A supramolecular recyclable catalyst for aqueous Suzuki-Miyaura coupling

Article abstract of DOI:10.1039/c4ra13953d

A water-soluble, supramolecular catalytic system has been designed based on inclusion complexation between a hydrophobic palladium(ii)-dipyrazole complex bearing an adamantyl (Ad) molecular recognition moiety and a complementary, hydrophilic β-cyclodextrin (β-CD) derivative. The single-crystal molecular structure of the Pd(ii) complex was determined and its host-guest inclusion complexation with heptakis(2,6-di-O-methyl)-β-CD (dmβ-CD) in an aqueous medium was confirmed by 2D NOESY ¹H NMR spectroscopy. The catalyst showed high activity for Suzuki-Miyaura coupling of hydrophilic aryl bromides with aryl boronic acids in aqueous organic solvents. In the presence of n-Bu₄NBr as a stabilizer, the catalyst-containing reaction solution can be recycled and reused multiple times to catalyze the coupling reaction of fresh substrates once the product has been removed by centrifugation. This work demonstrates a supramolecular complex approach, non-covalently modifying a water insoluble metal complex to provide a water-soluble inclusion system to serve as a recyclable catalyst for potential application in green chemical synthesis. This journal is

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TOC
Host-guest
interactions
+
Water-insoluble
Pd(II) complex
Water-soluble
Supramolecular hybrid catalyst
A Pd(II) pyrazolyl complex is solubilized by host-guest inclusion to give an efficient, recyclable
catalyst for Suzuki-Miyaura couplings in aqueous-organic solvents.

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Green Chemistry
RSCPublishing
ARTICLE
A Supramolecular Recyclable Catalyst for Aqueous
Suzuki-Miyaura Coupling†
Cite this: DOI: 10.1039/x0xx00000x
Miao Qi,a,b Pei Zi Tan,a,b Fei Xue,a,b Haripal Singh Malhi,a,c ZhongꢀXing
a,b
Zhang,* * *
a David J. Young, a,c,d and T. S. Andy Hor
Received 00th January 2012,
Accepted 00th January 2012
A waterꢀsoluble, supramolecular catalytic system has been designed based on inclusion
complexation between a hydrophobic palladium(II)ꢀdipyrazole complex bearing an adamantyl
DOI: 10.1039/x0xx00000x
(Ad) molecular recognition moiety and a complementary, hydrophilic βꢀcyclodextrin (
βꢀCD)
derivative. The singleꢀcrystal molecular structure of the Pd(II) complex was determined and its
www.rsc.org/
hostꢀguest inclusion complexation with heptakis(2,6ꢀdiꢀOꢀmethyl)ꢀβꢀCD (dmβꢀCD) in aqueous
medium was confirmed by 2D NOESY 1H NMR spectroscopy. The catalyst showed high
activity for SuzukiꢀMiyaura coupling of hydrophilic aryl bromides with aryl boronic acids in
aqueous organic solvents. In the presence of
nꢀBu4NBr as stabilizer, the catalystꢀcontaining
reaction solution can be recycled and reused multiple times to catalyze the coupling reaction of
fresh substrates once the product has been removed by centrifugation. This work demonstrates
a supramolecular complex approach, nonꢀcovalently modifying a water insoluble metal
complex to provide a waterꢀsoluble inclusion system to serve as a recyclable catalyst for
potential application in green chemical synthesis.
inclusion complexes makes them among the most studied hosts
in supramolecular chemistry,11ꢀ16 with a wide range of
Introduction
applications
enantiomers20 and as
from drug delivery,17ꢀ19 to resolution of
Green chemistry addresses the environmental impact of both
chemical products and the processes by which they are
produced.1ꢀ4 Water is an ideal green solvent and may offer
additional benefits such as improved reactivities, selectivities,
simplified workup procedures and recycling of an expensive
metal catalyst.5, 6
catalysts.21ꢀ23 The supramolecular
structures formed between CDs and polymers have also
inspired interesting supramolecular biomaterials. Some of us
have recently constructed a series of supramolecular hydrogels,
nonꢀcovalently connected micelles, nanoꢀcapsules and pseudoꢀ
block copolymers based on the inclusion complexation between
The development of novel water soluble catalysts has elicited
interest from both industrial and academic researchers.7,
8
Designing catalytically active metal species to operate in an
aqueous phase has primarily focused on ligands with suitable
hydrophilic groups in addition to their functionality necessary
to support the stability, activity, and selectivity of the metal
center. Most commonly, ionic substituents such as sulfonate,
carboxylate, phosphonate, or ammonium are employed, but
neutral hydrophilic polyols, carbohydrates, and polyethylene
glycols have also been successfully used.9
We herein present a new approach to the design and preparation
of waterꢀsoluble metal catalysts by utilizing nonꢀcovalent rather
than covalent bonding. This strategy makes use of hostꢀguest
inclusion complexation to reversibly tether a hydrophilic
moiety to the hydrophobic ligand of the metal complex thereby
enhancing its solubility in aqueous media.
β
ꢀCD moieties and adamantyl (Ad) groups.24ꢀ27
On the basis of this experience with the selfꢀassembling
behavior of ꢀCD/Ad pairs and of transition metal complexes
β
bearing pyrazoleꢀderived ligands,28 we have now designed a
bidentate dipyrazole ligand tethered to an Ad group as the
molecular recognition moiety (AdꢀL). This ligand then reacted
with the Pd(II) precursor PdCl2(NCCH3)2 to form an Adꢀ
containing complex (AdꢀLꢀPdCl2) that is insoluble in water
because of the bulky hydrophobic group. Upon hostꢀguest
inclusion complexation of AdꢀLꢀPdCl2 with heptakis(2,6ꢀdiꢀOꢀ
methyl)ꢀ
complex dissolves completely at room temperature to form a
water soluble supramolecular assembly (AdꢀLꢀPdCl2 ꢀCD)
βꢀCD (dmβꢀCD) in aqueous media, however, the Pd(II)
⊂
β
Cyclodextrins (CDs) are wellꢀknown cyclic oligosaccharides
formed from the enzymatic degradation of starch.10 Their
partial water solubility, homochirality and ability to form
that efficiently catalyzes SuzukiꢀMiyaura coupling between
hydrophilic aryl bromides with aryl boronic acid at room
temperature. By comparison, the Pd(II) complex (AdꢀLꢀPdCl2),
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κ2(N,N) coordination gives rise to a puckered 8ꢀmembered
metallocyclic ring ꢀPd1ꢀN1ꢀN2ꢀC6ꢀN5ꢀC12ꢀN4ꢀN3ꢀ which is
best described as a boatꢀchair like conformation. The Pdꢀ
N(pyrazolyl) bond lengths are 2.019(2) Å and 2.024(2) Å
which are consistent with literature values 32ꢀ34 as are the PdꢀCl
distances of 2.2777(6) Å and 2.2858(6) Å.32ꢀ35
that is present heterogeneously in the aqueous reaction mixture
exhibits much lower catalytic efficiency under similar
conditions.
Results and discussion
Table 1. Selected bond lengths (Å) and bond angles (°)
Synthesis and characterization of Ad-L and Ad-L-PdCl2
Bond Length (Å)
Pd(1)ꢀN(3) 2.019(2)
Pd(1)ꢀN(1) 2.024(2)
Pd(1)ꢀCl(1) 2.2777(6)
Pd(1)ꢀCl(2) 2.2858(6)
Bond Angle (°)
H2N
N(3)ꢀPd(1)ꢀN(1) 88.44(8)
N(3)ꢀPd(1)ꢀCl(1) 177.60(6)
N(1)ꢀPd(1)ꢀCl(1) 89.20(6)
N(3)ꢀPd(1)ꢀCl(2) 90.01(6)
N(1)ꢀPd(1)ꢀCl(2) 177.62(6)
Cl(1)ꢀPd(1)ꢀCl(2) 92.33(3)
Pd(CH3CN)2Cl2
Anhydrous MeCN
r.t., 1 day
N
N
OH
+
2
Dry CH2Cl2
r.t., 12 h
N
N
N
N
N
N
N
N
N
N
Pd
Cl
Cl
Ad-L
Ad-L-PdCl2
Scheme 1. Synthesis of AdꢀL and AdꢀLꢀPdCl2.
Host-guest inclusion complexation between Ad-L-PdCl2 and
-CD derivative
β
The ligand AdꢀL was synthesized by the nucleophilic
substitution reaction of one equivalent of 1ꢀ
adamantanemethylamine with two equivalents of (3,5ꢀ
dimethylꢀ1 ꢀpyrazolyl)methanol in anhydrous acetonitrile at
The adamantyl (Ad) group and βꢀCD moiety is a wellꢀknown
hostꢀguest pair with a stability constant (log K) up to 5 at room
temperature.36ꢀ38 To confirm the hostꢀguest inclusion
complexation of the adamantylꢀcontaining Pd(II) complex with
H
room temperature over 24 h (Scheme 1). This facile procedure
resulted in good yields with little side products. The central
amine and the two pyrazolyl nitrogen atoms of this ligand are
potential ligand donors to the metal centre and hence this
hybrid molecule can possibly bind to a metal in a κ2(N,N) or
heptakis(2,6ꢀdiꢀOꢀmethyl)ꢀ
NMR measurements were made in aqueous DMSO. Dm
was chosen for this analysis because of its enhanced solubility
in water relative to
ꢀCD.25
The sample was prepared by adding a solution of AdꢀLꢀPdCl2
(guest) in DMSOꢀd6 into a solution of dm ꢀCD (host) in D2O.
β
ꢀCD (dm
β
ꢀCD), 2DꢀNOESY 1H
ꢀCD
β
β
κ3(
N,N’,N) fashion depending on the electronic state and steric
constraints around the metal.29 The coꢀpresence of a tertiary
amine and pyrazolyl nitrogen donors in proximity also
enhances the hemilability which gives it coordinative freedom
and conformational freedom to adapt to the coordination and
geometry changes of the metal during the catalytic cycle.30, 31
The adamantylꢀcontaining Pd(II) complex (AdꢀLꢀPdCl2) was
quantitatively prepared by reacting AdꢀL with an equal amount
β
The final hostꢀguest mixture (molar ratio 1:1) in D2O/DMSOꢀd6
(1:1, v/v) was filtered before measurement. It can be seen in the
2D NOESY spectrum (Figure 2, left) that the peaks of the
Pd(II) complex were only present at low intensity compared to
the peaks belonging to dmβꢀCD. This is most likely due to
longer proton relaxation times and the high hydrophobicity of
the former. This is a common phenomenon for amphiphilic
1
of PdCl2(NCCH3)2 in dry CH2Cl2 at room temperature. The H
materials like copolymers in aqueous solution.26 The C(3)ꢀ
H
NMR spectrum of the ligand showed a 0.1ꢀ0.4 ppm downfield
shift upon coordination. Most affected was the –CH2ꢀ group
bridging the central amine and the pyrazolyl group. From a
singlet in the free ligand, this signal became two doublets at
7.11 and 5.23 ppm with a geminal coupling constant of 15 Hz
(see Supporting Information, Figure S1).
Single crystals of adamantylꢀcontaining Pd(II) complex suitable
for SingleꢀCrystal Xꢀray Diffraction analysis (Figure 1) were
obtained by slow diffusion of diethyl ether into a solution of
complex in CH2Cl2 at ꢀ20 °C. Selected bond lengths and bond
angles are summarized in Table 1.
and C(5)ꢀ
hydrophobic cavity of
the protons (1.6 to 2.0 ppm) on the guest Ad group (Figure 2,
right), indicating that the Ad moiety has inserted into the ꢀCD
H
of dm
β
ꢀCD (3.6 to 3.7 ppm) point into the
β
ꢀCD and exhibit correlation signals with
β
cavity. This observation is in agreement with literature reports
by us and by other groups.26, 27, 39
1
Figure 2. (left) 2D NOESY H NMR spectrum of AdꢀLꢀPdCl2
and dmβꢀCD in D2O/DMSOꢀd6 (1:1, v/v) with water
Figure 1. ORTEP diagram of adamantylꢀcontaining Pd(II)
complex shown with 50% probability ellipsoids (hydrogen
atoms are omitted for clarity).
suppression (500 MHz, 25oC); (right) Expanded 2D NOESY 1H
NMR spectrum.
The Pd(II) centre in AdꢀLꢀPdCl2 is slightly distorted from the
ideal square planar geometry that is typically found in a d8
metal centre. The bidentate chelating ligand binds the Pd(II)
centre through the two pyrazolyl nitrogen atoms N3 and N1.
The nonꢀcoordinating [N5···Pd] distance is 3.683 Å. This
Suzuki-Miyaura coupling reaction
Selection of solvent. The SuzukiꢀMiyaura coupling reaction is
one of the most important synthetic methodologies for the
2 | J. Name., 2012, 00, 1-3
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41
formation of carbonꢀcarbon bonds.40,
These reactions are the first two hours in the presence of the solubilizing host
generally catalyzed by soluble palladium complexes with (Figure 3, curve a and b). The series of photographs in Figure 3
various Pd(0) stabilizing ligands in organic media. A number of illustrates the improved solubility of AdꢀLꢀPdCl2 in the
43
protocols have also been developed by us42,
and other presence of dmβꢀCD. The presence of the latter resulted in the
44ꢀ48
groups7,
using water or aqueous mixed solvents as the Pd(II) complex dissolving completely to result in a clear yellow
reaction media to reduce the negative environmental impact of solution (Figure 3, bottom a1). The solution remained clear on
conducting this reaction on an industrial scale. addition of the 4ꢀbromobenzoic acid and the base Na2CO3
In this work, SuzukiꢀMiyaura cross coupling of 4ꢀ (Figure 3, bottom a2). Subsequently, when the water soluble
bromobenzoic acid and phenylboronic acid was used to phenylboronic acid was added and the coupling reaction
evaluate the catalytic performance of our supramolecular initiated, the reaction mixture became increasingly turbid on the
generation of water insoluble product (Figure 3, bottom a3).
Without the host dm ꢀCD, the Pd(II) complex was not
dissolved in the reaction medium H2OꢀCH3OH (3/1, v/v) but
dispersed in a light yellow suspension. The reaction mixture
was also less turbid over the same reaction period suggesting a
slower reaction rate (Figure 3, bottom b1ꢀb3).
catalyst (AdꢀLꢀPdCl2⊂dmβꢀCD) (Scheme 2) in a series of
β
waterꢀorganic solvent mixtures (3/1, v/v). These reactions were
carried out in air at room temperature with a 0.5 mol% catalyst
loading. The supramolecular preꢀcatalyst and the substrates
dissolved in the waterꢀorganic solvent reaction media to form a
homogeneous reaction mixture. Product yields after 2 hours are
given in Table 2.
100
80
a, with dmβ−CD
b, without dmβ-CD
+
60
40
20
0
Ad-L-PdCl ⊂dmβ-CD
2
0
60
120
180
240
Reaction time (min)
Scheme 2. SuzukiꢀMiyaura coupling reaction of 4ꢀ
bromobenzoic acid and phenylboronic acid in aqueous media
catalyzed by supramolecular inclusion complex catalyst (AdꢀLꢀ
Catalyst in H2OꢀCH3OH Catalyst + aryl bromide, base Coupling reaction, 30min
PdCl2⊂dmβꢀCD).
a1
a3
a2
Table 2. Yield of SuzukiꢀMiyaura coupling reaction in
different aqueous solvent mixtures after 2 hours[a]
dmβ-CD
Entry
Reaction media
H2OꢀCH3OH
H2OꢀDMF
Yield (%)[b]
>97
1
2
87.7
3
4
H2OꢀCH3CN
H2OꢀAcetone
31.3
61.2
b2
b3
b1
[a]
Reaction conditions: 0.5 mol% supramolecular catalyst (AdꢀLꢀ
No
dmβ-CD
PdCl2 complexed with an equal amount of dmβꢀCD), 0.5 mmol of 4ꢀ
bromobenzoic acid, 0.6 mmol of phenylboronic acid, 1.2 mmol of
Na2CO3, 4 mL of waterꢀorganic mix solvent (3/1, v/v), room
temperature for 2h in air.
[b]
Yields were determined by 1H NMR analysis in d6ꢀacetone using
an internal standard (dodecane) and calculated using a product
calibration plot with R2=0.998 (see Supporting Information).
Figure 3. (top) Comparison of SuzukiꢀMiyaura coupling
reactions performed in H2OꢀCH3OH (3/1, v/v) with and without
It can be seen from Table 2 that the yield of the Suzukiꢀ dm
β
ꢀCD in air at room temperature over 4h. Each point
Miyaura coupling product after 2 hours decreased in the order represents the mean value
±
SD of runs; (bottom)
2
H2OꢀCH3OH > H2OꢀDMF > H2OꢀAcetone > H2OꢀCH3CN. Photographs comparing the homogeneity of catalyst and
Fortuitously, the H2OꢀCH3OH mixture is also the ‘greenest’ of catalyst mixed with 4ꢀbromobenzoic acid/Na2CO3 in H2Oꢀ
these waterꢀorganic solvent mixtures.49
CH3OH (3/1, v/v), as well as the turbidity of the reaction
mixtures after adding phenylboronic acid in 30 min with (a1ꢀ
Contribution of host-guest inclusion complexation to a3) and without (b1ꢀb3) the host dm
Suzuki-Miyaura coupling reaction. Next, the efficacy of host
βꢀCD, respectively.
dm
presence of dm
(>98%) after 4 hours. In the absence of dm
proceeded in a slightly reduced yield (ca. 93%) over the same
period. Importantly, the reaction was significantly faster over
β
ꢀCD was evaluated in the optimal solvent (Figure 3). The
ꢀCD resulted in a very high product yield
ꢀCD, the reaction
β
The influence of solubility was further investigated by varying
the propotion of organic solvent in the presence and absence of
the host dmβꢀCD (Figure 4). The reactions in the presence of
β
dm
β
ꢀCD always afforded the product in higher yields (94% ꢀ
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99%) over a volume ratio of H2O/CH3OH ranging from 0.5 to Table 3. Catalyst recycling for the SuzukiꢀMiyaura coupling
5. The reactions in the absence of dm ꢀCD also afforded the reaction of 4ꢀbromobenzoic acid and phenylboronic acid with
product in good yields (94% ꢀ 98%), but only when the volume and without stabilizer.a
β
Entry Stabilizer Stabilizer/Aryl Yield for each recycling step (%)b
ratio of H2O/CH3OH was below 3. Interestingly, when the
volume ratio of H2O/CH3OH was higher than 3, the yields
dropped to around 50% because of poor aqueous solubility of
the catalyst. When the volume ratio of H2O/CH3OH was in the
range 0.5ꢀ2, the Pd(II) complex either dissolved or was well
bromide
(mol/mol)
ꢀ
Step Step Step Step Step
0
1
2
3
4
1
2
3
4
5
6
ꢀ
100
100
59.4 21.9 15.1 9.0
62.4 32.8 21.4 18.8
TBAB
TBAB
TBAB
TBAB
TBAB
NaBr
0.1
0.15
0.20
0.25
1.0
83.0 100
77.5 53.0 20.6
dispersed in the reaction medium, even in the absence of dm
CD. Therefore the yields in both cases (i.e. with and without
dm ꢀCD) were similar. When the volume ratio of H2O/CH3OH
was 3, the Pd(II) complex was kept soluble in the reaction
medium by the dm ꢀCD. However, when dm ꢀCD was absent,
βꢀ
69.2 92.2 69.7 52.4 15.6
69.7 81.1 49.8 35.0 15.5
β
8.4
100
25.6 15.4 18.7 14.6
43.0 19.0 11.8 11.5
7
1.0
a
β
β
Reaction conditions: 4ꢀbromobenzoic acid (1.0 equiv., 0.125 mol/L),
phenylboronic acid (1.2 equiv.), initial catalyst loading (0.5 mol%, for step
0), pH (11.0, at the beginning of each step), room temperature for 2 h in air in
the Pd(II) complex dissolved poorly resulting in a lower yield
(around 86%) and this was exacerbated by increasing the
volume ratio of H2O/CH3OH to 4 and 5 (yield around 50%).
waterꢀMeOH (3:1, v/v).
1
b Yields were determined by H NMR analysis in
d6ꢀacetone using an
internal standard (dodecane) and calculated using a product calibration
plot with R2 = 0.998 (see Supporting Information).
a, with dm
b, without dm
β
-CD
-CD
β
The SuzukiꢀMiyaura coupling reaction of 4ꢀbromobenzoic acid
and phenylboronic acid in waterꢀMeOH was quantitative after 2
h (Table 3, entry 1). However, this high catalytic activity was
not maintained using the recycled catalyst. The yield dropped to
ca. 60% at the first recycle (i.e. step 1) and was less than 10%
by the 4th recycling step. Palladium black was observed in these
reactions, thus suggesting catalyst decomposition.
100
80
60
40
20
Pd(0) intermediates are the catalytically active species in
SuzukiꢀMiyaura cross coupling reactions.52ꢀ54 Catalyst
decomposition to form palladium black is also frequently
observed. This phenomenon is usually explained by assuming
that the oxidative addition step which starts the catalytic cycle
is in competition with an illꢀdefined sequence of reactions
leading to palladium nanoparticles (Pd–NPs) that eventually
aggregate irreversibly to form larger, catalytically inactive,
palladium metal particles (palladium black).55 Obviously a low
conversion will result if the aggregation is faster than the cross
coupling. Catalyst decomposition also hampers recycling. A
simple and effective approach to prevent the catalyst from
losing activity is to use quaternary ammonium salts which
stabilize Pd–NPs and slow the aggregation process.56ꢀ58
Stabilization of Pd–NPs can increase the catalytic activity
because dispersible Pd–NPs are themselves active catalysts57 or
act as a reservoir of soluble, catalytically active Pd(0).59, 60 Both
the cation and anion of ammonium salt play a combined role in
stabilizing Pd–NPs, the anion being coordinated to the
electrophilic metal nanoparticles with the cation surrounding
the negativelyꢀcharged anionꢀmetal sphere.55
In our work, a suitable amount of tetrabutylammonium bromide
(TBAB) was found to be effective to stabilize the catalyst
against decomposition and made recycling feasible.
Experiments carried out using different TBAB/4ꢀbromobenzoic
acid molar ratios showed that the catalytic performance for
each recycling step increased significantly with increasing the
stabilizer until a maximum was reached at the TBAB/4ꢀ
bromobenzoic acid molar ratio of 0.15:1 (Table 3, entries 2ꢀ6).
When higher amounts of stabilizer were used, the substrate
conversion decreased. When TBAB in recycling reaction 1 was
0
1
2
3
4
5
Volume ratio of H2O/CH3OH (v/v)
Figure 4. Comparison of SuzukiꢀMiyaura coupling performed
in various proportions of H2O and CH3OH, with and without
dmβꢀCD (conditions: room temperature, 2 h in air). Each point
represents the mean value ± SD of 2 runs.
Recycling of the catalyst
High precious metal prices and toxicity make recycling of the
Pd catalyst attractive from an economic and environmental
perspective. Recycling experiments were performed using the
standard SuzukiꢀMiyaura coupling reaction of 4ꢀbromobenzoic
acid and phenylboronic acid in waterꢀMeOH (3:1, v/v). The
coupling product was easily isolated by centrifugation. The
aqueous filtrate was recovered and investigated for its ability to
catalyze the reaction of freshly added substrates (Table 3).
It has been reported that pH strongly influences catalyst activity
for SuzukiꢀMiyaura cross coupling reactions conducted in
aqueous media50 and that a pH of around 11 is optimal.50, 51
In this work, the pH value of the original reaction mixture was
measured to be ca. 11.0 at the beginning of the coupling
reaction. However, by the end of the reaction, the pH value of
the recycled filtrate dropped to be ca. 10.0 and then ca. 9.0 after
the second reaction. Therefore, the pH of the reaction mixture
was adjusted back to 11.0 with dilute aqueous NaOH before
each recycling experiment.
increased from 0 to 0.15 equiv., the yield increased from ca
60% (entry 1) to 100% (entry 3). When the TBAB was further
increased to 0.25 equiv., the yield decreased from 100% to ca
.
.
80% (entry 5) and to ca. 25% when 1.0 equivalents of TBAB
were employed (entry 6). No catalyst decomposition was
observed in these TBAB stabilized reactions. These results
indicate that the optimal molar ratio of TBAB to substrate was
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0.15 and that high loadings of TBAB actually inhibited the [2M+Na]+ = 784(30). Anal. Calcd for C23H35N5: C, 72.40; H,
reaction, presumably at the oxidative addition step. By contrast, 9.25; N, 18.35. Found: C, 72.35; H, 8.38; N, 18.12.
NaBr did not stabilize the catalyst and slight inhibition was
observed (entry 7).
Synthesis of adamantyl-containing Pd(II) complex (Ad-L-
PdCl2)
2h
5h
24h
100
80
60
40
20
0
PdCl2(NCCH3)2 was synthesized following
a
literature
procedure.61 A suspension of PdCl2 (1.00 g, 5.65 mmol) was
heated under reflux in CH3CN (50 mL) with vigorous stirring
for 10 h under N2. The resultant wineꢀred colored solution was
o
cooled for 16 h at 4 C and a yellowꢀorange solid was filtered,
washed with Et2O and dried in vacuo at room temperature.
Solutions of PdCl2(NCCH3)2 (0.070 g, 0.27 mmol) in dry
CH2Cl2 (10 mL) and AdꢀL (0.103 g, 0.27 mmol) in dry CH2Cl2
(5 mL) were mixed and stirred at room temperature for 12 h62
and then concentrated under vacuum. Et2O (5 mL) was added
to induce precipitation. A yellowꢀorange solid was obtained,
washed with Et2O, and dried under vacuum. The product was
crystallized from a CH2Cl2/Et2O mixture to give bright orange
1
2
3
4
5
Step 1
Step 0
Step 2
Step 3
Step 4
Catalytic run
Figure 5. Variation of yield with increasing reaction time in
catalyst recycling experiments; 4ꢀbromobenzoic acid (1.0
equiv., 0.125 mol/L), phenylboronic acid (1.2 equiv.), initial
catalyst loading (0.5 mol%, for step 0), TBAB (0.15 equiv.), pH
(11.0, at the beginning of each step), room temperature, air,
waterꢀmethanol (3:1, v/v). Each point represents the mean value
± SD of 2 runs.
1
crystals (0.14 g, yield 92%). H NMR (500 MHz, CDCl3): 1.64
(s, 6H, Ad –CH2ꢀ), 1.70 (d, 3H,
(d, 3H, = 11.9 Hz, Ad –CHH’ꢀ), 2.07 (s, 3H, Ad –C
(s, 2H, AdꢀCH2ꢀNꢀ), 2.36 (s, 6H, PzꢀCH3), 2.78 (s, 6H, Pzꢀ
J
= 18.9 Hz, Ad –C
H
H’ꢀ), 1.78
J
H
), 2.14
C
H3), 5.23 (d, 2H,
), 7.11 (d, 2H,
(ppm) 13.6 (Pz
), 37.4 (Ad H2), 41.8 (Ad
H2ꢀNꢀ), 70.7 (Nꢀ H2ꢀPz), 108.8 (Pzꢀ H), 143.7 (Pz C
J
J
= 15.1 Hz, PzꢀC
= 15.7 Hz, PzꢀCHH’ꢀNꢀ). 13C NMR (125
H3), 15.8 (Pz H3), 28.8 (Ad
H), 57.6 (Ad ꢀ
), 151.9
HH’ꢀNꢀ), 5.87 (s, 2H, Pz
CH
MHz, CDCl3):
δ
C
C
C
CH2), 37.2 (Ad
C
C
Although 0.15 equiv. of TBAB significantly enhanced the
catalytic performance in subsequent recycling steps (Table 3,
entry 3, step 1ꢀ4), this was not the case for the initial run (Table
3, entry 3, step 0). The yield for this step was quantitative
without stabilizer and approximately 80% with stabilizer. It is
possible that the higher stability gained from the TBAB
stabilization leads to longer catalytic induction period. Further,
a series of catalytic reactions and recycling experiments was
carried out for 5 h and 24 h, and compared with those
performed at 2h in the presence of 0.15 equiv. of TBAB (Figure
5). At a reaction time of 5 h (red bars), the aqueous solution
with supramolecular catalyst can be recycled and reused twice
before the yield dropped to below 90% and three times for a
reaction time of 24 h (blue bars).
C
(Pz
C
C
C
). ESIꢀMS (in CH2Cl2, m/z(%)): [M−Cl]+ = 524(100),
[M+Na]+ = 576(20). Anal. Calcd for C23H35Cl2N5Pd: C, 49.43;
H, 6.31; N, 12.53. Found: C, 48.66; H, 5.71; N, 11.91.
Measurements and Experimental Methods
General procedure for Suzuki-Miyaura coupling reaction.
(Method 1) Palladium (II) complex (AdꢀLꢀPdCl2) (1.4 mg, 0.0025
mmol) was dissolved in 0.5 mL of MeOH and 0.03 mL of acetone in
a clean vial with stirring at 40 oC until a bright yellow solution
resulted. The acetone assists complete dissolution of the complex.
This solution was then added dropwise to dmβꢀCD (3.5 mg, 0.0025
mmol) in deionized water (1.5 ml) with stirring at room temperature.
A clear, bright yellow solution (2 ml) was formed. 4ꢀBromobenzoic
acid (0.101 g, 0.5 mmol), phenylboronic acid (0.073 g, 0.6 mmol),
and Na2CO3 (0.127 g, 1.2 mmol) were dissolved in 2 ml of waterꢀ
methanol (3:1, v/v) with stirring at room temperature until a clear,
pale yellow solution was formed. The catalyst solution and substrate
solution were mixed together and stirred at room temperature. After
the required time had elapsed, the reaction mixture was neutralized
with dilute, aqueous HCl. The resulting white precipitate was
filtered, washed with water and dried under vacuum at 50 oC.
(Method 2) Palladium (II) complex (AdꢀLꢀPdCl2) (1.4 mg, 0.0025
mmol) was dissolved in 1.0 mL of methanol and 0.03 mL of acetone
Experimental
Synthesis of bis[(3,5-dimethyl-1H-pyrazolyl)methyl][(1-
adamantyl)methyl] amine (Ad-L)
The synthesis of AdꢀL was modified from a previous report by
our group.28 (3,5ꢀDimethylꢀ1Hꢀpyrazolyl)methanol (0.252 g, 2
mmol) was dissolved in anhydrous CH3CN (30 mL). 1ꢀ
Adamantanemethylamine (0.166 g, 1 mmol) was added and the
solution stirred in a closed vessel for 24 h at room temperature.
The solvent was removed under reduced pressure and the
resultant white solid reꢀdissolved in 10 mL of nꢀhexane, filtered
o
with stirring at 40 C until a bright yellow solution resulted. This
solution was then added dropwise to dmβꢀCD (3.5 mg, 0.0025
mmol) in deionized water (3.0 ml) with stirring at room temperature.
Then 4ꢀbromobenzoic acid (0.101 g, 0.5 mmol) and Na2CO3 (0.127
g, 1.2 mmol) were added with stirring until a clear, pale yellow
solution was formed. Phenylboronic acid (0.073 g, 0.6 mmol) was
added and the reaction mixture was stirred for the prescribed time at
room temperature before being neutralized with dilute aqueous HCl.
The white precipitate was separated by filtration, washed with water
and dried under vacuum at 50 oC.
o
and the clear solution cooled overnight at 4 C, yielding white
crystals (0.26 g, yield 68%). H NMR (300 MHz, CDCl3): 1.21
1
(s, 6H, Ad –CH2ꢀ), 1.54 (d, 3H,
(d, 3H, = 12.3 Hz, Ad –CHH’ꢀ), 1.84 (s, 3H, Ad –C
(s, 6H, PzꢀCH3), 2.27 (s, 6H, PzꢀCH3), 2.37 (s, 2H, AdꢀCH2ꢀNꢀ
), 4.91 (s, 4H, PzꢀCH2ꢀNꢀ), 5.79 (s, 2H, Pz C
). 13C NMR (75.5
MHz, CDCl3): (ppm) 12.1 (Pz H3), 14.2 (Pz H3), 29.1 (Ad
), 37.7 (Ad H2), 41.1 (Ad H), 62.2 (Ad ꢀ
H2ꢀNꢀ), 69.0 (Nꢀ H2ꢀPz), 106.3 (Pz H), 140.2 (Pz ), 147.9
). ESIꢀMS (in CH2Cl2, m/z(%)): [M+H]+ = 381(100),
J
=16.3 Hz, Ad –C
H
H’ꢀ), 1.61
J
H
), 2.19
H
δ
C
C
C
C
C
(Pz
H2), 35.4 (Ad
C
C
Yield calculation for Suzuki-Miyaura coupling reaction. Yields
were calculated by 1H NMR spectroscopy based on the 4ꢀ
bromobenzoic acid used using hexadecane as an internal standard.
C
C
C
C
This journal is © The Royal Society of Chemistry 2012
J. Name., 2012, 00, 1-3 | 5

Page 7 of 8
ARTICLE
RSC Advances
VJieowuArrtnicalelONnlainme e
DOI: 10.1039/C4RA13953D
d School of Science, Monash University Malaysia, 47500 Bandar Sunway,
Selangor D.E., Malaysia
After the SuzukiꢀMiyaura coupling reaction, the reaction mixture
was neutralized with dilute aqueous HCl and a measured amount of
hexadecane (usually 14 mg) in ethyl acetate (4 mL) was added. The
organic phase was separated, and the reaction mixture extracted with
fresh ethyl acetate (3×3 mL). The organic extracts were combined,
washed twice with water (5 mL), dried over anhydrous Na2SO4 and a
0.9 mL aliquot was filtered, evaporated at room temperature and reꢀ
dissolved in deuterated solvent (acetoneꢀd6). The yield of the product
was calculated from a calibration curve (Figure S2, R2 = 0.998).
Catalyst recycling. After a standard SuzukiꢀMiyaura coupling
reaction of 4ꢀbromobenzoic acid and phenylboronic acid in
waterꢀmethanol (3:1, v/v), the white coupling product was
isolated by centrifugation (6000 rpm, r.t.). The clear filtrate was
transferred to a clean vial, and measured amounts of fresh
substrate were added with stirring at room temperature. The pH
was adjusted to 11.0 using dilute aqueous NaOH. After the
required time had elapsed, the white coupling product was
isolated by centrifugation, and the clear filtrate was recycled
and reused for the next coupling reaction.
Email: david.james.young@monash.edu
Telephone: (+603) 5514 5674 (Prof. D. J. Young)
†Electronic Supplementary Information (ESI) available: General
measurement and experimental methods; A table of single crystal data
and structure refinement parameters for adamantylꢀcontaining Pd(II)
complex (AdꢀLꢀPdCl2); 1H NMR spectra of AdꢀL and AdꢀLꢀPdCl2;
1
Calibration curve based on H NMR analysis for the yield calculation for
SuzukiꢀMiyaura coupling reaction. CCDC Deposition Number (CCDC
1031688). See DOI: 10.1039/b000000x/
1.
2.
3.
R. A. Sheldon, Chemical Society Reviews, 2012, 41, 1437ꢀ1451.
G. Centi and S. Perathoner, Catalysis Today, 2003, 77, 287ꢀ297.
P. T. Anastas, T. C. Williamson, D. Hjeresen and J. J. Breen,
Environmental Science & Technology, 1999, 33, 116Aꢀ119A.
P. T. Anastas and J. C. Warner, Green Chemistry: Theory and
Practice, Oxford University Press, Oxford, 1998.
M.ꢀO. Simon and C.ꢀJ. Li, Chemical Society Reviews, 2012, 41,
1415ꢀ1427.
4.
5.
6.
Conclusions
A key catalytic design in this system is the incorporation of an
adamantyl tether onto the ligand backbone that does not 7.
interfere with the catalytic process but activating its inclusion
property to capture a βꢀcyclodextrin moiety and uses that to
C. J. Li, Chemical Reviews, 2005, 105, 3095ꢀ3165.
V. Polshettiwar, A. Decottignies, C. Len and A. Fihri,
Chemsuschem, 2010, 3, 502ꢀ522.
8.
R. A. Sheldon, I. Arends, G. J. Ten Brink and A. Dijksman,
Accounts of Chemical Research, 2002, 35, 774ꢀ781.
K. H. Shaughnessy, Chemical Reviews, 2009, 109, 643ꢀ710.
J. Szejtli, Chemical Reviews, 1998, 98, 1743ꢀ1753.
G. Wenz, B.ꢀH. Han and A. Muller, Chem. Rev., 2006, 106, 782ꢀ
817.
solubilise the entire supramolecular hybrid in an aqueous or
aqueousꢀorganic mixed media. The main challenge in this
design is the chemical and thermal stability of the
supramolecular hybrid catalysts and, very importantly,
introduction of the inclusion pair (adamantyl and cyclodextrin
here) must not infringe with the catalytic site thereby hurting
the catalytic efficacy. The crystal and molecular structure of the
adamantylꢀtethered complex reported herein gives clear
evidence that the bulky pendant is pointing away from the
metal center and that its introduction does not interfere with the
coordination sphere of the Pd(II). It also does not impose
undesirable bonding of the amine with the metal, which has
been witnessed in other functional hybrid ligand systems.28
Encouraged by these results, we are actively applying this
simple yet powerful design to a range of other metal catalysts
and catalytic reactions.
9.
10.
11.
12.
F. Hapiot, S. Tilloy and E. Monflier, Chem. Rev., 2006, 106, 767ꢀ
781.
13.
14.
15.
16.
A. Douhal, Chem. Rev., 2004, 104, 1955ꢀ1976.
A. Harada, Accounts of Chemical Research, 2001, 34, 456ꢀ464.
M. V. Rekharsky and Y. Inoue, Chem. Rev., 1998, 98, 1875ꢀ1918.
S. A. Nepogodiev and J. F. Stoddart, Chem. Rev., 1998, 98, 1959ꢀ
1976.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
J. Li and X. J. Loh, Advanced Drug Delivery Reviews, 2008, 60,
1000ꢀ1017.
M. E. Davis and M. E. Brewster, Nat. Rev. Drug Discov., 2004, 3,
1023ꢀ1035.
K. Uekama, F. Hirayama and T. Irie, Chem. Rev., 1998, 98, 2045ꢀ
2076.
D. W. Armstrong, T. J. Ward, R. D. Armstrong and T. E. Beesley,
Science, 1986, 232, 1132ꢀ1135.
B. L. Zhang and R. Breslow, Journal of the American Chemical
Society, 1997, 119, 1676ꢀ1681.
Acknowledgements
M. T. Reetz and S. R. Waldvogel, Angewandte Chemieꢀ
International Edition in English, 1997, 36, 865ꢀ867.
E. Monflier, E. Blouet, Y. Barbaux and A. Mortreux, Angewandte
ChemieꢀInternational Edition in English, 1994, 33, 2100ꢀ2102.
Z.ꢀX. Zhang, K. L. Liu and J. Li, Angewandte Chemieꢀ
International Edition, 2013, 52, 6180ꢀ6184.
J.ꢀL. Zhu, K. L. Liu, Z. Zhang, X.ꢀZ. Zhang and J. Li, Chemical
Communications, 2011, 47, 12849ꢀ12851.
Z.ꢀX. Zhang, K. L. Liu and J. Li, Macromolecules, 2011, 44,
1182ꢀ1193.
Z.ꢀX. Zhang, X. Liu, F. J. Xu, X. J. Loh, E.ꢀT. Kang, K.ꢀG. Neoh
and J. Li, Macromolecules, 2008, 41, 5967ꢀ5970.
F. Xue, J. Zhao and T. S. A. Hor, Dalton Transactions, 2011, 40,
8935ꢀ8940.
R. Mathieu, G. Esquius, N. Lugan, J. Pons and J. Ros, Eur. J.
Inorg. Chem., 2001, 2683ꢀ2688.
P. Braunstein and F. Naud, Angewandte ChemieꢀInternational
Edition, 2001, 40, 680ꢀ699.
Z. Weng, S. Teo and T. S. A. Hor, Accounts of Chemical
Research, 2007, 40, 676ꢀ684.
This work was supported by EDB (Singapore)ꢀGSK
(GlaxoSmithKline) (Grant ID: R143ꢀ000492ꢀ592) and Institute
of Materials Research and Engineering (IMRE), A*STAR
(Agency for Science, Technology and Research), Singapore.
Notes and references
a
Institute of Materials Research and Engineering, A*STAR (Agency for
Science, Technology and Research), 3 Research Link, Singapore 117602,
Republic of Singapore
Email: andyhor@imre.aꢀstar.edu.sg; zhangzx@imre.aꢀstar.edu.sg
Telephone: +65ꢀ68744341 (Prof. T. S. A. Hor)
b
Department of Chemistry, Faculty of Science, National University of
Singapore, 3 Science, Drive 3, Singapore, 117543
Email: andyhor@nus.edu.sg
c
Faculty of Science, Universiti Brunei Darussalam, Jalan Tungku Link,
Gadong BE1410, Brunei Darussalam
A. Boixassa, J. Pons, X. Solans, M. FontꢀBardia and J. Ros,
Inorganica Chimica Acta, 2003, 346, 151ꢀ157.
6 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 2012

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DOI: 10.1039/C4RA13953D
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
J. GarciaꢀAnton, J. Pons, X. Solans, M. FontꢀBardia and J. Ros,
Eur. J. Inorg. Chem., 2002, 3319ꢀ3327.
A. John, M. M. Shaikh, R. J. Butcher and P. Ghosh, Dalton
Transactions, 2010, 39, 7353ꢀ7363.
R. S. Rowland and R. Taylor, Journal of Physical Chemistry,
1996, 100, 7384ꢀ7391.
M. V. Rekharsky and Y. Inoue, Chemical Reviews, 1998, 98,
1875ꢀ1918.
M. Weickenmeier and G. Wenz, Macromolecular Rapid
Communications, 1996, 17, 731ꢀ736.
R. I. Gelb, L. M. Schwartz and D. A. Laufer, Journal of the
Chemical Society, Perkin Transactions 2, 1984, 15ꢀ21.
Y. Hasegawa, M. Miyauchi, Y. Takashima, H. Yamaguchi and A.
Harada, Macromolecules, 2005, 38, 3724ꢀ3730.
T. Hanazawa, A. Koyama, T. Wada, E. Morishige, S. Okamoto
and F. Sato, Organic Letters, 2003, 5, 523ꢀ525.
N. Miyaura and A. Suzuki, Chemical Reviews, 1995, 95, 2457ꢀ
2483.
F. Li and T. S. A. Hor, Advanced Synthesis & Catalysis, 2008,
350, 2391ꢀ2400.
S.ꢀQ. Bai and T. S. A. Hor, Chemical Communications, 2008,
3172ꢀ3174.
G. Herve, G. Sartori, G. Enderlin, G. Mackenzie and C. Len, Rsc
Advances, 2014, 4, 18558ꢀ18594.
J. Tauchman, I. Cisarova and P. Stepnicka, Organometallics,
2009, 28, 3288ꢀ3302.
D. Dallinger and C. O. Kappe, Chemical Reviews, 2007, 107,
2563ꢀ2591.
47.
48.
N. E. Leadbeater, Chemical Communications, 2005, 2881ꢀ2902.
R. Franzen and Y. J. Xu, Canadian Journal of ChemistryꢀRevue
Canadienne De Chimie, 2005, 83, 266ꢀ272.
49.
50.
51.
C. Capello, U. Fischer and K. Hungerbuhler, Green Chemistry,
2007, 9, 927ꢀ934.
S. Ogo, Y. Takebe, K. Uehara, T. Yamazaki, H. Nakai, Y.
Watanabe and S. Fukuzumi, Organometallics, 2006, 25, 331ꢀ338.
A. N. Marziale, D. Jantke, S. H. Faul, T. Reiner, E. Herdtweck
and J. Eppinger, Green Chemistry, 2011, 13, 169ꢀ177.
G. C. Fu, Accounts of Chemical Research, 2008, 41, 1555ꢀ1564.
C. C. C. Johansson Seechurn, M. O. Kitching, T. J. Colacot and
V. Snieckus, Angewandte Chemie International Edition, 2012, 51,
5062ꢀ5085.
52.
53.
54.
55.
A. Suzuki, Angewandte Chemie International Edition, 2011, 50,
6722ꢀ6737.
E. Amadio, A. Scrivanti, M. Bortoluzzi, M. Bertoldini, V.
Beghetto, U. Matteoli and G. Chessa, Inorganica Chimica Acta,
2013, 405, 188ꢀ195.
56.
H. Bonnemann, G. Braun, W. Brijoux, R. Brinkmann, A. S.
Tilling, K. Seevogel and K. Siepen, Journal of Organometallic
Chemistry, 1996, 520, 143ꢀ162.
57.
58.
59.
60.
61.
62.
L. S. Ott and R. G. Finke, Coordination Chemistry Reviews, 2007,
251, 1075ꢀ1100.
M. T. Reetz and W. Helbig, Journal of the American Chemical
Society, 1994, 116, 7401ꢀ7402.
V. P. Ananikov and I. P. Beletskaya, Organometallics, 2012, 31,
1595ꢀ1604.
I. W. Davies, L. Matty, D. L. Hughes and P. J. Reider, Journal of
the American Chemical Society, 2001, 123, 10139ꢀ10140.
M. S. Kharasch, R. C. Seyler and F. R. Mayo, Journal of the
American Chemical Society, 1938, 60, 882ꢀ884.
A. Panella, J. Pons, J. GarciaꢀAnton, X. Solans, M. FontꢀBardia
and J. Ros, Eur. J. Inorg. Chem., 2006, 1678ꢀ1685.
This journal is © The Royal Society of Chemistry 2012
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