Palladium-catalyzed Mizoroki-Heck reactions in water using thermoresponsive polymer micelles

Article abstract of DOI:10.1016/j.tet.2019.01.047

Palladium-catalyzed Mizoroki-Heck reactions were carried out in water using thermoresponsive polymer micelles. The micelles were generated from thermoresponsive block copolymers consisting of a poly(N-isopropylacrylamide) (PNIPAAm) segment and a hydrophilic segment such as nonionic poly(ethylene glycol) (PEG) (2) and anionic poly(sodium p-styrenesulfonate) (PSSNa) (9). These copolymers exhibited lower critical solution temperature (LCST) behavior at ca. 40–50 °C and showed thermal stimuli-induced formation and dissociation of micelles. The copolymers formed micelles in aqueous solution at higher temperature, where catalytic reactions proceeded. At lower temperature, the micelles dissociated to form a clear solution, enabling efficient extraction of the products from aqueous reaction mixture. In the presence of these copolymers, palladium complexes catalyzed the coupling reactions between aryl iodides and alkene compounds inside the hydrophobic micelle cores in water under relatively milder conditions. Extraction of the products from the aqueous solution of 2 or 9 was found to be efficient enough in comparison with conventional surfactants.

Full text of DOI:10.1016/j.tet.2019.01.047

Accepted Manuscript
Palladium-catalyzed Mizoroki-Heck reactions in water using thermoresponsive
polymer micelles
Noriyuki Suzuki, Taiga Takabe, Yoshiko Yamauchi, Shun Koyama, Rina Koike,
Masahiro Rikukawa, Wei-Ting Liao, Wen-Sheng Peng, Fu-Yu Tsai
PII:
S0040-4020(19)30083-3
https://doi.org/10.1016/j.tet.2019.01.047
TET 30099
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 25 August 2018
Revised Date: 12 January 2019
Accepted Date: 18 January 2019
Please cite this article as: Suzuki N, Takabe T, Yamauchi Y, Koyama S, Koike R, Rikukawa M, Liao W-
T, Peng W-S, Tsai F-Y, Palladium-catalyzed Mizoroki-Heck reactions in water using thermoresponsive
polymer micelles, Tetrahedron (2019), doi: https://doi.org/10.1016/j.tet.2019.01.047.
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ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Palladium-catalyzed Mizoroki-Heck Reactions in Water using Thermoresponsive
Polymer Micelles
1
,*
1
1
1
1
Noriyuki Suzuki , Taiga Takabe , Yoshiko Yamauchi , Shun Koyama , Rina Koike ,
1
1,2,†
1,2,‡
2,*
Masahiro Rikukawa , Wei-Ting Liao , Wen-Sheng Peng , Fu-Yu Tsai
1
) Department of Materials and Life Science, Faculty of Science and Technology, Sophia
University, 7-1 Kioi-cho, Chiyoda-ku, Tokyo 102-8554, Japan
) Institute of Organic and Polymeric Materials, National Taipei University of Technology, 1,
2
Sec. 3, Chung-Hsiao E. Rd., Taipei 10608, Taiwan
Abstract:
Palladium-catalyzed Mizoroki-Heck reactions were carried out in water using
thermoresponsive polymer micelles. The micelles were generated from thermoresponsive
block copolymers consisting of a poly(N-isopropylacrylamide) (PNIPAAm) segment and a
hydrophilic segment such as nonionic poly(ethylene glycol) (PEG) (2) and anionic
poly(sodium p-styrenesulfonate) (PSSNa) (9). These copolymers exhibited lower critical
solution temperature (LCST) behavior at ca. 40–50 °C and showed thermal stimuli-induced
formation and dissociation of micelles. The copolymers formed micelles in aqueous solution
at higher temperature, where catalytic reactions proceeded. At lower temperature, the micelles
dissociated to form a clear solution, enabling efficient extraction of the products from aqueous
reaction mixture. In the presence of these copolymers, palladium complexes catalyzed the
coupling reactions between aryl iodides and alkene compounds inside the hydrophobic
micelle cores in water under relatively milder conditions. Extraction of the products from the
aqueous solution of 2 or 9 was found to be efficient enough in comparison with conventional
surfactants.
Keywords: thermoresponsive polymer, polymer micelle, palladium, Mizoroki-Heck reaction,
N-isopropylacrylamide
†
‡
) Visiting Researcher at Sophia University (March–April 2017).
) Visiting Researcher at Sophia University (May–June 2018).
*
Corresponding author. e-mail: norisuzuki@sophia.ac.jp, fuyutsai@ntut.edu.tw
1
. Introduction
Applying water as a solvent for organic processes attracts chemists since reducing organic
waste is an urgent subject from the point of view of global environment. Palladium-catalyzed
reactions are also studied in water; and conducting such catalytic reactions in water in the
1
-5
presence of surfactants would provide promising methodology. Reactions inside the micelle
core bring about not only reduce organic solvents but also possess benefits such as
3
,4,6,7
acceleration of reactions due to concentrated substrates by hydrophobic effects.
Nevertheless, the organic products generated in an aqueous reaction mixture must be
1

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separated by an extraction process that requires organic solvents. Thus, efficient extraction
system must be developed to realize more practical aqueous reactions. We envisioned that
stimuli-induced turning on/off the formation of micelles in the aqueous reaction mixture
would be able to achieve more efficient extraction. For instance, a thermoresponsive micelle
that dissociates at lower temperature might allow more efficient extraction with less organic
solvents. Poly(N-isopropylacrylamide) (PNIPAAm) is known as a thermoresponsive polymer
owing to its lower critical solution temperature (LCST) of 32 °C in water. Its application for
8
-12
thermoresponsive materials have received much attention.
Preparation of
1
3-16
thermoresponsive micelles by using copolymers of PNIPAAm has also been well studied.
Their application for organic synthesis seems attractive because of tunable formation and
dissociation of micelles in water.
On the basis of this idea, we previously reported amphiphilic block copolymers that form
1
7,18
thermoresponsive micelles in water depending upon temperature (Figure 1).
We utilized
block copolymers that consisted of PNIPAAm and poly(ethylene glycol) (PEG) blocks. The
PNIPAAm chain included L-proline groups, that serve as organocatalysts, by random
copolymerization of NIPAAm and 4-hydroxy-
dissolved in water at rt to give a clear solution, whilst these formed micelles at 50 °C (Figure
). Asymmetric cross-aldol reactions were catalyzed by the polymer in water at 50 °C with
L-proline acrylate. The copolymers were
1
excellent yield and enantiomeric excess. The mixture was cooled after the reaction, and the
products were taken up by extraction. O’Reilly, Monteiro and coworkers reported L-proline
tethered
thermoresponsive
copolymer
that
include
PNIPAAm
and
1
9
poly(N-dimethylacrylamide) based on the same idea.
Figure 1. Thermo-responsive micelles switched on/off by temperature.
In order to avoid leaching out of catalyst, immobilizing catalyst molecules onto the polymer
chain with a covalent bond is effective for catalytic reactions. However, tethering transition
metal catalysts often requires a tedious procedure. Thus, in this study, we investigated a
palladium-catalyzed reaction in an emulsified aqueous medium by adding palladium
2

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complexes from outside of the micelle. We employed two thermoresponsive amphiphilic
block copolymers that have nonionic and anionic segments. The former contains a PEG chain,
and the latter a poly(sodium p-styrenesulfonate) (PSSNa) segment. Synthesis of both the
2
0-24
25-31
block copolymers PNIPAAm-b-PEG
and PNIPAAm-b-PSSNa
and their
thermoresponsive behavior in aqueous solutions have been reported. To the best of our
knowledge, reports on palladium-catalyzed reactions using thermoresponsive micelles are
3
2,33
rare.
It is therefore interesting to investigate palladium-catalyzed reactions in water using
thermoresponsive micelles. We also studied the efficiency in extraction of the products from
the reaction mixture and compared the copolymers with conventional surfactants.
2
. Results and Discussion
2
. 1 Thermoresoponsive block copolymer with a nonionic PEG segment
Scheme 1. Preparation of NIPAAm-b-PEG 2 with PEGylated ATRP agent.
We first prepared a thermoresponsive amphiphilic block copolymer 2 that has a nonionic PEG
chain via an atom-transfer radical polymerization (ATRP) technique (Scheme 1). NIPAAm
was polymerized using the ATRP initiator tethered on a PEG chain 1 to afford the block
2
1
copolymer 2. The molecular weight (M ) of 2 was typically observed to be 8,500 with
n
narrow distribution (M /M = 1.03). The block copolymer 2 was soluble in water at room
w
n
temperature, which became opaque when heated. Dynamic light scattering (DLS) analysis
showed that the copolymer 2 has LCST at 40–45 °C (Figure 2a). The particle size distribution
of 2 in aqueous solution at 25 °C and 60 °C are depicted in Figure 2b. The hydrodynamic
diameter found to be larger than 70 nm at 60 °C, while it was 15-20 nm at 25 °C. The DLS
results supported the formation of polymer-aggregated micelles at 60 °C. Larger particles (80
nm) were also found in part and these could be caused by the aggregation of
2
6
polymer-micelles. These results clearly demonstrated that the formation of polymer micelles
by 2 was stimuli-induced.
3

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Figure 2. DLS of 2 in aqueous solution; (a) intensity at various temperatures, and (b) particle
size distribution.
We then studied palladium-catalyzed Mizoroki-Heck reaction in water in the presence of 2.
Iodobenzene (3a) and n-butyl acrylate (4a) were suspended in 4 mL of water in the presence
of 2 mol% of Pd catalyst and 4 wt% of 2, and the mixture was stirred at 70 °C (Table 1). The
product was taken up by repeated extraction with diethyl ether until the product was not
observed in the organic layer by thin layer chromatography (TLC). (E)-n-Butyl cinnamate
(
5aa) was obtained in 96% yield after 48 h (entry 1). No Z-isomer was detected on the basis
1
of H NMR spectroscopy. The yield at 24 h was 71% (entry 2), showing that the reaction
requires 48 h. Decreasing the amount of 2 (1 wt%) even resulted in good yield of 3 (92%,
entry 3), although reaction with 0.5 wt% of 2 yielded 5aa only in 52% (entry 4). It is
noteworthy that the reaction in the absence of 2 afforded 5aa in 43% (entry 5), showing that 1
wt% of 2 significantly accelerate the reaction. Conducting the reaction at 80 °C resulted in
lower yield of 5aa, although the reason is unclear (entry 6). At 60 °C, the reaction was slow
even in the presence of 4 mol% of Pd (entry 7). With 1 mol% of Pd yield was unsatisfactory
4

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(entry 8).
Table 1. Mizoroki-Heck reaction in water in the presence of 2.
Pd
x mol%
2
Entry
Temp/°C
Time/h
Yield
/
/y wt%
1
2
3
4
5
6
7
8
2
2
2
2
2
2
4
1
4
4
70
70
70
70
70
80
60
70
48
24
48
48
48
48
48
48
96
71
92
52
43
58
58
39
1
0.5
None
4
4
4
2
.2 Thermoresponsive block copolymer with an anionic PSSNa segment
5

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Scheme 2. Preparation of PNIPAAm-b-PSSNa 9 by RAFT polymerization technique.
Although the copolymer with nonionic segment 2 showed good performance in
palladium-catalyzed Mizoroki-Heck reaction, the reaction required 2 mol% of palladium load
to achieve good yield. In our previous report on proline-tethered thermoresponsive block
1
7
copolymer, we found that addition of sodium chloride improved the yield. It is because of
salting-out effect that is generally observed in organic reactions in micelles; e.g. more organic
solutes move into micelle cores because their solubility in aqueous solution decreases due to
3
4
the presence of electrolytes in the aqueous phase. Here, we envisioned that salting-out effect
owing to the ionic sodium sulfonate groups can be expected if a copolymer with an anionic
segment is employed. More concentrated substrates in micelles cores would accelerate the
reaction. Thus, we next synthesized a thermoresponsive block copolymer with anionic
polymer chain. The block copolymer was prepared by reversible addition-fragmentation chain
transfer (RAFT) polymerization (Scheme 2). N-Isopropylacrylamide and sodium
p-styrenesulfonate were polymerized in this order in the presence of the RAFT agent 6,
followed by the removal of trithiocarbonate moiety at the end of the polymer-chain to afford 9.
The polymerization degree of the PSSNa segment in 9 was smaller than that in 8 on the basis
1
of H NMR analysis. This might be because of depolymerization of p-styrenesulfonate during
the radical desulfurization process.
6

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Figure 3. LCST behavior of copolymer with anionic chain 9.
The DLS analysis of 9 exhibited its LCST behavior at 40–55 °C, although the change was not
as steep as that observed in 2 (Figure 3a). The particle size of 9 was 40–60 nm at 25 °C, while
1
60–220 nm at 50 °C. The larger particle size of 9 compared to 2 is probably due to
electrostatic repulsion among the anionic polymer chains. Possibility of the formation of
small micelle at 25 °C, however, cannot be ruled out. Palladium-catalyzed Mirozoki-Heck
reaction in water in the presence of 9 was studied (Table 2). It should be noted that only 1
wt% of 9 prompted the reaction (entry 1). Moreover, 1 mol% of Pd gave good yield (entry 2).
Even 0.5% of Pd resulted in moderate yield (entry 3). We examined various palladium source
for the reaction. In order to compare the catalytic activity, we fixed the amount of Pd atom as
0
.5 mol% (entry 5-9). The combination of Pd(OAc) and 3 equiv PPh gave an optimal yield
2 3
(
entry 7), and that was superior to PdCl (PPh ) . It is noteworthy that the reaction using
2 3 2
conventional anionic surfactant sodium dodecyl sulfate (SDS) gave 5aa in a siginificantly
lower yield compared to entry 1 (entry 10). These results demonstrated that the copolymer
7

ACCEPTED MANUSCRIPT
with anionic segment 9 was more effective for Mizoroki-Heck reaction in water than 2 that
contains nonionic polymer chain.
Table 2. Mizoroki-Heck reaction in water in the presence of 9.
Entry
9
Pd source
Pd
yield
/x wt%
/mol%
1
2
3
4
5
6
7
8
1
1
1
PdCl (PPh )
2
99
92
58
67
40
19
71
42
18
2
3 2
PdCl (PPh )
1
2
3 2
PdCl (PPh )
0.5
2
2
3 2
0.5
1
PdCl (PPh )
2
3 2
PdCl + 2 PPh
0.5
0.5
0.5
0.5
0.5
2
3
1
Pd(OAc) + 2 PPh
2
3
3
3
1
Pd(OAc) + 3 PPh
2
1
Pd(OAc) + 5 PPh
2
9
1
Pd(OAc) + 3 PCy
2
3
a
1
0
SDS
PdCl (PPh )
2
47
2
3 2
a) SDS (1 wt%) was added instead of 9.
2
.3. Mizoroki-Heck reactions in water in the presence of 2 or 9 with various substrates.
To study the scope of substrates, we carried out the reactions with various aryl halide and
alkenes in water in the presence of 2 or 9 (Table 3). The aqueous reaction mixtures were
extracted with diethyl ether or ethyl acetate repeatedly until the products were not observed in
the organic layer by TLC. Besides n-butyl acrylate (4a), a few acrylates 4g-h and N-isopropyl
acrylamide (4b) gave the corresponding cinnamates 5ag, 5ah and cinnamamide 5ab in good
yields (entries 2,12, 13). Styrene (4c) and 2-vinylnaphthalene (4d) afforded (E)-stilbene (5ac)
and 5ad in good yields (entries 3,4, 14). 2-Phenylpropene (4e), however, resulted in low yield
probably because of a steric reason (entries 5, 19). Other substituted styrenes 4i-l afforded
5
ai-5al in moderate to good yields (entries 15–18).
Linear alkene such as 1-hexene (4f), however, furnished 5af in low yields (entries 6, 20).
-Iodonaphthalene (3b) and other substituted iodobenzenes (3c, 3e-g) also gave the
1
corresponding products (5ab-ac, 5ae-eg) in good yields (entries 7-8, 21-23). When 3c and 4d,
both are solid at ambient temperature, were employed, 5cd was given in 14%.
Bromo- and chlorobenzene afforded no desired products under the standard reaction
conditions, although bromobenzene (3d) gave 5aa in low yield when PdCl (dtbpf) [dtbpf =
2
8

ACCEPTED MANUSCRIPT
1
,1′-bis(di-tert-butylphosphino)ferrocene] was used as a catalyst precursor (entry 10).
Table 3. Mizoroki-Heck reactions with various aryl halides and alkenes in water
Copoly
mer
Polymer
/ x wt%
a
Entry
1
Aryl halide
Alkene
Produnct
Yield
b
2
2
4
1
96
3
3
a
a
4a
5
aa
ab
2
3
4
5
82
62
58
12
4b
5
2
2
2
4
1
4
3
a
a
4c
5
ac
3
4d
5
ad
3
a
a
4
e
5
ae
6
7
4f
2
2
4
1
trace
93
3
5af
4a
3b
5
ba
8
2
2
2
1
1
1
73
14
8
4
a
3
c
5
ca
9
4
d
3c
5
cd
aa
c
1
0
3
d
4a
5
9

ACCEPTED MANUSCRIPT
b
1
1
7
7
7
7
1
1
1
1
99
3
3
3
a
a
a
4a
4g
5
aa
12
13
14
86
78
98
5
ag
ah
d
4h
5
3
3
3
a
a
a
4c
5
ac
1
5
6
7
7
1
1
60
56
4i
5
ai
1
4j
5
aj
1
1
1
7
8
9
7
7
7
1
1
1
69
80
12
3
a
a
4k
4l
5
ak
3
5
al
3
a
a
4
e
5
ae
2
0
1
4f
7
7
1
1
10
73
3
5af
2
4a
3e
5
ea
2
2
3
7
7
1
1
79
77
4
a
3
f
5
fa
2
4
a
3
g
1
0

ACCEPTED MANUSCRIPT
5
ga
a) isolated yield
b) determined by gas chromatography.
c) PdCl (dtbpf) was used as catalyst
2
d) 2-ethylhexyl acrylate
2
.4 Efficiency of extraction of the product
When reactions are conducted in water, the separation of products from the reaction mixture
usually requires an extraction process with organic solvents. Therefore, it is important to
reduce the amount of extraction solvents to achieve an environmentally benign system. We
examined the extraction efficiency in extracting the Mizoroki-Heck product 5aa from
aqueous model suspension of various surfactants containing the block copolymers 2 or 9, as
well as a few conventional low-molecular surfactants such as SDS and Triton X-100®.
The model mixture was prepared by adding surfactants (1 wt%) and 5aa to water and stirred
at 70 °C. This aqueous mixture was cooled and extracted once with 3 mL of ethyl acetate. The
extraction was conducted at 0 °C for 15 min or 30 min with moderate shaking using a shaking
apparatus at 120 rpm, and the amounts of extracted 5aa into the organic layer were
determined by gas chromatography. The experiments were repeated to ensure the
reproducibility.
The results are summarized in Table 4. The extraction efficiency was estimated on the basis of
the amount of the recovered 5aa within a given period of extraction time. In the absence of
any surfactants, 84±6% of 5aa was recovered within 15 minutes (entry 1). Lower extraction
(61±8%) at 30 min in entry 1 is due to a technical problem in pure water suspension, where
considerable amounts of dispersed organic particles attached on the wall of the vessel. The
extraction efficiency from the suspension of SDS was comparable to that from the water
(entry 5), although palladium-catalyzed reaction did not proceed in SDS suspension under the
present reaction conditions. Extraction from the solution of the nonionic copolymer 2 was
efficient enough that it was slightly lower than the solution of SDS (entry 2). The study on the
anionic block copolymer 9, on the other hand, encountered poor reproducibility. Anyhow the
product was obtained in moderate recovery in average (entry 3). Extraction from the actual
reaction mixture also gave a similar result (entry 4). Only 6% of 5aa was extracted in 30 min
when Triton X-100 was added (entry 6).
a
Table 4. Extraction study with ethyl acetate from aqueous solution
Entry
Surfactant
Description
Recovery of 5aa/%
1
5 min
30 min
61(±8)
58(±3)
1
2
None
2
Only water
PNIAAm-b-PEG
84(±6)
–
38(±21)
–
b
b
3
4
5
6
9
PNIPAAm-b-PSSNa
PNIPAAm-b-PSSNa
Anionic surfactant
Nonionic surfactant
40(±23)
c
c
9
45
SDS
Triton X-100
61(±7)
–
75(±0)
6(±2)
11

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SDS: sodium dodecyl sulfate, Triton X-100®: octylphenol ethoxylate
a) conditions: 5aa (0.5 mmol), surfactant 0.042 g, water 4mL, extracted at 0 °C.
b) an average value with sample standard deviation in parenthesis
c) 5aa was extracted from the reaction mixture with 9.
Extraction study using diethyl ether as an extrant was also performed (Table 5). In general,
the extraction with diethyl ether was less efficient than that with ethyl acetate. A significantly
less amount of 5aa was recovered, in general, compared to the results when ethyl acetate was
used. The results showed similar tendency to that observed ethyl acetate. The polymer 9,
however, was more efficient than 2 (entries 2, 3), although the amount of recovered 5aa was
one half to that from pure water (entry 1).
Table 5. Extraction study with diethyl ether from aqueous solution a
Entry
Surfactant
Description
Only water
PNIAAm-b-PEG
PNIPAAm-b-PSSNa
Anionic surfactant
Nonionic surfactant
Recovery of 5aa/%
1
2
3
4
5
None
2
9
SDS
49
17
25
33
3
Triton X-100
a) conditions: 5aa (0.5 mmol), surfactant 0.042 g, water 4mL, extracted at 0 °C for 30 min.
These results indicate that the thermoresponsive block copolymers PNIPAAm-b-PEG 2 and
PNIPAAm-b-PSSNa 9 were effective not only for palladium-catalyzed Mirozoki-Heck
reaction in water but also for efficient extraction from the aqueous reaction mixture.
3
. Experimental
3
.1. General
The preparation of copolymers was conducted under an argon atmosphere by using either
standard Schlenk techniques, unless otherwise mentioned. N-Isopropyl acrylamide (NIPAAm)
was purchased from Kanto Chemical Co., Inc. and recrystallized from hexane/toluene prior to
use. 2,2'-Azobis(isobutyronitrile) (AIBN), copper(I) chloride and dimethylacetamide (DMA)
were purchased from Kanto Chemical Co., Inc. and used without further purification. Sodium
dodecyl sulfate (SDS) and 4,4'-azobis(4-cyanovaleric acid) (V-501) were purchased from
FUJIFILM Wako Pure Chemical Corporation and used as received. Iodobenzene, sodium
p-styrenesulfonate, n-butyl acrylate, tris[2-(dimethylamino)ethyl]amine and α-methylstyrene
were purchased from Tokyo Chemical Industry Co., Ltd. and used as received. Styrene and
1
-hexene were purchased from Tokyo Chemical Industry Co., Ltd., distilled and kept under
argon. Other aryl halides, alkenes and palladium catalysts were purchased and used as
received. Triton X-100 was purchased from Sigma-Aldrich Co. LLC. and used without further
purification. The PEGylated ATRP agent 1 was synthesized from 4-chloromethylbenzoic acid
3
5
poly(ethylene glycol) monomethyl ether according to the literature. The RAFT agent 6 was
3
6
prepared according to the reported method in the literature.
Triethylammonium
1
2

ACCEPTED MANUSCRIPT
hypophosphite was prepared from triethylamine and hypophosphinic acid in toluene. Dialysis
was performed using Spectra/Por® RC tubing (MWCO: 3.5kD). Deionized water was
obtained on WE-200 (Yamato Scientific Co., Ltd.). NMR spectra were recorded on JEOL
ECX 300, ECA 500 and Bruker Avance III HD400 spectrometers. Gel permeation
chromatography (GPC) was measured on HLC-8320 GPC (Tosoh Corporation) equipped with
Shodex GPC LF-804 columns (Showa Denko K.K.) using N,N-dimethylformamide (DMF)
(0.1 wt% LiBr) as eluent; the molecular weight of the polymers was determined based on
monodispersed poly(ethylene oxide) as standard. Dynamic light scattering (DLS)
measurements were made with DLS-8000 (Otsuka Electronics Co., Ltd.).
3
.2. Preparation of the thermoresponsive amphiphilic block copolymer with nonionic PEG
3
7
segment 2.
In a dried 100 mL Schlenk tube, 1 (0.39 g, 0.18 mmol), NIPAAm (1.14 g, 10 mmol), DMF
2.51 mL) and deionized water (1.56 mL) were added. The mixture was degassed in three
(
freeze-pump-thaw cycles, and the flask was filled with argon. Meanwhile, CuCl (1.17 g, 0.72
mmol) and tris[2-(dimethylamino)ethyl]amine (0.166g, 0.72 mmol) were dissolved in
degassed water (0.48 mL) to form a blue solution. The Schlenk tube was immersed in a water
bath and the blue solution (0.12 mL) was added. The mixture was stirred overnight and
tetrahydrofuran (1.2 mL) was added. The mixture was purified with column chromatograph
(alumina, methanol/chloroform = 1/1) and the volatiles were removed in vacuo to leave blue
oil. The crude product was dissolved in water and purified by dialysis affording 2 as a white
1
solid (1.354 g, 81%). The molecular weight was determined by H NMR (M = 8,500) and
n
polydispersity was evaluated by GPC (M /M = 1.03).
w
n
1
H NMR (D O, 500 MHz): δ 1.15 (CH(CH ) ), 1.4–1.7 (CH in the NIPAAm chain), 2.0–2.1
2
3 2
2
(
CH in the NIPAAm chain), 3.38 (s, 3H, OCH ), 3.67-3.71 (br, OCH ), 3.81-3.96 (br,
3 2
CH(CH ) ), 4.50 (br, CH O(CO)C H -), 7.37 (d, J = 7.4 Hz, 2H) 7.99 (d, J =7.4 Hz, 2H).
3
2
2
6
4
3
.3. Preparation of the amphiphilic block copolymer with anionic PSSNa segment 8.
A Schlenk tube (25 mL) was thoroughly dried by heating under vacuum and the tube was
filled with argon. In this tube, RAFT agent 6 (97 mg, 0.38 mmol), NIPAAm (829 mg, 7.3
mmol), AIBN (18 mg, 0.11 mmol) were dissolved in DMA (6 mL) and degassed in three
freeze-pump-thaw cycles. The mixture was stirred at 60 °C for 20 h, and the reaction mixture
was poured into hexane/diethyl ether (150/150 mL) to precipitate yellow solid. After the
solvent was decanted, the yellow solid was dissolved in chloroform, the solution was
collected and dried in vacuo to leave the intermediate 7 as yellow solid (549 mg, 61%). The
1
molecular weight was determined by H NMR spectroscopy. DP (degree of polymerization) =
1
3
0, M = 3,650 by H NMR.
n
The obtained PNIPAAm (7) (549 mg, 0.15 mmol) was added to a dried Schlenk tube, and
sodium p-styrenesulfonate (367 mg, 1.78 mmol) and AIBN (13 mg, 0.08 mmol) werer
dissolved in DMSO (7 mL) in the tube. The mixture was degassed in three freeze-pump-thaw
cycles. The tube was stirred at 65 °C for 23 h, and the yellow mixture was purified by dialysis
for 3 days. The dialyzed yellow solution was dried in vacuo to afford the product polymer 8
1
as yellow solid (660 mg, 72%). The molecular weight was determined by H NMR
1
3

ACCEPTED MANUSCRIPT
1
spectroscopy. DP of the PSSNa segment was 19, M = 7,600 by H NMR.
n
1
H NMR (D O, 400 MHz): δ: 1.1 (br, CH(CH ) ), 1.4–1.7 (br, CH in the main chain), 2.0–
2
3 2
2
2
.2 (CH in the main chain), 3.9 (br, CH(CH ) ), 4.5 (s, ph-CH -CH ), 6.6–7.7 (br, Ar).
3 2 2 2
3
8
3
.4 Removal of the trithiocarbonate terminus in the PNIPAAm-b-PSSNa 8: Preparation of 9.
The PNIAAm-b-PSSNa 8 (506 mg, 0.067 mmol), triethylammonium hypophosphite (101 mg,
.5 mmol) and V-501 (17 mg, 0.06 mmol) were dissolved in DMSO (6 mL) and degassed by
the freeze-pump-thaw method. The mixture was stirred at 80 °C for 3 h, and additional V-501
17 mg, 0.06 mmol) was added to the solution. After the mixture was stirred at 70 °C for 21 h,
0
(
the yellow solution was dialyzed. The resultant colorless solution with white precipitate was
dried in vacuo to obtain the product as white solid (348 mg, 70%). The molecular weight was
1
determined by H NMR spectroscopy. DP of the PNIPAAm segment was 30, while PSSNa
1
segment was 12, M = 6,000 by H NMR.
n
1
H NMR (D O, 400 MHz): δ 1.1 (br, CH(CH ) ), 1.4–1.7 (br, CH in the main chain), 2.0–2.2
2
3 2
2
(
CH in the main chain), 3.9 (br, CH(CH ) ), 4.5 (s, ph-CH -CH ), 6.6–7.7 (br, Ar).
3 2 2 2
3
.5 Mizoroki-Heck reactions in water in the presence of thermoresponsive block copolymer.
Typically, in a test tube with a screw cap 9 (42 mg) was dissolved in water (4 mL) and the
mixture was stirred at rt for 0.5 h. To this mixture iodobenzene (3a, 102 mg, 0.5 mmol), butyl
acrylate (4a, 128 mg, 1.0 mmol), PdCl (PPh ) (7 mg, 0.01 mmol) and diisopropylethylamine
2
3 2
(129 mg, 1.0 mmol) were added and stirred at 70 °C for 48 h. The gray mixture was cooled in
an ice bath, and diethyl ether (3 mL) was added and stirred for 1 h to extract organic
compounds. After stirring the organic layer was collected, and the extraction was repeated.
The organic layers were combined and tetradecane (99.2 mg, 0.5 mmol) was added as an
internal standard when yield was determined by gas chromatography (99%). Purification by
column chromatograph gave n-butyl cinnamate (5aa).
3
.6 Evaluation of extraction efficiencies
Typically, in a test tube with screw cap, the block copolymer 9 (42 mg) was dissolved in
deionized water (4 mL) and the solution was stirred for 0.5 h at rt. To this solution, n-butyl
cinnamate (5aa, 102 mg, 0.5 mmol) was added and the mixture was stirred at 70 °C for 1 h.
Ethyl acetate was added to this mixture, and this mixture was shaken at 120 rpm in a shaking
apparatus at 0 °C for 0.5 h. The mixture was allowed to stand still for 0.5 h at ambient
temperature, and then the organic layer was taken up and analyzed by gas chromatograph
using tetradecane as an internal standard.
Conclusion
In summary, palladium-catalyzed Mizoroki-Heck reactions were studied in water in the
presence of thermoresponsive amphiphilic block copolymers. The reactions were examined
using two kinds of copolymers; one consisted of PNIPAAm and a nonionic PEG segment 2
and the other PNIPAAm and an anionic PSSNa segment 9. The study demonstrated that the
copolymer 9 with anionic chain was more effective than 2 for catalytic reactions. Extraction
study indicated that extracting n-butyl cinnamate form aqueous suspension of 2 or 9 was
1
4

ACCEPTED MANUSCRIPT
considerably efficient.
Acknowledgments
This study was financially supported by The Science Research Promotion Fund of The
Promotion and Mutual Aid Corporation for Private Schools of Japan.
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