A palladium complex with functionalized β-cyclodextrin: A promising catalyst featuring recognition abilities for Suzuki-Miyaura coupling reactions in water

Article abstract of DOI:10.1039/c3gc40645h

A water-soluble palladium complex (PdL_nβ-CD) was designed and prepared based on functionalized β-cyclodextrin. It showed high turnover numbers (TONs) and turnover frequencies (TOFs) of up to 9.9 × 10⁸ and 4.9 × 10⁸ h^-1, respectively, in aqueous Suzuki-Miyaura coupling reactions. The detailed reason for the excellent catalytic activity was studied.

Full text of DOI:10.1039/c3gc40645h

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A palladium complex with functionalized
β-cyclodextrin: a promising catalyst featuring
recognition abilities for Suzuki–Miyaura coupling
reactions in water†
Cite this: Green Chem., 2013, 15, 2081
Received 5th April 2013,
Accepted 3rd June 2013
DOI: 10.1039/c3gc40645h
Guofu Zhang, Yuxin Luan, Xingwang Han, Yong Wang, Xin Wen, Chengrong Ding*
and Jianrong Gao
www.rsc.org/greenchem
A water-soluble palladium complex (PdLn@β-CD) was designed
Recently, interest in the exploration of catalytic reactions in
and prepared based on functionalized β-cyclodextrin. It showed neat water is increasing dramatically due to advantages such
high turnover numbers (TONs) and turnover frequencies (TOFs) of as reaction rate acceleration, work-up procedure simplification,
up to 9.9 × 108 and 4.9 × 108 h−1, respectively, in aqueous Suzuki– etc. offered by this green and commercially available solvent.6
Miyaura coupling reactions. The detailed reason for the excellent Hence during the past years, many efforts have been made to
catalytic activity was studied.
design novel ligands/catalysts to promote aqueous organic
transformations. A great array of endeavours mainly focus on
the conjunction of efficient homogeneous ligands/catalysts
with water-soluble polymers (polyethylene glycol) or salts (sul-
fonate salt or quaternary ammonium salt).7 In particular,
cyclodextrin (CD) has also drawn much attention due to its
water-solubility and special hydrophobic cavity. Indeed, CDs
and their derivatives have shown excellent performances in
aqueous organic reactions including oxidation, reduction,
hydrolysis, hydroformylation, and so on.8 However, the appli-
cation of hydrophilic CD derivatives as ligands in organometal-
lic catalysis has not been fully explored, especially for aqueous
coupling reactions.9
In this context, we wish to report a triazolyl β-cyclodextrin
supported palladium complex (PdLn@β-CD) and its appli-
cation for Suzuki–Miyaura coupling reactions in neat water.
The detailed preparation route for PdLn@β-CD is shown
in Scheme 1. First, commercially available β-cyclodextrin
was treated successively with TsCl and NaN3 to afford 6-mono-
deoxy-6-monoazido-β-CD, which was further reacted with
The palladium-catalyzed Suzuki–Miyaura cross-coupling reac-
tion has attracted tremendous attention in the construction of
biaryl compounds due to its benefits of functional group com-
patibility, mild reaction conditions, and excellent yields of pro-
ducts.1 However, drawbacks like the high cost of palladium
catalysts and toxic noble metal residuals greatly hamper its
large-scale practical applications, especially in the pharma-
ceutical industry.2 To try to overcome these issues, consider-
able efforts have been made on the exploration of catalytic
Suzuki–Miyaura coupling reactions with
a low catalyst
loading.3 For instance, Bedford and Welch4 reported that
coupling reactions between aryl bromides and phenylboronic
acid were catalyzed by phosphinite-based palladacycles in
toluene at 130 °C, with a turnover number (TON) of up to
9.1 × 108. Sémeril and co-workers5 synthesized several calix[4]arene-
based monophosphanes and combined them with 10−4 mol%
palladium acetate for Suzuki–Miyaura reactions in dioxane/
decane at 100 °C, which provided coupling products in 3.2%–
32.1% yields and exhibited a turnover frequency (TOF) of up to
3.2 × 105 h−1. Although great progress has been made, these
aforementioned catalytic procedures usually occurred in
organic solvents, which from an environmental and economic
perspective, were undesirable media and might induce toxicity
and waste treatment issues.
College of Chemical Engineering and Materials Science, Zhejiang University of
Technology, Hangzhou 310014, People’s Republic of China.
E-mail: dingcr2004@yahoo.com.cn; Fax: (+86)-571-8832-0147;
Scheme 1 Synthesis of PdLn@β-CD. Reaction conditions: (a) TsCl, NaOH, H2O,
0–5 °C, 4 h, 24.3%; (b) NaN3, DMF, 75 °C, 4 h, 93.6%; (c) 2-ethynylpyridine,
CuSO4/sodium ascorbate, DMSO–H2O, r.t., 1 d, 92.1%; (d) Pd(OAc)2, toluene,
r.t., 12 h.
Tel: (+86)-571-8832-0147
†Electronic supplementary information (ESI) available: Detailed synthetic pro-
cedure of PdLn@β-CD and characterization date of the products. See DOI:
10.1039/c3gc40645h
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2-ethynylpyridine via a click reaction10 in DMSO–H2O at room
temperature to give functionalized Ln@β-CD. Then the
obtained ligand was stirred with Pd(OAc)2 in anhydrous
toluene for 12 h, and the desired complex PdLn@β-CD was
obtained as light yellow powder. Notably, the catalyst has
shown excellent solubility in the aqueous phase. The palla-
dium content in PdLn@β-CD, measured using inductively
coupled plasma atomic emission spectrometry (ICP-MS), was
0.1550 mmol g−1
.
To gain insight into the coordinative conformation of palla-
dium in the PdLn@β-CD complex, 1H NMR spectra were
obtained and the results are displayed in Fig. 1. It was gratify-
ing to find that all the proton signals on both the triazole- and
pyridine-rings of PdLn@β-CD shifted over a certain scale when
compared with its uncoordinated ligand Ln@β-CD (Fig. 1a and
b). In addition, the above proton signal differentiation was
further confirmed by comparison of the corresponding ligand
(1-methyl-4-(2′-pyridyl)-1,2,3-triazole, Fig. 1c) and palladium
complex (PdL′n, Fig. 1d). Hence the 1H NMR data indicates
that the palladium was coordinated with the nitrogen atoms in
the triazole- and pyridine-rings. Then a two-dimensional
ROESY NMR experiment was conducted, with the aim of exam-
ining the potential spatial proximities among the different
protons of PdLn@β-CD (Fig. 2). From the spectrum, it turned
out that no contacts were observed among the aromatic
protons of triazole-pyridine and the cyclodextrin protons,
implying that the functional group was not embraced in the
hydrophobic cavity of the β-CD-fragment.
Fig. 2 2D ROESY NMR spectrum of saturated PdLn@β-CD in D2O (25 °C).
Table 1 Optimization of the reaction conditionsa
Entry
PdLn@β-CD (mol%)
Base
Yieldb (%)
With water soluble PdLn@β-CD in hand, we next evaluated
its catalytic activity in Suzuki–Miyaura coupling reactions.
Initially, p-bromobenzaldehyde and phenylboronic acid were
selected as the model substrates to probe the optimal reaction
conditions, and the results are shown in Table 1. A 41% yield
of the desired product was obtained when the reaction was
carried out with 10−2 mol% PdLn@β-CD in water at 50 °C for
1c
2d
3
4
5
10−2
10−2
10−7
10−7
10−7
10−7
Na2CO3
Na2CO3
Na2CO3
K2CO3
K3PO4
NaHCO3
41
98
98
95
96
90
6
a All the reactions were carried out under reflux in the presence of
p-bromobenzaldehyde (1.0 mmol), phenylboronic acid (1.5 mmol),
PdLn@β-CD, base (1.5 mmol), and H2O (2.0 mL), for 4 h, unless
otherwise stated. b Isolated yields based on the amount of
p-bromobenzaldehyde used. c The reaction was performed at 50 °C.
d The reaction was carried out for 1 h.
4 h (entry 1). We were pleased to obtain 4-formylbiphenyl with
98% yield when the reaction was conducted under reflux for
only 1 h (entry 2). Notably, the amount of palladium catalyst in
the reaction can be further reduced to 10−7 mol% while main-
taining 98% yield of the reaction outcome (entry 3). Later on,
different bases were also screened and Na2CO3 turned out to
be the optimal base when compared with other bases like
K2CO3, K3PO4 and NaHCO3 (entries 3–6). Thus, we gained the
optimal conditions: 1.0 mmol aryl halide, 1.5 mmol phenyl-
boronic acid, 10−7 mol% catalyst PdLn@β-CD, 1.5 mmol
Na2CO3, 2.0 mL H2O under reflux.
Having determined the optimal conditions, we proceeded
to investigate the substrate scope of the catalytic system.
Representative results are summarized in Table 2. Generally,
different aryl halides underwent coupling reactions with
Fig. 1 Partial 1H NMR spectra (500 MHz, DMSO-d6, 298 K) of (a) the ligand
Ln@β-CD, (b) the palladium complex PdLn@β-CD, (c) the ligand L’n and (d) the
palladium complex PdL’n.
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phenylboronic acid to give the corresponding biaryl products biaryl products with good to excellent yields in neat water
in good to excellent yields (entries 1–8, 9c, 10b, 11b, 12, 13, (entries 15–20). Functional groups including methoxyl, methyl
14b). Remarkably, the catalyst PdLn@β-CD has shown extre- and chlorine were all well tolerated.
mely high catalytic efficiency during the coupling transform-
Prompted by the aforementioned interesting observations
ation, whose TONs and TOFs could reach up to 9.9 × 108 and like the high catalytic efficiency and the catalytic activity differ-
4.9 × 108 h−1, respectively. It was also worth noting that the entiation among different substrates, we set out to further
hydrophilic/hydrophobic property of the substituents on aro- clarify the advantage of PdLn@β-CD, especially the role of the
matic ring had a profound influence on the products’ yields. β-CD-fragment, in promoting aqueous Suzuki–Miyaura reac-
Specifically, for substrates with hydrophilic functional groups, tions. Control experiments were carried out with Pd(OAc)2
such as formoxyl, acetyl, hydroxyl, hydroxymethyl, carboxyl or PdL′n as the catalyst and the results are shown in Table 3.
etc., biaryl compounds were obtained in 93–99% yields under From the table, it was obvious that when the coupling reac-
standard conditions (entries 1–8). For the coupling reactions tions of hydrophilic aryl halides like p-bromobenzaldehyde
of some other substrates, like m-bromonitrobenzene, p-chloro- were catalyzed by Pd(OAc)2 or PdL′n instead of PdLn@β-CD, the
bromobenzene and p-bromotoluene, the catalytic activity yields of the coupling products decreased dramatically even
of PdLn@β-CD at 10−7 mol% loading was not satisfactory with a prolonged reaction time (entries 1–3). Interestingly,
(entries 9a, 10a, 11a), which might be caused by the poor although substrates bearing hydrophobic functional groups
water-solubility of tested substrates and limited β-CD cavities performed poorly (less than 20% yields) with 10−7 mol%
in the system. Fortunately, when we increased the amount of PdLn@β-CD, their coupling reactions catalyzed by Pd(OAc)2 or
PdLn@β-CD, the coupling reactions of these substrates were PdL′n barely proceeded in the aqueous phase, and no coupling
greatly improved, yielding the desired products in good yields products were detected during the reactions (entries 4–6). We
(Table 2, entries 9b, 9c, 10b, 11b, 12, 13). As demonstrated by believe that the differences in catalytic efficiency among
entry 14, this catalytic method was also suitable for sterically unsupported palladiums and PdLn@β-CD may be partially
hindered materials such as 2-iodoanisole.
ascribed to the employment of β-CD into the catalytic system,
Gratifyingly, substituted arylboronic acids also proved to be which was regarded as an excellent phase-transfer-catalyst to
good coupling partners in this system, providing the desired accelerate aqueous organic transformation.
Table 2 Suzuki–Miyaura coupling reactions between aryl halides and arylboronic acid using PdLn@β-CDa
Entry
R1
X
R2
n
Time (h)
Yieldb (%)
TON
TOF (h−1
)
1
2
3
4
5
6
7
8
9a
9b
9c
10ac
10bc
11a
11b
12
13
14a
14b
15
16a
16b
17
18
19
20
H
I
I
I
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
OCH3
OCH3
OCH3
OCH3
OCH3
CH3
Cl
1 × 10−7
1 × 10−7
1 × 10−7
1 × 10−7
1 × 10−7
1 × 10−7
1 × 10−7
1 × 10−7
1 × 10−7
1 × 10−5
1 × 10−3
1 × 10−7
1 × 10−3
1 × 10−7
1 × 10−3
1 × 10−3
1 × 10−3
1 × 10−5
1 × 10−3
1 × 10−5
1 × 10−5
1 × 10−3
1 × 10−3
1 × 10−3
1 × 10−3
1 × 10−3
2
4
3
2
4
6
8
6
12
12
12
12
12
12
24
15
20
20
15
10
15
12
6
99
95
94
98
98
94
93
94
18
54
90
19
96
8
85
92
93
45
94
95
35
94
93
90
93
82
9.9 × 108
9.5 × 108
9.4 × 108
9.8 × 108
9.8 × 108
9.4 × 108
9.3 × 108
9.4 × 108
1.8 × 108
5.4 × 106
9.0 × 104
1.9 × 108
9.6 × 104
8.0 × 107
8.5 × 104
9.2 × 104
9.3 × 104
4.5 × 106
9.4 × 104
9.5 × 106
3.5 × 106
9.4 × 104
9.3 × 104
9.0 × 104
9.3 × 104
8.2 × 104
4.9 × 108
2.3 × 108
3.1 × 108
4.9 × 108
2.4 × 108
1.5 × 108
1.1 × 108
1.5 × 108
1.5 × 107
4.5 × 105
7.5 × 103
1.5 × 107
8.0 × 103
6.6 × 106
3.5 × 103
6.1 × 103
4.6 × 103
2.2 × 105
6.2 × 103
9.5 × 105
2.3 × 105
7.8 × 103
1.5 × 104
9.0 × 103
3.8 × 103
3.4 × 103
COCH3
OH
H
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
I
CHO
COCH3
COOH
CH2OH
3-NO2
3-NO2
3-NO2
Cl
Cl
CH3
CH3
3-NO2
3-OCH3
2-OCH3
2-OCH3
H
COCH3
COCH3
F
Br
I
I
I
Br
Br
I
I
I
COCH3
3-NO2
COCH3
10
24
24
Br
a The reactions were carried out in refluxing water (2.0 mL) in the presence of aryl halide (1.0 mmol), arylboronic acid (1.5 mmol), catalyst
PdLn@β-CD (1 × 10−7–1 × 10−3 mol%), and Na2CO3 (1.5 mmol), unless otherwise stated. b Isolated yields based on the amount of aryl halide
used. c Only 4-chlorobiphenyl was obtained.
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Table 3 The effect of the palladium complex on Suzuki–Miyaura coupling reactionsa
Pd(OAc)2
PdL′n
PdLn@β-CD
Entry
R
X
Time (h)
Yieldb (%)
Time (h)
Yieldb (%)
Time (h)
Yieldb (%)
1
2
3
4
5c
6
OH
I
12
12
12
12
12
12
28
12
30
NR
NR
NR
12
12
12
12
12
12
10
10
40
NR
NR
NR
3
4
6
12
12
12
94
98
94
18
19
8
CHO
CH2OH
3-NO2
Cl
Br
Br
Br
Br
Br
CH3
a The reactions were carried out in refluxing water (2.0 mL) in the presence of aryl halide (1.0 mmol), phenylboronic acid (1.5 mmol), catalyst (1 ×
10−7 mol%), and Na2CO3 (1.5 mmol), unless otherwise stated. b Isolated yields based on the amount of aryl halide used. c Only 4-chlorobiphenyl
was obtained.
system was sensitive to the hydrophilicity of the examined sub-
strates. Further study verified that the recognition ability of the
catalyst partially contributed to the significant enhancement in
the conversions of the tested substrates. This newly developed
system represents an efficient and environmentally benign
coupling protocol, and could provide a valuable approach for
the design of water-soluble catalysts to mediate aqueous organic
reactions.
Acknowledgements
We gratefully acknowledge the financial support from the
National Natural Science Foundation of China (No. 20702051),
the Natural Science Foundation of Zhejiang Province
(LY13B020017) and the Key Innovation Team of Science and
Technology in Zhejiang Province (No. 2010R50018).
Fig. 3 2D ROESY NMR spectrum of a mixture of p-bromobenzaldehyde and
Notes and references
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