Pd-catalyzed C#C cross-coupling reactions within a thermoresponsive and pH-responsive and chelating polymeric hydrogel

Article abstract of DOI:10.1021/jo802427k

A porous, thermoresponsive and pH-responsive, and chelating hydrogel of poly(N-isopropylacrylamide)co-poly[2-methacrylic acid 3-(bis-carboxymethylamino) -2-hydroxypropyl ester] (PNIP AM-co-PMACHE) is proposed as both a reaction medium and the Pd catalyst support for organic synthesis. Organic synthesis within the PNIPAM-co-PMACHE hydrogel has three merits. First, organic reactions such as Suzuki and Heck reactions within the hydrogel can be accelerated due to the enriched Pd catalyst and reactants within the hydrogel by the reversible deswelling/swelling. Second, organic synthesis within the PNIPAM-co-PMACHE hydrogel, which holds about ～300 times of water and is similar to the environmentally benign reaction medium of water, can be performed efficiently without surfactant or cosolvent being added. Third, the PNIPAM-co-PMACHE hydrogel itself and the therein-immobilized Pd catalyst can be easily recycled since the hydrogel/Pd composite can reversibly swell/deswell.

Full text of DOI:10.1021/jo802427k

Pd-Catalyzed C-C Cross-Coupling Reactions within a
Thermoresponsive and pH-Responsive and Chelating Polymeric
Hydrogel
Yao Wang, Jianzheng Zhang, Wangqing Zhang,* and Minchao Zhang
Key Laboratory of Functional Polymer Materials of Ministry of Education, Institute of Polymer Chemistry,
Nankai UniVersity, Tianjin 300071, China
wqzhang@nankai.edu.cn
ReceiVed October 31, 2008
A porous, thermoresponsive and pH-responsive, and chelating hydrogel of poly(N-isopropylacrylamide)-
co-poly[2-methacrylic acid 3-(bis-carboxymethylamino)-2-hydroxypropyl ester] (PNIPAM-co-PMACHE)
is proposed as both a reaction medium and the Pd catalyst support for organic synthesis. Organic synthesis
within the PNIPAM-co-PMACHE hydrogel has three merits. First, organic reactions such as Suzuki and
Heck reactions within the hydrogel can be accelerated due to the enriched Pd catalyst and reactants
within the hydrogel by the reversible deswelling/swelling. Second, organic synthesis within the PNIPAM-
co-PMACHE hydrogel, which holds about ∼300 times of water and is similar to the environmentally
benign reaction medium of water, can be performed efficiently without surfactant or cosolvent being
added. Third, the PNIPAM-co-PMACHE hydrogel itself and the therein-immobilized Pd catalyst can be
easily recycled since the hydrogel/Pd composite can reversibly swell/deswell.
1. Introduction
proceed sluggishly in pure water, probably because most organic
reagents are not completely dissolved in water.6 Thus, when
organic synthesis is performed in water, surfactants such as
tetrabutylammonium bromide (TBAB) or polar cosolvents such
as N,N-dimethylformamide (DMF) are usually used to improve
solvation of the organic substrates.7 Therefore, great effort
should be made to perform organic synthesis in a suitable green
medium similar to water.
Organic synthesis in water has drawn much attention because
water is an eco-friendly, nontoxic, and economic solvent.1 Up
to date, although a variety of media such as ionic liquids,2
fluorous solvents,3 supercritical fluids,4 and poly(ethylene gly-
col)5 have been promoted to replace water, water represents
one of the most economically and environmentally viable
options. However, a good many of these organic reactions
The Suzuki reaction,8 the Pd-catalyzed cross-coupling of
arylboronic acids with aryl halides, is recognized as the most
promising and versatile method for construction of biaryls. As
to the Heck reaction, it is a well-established method for the
* Corresponding author. Phone: 86-22-23509794. Fax: 86-22-23503510. .
(1) (a) Li, C.-J. Chem. ReV. 1993, 93, 2023. (b) Herrmann, W. A.;
Kohlpaintner, C. W. Angew. Chem., Int. Ed. 1993, 32, 1524. (c) Lindstrom,
U. M. Chem. ReV. 2002, 102, 2751.
(2) (a) Mathews, C. J.; Smith, P. J.; Welton, T. Chem. Commun. 2000, 1249.
(b) McLachlan, F.; Mathews, C. J.; Smith, P. J.; Welton, T. Organometallics
2003, 22, 5350. (c) Wang, R.; Twamley, B.; Shreeve, J. M. J. Org. Chem. 2006,
71, 426.
(6) Kobayashi, S.; Wakabayashi, T.; Nagayama, S.; Oyamada, H. Tetrahedron
Lett. 1997, 38, 4559.
(7) (a) Bedford, R. B.; Blake, M. E.; Butts, C. P.; Holder, D. Chem. Commun.
2003, 466. (b) Molander, G. A.; Biolatto, B. Org. Lett. 2002, 4, 1867. (c) Arcadi,
A.; Cerichelli, G.; Chiarini, M.; Correa, M.; Zorzan, D. Eur. J. Org. Chem. 2003,
4080.
(8) For general reviews on the Suzuki reaction, see: (a) Miyaura, N.; Suzuki,
A. Chem. ReV. 1995, 95, 2457. (b) Suzuki, A. J. Organomet. Chem. 1999, 576,
147. (c) Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem.
ReV. 2002, 102, 1359. (d) Phan, N. T. S.; Van Der Sluys, M.; Jones, C. W. AdV.
Synth. Catal. 2006, 348, 609.
(3) (a) Gerig, J. T. J. Am. Chem. Soc. 2005, 127, 9277. (b) Moreno-Manas,
M.; Pleixats, R.; Villarroya, S. Organometallics 2001, 20, 4524.
(4) (a) Gronnow, M. J.; White, R. J.; Clark, J. H.; Macquarrie, D. J. Org.
Process Res. DeV. 2005, 9, 516. (b) Leeke, G. A.; Santos, R. C. D.; Al-Duri, B.;
Seville, J. P. K.; Smith, C. J.; Lee, C. K. Y.; Holmes, A. B.; McConvey, I. F.
Org. Process Res. DeV. 2007, 11, 144.
(5) (a) Corma, A.; Garcia, H.; Leyva, A. Tetrahedron 2005, 61, 9848. (b)
Corma, A.; Garcia, H.; Leyva, A. J. Catal. 2006, 240, 87.
10.1021/jo802427k CCC: $40.75
Published on Web 01/27/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 1923–1931 1923

Wang et al.
SCHEME 1. Schematic Organic Synthesis within the PNIPAM-co-PMACHE Hydrogel
coupling of aryl halides with olefins.9 Usually, Suzuki and Heck
reactions are performed in organic solvent. However, when a
hydrophilic ligand is used or the Pd catalyst is immobilized on
a hydrophilic or amphiphilic support, they can be performed in
water or aqueous solution.10 For examples, Weberskirch et al.
immobilized Pd catalyst in amphiphilic block copolymer mi-
celles and found the Heck reaction using this micelle-Pd catalyst
could be performed efficiently in water at 90 °C.11 Uozumi et
al. found the Pd catalyst immobilized on the amphiphilic resin
of polystyrene-poly(ethylene glycol) was efficient for the Heck
reaction performed in water.12
present hydrogel seemly can be regarded as a green medium,
since it is composed of about 99.7 wt % water and 0.3 wt %
polymer). Last, both the immobilized Pd catalyst and the
hydrogel itself can be easily recovered and reused, because the
PNIPAM-co-PMACHE hydrogel can reversibly swell/deswell.
2. Results and Discussion
The main content of the present study is shown in Scheme
1. First, PNIPAM-co-PMACHE hydrogel is synthesized. This
hydrogel is designed to be porous, thus the hydrogel has the
ability to encapsulate reactants. Second, the Pd catalyst is
immobilized and the reactants are encapsulated within the
hydrogel matrix. Third, the hydrogel holding the Pd catalyst
and reactants deswells to enrich the reactants and Pd catalyst
within the gel by increasing the temperature or adjusting pH,
and then organic synthesis occurs with concentrated reactants
and Pd catalyst. Last, when organic synthesis is completed,
temperature decreases and pH is adjusted; ether is added to
extract the synthesized product; and the hydrogel containing
Pd catalyst reversibly swells and is reused in the next run. In
the subsequent study, the synthesis and characterization of the
PNIPAM-co-PMACHE hydrogel, the immobilization of Pd(II)
or Pd(0) catalyst, the encapsulation and enrichment of the
Hydrogels are three-dimensional networks of cross-linked
polymers, which can hold up to 1000 times of water.13 Of all
the hydrogels, the poly(N-isopropylacrylamide) (PNIPAM)
hydrogel is a typical one, which is thermoresponsive and
undergoes a large volume change at the volume-phase-transition
temperature (VPTT) of ∼32 °C.14 When heated above VPTT,
PNIPAM hydrogel exhibits a hydrophilic/hydrophobic transition
in aqueous medium; water is expelled from the hydrogel matrix;
the PNIPAM hydrogel shrinks or deswells and becomes partly
hydrophobic. This shrunk gel can provide a hydrophobic
environment for hydrophobic guest molecules. Hydrogels have
been utilized in many fields such as controlled drug release,
molecular separation, tissue engineering, enzyme immobiliza-
tion, and chemical valves.15 Besides, hydrogels have also been
used as a scaffold to in situ synthesize inorganic nanoparticles
within the three-dimensional hydrogel networks.16 However,
organic synthesis within hydrogel is rarely studied, although a
few samples within gel matrix have been reported recently.17
Herein, a thermoresponsive and pH-responsive, chelating, and
superabsorbent hydrogel of poly(N-isopropylacrylamide)-co-
poly[2-methacrylic acid 3-(bis-carboxymethylamino)-2-hydrox-
ypropyl ester] (PNIPAM-co-PMACHE) is synthesized and
Suzuki and Heck reactions within the hydrogel are explored.
The PNIPAM-co-PMACHE hydrogel contains a thermorespon-
sive segment of PNIPAM and a pH-responsive segment of
PMACHE. Besides, the PMACHE segment contains a pendent
ligand of iminodiacetic acid (IDA). It is found that the Pd
catalyst and either hydrophilic or hydrophobic reactants can be
immobilized or encapsulated within the PNIPAM-co-PMACHE
hydrogel matrix, and Suzuki and Heck coupling reactions can
be efficiently performed within the hydrogel without cosolvent
or surfactant being added. The results suggest that organic
synthesis within the PNIPAM-co-PMACHE hydrogel has three
advantages. First, the reactants and Pd catalyst can be highly
enriched within the PNIPAM-co-PMACHE hydrogel by revers-
ible deswelling, which therefore affords efficient organic
synthesis at condensed concentration. Second, no additional
surfactant or cosolvent is needed, since the reactants are
encapsulated within the three-dimensional hydrogel matrix (the
(9) For general reviews on the Heck reaction, see: (a) Heck, R. F. Acc. Chem.
Res. 1979, 12, 146. (b) Whitcombe, N. J.; Hii, K. K.; Gibson, S. E. Tetrahedron
2001, 57, 7449. (c) Alonso, F.; Beletskaya, I. P.; Yus, M. Tetrahedron 2005,
61, 11771. (d) Beletskaya, I. P.; Cheprakov, A. V. Chem. ReV. 2000, 100, 3009.
(e) Dounay, A. B.; Overman, L. E. Chem. ReV. 2003, 103, 2945.
(10) (a) Bedford, R. B.; Blake, M. E.; Butts, C. P.; Holder, D. Chem.
Commun. 2003, 466. (b) Zou, G.; Wang, Z.; Zhu, J.; Tang, J.; He, M. Y. J. Mol.
Catal. A: Chem. 2003, 206, 193. (c) Hesse, S.; Kirsch, G. Synthesis 2001, 755.
(d) Bumagin, N. A.; Bykov, V. V. Tetrahedron 1997, 53, 14437. (e) Molander,
G. A.; Biolatto, B. Org. Lett. 2002, 4, 1867. (f) DeVasher, R. B.; Moore, L. R.;
Shaughnessy, K. H. J. Org. Chem. 2004, 69, 7919. (g) Anderson, K. W.;
Buchwald, S. L. Angew. Chem., Int. Ed. 2005, 44, 26173.
(11) Schonfelder, D.; Fischer, K.; Schmidt, M.; Nuyken, O.; Weberskirch,
R. Macromolecules 2005, 38, 254.
(12) Uozumi, Y.; Kimura, T. Synlett. 2002, 12, 2045.
(13) Kazanskii, K. S.; Dubrovskii, S. A. AdV. Polym. Sci. 1992, 104, 97.
(14) (a) Lyer, G.; Iyer, P.; Tillekeratne, L. M. V.; Coleman, M. R.; Nadarajah,
A. Macromolecules 2007, 40, 5850. (b) Hirashima, Y.; Sato, H.; Suzuki, A.
Macromolecules 2005, 38, 9280. (c) Quijada-Garrido, I.; Prior-Cabanillas, A.;
Garrido, L.; Barrales-Rienda, J. M. Macromolecules 2005, 38, 7434. (d) Wang,
J.; Gan, D.; Lyon, L. A.; El-Sayed, M. A. J. Am. Chem. Soc. 2001, 123, 11284.
(e) Zhang, J.; Peppas, N. A. Macromolecules 2000, 33, 102.
(15) For general reviews on hydrogel, see: (a) Erdodi, G.; Kennedy, J. P.
Prog. Polym. Sci. 2006, 31, 1. (b) Sangeetha, N. M.; Maitra, U. Chem. Soc.
ReV. 2005, 34, 821.
(16) (a) Mohan, Y. M.; Premkumar, T.; Lee, K.; Geckeler, K. E. Macromol.
Rapid Commun. 2006, 27, 1346. (b) Li, J.; Hong, X.; Liu, Y.; Li, D.; Wang, Y.;
Li, J.; Bai, Y.; Li, T. AdV. Mater. 2005, 17, 163. (c) Kim, J.-H.; Lee, T. R.
Langmuir 2007, 23, 6504. (d) Sahiner, N. Colloid Polym. Sci. 2006, 285, 283.
(e) Mohan, Y. M.; Lee, K.; Premkumar, T.; Geckeler, K. E. Polymer 2007, 48,
158. (f) Pong, F. Y.; Lee, M.; Bell, J. R.; Flynn, N. T. Langmuir 2006, 22,
3851.
(17) (a) Hamamoto, H.; Kudoh, M.; Takahashi, H.; Ikegami, S. Org. Lett.
2006, 8, 4015. (b) Thiot, C.; Schmutz, M.; Wagner, A.; Mioskowski, C. Angew.
Chem., Int. Ed. 2006, 45, 2868.
1924 J. Org. Chem. Vol. 74, No. 5, 2009

Pd-Catalyzed C-C Cross-Coupling Reactions
FIGURE 2. Temperature dependence of the swelling ratio of the
PNIPAM-co-PMACHE hydrogel in neutral water, where the swelling
time at a given temperature is 24 h.
FIGURE 1. The SEM image of the PNIPAM-co-PMACHE hydrogel.
reactants, and the Suzuki and Heck reactions within the hydrogel
are discussed.
2.1. Synthesis and Characterization of the PNIPAM-co-
PMACHE Hydrogel. Usually, PNIPAM-based hydrogel is
synthesized by free-radical polymerization in organic solvents
or water.14 In the present study, the polymerization of the two
hydrophilic monomers of N-isopropylacrylamide (NIPAM) and
2-methacrylic acid 3-(bis-carboxymethylamino)-2-hydroxypro-
pyl ester (MACHE) was performed in the solvent mixture of
water and THF with the existence of the cross-linker of N,N′-
methylenebisacrylamide (BIS), the redox initiator of K2S2O8,
and the accelerator of N,N,N′,N′-tetramethylethylenediamine
(TEMED). As discussed elsewhere,18 synthesis of PNIPAM-
based hydrogel in the mixture of a polar organic solvent and
water favors formation of a porous structure in the hydrogel
matrix. Herein, it is found that porous hydrogel as shown in
Figure 1 is synthesized. This porous structure in hydrogel
provides the potential of encapsulation of reactants within the
hydrogel matrix, which will be discussed subsequently.
The PNIPAM-co-PMACHE hydrogel has a high swelling
ratio of ∼300 in double-distilled water (pH ∼6) at room
temperature. This means that the hydrogel is composed of 99.7
wt % water and 0.3 wt % polymer at room temperature. The
super absorbability suggests that the PNIPAM-co-PMACHE
hydrogel has a potential of being used as an environmentally
benign reaction medium similar to water. Besides, the PNIPAM-
co-PMACHE hydrogel is thermoresponsive and pH-responsive
since it contains a thermoresponsive segment of PNIPAM and
a zwitterionic, pH-responsive segment of PMACHE. When
temperature increases above 32 °C, it is optically observed that
the hydrogel deswells and becomes opaque, and the swelling
ratio decreases from ∼300 at 32 °C to a constant of ∼125 at
40 °C as shown in Figure 2. These results suggest that phase
transition occurs and the PNIPAM-co-PMACHE hydrogel has
a VPTT at 32 °C similar to that of the homopolymer of
PNIPAM.19 The PNIPAM-co-PMACHE hydrogel is also pH-
responsive as shown in Figure 3. The swelling ratio almost
FIGURE 3. pH-dependence of the swelling ratio of the PNIPAM-co-
PMACHE hydrogel at room temperature, where the swelling time is
1 h.
remains constant at ∼300 in the pH range of 4-10, suggesting
that the PNIPAM-co-PMACHE hydrogel is highly swollen at
this pH range. When the pH value is below 4 or above 10, water
is expulsed off the hydrogel, the hydrogel collapses, and the
swelling ratio gradually decreases until it reaches a minimum
of ∼10. It is known that addition of inorganic compounds such
as inorganic salt, acid, or base can decrease the VPTT of
PNIPAM.20 Thus, the deswelling of the hydrogel at pH below
4 or above 10 is partly ascribed to the pH-responsive segment
of PMACHE, partly ascribed to the phase transition of the
PNIPAM segment induced by the inorganic compound of NaOH
and HCl.
2.2. Immobilization of Pd(II) or Pd(0) Catalyst within
the PNIPAM-co-PMACHE Hydrogel. To achieve organic
synthesis within hydrogel, two factors including immobilization
of the Pd catalyst and encapsulation of organic reactants within
the three-dimensional hydrogel networks should be concerned
and they are discussed in the subsequent sections.
Because the ligand of IDA can coordinate with various
transition metal ions such as Cu(II), Ni(II), Pd(II), etc.,21 Pd(II)
(20) (a) Zhang, Y.; Furyk, S.; Bergbreiter, D. E.; Cremer, P. S. J. Am. Chem.
Soc. 2005, 127, 14505. (b) Krasovitski, E.; Cohen, Y.; Bianco-Peled, H. J. Polym.
Sci. Part B: Polym. Phys. 2004, 42, 3713.
(18) Zhang, X.-Z.; Yang, Y.-Y.; Chung, T.-S. Langmuir 2002, 18, 2538.
(19) Fujishige, S.; Kubota, K.; Ando, I. J. Phys. Chem. 1989, 93, 3311.
J. Org. Chem. Vol. 74, No. 5, 2009 1925

Wang et al.
SCHEME 2. Schematic Structure of the
It is known that amphiphilic hydrogels can swell both in
organic solvents and in water. When swelling in water,
amphiphilic hydrogels can adsorb a significant amount of
hydrophobic substances.23 The present PNIPAM-co-PMACHE
hydrogel contains a thermoresponsive segment of PNIPAM and
a hydrophilic segment of PMACHE and it becomes amphiphilic
above VPTT of the PNIPAM segment. Therefore, the PNIPAM-
co-PMACHE hydrogel has the potential of adsorption or
encapsulation of hydrophobic substrates. In fact, when temper-
ature increases above VPTT and a base such as K2CO3 or Et3N
is added, the PNIPAM-co-PMACHE hydrogel undergoes a
transition from a hydrophilic structure to a partly hydrophobic
one; water is expelled from the gel matrix and the hydrophobic
substrates are encapsulated and enriched within the gel by
deswelling. For example, the hydrophobic reactant of bro-
mobenzene (4.0 mmol, 0.63 g) is almost absolutely encapsulated
within the hydrogel (10 g) (Figure S5, Supporting Information).
At 90 °C, the hydrogel containing the encapsulated bromoben-
zene deswells, and the deswelled gel phase (∼1 g) contains 60
wt % organic reactants (∼0.6 g), 40 wt % water (∼0.4 g), and
0.3 wt % polymer. At 40 °C, the gel phase contains about 30
wt % organic substrates, 70 wt % water, and 0.3 wt % polymer.
Clearly, the water content in the deswelled gel phase at lower
temperature is a litter higher than those at high temperature.
Different from the hydrogen bonding between the PNIPAM
segment and the hydrophilic substrates, the driven force for
encapsulation of hydrophobic substrates within the hydrogel is
mainly ascribed to the hydrophobic-hydrophobic interaction
between the substrates and the hydrogel.
2.4. Suzuki Reaction within the PNIPAM-co-PMACHE
Hydrogel with Pd(II) Catalyst. As discussed above, the
immobilization of Pd catalyst and encapsulation of the reactants
afford the potential for organic synthesis within the hydrogel.
In preliminary organic synthesis, the Suzuki reaction of 4-bro-
moacetophenone with phenylboronic acid within the PNIPAM-
co-PMACHE hydrogel is studied. To explore the hydrogel
effect, the Suzuki reaction of 4-bromoacetophenone within
different amounts of hydrogel is studied. As shown in Figure
4, the hydrogel plays an important role in the Suzuki reaction
of 4-bromoacetophenone. Without the hydrogel, the Suzuki
reaction employing 0.050 mol % of IDA-Pd(II) catalyst just
affords 47% yield of 4-acetylbiphenyl in 2.5 h at 40 °C. In the
presence of the PNIPAM-co-PMACHE hydrogel, the yields
dramatically increase. For example, when the ratio of hydrogel
to 4-bromoacetophenone equals 0.50 g/mmol, 92% yield is
achieved. When the ratio further increases above 1.0 g/mmol,
more than 98% yield is achieved. In the following study, the
ratio of the hydrogel to aryl halide is set at 2.5 g/mmol if not
specifically pointed out.
PNIPAM-co-PMACHE Hydrogel/Pd(II) Composite and
Encapsulation and Enrichment of the Pd Catalyst and
Reactants within the Hydrogel
can be easily immobilized in the PNIPAM-co-PMACHE
hydrogel to form hydrogel/Pd(II) composite as shown in Scheme
2. In fact, when a suitable amount of the PNIPAM-co-PMACHE
hydrogel is placed in PdCl2 aqueous solution for about 5 min,
the hydrogel becomes yellow, indicating immobilization of
Pd(II) catalyst in the hydrogel matrix (Figure S2, Supporting
Information).
Synthesis of inorganic nanoparticles with hydrogel as the
scaffold has been extensively reported recently.16 The introduc-
tion of the Pd(0) catalyst into the PNIPAM-co-PMACHE
hydrogel is easily achieved by reducing the hydrogel/Pd(II)
composite, which was just discussed above, with NaBH4
aqueous solution. The average size of the Pd nanoparticles in
situ synthesized within the hydrogel matrix observed by TEM
is ∼3 nm (Figure S3, Supporting Information).
2.3. Encapsulation and Enrichment of Reactants within
the PNIPAM-co-PMACHE Hydrogel. To fulfill organic
synthesis within the PNIPAM-co-PMACHE hydrogel, the
substrates should be first encapsulated. For hydrophilic mol-
ecules such as phenol, benzoic acid, and their derivatives, the
PNIPAM-based hydrogel has the ability to entrap them due to
strong hydrogen bonding between the PNIPAM segment and
the hydrophilic molecules.22 In fact, when the hydrophilic
substrates such as phenylboronic acid, 4-bromophenol, and
4-bromobenzoic acid are mixed with the hydrogel at room
temperature, the transparent hydrogel becomes opaque in several
minutes, indicating that these substrates are encapsulated within
the hydrogel (Figure S4, Supporting Information). Besides the
strong hydrogen bonding between the PNIPAM segment and
the hydrophilic substrates, the porous structure of the hydrogel
also provides fast encapsulation of these hydrophilic substrates
within the hydrogel matrix. Furthermore, the PNIPAM-co-
PMACHE hydrogel is thermoresponsive and pH-responsive, and
therefore the hydrophilic substrates encapsulated within the
hydrogel can be enriched due to the hydrogel deswelling either
by increasing temperature above VPTT (Figure S4, Supporting
Information) or adding a suitable base such as K2CO3 or Et3N
as shown in Scheme 2.
To further evaluate the hydrogel effect, the Suzuki reaction
of 4-bromoacetophenone within the PNIPAM-co-PMACHE
hydrogel is further compared with that in water. As shown in
Figure 5, when the Suzuki reaction employing the IDA-Pd(II)
catalyst is performed in water at 40 °C, the yield of 4-acetyl-
biphenyl increases to 40% in 1 h and further slowly increases
to 48% in 3 h. Compared with the Suzuki reaction performed
in water, the Suzuki reaction performed within the hydrogel
runs more efficiently, wherein the yield of 4-acetylbiphenyl
increases almost linearly with time until it reaches 98% in 2.5 h.
We think the encapsulation and enrichment of the hydrophobic
(21) (a) Vilchez, F. G.; Castillo-Martos, M.; Gargallo, M. F. Transition Met.
Chem. 1977, 2, 67. (b) Tseng, C.-H.; Wang, C.-C.; Chen, C.-Y. J. Phys. Chem.
B 2006, 110, 4020.
(22) (a) Kawashima, T.; Koga, S.; Annaka, M.; Sasaki, S. J. Phys. Chem. B
2005, 109, 1055. (b) Laszlo, K.; Kosik, K.; Rochas, C.; Geissler, E. Macro-
molecules 2003, 36, 7771.
(23) Patrickios, C. S.; Georgiou, T. K. Curr. Opin. Colloid Interface Sci.
2003, 8, 76.
1926 J. Org. Chem. Vol. 74, No. 5, 2009

Pd-Catalyzed C-C Cross-Coupling Reactions
performed efficiently and 95-99% yields of biaryls are achieved
employing a low content of 0.050 mol % of Pd catalyst (Table
1, entries 1-5). At a much lower temperature of 40 °C, the
reactants are also relatively enriched within the gel and the
Suzuki reactions within the hydrogel afford reasonable yields
(Table 1, entries 1-5). For the hydrophilic substrates such as
4-bromophenol, 4-bromobenzoic acid, 4-iodophenol, and 4-io-
dobenzoic acid, they can be encapsulated and enriched within
the gel by hydrogen bonding whether at room temperature below
VPTT or above VPTT of the hydrogel. Therefore, the Suzuki
reactions of these hydrophilic aryl halides within the hydrogel
run efficiently and 93-99% yields are achieved even at room
temperature employing a low content of 0.050 mol % of Pd
catalyst (Table 1, entries 6-9). Furthermore, for the electron-
deficient and therefore active aryl halide of 4-iodobenzoic acid,
0.0010 mol % of Pd catalyst affords a turnover frequency (TOF)
of 4.3 × 104 h-1 and 99% yield in 4 h (Table 1, entry 6).
Considering that the hydrogel is composed of 99.7 wt % water
and 0.3 wt % polymer, it can be regarded as a green medium
similar to water. Therefore, we think, the present TOF value
for the Suzuki reaction within the hydrogel compares favorably
with those performed in the sole solvent of water.25
FIGURE 4. The hydrogel effect on the Suzuki reaction of 4-bromoac-
etophenone with phenylboronic acid. Reaction conditions: 4-bromoac-
etophenone (1.0 mmol) and phenylboronic acid (1.5 mmol, 1.5 equiv),
K2CO3 (3.0 mmol, 3 equiv), Pd catalyst (0.50 µmol, 0.050 mol % of
Pd(II) catalyst within the PNIPAM-co-PMACHE hydrogel or 0.050
mol % of IDA-Pd(II) catalyst in water), total weight of the hydrogel
and water being 3.0 g, 2.5 h, and 40 °C.
2.5. Heck Reaction within the PNIPAM-co-PMACHE
Hydrogel with Pd(II) Catalyst. Heck reactions of aryl halides
with acrylic acid within the PNIPAM-co-PMACHE hydrogel
are also studied. As discussed elsewhere, teh Heck reaction is
generally performed in organic solvent or aqueous solution at
a relatively high temperature employing a high content of Pd
catalyst.26 Herein, all Heck reactions within the PNIPAM-co-
PMACHE hydrogel are performed at 100 °C employing 0.20
mol % of Pd catalyst. As shown in Table 2, Heck reactions of
aryl iodides are efficiently performed within the gel and
91-99% yields are achieved in 12 h (Table 2, entries 1-3).
For aryl bromides, Heck reactions also run efficiently and high
yields are achieved when reaction time increases to 24 h (Table
2, entries 4 and 5).
2.6. Suzuki Reaction within the PNIPAM-co-PMACHE
Hydrogel with Pd(0) Catalyst. Besides the Pd(II) catalyst, Pd
nanoparticles are also immobilized within the PNIPAM-co-
PMACHE hydrogel (Figure S3, Supporting Information). To
further explore organic synthesis within the hydrogel, a typical
Suzuki reaction of 4-bromoacetophenone with phenylboronic
acid at 40 °C employing 0.050 mol % of Pd catalyst of 3-nm
Pd nanoparticles is studied. At these conditions, the reactants
are encapsulated and relatively enriched within the hydrogel.
As shown in Figure 6, the Suzuki reaction within the hydrogel
employing the catalyst of 3-nm Pd nanoparticles runs efficiently,
similar to those employing the Pd(II) catalyst. That is, the yield
of 4-acetylbiphenyl increases almost linearly with time until it
reaches 95% in 2 h.
FIGURE 5. The kinetics of Suzuki reaction of 4-bromoacetophenone
with benzenboronic acid within the PNIPAM-co-PMACHE hydrogel
(b) and in water (0). Reaction conditions: 1.0 mmol of 4-bromoac-
etophenone, 1.5 mmol of benzenboronic acid, 3.0 mmol of K2CO3,
2.5 g of hydrogel containing 0.050 mol % of Pd(II) catalyst or 2.5 mL
of water containing 0.050 mol % of IDA-Pd(II) catalyst, 40 °C. The
molar ratio of the IDA ligand to Pd in the IDA-Pd(II) catalyst is the
same as those in the hydrogel/Pd(II) composite.
reactants and the Pd catalyst within the hydrogel increases the
accessibility of the active catalytic site and therefore accelerates
the reaction within the hydrogel. When the Suzuki reaction is
performed in water at a higher temperature of 90 °C, it is found
that the IDA-Pd(II) catalyst is not stable and formation of black
Pd can be optically observed just after the Suzuki reaction begins
in 1 h,24 whereas the Pd catalyst immobilized in the hydrogel
is stable and the Suzuki reaction runs smoothly at 90 °C as
discussed below. These results suggest that the hydrolgel not
only increases the stability of the immobilized Pd catalyst at
high temperature but also accelerates the reaction.
A wide range of Suzuki reactions of iodinated and brominated
aromatic compounds within the PNIPAM-co-PMACHE hydro-
gel are further studied and the results are summarized in Table
1. At a high temperature of 90 °C, the reactants and Pd catalyst
are encapsulated and highly enriched within the gel; the Suzuki
reactions of the hydrophobic aryl bromides and aryl iodides are
Up to now, various catalysts of Pd nanoparticles used in the
C-C cross-coupling reaction in different reaction media are
reported.27 To evaluate the efficiency of the Suzuki reaction
(25) (a) Najera, C.; Gil-Molto, J.; Karlstrom, S.; Falvello, L. R. Org. Lett.
2003, 5, 1451. (b) Jiang, N.; Ragauskas, A. J. Tetrahedron Lett. 2006, 47, 197.
(c) Korolev, D. N.; Bumagin, N. A. Tetrahedron Lett. 2005, 46, 5751. (d) Wu,
W.-Y.; Chen, S.-N.; Tsai, F.-Y. Tetrahedron Lett. 2006, 47, 9267. (e) Yamada,
Y. M. A.; Takeda, K.; Takahashi, H.; Ikegami, S. J. Org. Chem. 2003, 68, 7733.
(f) Huang, R.; Shaughnessy, K. H. Organometallics 2006, 25, 4105. (g) Baleizo,
C.; Corma, A.; Garca, H.; Leyva, A. J. Org. Chem. 2004, 69, 439.
(26) (a) Jeffery, T. Tetrahedron Lett. 1994, 35, 3051. (b) Caporusso, A. M.;
Innocenti, P.; Aronica, L. A.; Vitulli, G.; Gallina, R.; Biffis, A.; Zecca, M.; Corain,
B. J. Catal. 2005, 234, 1. (c) Cui, X.; Li, Z.; Tao, C.-Z.; Xu, Y.; Li, J.; Liu, L.;
Guo, Q.-X. Org. Lett. 2006, 8, 2467. (d) Kim, J.-H.; Kim, J.-W.; Shokouhimehr,
M.; Lee, Y.-S. J. Org. Chem. 2005, 70, 6714.
(24) Zhang, J.; Zhang, W.; Wang, Y.; Zhang, M. AdV. Synth. Catal. 2008,
350, 2065.
J. Org. Chem. Vol. 74, No. 5, 2009 1927

Wang et al.
TABLE 1. Suzuki Reaction within the PNIPAM-co-PMACHE Hydrogel with Pd(II) Catalysta
a Reaction conditions: aryl halide (1.0 mmol) and phenylboronic acid (1.5 mmol, 1.5 equiv), K2CO3 (3.0 mmol,
3 equiv), 2.5 g of
b
PNIPAM-co-PMACHE hydrogel. Isolated yield and the purity of isolated product being confirmed by H NMR. c Et3N instead of K2CO3 being used as
1
base. d TOF was measured as moles of product per mole of Pd catalyst per hour at the initial reaction time.
within the hydrogel, the present hydrogel/Pd(0) system is
compared with five other catalysts of Pd nanoparticles by using
the Suzuki reaction of 4-bromoacetophenone with phenylboronic
acid as a typical example under other similar conditions. The
first TBAA-Pd catalyst is the Pd nanoparticles stabilized by a
surfactant of tetrabutylammonium acetate (TBAA) by Nacci et
al.28 The second microgel-Pd catalyst is the Pd nanoparticles
stabilized with polymeric microgel by Biffis et al.29 The third
Pd/cyclodextrin is the Pd nanoparticles stabilized with surface-
attached perthiolated cyclodextrin by Kaifer et al.30 The fourth
PS-co-P4VP-Pd catalyst is the Pd nanoparticles stabilized with
poly(styrene-co-4-vinylpyridine) core-shell micospheres pro-
1928 J. Org. Chem. Vol. 74, No. 5, 2009

Pd-Catalyzed C-C Cross-Coupling Reactions
TABLE 2. Heck Reaction within the PNIPAM-co-PMACHE Hydrogel with Pd(II) Catalysta
a Reaction conditions: aryl halide (1.0 mmol) and acrylic acid (1.5 mmol, 1.5 equiv), K2CO3 (3.0 mmol, 3 equiv), 5.0 g of hydrogel, 0.20 mol % of
c
Pd(II) catalyst. b Time is not optimized. Isolated yield and the purity of isolated product being confirmed by H NMR. d Et3N instead of K2CO3 being
1
used as base.
quently, organic synthesis within the present hydrogel is believed
to be a promising alternative.
2.7. Reuse of the PNIPAM-co-PMACHE Hydrogel/Pd
Composite. The Suzuki reaction of 4-bromoacetophenone with
phenylboronic acid is chosen as a typical example to investigate
the reuse of the PNIPAM-co-PMACHE hydrogel/Pd(II) com-
posite. To minimize the base/salt effect during the reuse of the
hydrogel/Pd(II) composite, a volatile base of Et3N instead of
K2CO3 is used. After the extraction of the organics with diethyl
ether, the pH value of the hydrogel phase is adjusted to 7, and
the deswelled hydrogel/Pd(II) composite reversibly swells in
water until the aqueous phase disappears. The swelled hydrogel/
Pd(II) composite, which is just like a “soft” solid phase as shown
in Scheme 1, is reused in the next run of organic synthesis.
The reversible swelling of the deswelled hydrogel/Pd(II)
composite affords two great advantages for the catalyst recy-
cling. First, no Pd catalyst leaching occurs since the potential
FIGURE 6. The kinetics plot of Suzuki reaction of 4-bromoacetophe-
none with phenylboronic acid within the PNIPAM-co-PMACHE
Pd leaching into water and the water itself are readsorbed into
the swelled hydrogel phase during the reversible swelling of
the deswelled gel. Second, no separation of Pd catalyst is need.
To further explore the possible catalyst leaching into the organic
phase during the extraction with ether, the analysis of the organic
phase is made by atomic absorption spectrum (AAS). No Pd
catalyst leached into the ether phase is detected whether the
hydrophobic substrate of 4-bromoacetophenone or the hydro-
philic 4-bromobenzoic acid is employed in the Suzuki reation
(detection limit is 0.03 ppm). The results shown in Table 4
further demonstrate that the product yield does not decrease
and the Pd catalyst is not deactivated at the fourth cycle (Figure
hydrogel with the catalyst of 3-nm Pd nanoparticles. Reaction condi-
tions: 1.0 mmol of 4-bromoacetophenone, 1.5 mmol of phenylboronic
acid, 3.0 mmol of K2CO3, 2.5 g of hydrogel, 0.050 mol % of Pd(0)
catalyst, 40 °C.
posed by us recently.31 The last GnDenP-Pd catalyst is the Pd
nanoparticles stabilized with phosphine dendrimer by Fan et
al.32 As shown in Table 3, the present Suzuki reaction within
the PNIPAM-co-PMACHE hydrogel is the most efficient and
affords the highest apparent turnover frequencies (TOF) of 780
h-1 (Table 3, entries 1-6) even at the lowest temperature of
40 °C in all six examples. For example, the apparent TOF value
of the present hydrogel/Pd(0) system is about 14 times of the
moderately efficient catalyst of microgel-Pd (Table 3, entry 3)
and even the later Suzuki reaction is performed in a solvent
mixture of DMF/H2O at a high temperature of 80 °C. Compared
with the Suzuki reaction in water employing the PS-co-P4VP-
Pd catalyst, the present Suzuki reaction within the hydrogel
affords an 8-times-higher TOF value even at a much lower
temperature. Considering the easy synthesis, high efficiency,
and easy reuse of the hydrogel/Pd system discussed subse-
(27) Astruc, D. Inorg. Chem. 2007, 46, 1884.
(28) Calo, V.; Nacci, A.; Monopoli, A.; Montingelli, F. J. Org. Chem. 2005,
70, 6040.
(29) Biffis, A.; Sperotto, E. Langmuir 2003, 19, 9548.
(30) Strimbu, L.; Liu, J.; Kaifer, A. E. Langmuir 2003, 19, 483.
(31) Wen, F.; Zhang, W.; Wei, G.; Wang, Y.; Zhang, J.; Zhang, M.; Shi, L.
Chem. Mater. 2008, 20, 2144.
(32) Wu, L.; Li, B.-L.; Huang, Y.-Y.; Zhou, H.-F.; He, Y.-M.; Fan, Q.-H.
Org. Lett. 2006, 8, 3605.
J. Org. Chem. Vol. 74, No. 5, 2009 1929

Wang et al.
TABLE 3. Suzuki Reactions of 4-Bromoacetophenone with Phenylboronic Acid Employing Pd(0) Catalyst in Different Reaction Medium
yield (%)/
entry
ref
Pd catalyst (mol %)
temp/time
medium
TOFa (h-1
)
1
2
3
4
5
6
hydrogel/Pd (0.050)
TBAA-Pd (2.5)
microgel-Pd (1)
Pd/cyclodextrin (1)
PS-co-P4VP-Pd (0.25)
GnDenP-Pd (0.06)
40 °C/2.5 h
60 °C/16 h
80 °C/2 h
88 °C/7 h
90 °C/4 h
101 °C/20 h
hydrogel
ionic liquid
DMF/H2O
H2O/CH3CN
H2O
98/780b
100/2.5
100/55
88/13
99/99
99/82
28
29
30
31
32
dioxane
b
a The apparent TOF value, which is calculated from the yield at the time just when the reaction is completed. The real TOF value is 1.1 × 103 h-1
,
which is also shown in Table 1.
TABLE 4. Reuse of the PNIPAM-co-PMACHE Hydrogel/Pd(II)
highly dispersed in the reaction medium and their size is usually
smaller than 100 nm. Compared with the Pd catalyst im-
mobilized in amphiphilic block copolymer micelles, the present
hydrogel system has the advantages of easy synthesis of the
polymeric materials and the convenient reuse of the Pd catalyst.
Besides, the present hydrogel system has the other advantage
to encapsulate and enrich the reactants and catalyst, and therefore
to accelerate the reaction as discussed above.
Compositea
fresh use
99
1st reuse
99
2nd reuse
99
3rd reuse
99
yieldb (%)
a Reaction conditions: 4-bromoacetophenone (1.0 mmol), phenylbo-
ronic acid (1.5 mmol, 1.5 equiv), Et3N (3.0 mmol, 3 equiv), 2.5 g of
hydrogel, 0.050 mol % of Pd(II) catalyst, 1 h, 90 °C. b Isolated yield
1
and the purity of isolated product being confirmed by H NMR.
Bergbreiter et al. proposed a PNIPAM-based thermomorphic
system for organic synthesis.37 This thermomorphic system
employs the phase-selective solubility of PNIPAM in binary
or ternary organic solvent mixture to facilitate the catalyst
recovery and the product separation. Similar to the thermomor-
phic system, the recovery of the present hydrogel/palladium
composite and the separation of the synthesized products are
also convenient. However, the present hydrogel is much different
from those of the PNIPAM-based thermomorphic system. First,
the present PNIPAM-co-PMACHE hydrogel is used not only
as the Pd catalyst support, but also as the reaction medium. In
the former PNIPAM-based thermomorphic system, the soluble
PNIPAM-based polymer just acts as a catalyst support and the
reaction is performed in the binary or ternary organic solvent
mixture. Second, the substrates are encapsulated and highly
enriched within the hydrogel, and therefore organic synthesis
within the PNIPAM-co-PMACHE gel is, at least in principle,
more active than those in general solvents such as water, organic
solvent, or the above-mentioned binary/ternary solvent mixture.
Third, the cross-linked PNIPAM-co-PMACHE hydrogel instead
of the soluble PNIPAM-based thermomorphic polymer is used,
and this cross-linked hydrogel is insoluble and therefore easily
separable.
S6, Supporting Information). These results suggest the good
reusability of the hydrogel/Pd(II) composite.
2.8. Comparison. Cross-linked functional polymers (CFPs)
and some soluble polymers have been implemented in a wide
range of synthetic methodologies.33 Primarily, the synthetic use
of these polymers has fallen into one of two scenarios: (1) the
use of the polymer as support for reactants and/or (2) the use
of the polymer to support catalyst34 or encapsulate catalyst
(EnCat).35 As discussed above, the present hydrogel plays three
roles in the organic synthesis: (1) the support for the Pd catalyst,
(2) the encapsulant for reactants, and (3) the reaction medium.
Besides, the encapsulated reactants and the immobilized Pd
catalyst can even be highly enriched within the hydrogel matrix
by reversible deswelling of the hydrogel, which is beyond the
EnCat catalyst.
Usually, synthesis of an amphiphilic block copolymer is not
an easy thing and an amphiphilic block copolymer is much more
expensive than a random one. The Pd catalyst encapsulated in
amphiphilic block copolymer micelles has been demonstrated
to be very efficient in water and aqueous solution,11 possibly
since these micelles have the ability to encapsulate organic
reactants and can be used as a nanoreactor,36 whereas the
separation of the micelles system from the reaction mixture is
not easy since the amphiphilic block copolymer micelles are
3. Conclusion
A porous hydrogel of PNIPAM-co-PMACHE is synthesized.
The hydrogel is superabsorbent and it can hold ∼300 times of
water within the hydrogel matrix; it is thermoresponsive and
can reversibly swell and deswell at the phase-transition tem-
perature of about 32 °C; it is pH-responsive and the swelling
ratio almost remains constant at ∼300 in the pH range of 4-10,
and further gradually decreases until a minimum of ∼10 when
the pH value is below 4 or above 10; the PNIPAM-co-PMACHE
hydrogel contains a ligand of IDA, and therefore Pd(II) or 3-nm
Pd nanoparticles can be easily immobilized in the hydrogel
matrix. The PNIPAM-co-PMACHE hydrogel can encapsulate
(33) For general reviews on polymer-involved catalysis, see: (a) Dioos,
B. M. L.; Vankelecom, I. F. J.; Jacobs, P. A. AdV. Synth. Catal. 2006, 348,
1413. (b) Benaglia, M.; Puglisi, A.; Cozzi, F. Chem. ReV. 2003, 103, 3401. (c)
McNamara, C. A.; Dixon, M. J.; Bradley, M. Chem. ReV. 2002, 102, 3275. (d)
Dickerson, T. J.; Reed, N. N.; Janda, K. D. Chem. ReV. 2002, 102, 3325.
(34) (a) Rogers, C. J.; Dickerson, T. J.; Wentworth, P.; Janda, K. J.
Tetrahedron 2005, 61, 12140. (b) Kim, J.-W.; Kim, J.-H.; Lee, D.-H.; Lee, Y.-
S. Tetrahedron Lett. 2006, 47, 4745. (c) Yamada, Y. M. A.; Takeda, K.;
Takahashi, H.; Ikegami, S. Org. Lett. 2002, 4, 3371. (d) Kollhofer, A.; Plenio,
H. Chem. Eur. J. 2003, 9, 1416. (e) Uozumi, Y.; Nakai, Y. Org. Lett. 2002, 4,
2997. (f) Schweizer, S.; Becht, J.-M.; Le Drian, C. Org. Lett. 2007, 9, 3777. (g)
Parrish, C. A.; Buchwald, S. L. J. Org. Chem. 2001, 66, 3820.
(35) (a) Bolfa, C.; Zoleo, A.; Sassi, A. S.; Maniero, A. L.; Pears, D.; Jerabek,
K.; Corain, B. J. Mol. Catal. A: Chem. 2007, 275, 233. (b) Richardson, J. M.;
Jones, C. W. AdV. Synth. Catal. 2006, 348, 1207. (c) Broadwater, S. J.; McQuade,
D. T. J. Org. Chem. 2006, 71, 2131. (d) Motoyama, Y.; Mitsui, K.; Ishida, T.;
Nagashima, H. J. Am. Chem. Soc. 2005, 127, 13150. (e) Okamoto, K.; Akiyama,
R.; Kobayashi, S. Org. Lett. 2004, 6, 1987.
(37) (a) Bergbreiter, D. E.; Sung, S. D. AdV. Synth. Catal. 2006, 348, 1352.
(b) Bergbreiter, D. E.; Osburn, P. L.; Frels, J. D. J. Am. Chem. Soc. 2001, 123,
11105. (c) Bergbreiter, D. E.; Osburn, P. L.; Smith, T.; Li, C.; Frels, J. D. J. Am.
Chem. Soc. 2003, 125, 6254.
(36) Lee, M.; Jang, C.-J.; Ryu, J.-H. J. Am. Chem. Soc. 2004, 126, 8082.
1930 J. Org. Chem. Vol. 74, No. 5, 2009

Pd-Catalyzed C-C Cross-Coupling Reactions
with water and concentrated, and then the resulting product was
dried under vacuum at 40 °C, weighed, and analyzed by 1H NMR.
4.4. Typical Procedures for Suzuki Reaction within the
PNIPAM-co-PMACHE Hydrogel with Pd(0) Catalyst. The
hydrogel/Pd(0) composite was first prepared by reducing hydrogel/
Pd(II) with NaBH4 aqueous solution. To a screw-capped vial with
a side tube were added 2.5 g of hydrogel and 0.50 mL of 1.0
mmol/L of PdCl2 aqueous solution. The mixture was kept at room
temperature for 30 min with stirring. Subsequently, 0.10 mL of
0.10 mol/L of NaBH4 aqueous solution was added. The mixture
was kept overnight at room temperature with stirring. Then, 1.0
mmol of aryl halide, 1.5 mmol of phenylboronic acid, and 3.0 mmol
of K2CO3 were added and the mixture was degassed at room
temperature. The Suzuki reaction was performed at 40 °C for a
given time and the synthesized biaryls were extracted and analyzed
similar to what was described above.
hydrophilic reactants by hydrogen bonding between the PNIPAM
segment and the hydrophilic reactants. Hydrophobic reactants
can also be encapsulated within the hydrogel during the
reversible hydrophilic/hydrophobic phase transition of the
hydrogel. The encapsulated reactants and the immobilized Pd
catalyst can be highly enriched within the hydrogel by increasing
temperature above VPTT of the hydrogel or by adjusting pH,
and therefore organic synthesis can be efficiently performed at
concentrated reactants and Pd catalyst. Suzuki and Heck
reactions performed within the PNIPAM-co-PMACHE hydrogel
demonstrate that the hydrogel is a suitable reaction medium
within which organic synthesis can be accelerated, since the
reactants and Pd catalyst are highly enriched. The PNIPAM-
co-PMACHE hydrogel/Pd composite is easily recovered and
reused since the hydrogel/Pd composite can reversibly swell/
deswell.
4.5. Typical Procedures for the Heck Reaction within the
PNIPAM-co-PMACHE Hydrogel with Pd(II) Catalyst. To a
screw-capped vial with a side tube were added 5.0 g of hydrogel
and 0.50 mL of 4.0 mmol/L of PdCl2 aqueous solution. The mixture
was kept at room temperature for 30 min with stirring. Then, 1.0
mmol of aryl halide, 1.5 mmol of acrylic acid, and 3.0 mmol of
base such as K2CO3 were added. The mixture was degassed under
nitrogen purge for 10 min and then the vial content was heated in
an oil bath at 100 °C and magnetically stirred under nitrogen. After
the reaction was completed, the mixture was cooled to room
temperature instantly and then acidified with 1 mol/L of HCl
aqueous solution. The synthesized product was extracted from the
reaction mixture with diethyl ether (3 × 20 mL), washed with cold
water, and concentrated. Last, the resulting product was dried under
4. Experimental Section
4.1. Materials. The monomer of NIPAM (>99%) was purified
by recrystallization from a benzene/n-hexane mixture and dried
carefully under vacuum. Iminodiacetic acid (IDA, >99%) was used
as received. The IDA-functioned monomer of MACHE was
synthesized as described elsewhere.38 The reagents such as BIS
(>98%), TEMED (>99%), phenylboronic acid (>99%), 4-bro-
mophenol (>99%), 4-bromoacetophenone (>99%), iodobenzene
(>98%), 4-iodophenol (>99%), 4-iodobenzoic acid (>99%), 4-io-
dobenzaldehyde (>99%), 4-iodoanisole (>99%), bromobenzene
(>99%), and 4-bromobenzoic acid (>99%) were commercial
reagents and used as received. Double-distilled water was used in
the present experiments.
4.2. Synthesis of the PNIPAM-co-PMACHE Hydrogel. In a
500 mL beaker, NIPAM (10.85 g, 95.9 mmol), MACHE (4.47 g,
17.3 mmol), and BIS (0.66 g, 6.5 mmol) were dissolved in 200
mL of H2O/THF solvent mixture (4:1 by volume). Gelation was
initiated by K2S2O8 (0.32 g, 1.2 mmol) and accelerated by TEMED
(0.28 mL, 1.8 mmol) at ∼28 °C for 4 h. After the reaction, the
resulting hydrogel was immersed in deionized water at room
temperature for 72 h. During this period, water was replaced every
3 h to leach out the potential chemical residues.
4.3. Typical Procedures for Suzuki Reaction within the
PNIPAM-co-PMACHE Hydrogel with Pd(II) Catalyst. To a
screw-capped vial with a side tube were added 2.5 g of hydrogel
and 0.50 mL of 0.020-1.0 mmol/L of PdCl2 aqueous solution. The
mixture was kept at room temperature for 30 min with stirring.
Then, 1.0 mmol of aryl halide, 3.0 mmol of base such as K2CO3 or
triethylamine (Et3N), and 1.5 mmol of phenylboronic acid (50%
excess to the aryl halide) were added. The mixture was degassed
under nitrogen purge for 10 min. Subsequently, the vial content
was heated at a given temperature and magnetically stirred under
nitrogen for a given time. After the reaction was stopped, the
product was extracted with diethyl ether (3 × 20 mL) and then
washed with water. For the substrates of 4-halogenated phenols
and 4-halogenated benzoic acids, the reaction mixture was first
acidified with 1 mol/L of HCl aqueous solution and then the product
was extracted with diethyl ether. Last, the organic phase was washed
1
vacuum at 40 °C, weighed, and analyzed by H NMR.
4.6. Reuse of the Hydrogel/Pd Composite. The reuse of the
hydrogel/Pd composite was evaluated by using the Suzuki reaction
of 4-bromoacetophenone with phenylboronic acid as an example.
After the reaction was completed, the mixture was cooled to room
temperature and degassed under vacuum for 10 min to remove the
volatile base of Et3N. Then the reaction mixture was extracted with
diethyl ether; the organic phase was washed with water and then
concentrated; and the resulting product was dried, weighed, and
analyzed by 1H NMR. The pH of the hydrogel phase was adjusted
to 7 with 1 mol/L of HCl aqueous solution and then the composite
was reused in another run of the Suzuki reaction with the same
amounts of reactants being added as those in the fresh run.
Acknowledgment. The financial support by National Science
Foundation of China (No. 20504016) and the Program for New
Century Excellent Talents in University (No. NCET-06-0216)
is acknowledged.
Supporting Information Available: Text showing the
synthesis of PNIPAM-co-PMACHE hydrogel, optical photos
on the immobilization of Pd catalyst and the encapsulation and
enrichment of the typical reactants within the PNIPAM-co-
PMACHE hydrogel, the kinetics plot of the Suzuki reaction of
4-bromoacetophenone with phenylboronic acid within the
hydrogel employing Pd(II) catalyst at 90 °C, and the 1H NMR
spectra of the synthesized products. This material is available
free of charge via the Internet at http://pubs.acs.org.
(38) Wang, C.-C.; Chang, C.-Y.; Chen, C.-Y. Macromol. Chem. Phys. 2001,
202, 882.
JO802427K
J. Org. Chem. Vol. 74, No. 5, 2009 1931