sonogashira, Heck, Suzuki, Stille,
Hiyama and decarboxylative coupling reactions.
Received 3rd July 2017
Accepted 21st July 2017
DOI: 10.1039/c7ra07324k
rsc.li/rsc-advances
Transition metal-catalyzed transformations are one of the most catalyst on the ow reactor. Most cases have borrowed tools that
1
versatile synthetic tools in organic synthesis. In particular, were established in batch reaction systems. One of the most
coupling reactions catalyzed by late transition metals such as frequently used methods is the immobilization of the catalyst
palladium, copper, and nickel have been widely used to on polymer or inorganic supports packed in the channel of the
7
construct important organic building blocks in pharmaceutical ow reactor. However, this catalytic packing system gave rise to
2
and materials chemistry. The development of palladium- a backpressure owing to the high volume of supporting mate-
catalyzed coupling reactions was awarded the Nobel Prize in rials. As a solution to solve this problem, the immobilization of
3
Chemistry in 2010.
the catalyst on magnetic particles was employed in the reaction
8
The considerable attention paid to green chemistry has ow system (Fig. 1a). However, with this method, only a small
triggered a need to develop of environmentally friendly chem- portion of the reagents might encounter the catalyst particles,
ical processes. To meet this demand, recyclable catalytic and the efficiency of the reaction is very low because the catalyst
systems with immobilized catalysts have been developed for is immobilized on the surface of the channel by a magnetic
organic transformations that proceed via homogeneous catal- eld.
4
ysis. The most common method for immobilization of catalysts
To address these issues, we introduced an alternating
uses polymer or inorganic supports bearing ligands that can magnetic eld into the continuous ow reaction system with
bind to the metal catalyst. To make the process for recycling the palladium magnetic particles as an immobilized catalyst. In
catalyst easier, magnetic particles were employed and encap- addition, to arrange and vibrate the catalyst in the reaction
5
sulated by the immobilized catalyst.
channel, the induced magnetic eld was periodically changed
The continuous ow reaction system has been developed to improve the mixing efficiency. For microuidic systems,
and applied to a variety of transition metal-catalyzed trans- some simulations have been reported for magnetic particles in
6
formations. Compared with traditional batch reactions, this an induced magnetic eld and showed improved mixing
continuous ow chemistry has several benets, including
excellent mass transfer and thermal control due to the high
surface-to-volume area. Moreover, continuous ow systems can
be easily scaled by using parallel reactors. To apply this
continuous ow reaction system in metal-catalyzed trans-
formations, the most important factor is the immobilization of
a
Department of Chemical & Biological Engineering, Korea University, Seoul 02841,
Republic of Korea. E-mail: khsong@korea.ac.kr
b
Department of Chemistry, Chonnam National University, Gwangju, 61186, Republic
of Korea. E-mail: sunwoo@chonnam.ac.kr
c
LG Chem Research Park, Daejeon 34122, Republic of Korea
Fig. 1 (a) Continuous flow reactor with a magnetic catalyst and an
external permanent magnet; (b) electromagnetic micro-reactor with
a magnetic catalyst and a Helmholtz coil using alternating current.
†
Electronic supplementary information (ESI) available. See DOI:
0.1039/c7ra07324k
1
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efficiency for electromagnetic micro reactors. Here, we report
the continuous ow reactions using an immobilized magnetic
palladium catalyst under an induced magnetic eld (Fig. 1b).
To achieve our goal, we attempted to optimize conditions
such as catalyst particle size, ow rate, and strength and
frequency of the magnetic eld. It is important to nd condi-
tions under which the catalyst particles stay in the reaction
channel with the appropriate ow rate without loss of particles.
To determine the optimal particle size and ow rate, we chose
four different sizes of magnetic palladium particles and inves-
tigated the relationship between particle size, magnetic eld
strength, and ow rate of the reaction mass. As most of the
catalyst particle consists of iron oxide, the size of the catalyst
particles was controlled by using iron oxides of different sizes.
The same amount of magnetic particles to each four different Fig. 2 Retention range according to magnetic field intensity, the flow
rate and particle size.
sizes injected to 1/16 inch channel. It tested whether magnetic
particles are spilled out from the channel in the condition of
4
1
00 G and 560 G at various ow rates. As shown in Fig. 2, 0.3 and
mm particles did not stay in the reaction channel under ow
ꢀ1
rates in the range of 4–30 mL min in either 400 or 560 G
magnetic elds. The 15 mm particles were retained in the reac-
tion channel under a ow rate of 12 mL min in a 560 G
magnetic eld. The 70 mm particles did not stay in the reaction
ꢀ
1
ꢀ
1
channel under a ow rate of 28 mL min . When the ow rate
ꢀ1
was decreased to 20 mL min , the 70 mm particles were retained
in the reaction channel in a 560 G magnetic eld, but not in
a 400 G magnetic eld. However, the 70 mm particles were
retained at a ow rate of 14 mL min in both 400 and 560 G
magnetic elds. In retention range of Fig. 2, we found that this
ꢀ
1

ow system hold 98% of the catalyst during 1.5 h.
From the above experiment, a magnetic eld of at least 560 G
is required to retain 15 mm in the reaction channel. We con-
9,10
ducted a Villermaux–Dushman reaction.
to observe the
Fig. 3 Mixing performance according to magnetic field intensity and
frequency (I is the current, V is the voltage, f is the frequency, L is the
inductance, B is the magnitude of magnetic field, n is the number of
turns in the coil).
change in mixing efficiency of the electromagnetic microreactor
at various magnetic elds and frequencies. The results of the
Villermaux–Dushman reaction experiment, as shown in Fig. 3,
indicate that magnetic particles move more at high frequencies
than at low frequencies and move further at high intensities
than at low intensities. For the Helmholtz coil, the magnitude of
magnetic ux density and frequency are inversely proportional
area. Equations that show the relation of the magnitude of
magnetic ux density and the frequency are displayed in Fig. 3.
Accordingly, the experiment had to be conducted in a fan-
shaped. In this area, we chose the condition that has better
mixedness ratio than the darker area, and carried out the
experiments in the condition of marked point (5 Hz, 560 G).
With this result in hand, we chose to use 15 mm magnetic
particles to prepare the magnetic palladium catalyst using
Fig. 4 Schematic figure of electromagnetic micro reactor.
11
a well-established method. These magnetic catalyst particles
were packed in a ow reaction tube, which was placed in
a Helmholtz coil, as shown Fig. 4.
expected, the Helmholtz coil system showed higher yields than
3
To evaluate the magnetic ow reaction system, Sonogashira the permanent magnet system. With organic bases such as Et N
coupling reaction was tested using ow reaction systems with and DBU, the Helmholtz coil system afforded the desired
either permanent magnet or the Helmholtz coil. As shown in product, but no desired product was formed using the perma-
Table 1, phenylacetylene and iodobenzene were reacted under nent magnet system (entries 4 and 5).
a variety of conditions. With increasing temperature, the
Using this condition, various aryl iodides were employed in
product yields were increased in both cases (entries 1–3). As this ow reaction system. As shown in Scheme 1, iodotoluenes
37182 | RSC Adv., 2017, 7, 37181–37184
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a
Table 1 Sonogashira reaction in a continuous flow reaction system Table 2 Coupling reaction using flow reaction system
under alternating and permanent magnetic fields
a
b
Yield
Entry Reactant 1/reactant 2
Base Product
(%)
1
C
6
H
5
I/CH
2
CHCO
2
(n-Bu) Et
3
N
N
85
2
3
4
4-MeC
4-MeC
4-MeC
6
6
6
H
H
H
4
I/C
I/C
I/C
6
6
6
H
5
H
5
H
5
B(OH)
2
Et
3
74
87
95
ꢁ
d
b
b,c
Entry
Temp ( C)
Base
Yield (%)
Yield (%)
1
2
3
4
5
90
TBAF
TBAF
TBAF
TEA
66
82
89
77
77
—
11
12
—
—
4
4
SnBu
3
—
110
130
110
130
Si(OEt)
3
TBAF
TBAF
DBU
a
Reaction condition: iodobenzene (0.1 mmol), phenylacetylene (0.12
mmol), base (0.2 mmol) were dissolved in DMF (dimethylformamide,
5
C
6
H
5
I/C
6
H
5
CCCO
2
H
85
2
0 mL). Magnetic catalyst (0.125 mol% based on Pd); ow rate: 12 mL
ꢀ
1
b
min ; residence time: 90 min. Yield of diphenyl acetylene was
determined by gas chromatography analysis. Yield of diphenyl
acetylene under permanent magnet eld.
c
a
Reaction conditions: reactant 1 (0.1 mmol), reactant 2 (0.12 mmol),
d
Base: TBAF
¼
and base (0.2 mmol) were dissolved in DMF (20 mL) and owed.
ꢀ1
tetrabutylammonium uoride; TEA ¼ triethylamine; DBU ¼ [1,8- Magnetic catalyst (0.125 mol% based on Pd); ow rate: 12 mL min
;
b
diazabicyclo-5.4.0]undec-7-ene.
residence time: 90 min.
chromatography.
Yields were determined by gas
Heck, Suzuki, Stille, Hiyama and decarboxylative coupling
reactions. In addition, all reactions could be scalable by using
parallel reactors.
Acknowledgements
This research was supported by the National Research Foun-
dation of Korea (NRF) grant funded by the Korea government
(NRF-2012R1A1A2044286 and NRF-2015R1A4A1041036).
Scheme 1 Sonogashira coupling reaction using the flow reaction
system.
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