Superparamagnetic nanoparticle-supported catalysis of Suzuki cross-coupling reactions

Article abstract of DOI:10.1021/ol050218w

(Figure Presented) Emulsion polymerization was examined as a novel route for the synthesis of core/shell superparamagnetic nanoparticles consisting of a highly crystalline γ-Fe2O3 core and a very thin polymeric shell wall. These nanoparticles were used as soluble supports for immobilizing Pd catalysts to promote Suzuki cross-coupling reactions. Recovery of catalysts was facilely achieved by applying a permanent magnet externally. Isolated catalysts were reused for new rounds of reactions without significant loss of their catalytic activity.

Full text of DOI:10.1021/ol050218w

ORGANIC
LETTERS
2
005
Vol. 7, No. 11
085-2088
Superparamagnetic
Nanoparticle-Supported Catalysis of
Suzuki Cross-Coupling Reactions
2
†
†
†
‡
Philip D. Stevens, Jinda Fan, Hari M. R. Gardimalla, Max Yen, and
Yong Gao*
,
†
Department of Chemistry and Biochemistry, Mailcode 4409, Southern Illinois
UniVersity, Carbondale, Illinois 62901-4409, and Materials Technology Center,
Southern Illinois UniVersity, ENGR A-120, Carbondale, Illinois 62901-6603
ygao@chem.siu.edu
Received February 2, 2005 (Revised Manuscript Received April 17, 2005)
ABSTRACT
Emulsion polymerization was examined as a novel route for the synthesis of core/shell superparamagnetic nanoparticles consisting of a
highly crystalline -Fe2O3 core and a very thin polymeric shell wall. These nanoparticles were used as soluble supports for immobilizing Pd
γ
catalysts to promote Suzuki cross-coupling reactions. Recovery of catalysts was facilely achieved by applying a permanent magnet externally.
Isolated catalysts were reused for new rounds of reactions without significant loss of their catalytic activity.
Recycling of homogeneous catalysts is a task of great
economic and environmental importance in chemical and
pharmaceutical industries, especially when expensive and/
and synthetic difficulties in transferring standard solution-
phase reactions to the solid phases.
During recent years, development of novel soluble ma-
trixes for supporting solution-phase organic reactions has
1
or toxic heavy metal complexes are employed. Immobiliza-
3
tion of homogeneous catalysts on various insoluble supports,
especially porous materials with high surface areas, is usually
the method of choice since the immobilized catalysts can
be facilely recovered via a simple filtration process after
reactions. However, a substantial decrease in activity and
selectivity of the immobilized catalysts is frequently observed
due to the heterogeneous nature of these support materials
in reaction media. The loaded catalysts also encounter other
received a great deal of research attention. Many of the
aforementioned problems associated with heterogeneous
insoluble matrixes can be addressed by adopting a soluble
4
5
6
support. JandaJel, perfluorinated tags, ROMP gels, and
7
other types of synthetic soluble polymers have been well
explored for immobilizing catalysts, reagents, and scavengers.
(3) For some recent reviews: (a) Tzschucke, C. C.; Markert, C.;
Bannwarth, W.; Roller, S.; Hebel, A.; Haag, R. Angew. Chem., Int. Ed.
2002, 41, 3964. (b) Bergbreiter, D. E. Chem. ReV. 2002, 102, 3345. (c)
Barrett, A. G. M.; Hopkins, B. T.; K o¨ bberling, J. Chem. ReV. 2002, 102,
2
problems in solid-phase-supported organic reactions: non-
linear kinetic behavior, unequal access to chemical reactions,
3
301. (d) Dickerson, T. J.; Reed, N. N.; Janda, K. D. Chem. ReV. 2002,
102, 3325. (e) Fan, Q.-H.; Li, Y.-M.; Chan, A. S. C. Chem. ReV. 2002,
†
Department of Chemistry and Biochemistry.
Materials Technology Center.
102, 3385. (f) Yoshida, J.-i.; Itami, K. Chem. ReV. 2002, 102, 3693.
(4) Gambs, C.; Dickerson, T. J.; Mahajan, S.; Pasternack, L. B.; Janda,
K. D. J. Org. Chem. 2003, 68, 3673.
‡
(
(
1) For a review: Cole-Hamilton, D. J. Science 2003, 299, 1702.
2) For a review: Vaino, A. R.; Janda, K. D. J. Comb. Chem. 2000, 2,
(5) (a) Luo, Z.; Zhang, Q.; Oderaotoshi, Y.; Curran, D. P. Science 2001,
291, 1766. (b) Dinh, L. V.; Gladysz, J. A. Chem. Commun. 2004, 8, 998.
5
79.
1
0.1021/ol050218w CCC: $30.25
© 2005 American Chemical Society
Published on Web 04/29/2005

By replacing insoluble resins with these soluble scaffolds,
the solution-phase reaction conditions will be reinstated. After
reactions, a second solvent is usually introduced for the
selective precipitation of matrixes out of the reaction mixtures
consisting of a magnetic iron oxide core surrounded by a
layer of lightly cross-linked polymeric shell wall. The organic
polymer shells stabilize nanoparticles by preventing aggrega-
tion of inorganic cores and offer a platform for immobiliza-
tion of catalysts. For the solubility of nanoparticles in organic
media, shell walls are usually thin (∼nm) and the shell
(JandaJel and ROMP gels) or for the extraction of the
scaffolds into the orthogonal liquid phase (perfluorinated
tags). Although tremendous progress has been made in this
area, there is still a need to develop new types of soluble
supports, especially those that can be widely employed in
chemical and pharmaceutical industries. The large-scale
introduction of a second solvent in an industrial process can
potentially increase the costs and generate more waste,
leading to environmental concerns.
10
polymers are preferred to have low molecular weights. Iron
oxide cores will respond to a magnetic field but retain no
magnetization properties when the field is removed. The lack
of magnetic remanence prevents nanoparticles from forming
magnetized clumps in the reaction media. In addition,
unusually high magnetization moments of “super”paramag-
netic materials allow the use of low-field magnets to
efficiently concentrate magnetic nanoparticles. In this paper,
we would like to report our preliminary studies demonstrating
the feasibility of using this new class of materials for
supporting homogeneous catalysts. The Pd catalysts im-
mobilized on magnetic core/shell nanoparticles can be
facilely recovered by using an external permanent magnet
that is readily available at a low cost from many commercial
vendors.
Nanoparticles have emerged as alternative soluble matrixes
8
for supporting homogeneous organic reactions. This is
because when the size of the support materials is decreased
to the nanometer scale, the surface area of nanoparticles will
increase dramatically. As a consequence, nanoparticle sup-
ports could have higher catalyst loading capacity than many
conventional support matrixes, leading to the improved
catalytic activity of the nanoparticle-supported catalysts. In
addition, catalysts are usually immobilized on the surface
of nanoclusters. Reactants in solution have easy access to
the active sites on the surface of nanoparticles, avoiding the
problems encountered in many heterogeneous support ma-
trixes where a great portion of catalysts are present deep
inside the matrix backbones and reactants have the limited
access to the catalytic sites. Among many nanomaterials,
monolayer-protected Au nanoclusters (Au MPCs) have
received particular research attention due to their stability
and solubility in organic solvents. Recent studies have
confirmed the high catalytic activity of Au MPC-supported
The core/shell iron oxide/polymer nanocrystals used for
immobilizing Pd catalysts were synthesized via a novel
emulsion polymerization approach (Scheme 1).11 Vigorous
Scheme 1. Emulsion Polymerization Synthesis of Core/Shell
Iron Oxide/Polymer Nanocrystalsa
8c
catalysts. However, facile isolation and recycling of nano-
particle supports from reaction media have remained a
challenge. Additional laboratory work is usually required for
the judicious selection of addition of a second solvent to
selectively precipitate Au nanoparticles out of the reaction
medium.
a
Organic polymeric shell consists of lightly cross-linked poly-
Superparamagnetic nanoparticles are a new type of soluble
matrix that potentially can address the isolation and recycling
problems encountered in Au MPCs and other soluble
supports for immobilization of homogeneous catalysts. These
mers of styrene and VBC. DVB: 1,4-divinylbenzene. VBC: 1,4-
vinylbenzyl chloride.
9
stirring facilitated the formation of micelles of pluronic
surfactant P-123 in an aqueous medium. Highly crystalline
magnetic nanoparticles usually have a core/shell structure
(6) (a) Harned, A. M.; He, H. S.; Toy, P. H.; Flynn, D. L.; Hanson, P.
and monodisperse γ-Fe
2
O
3
nanocrystals (∼11 nm) coated
R. J. Am. Chem. Soc. 2005, 127, 52. (b) Ralph, C. K.; Akotsi, O. M.;
Bergens, S. H. Organometallics 2004, 23, 1484. (c) Enholm, E. J.; Gallagher,
M. E. Org. Lett. 2001, 3, 3397. (d) Årstad, E.; Barrett, A. G. M.; Hopkins,
B. T.; K o¨ bberling, J. Org. Lett. 2002, 4, 1975.
1
2
with a layer of oleate were encapsulated inside the interior
cores of micelles due to the hydrophobic alkyl chains of the
oleate molecules. Styrene, 4-vinylbenzene chloride (VBC),
and 1,4-divinylbenzene (DVB) were added and entrapped
(7) For some recent references: (a) Bergbreiter, D. E.; Osburn, P. L.;
Smith, T.; Li, C.; Frels, J. D. J. Am. Chem. Soc. 2003, 125, 6254. (b) Lau,
K. C. Y.; He, H. S.; Chiu, P.; Toy, P. H. J. Comb. Chem. 2004, 6, 955. (c)
Hebel, A.; Haag, R. J. Org. Chem. 2002, 67, 9452. (d) Zhong, J.-H.;
Fishman, A.; Lee-Ruff, E. Org. Lett. 2002, 4, 4415.
(e) Dyal, A.; Loos, K.; Noto, M.; Chang, S. W.; Spagnoli, C.; Shafi, K. V.
P. M.; Ulman, A.; Cowman, M.; Gross, R. A. J. Am. Chem. Soc. 2003,
125, 1684. (f) Gu, H.; Ho, P.-L.; Tsang, K. W. T.; Wang, L.; Xu, B. J. Am.
Chem. Soc. 2003, 125, 15702.
(10) Commercial magnetic beads with a size over several microns are
usually suspended in most organic media due to the high molecular weights
of their shell walls.
(11) Similar approach was used for the synthesis of polystyrene nano-
particles using micelle templates: Jang, J.; Ha, H. Langmuir 2002, 18, 5613.
(12) (a) Hyeon, T.; Lee, S. S.; Park, J.; Chung, Y.; Na, H. B. J. Am.
Chem. Soc. 2001, 123, 12798. (b) Lu, J.; Fan, J.; Xu, R.; Roy, S.; Ali, N.;
Gao, Y. J. Colloid Interface Sci. 2003, 258, 427.
(8) (a) Templeton, A. C.; Hostetler, M. J.; Warmoth, E. K.; Chen, S.;
Hartshorn, C. M.; Krishnamurthy, V. M.; Forbes, M. D. E.; Murray, R. W.
J. Am. Chem. Soc. 1998, 120, 4845. (b) Fan, J.; Chen, S.; Gao, Y. Colloids
Surf., B 2003, 28, 199. (c) Marubayashi, K.; Takizawa, S.; Kawakusu, T.;
Arai, T.; Sasai, H. Org. Lett. 2003, 5, 4409. (d) Kell, A. J.; Stringle, D. L.
B.; Workentin, M. S. Org. Lett. 2000, 2, 3381. (e) Yoon, T.-J.; Lee, W.;
Oh, Y.-S.; Lee, J.-K. New J. Chem. 2003, 27, 227.
(
9) (a) Li, G.; Fan, J.; Jiang, R.; Gao, Y. Chem. Mater. 2004, 16, 1835.
(
b) Vestal, C. R.; Zhang, Z. J. J. Am. Chem. Soc. 2002, 124, 14312. (c)
Wang, Y.; Teng, X.; Wang, J.-S.; Yang, H. Nano Lett. 2003, 3, 789. (d)
Kohler, N.; Fryxell, G. E.; Zhang, M. J. Am. Chem. Soc. 2004, 126, 7206.
2086
Org. Lett., Vol. 7, No. 11, 2005

into the micellar cores. 2,2′-Azobis(2-methylpropionitrile)
AIBN) was used as a free radical initiator for the formation
(
Scheme 2. Schematic Representation of the Preparation of Iron
Oxide Nanoparticle-Supported Pd-NHC Complexes
of a layer of organic polymers surrounding the iron oxide
core inside a micelle. VBC served as a linkage point for
immobilization of catalysts. A small amount (1%) of DVB
was used to cross-link the shell polymers slightly to improve
1
3
the mechanical strength of the formed core/shell particles.
The generated core/shell nanoparticles were isolated by
applying an external permanent magnet (LifeSep 50sx
magnetic separator from Dexter Magnetic Technologies).
Iron oxide nanparticles were magnetically concentrated, while
P-123 surfactants and other excessive reagents remained in
the aqueous medium. Removal of the reaction solution out
of the flask separated nanoparticles from the reaction
mixtures. A TEM micrograph (Figure 1) has confirmed the
cleavage.14 Elemental analysis confirmed that about 0.72
mmol/g of Pd catalysts were loaded onto our nanoparticle
supports. This is higher than the 0.29 mmol/g loading of Pd
on chloromethyl polystyrene resins that were used for
immobilization of Pd catalysts by forming similar Pd-
1
5
methylimidazole NHC complexes.
Magnetic nanoparticle-supported Pd-NHC complexes
were then examined for catalysis of a group of Suzuki cross-
couplings of aryl halides with arylboronic acids (Scheme 3).
Scheme 3. Suzuki Cross-Couplings of Aryl Halides and
Arylboronic Acids Using Iron Oxide Nanocrystal-Supported
Pd-NHC Catalysts
Figure 1. TEM micrograph of core/shell iron oxide/polymer
nanoparticles. The lacey TEM grid consists of hollow woven-mesh-
like holes and Cu supports that are covered with Formvar/carbon.
Due to the lack of the Formvar/carbon coatings in the background,
polystyrene shells of nanoparticles can be seen at the edge of a
hole.
After several kinds of reaction variables such as the tem-
perature and reaction time were surveyed, the reaction
conditions were optimized, which typically involved an aryl
halide and an arylboronic acid in the mixed solution of DMF
formation of such a core/shell structure in these iron oxide
nanoparticles. Very thin polymer shells (∼2 nm) could be
observed at the edge of a hole on a TEM grid, while the
iron oxide cores were found to possess a diameter of about
2 3
and 1% Na CO aqueous solution in the presence of Pd-
-
2
iron oxide nanoparticles (1.52 × 10 mol %) at 50 °C for
about 12 h. After reaction, a permanent magnet (LifeSep 50sx
magnetic separator) was applied externally, and nanoparticle-
supported catalysts were magnetically concentrated at a side
wall of the flask. The reaction solutions were separated from
nanoparticles, and products were subjected to flash chroma-
tography purification followed by spectroscopic characteriza-
11 nm. Apparently, polymerization reactions did not alter
the size of the iron oxide cores, and the thickness of the
polymeric shell walls was decided by the dimension of the
interior cores of micellar templates.
To immobilize Pd catalysts, we first loaded 1-methylimi-
dazole onto the surface of core/shell nanoparticles by mixing
nanoparticles with 1-methylimidazole in a refluxing toluene
1
13
tions using IR, H NMR, C NMR, and high-resolution mass
spectrometry analyses (Supporting Information). The Pd
catalysts were washed several times with various solvents
and air-dried. More than 97% of Pd-iron oxide nanoparticles
could usually be recovered (based on the weights of
particles).
2 3
solution (Scheme 2). Then, Na CO was used as a base for
deprotonation of the imidazolium group to generate N-hetero-
cyclic carbenes (NHCs) that can form strong complexes with
1
4
Pd catalysts. NHCs were chosen as a ligand for chelating
Pd due to the fact that Pd-NHC bonding interactions were
known to be chemically and thermodynamically inert toward
Table 1 lists a group of Suzuki cross-couplings of aryl
halides with arylboronic acids that were investigated in our
laboratory using nanoparticle-supported Pd catalysts (Scheme
(
13) Vigorous control of reaction conditions is needed, as sometimes
the formation of aggregated insoluble nanoparticle composites was observed.
14) For a review: Herrmann, W. A. Angew. Chem., Int. Ed. 2002, 41,
290.
3
). An average isolation yield of 82% was obtained for 20
(
1
(15) Byun, J.-W.; Lee, Y.-S. Tetrahedron Lett. 2004, 1837.
Org. Lett., Vol. 7, No. 11, 2005
2087

reaction. To this end, iron oxide nanoparticle-supported Pd
catalysts were examined for five consecutive rounds of
reactions between p-iodotoluene and phenylboronic acid.
After a reaction, catalysts were magnetically isolated,
washed, air-dried, and used directly for a subsequent round
of reaction without further purification. An isolation yield
of 88 ( 3% was obtained each time. No significant loss of
the catalytic activity was observed during five consecutive
reactions.
In conclusion, core/shell iron oxide nanoparticles were
prepared via an emulsion polymerization approach for
immobilization of Pd-NHC catalysts. These nanoparticle-
supported catalysts are stable and demonstrated high catalytic
activity in promoting Suzuki cross-coupling reactions. More
importantly, recovery of catalysts was facilely achieved by
using a permanent magnet. Isolated catalysts were used for
subsequent new rounds of reactions without significant loss
of their catalytic activity. Our work here reveals the feasibility
of using this new class of supports for immobilizing
homogeneous catalysts. Such magnetic nanoparticlular ma-
trixes offer potential advantages over some alternative soluble
supports such as Au MPC in that they can be magnetically
concentrated by applying an external magnet. There is no
need to add a second solvent for the selective precipitation
of matrixes. As a consequence, magnetic nanoparticles could
be an ideal soluble support for immobilization of industrial
homogeneous catalysts. More detailed investigations of
nanoparticle structure effects on the catalytic activity of the
immobilized catalysts are in progress and will be reported
in due course.
Table 1. Suzuki Cross-Couplings of Aryl Halides and
Arylboronic Acids Using Nanoparticle-Supported Pd-NHC
Complexes (Scheme 3)
entry
R1
X
R2
yield (%)a
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
H
H
H
H
H
H
H
H
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
o-Me
86
88
84
83
89
89
82
82
87
83
88
74
81
83
80
77
74
70
72
78
m-Me
o-OMe
p-OMe
o-Ac
m-Ac
naph
p-CN
H
H
H
H
H
H
H
H
H
H
H
H
b
o-Me
m-Me
p-Me
o-OMe
m-OMe
p-OMe
p-Ac
1
1
1
1
1
1
1
1
1
1
2
o-Me
Br
Br
Br
Br
Br
m-Me
o-OMe
m-OMe
p-OMe
a
Isolation yields after separation by flash chromatography; average of
b
at least two runs. Reagent is 1-naphthaleneboronic acid.
reactions. On the whole, nanoparticle-supported Pd catalysts
showed better catalytic activity than chloromethyl polysty-
rene resin-supported counterparts reported in the litera-
1
5,16
-2
ture.
For example, 1.52 × 10 mol % Pd catalyst was
used to catalyze the reaction between p-iodotoluene and
phenylboronic acid (entry 11 of Table 1) for an average 88%
isolation yield, while more Pd catalyst (1.2 mol %) was
needed to achieve a similar reaction efficacy using resin-
supported catalysts.15 We also investigated the possibility
of repeated use of recovered catalysts for new rounds of
Acknowledgment. This investigation was generously
supported by partial funds provided by SIU Materials
Technology Center, American Cancer Society, and the NSF
through a career award to Y.G.
Supporting Information Available: Detailed experi-
mental procedures and characterization studies of Suzuki
cross-linking products. This material is available free of
charge via the Internet at http://pubs.acs.org.
(16) Pd nanoparticles were known to catalyze Suzuki cross-coupling
reactions: Li, Y.; Hong, X. M.; Collard, D. M.; El- Sayed, M. A. Org.
Lett. 2000, 2, 2385. However, iron oxide nanoparticles alone are not an
active catalyst for Suzuki coupling reactions. No detectable products were
formed when iron oxide nanoparticles without Pd were used in our
experiments.
OL050218W
2088
Org. Lett., Vol. 7, No. 11, 2005