Picolinamide modified β-cyclodextrin/Pd (II) complex: Asupramolecular catalyst for Suzuki-Miyaura coupling of aryl, benzyl and allyl halides with arylboronic acids in water

Article abstract of DOI:10.1016/j.carbpol.2018.07.089

Novel supramolecular catalysts for Suzuki-Miyaura coupling were prepared and characterized by NMR, FT-IR, TEM, XRD, TGA, and XPS. The resulting picolinamide-modified β-cyclodextrin/Pd(II) complex (Pd(II)@PCA-β-CD) showed very efficient catalytic activity for Suzuki-Miyaura coupling of aryl, benzyl, and allyl halides with arylboronic acids in an environmentally benign aqueous solution. Various organic halides including chlorides can produce good to excellent yields with phenyl-boronic acid and a catalytic amount of Pd(II)@PCA-β-CD. This hydro-soluble catalyst was capable of being reused for at least eight runs with only a slight loss of catalytic activity. A putative mechanism of the Pd(II)/Pd(IV) catalytic cycle was also explored and calculated by ab initio QM/MM methods.

Full text of DOI:10.1016/j.carbpol.2018.07.089

Accepted Manuscript
Title: Picolinamide modified ␤-cyclodextrin/Pd (II) complex:
a supramolecular catalyst for Suzuki-Miyaura coupling of
aryl, benzyl and allyl halides with arylboronic acids in water
Authors: Kaixiu Luo, Lu Zhang, Rui Yang, Yi Jin, Jun Lin
PII:
S0144-8617(18)30881-6
DOI:
Reference:
https://doi.org/10.1016/j.carbpol.2018.07.089
CARP 13889
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Received date:
Revised date:
Accepted date:
16-4-2018
23-7-2018
28-7-2018
Please cite this article as: Luo K, Zhang L, Yang R, Jin Y, Lin J, Picolinamide modified
␤-cyclodextrin/Pd (II) complex: a supramolecular catalyst for Suzuki-Miyaura coupling
of aryl, benzyl and allyl halides with arylboronic acids in water, Carbohydrate Polymers
(2018), https://doi.org/10.1016/j.carbpol.2018.07.089
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Picolinamide modified β-cyclodextrin/Pd (II)
complex: a supramolecular catalyst for
Suzuki-Miyaura coupling of aryl, benzyl
and allyl halides with arylboronic acids in
water
Kaixiu Luoa, Lu Zhanga, Rui Yang*b, Yi Jin*a and Jun Lin*a
a Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education
and Yunnan Province, School of Chemical Science and Technology, Yunnan
University, Kunming, 650091, P. R. China.
b
Faculty of Science, Kunming University of Science and Technology, Kunming,
650500, P. R. China
*E-mail: jinyi@ynu.edu.cn, yangrui911@163.com, linjun@ynu.edu.cn.
1

Highlights
 A novel series of supramolecular catalysts were prepared and
characterized by NMR, FT-IR, TEM, XRD, TGA, and XPS.
 The picolinamide-modified β-cyclodextrin/Pd(II) complex showed very
efficient catalytic activity for Suzuki-Miyaura coupling of aryl, benzyl,
and allyl halides with arylboronic acids in an environmentally benign
aqueous solution.
 A proposed mechanism of the Pd(II)/Pd(IV) catalytic cycle was explored
and calculated by ab initio QM/MM methods.
 This hydrosoluble catalyst can be reused several times without a
significant loss of activity.
2

Abstract
Novel supramolecular catalysts for Suzuki-Miyaura coupling were prepared and
characterized by NMR, FT-IR, TEM, XRD, TGA, and XPS. The resulting
picolinamide-modified β-cyclodextrin/Pd(II) complex (Pd(II)@PCA-β-CD) showed
very efficient catalytic activity for Suzuki-Miyaura coupling of aryl, benzyl, and allyl
halides with arylboronic acids in an environmentally benign aqueous solution.
Various organic halides including chlorides can produce good to excellent yields with
phenyl-boronic acid and a catalytic amount of Pd(II)@PCA-β-CD. This hydro-soluble
catalyst was capable of being reused for at least eight runs with only a slight loss of
catalytic activity. A putative mechanism of the Pd(II)/Pd(IV) catalytic cycle was also
explored and calculated by ab initio QM/MM methods.
Keywords: β-cyclodextrin/Pd (II) complex; supramolecular catalyst; Suzuki-Miyaura
coupling; eco-friendly.
3

1 Introduction
There has been great interest in developing novel water-soluble catalysts for
greener synthetic methods and chemical processes (Descorme, Gallezot, Geantet, &
George, 2012; La Sorella, Strukul, & Scarso, 2015; Li & Trost, 2008). Cyclodextrins
(CDs) have been exploited to elaborate aqueous biphasic catalytic systems that
allowed conversion of hydrophobic substrates using water-soluble organometallic
catalysts (Floresta et al., 2017; Ghatak, Khan, & Bhar, 2016; Gong, Wang, Ren,
Wang, & Chen, 2015; Frédéric Hapiot et al., 2017). With their hydrophobic cavity,
cyclodextrins selectively bind substrates and catalyze chemical reactions through the
formation of host-guest complexes via noncovalent interactions (Bai, Tian, Zhao,
Huang, & Wang, 2017; Hapiot, Bricout, Menuel, Tilloy, & Monflier, 2014).
CD-based supramolecular catalysts currently are being widely developed, but only a
few palladium complexes with modified CDs as catalysts (Figure 1A) have been
reported to be applied in C-C formation in aqueous solution, such as Suzuki-Miyaura,
Sonogashira, and Heck cross-coupling reactions (Cintas, Cravotto, Gaudino, Orio, &
Boffa, 2012; Kaboudin, Salemi, Mostafalu, Kazemi, & Yokomatsu, 2016; Kairouz &
Schmitzer, 2014; Khan & Pitchumani, 2016; Sollogoub, 2013; Zhang et al., 2013). A
critical setback for these catalytic systems is difficulty with synthesis or purification,
long reaction times, and low recyclability of the catalyst. Thereby, more versatile
4

CD-based supramolecular catalysts should be developed to achieve efficient metal
complexes, allowing for the improvement of catalytic activities.
Palladium-catalyzed Suzuki-Miyaura cross-coupling reactions are currently one of
the most important C-C bond-forming processes (Chatterjee & Ward, 2016; Hussain,
Capricho, & Yawer, 2016; Kumbhar, 2017; Martina, Manzoli, Gaudino, & Cravotto,
2017). Many types of homogeneous and heterogeneous catalysts have been used for
Suzuki-Miyaura coupling reactions, such as homogeneous palladium complexes with
phosphine (Hu, Qu, Gerlach, & Shaughnessy, 2017), N-heterocyclic carbene (Guitet
et al., 2013; Legrand, Menand, Sollogoub, Tilloy, & Monflier, 2011; Froese,
Lombardi, Pompeo, Rucker, & Organ, 2017), quinoline (Cui et al., 2007), oxazolones
(Lee, 2006), pyridines (Huang et al., 2012), imidazoles (Deng, Zhang, Zhu, & Tu,
2017), etc., and heterogeneous palladium immobilized on various supports, e.g.
carbon (Lee et al., 2017), silica (Shabbir et al., 2017), hydroxyapatites (Indra,
Gopinath, Bhaduri, & Kumar Lahiri, 2013). However, there are many shortcomings in
these catalytic systems, such as toxicity, high cost, air and thermal sensitivity, high
catalyst loadings, and contamination of products, making their application less
practical. Therefore, to overcome these problems, Engle and Yu reported a method of
ligand design in transition-metal catalysis for Pd(II)-catalyzed C-X (X=halide, C, H)
functionalization (Engle & Yu, 2013). The stability and activity of Pd complexes are
highly dependent on the characteristics of Pd complexation by ligands, i.e., the proper
geometry at the metal center. Hence, it is very important to select the proper ligands
for successful catalytic applications of metals.
5

Recently, picolinamide derivatives as bidentate ligands have been successfully
employed in C-C bond formation, such as the alkylation of γ-C(sp3)-H bonds
catalyzed by a picolinamide was reported by Zhang and Chen for (Zhang et al., 2013).
Additionally, Liu and Zhang developed an unprecedented picolinamide-directed
coupling of C(sp2)-H and C(sp2)-H to obtain quinoline and pyridone derivatives
(Zhang et al., 2015). Picolinamide complexes with palladium also employed as
catalyst for Ullmann-type C-N coupling reactions (Damkaci, Alawaed, & Vik, 2016).
According to the literature, the X-ray structure of Pd(II) with picolinamide indicates
that it acts as a bidentate chelating ligand and is bound through both the pyridyl-N and
amido-O atoms to the Pd(II) center. Further quantum chemical studies suggest that a
combination of steric hindrance of the ligand and the electronic effect of metal ions
may modulate the coordination preferences (Das et al., 2017). These results indicate
that picolinamide-modified CDs complexes with palladium can be used as a novel
catalyst for the Suzuki-Miyaura C-C bond-coupling reaction.
Herein, based on the unique features of picolinamide and CDs, in this article we
report three novel picolinamide-modified β-cyclodextrins as water-soluble ligands of
supramolecular catalyst (Figure 1B). We also hypothesize that the proper steric
hindrance effect of CDs could enhance the universality and activity of
Suzuki-Miyaura coupling reaction in various substrates such as aryl, benzyl and allyl
halides. Meanwhile, a possible reaction mechanism involving the Pd(II)/Pd(IV)
centers is proposed based on experimental methods and quantum chemical calculation.
The synthesized picolinamide-modified cyclodextrin/Pd(II) complexes are
6

water-soluble and exhibit efficient catalytic activity in Suzuki-Miyaura coupling of
aryl, benzyl, and allyl halides with arylboronic acids. Moreover, excellent
recyclability of the catalyst makes it potentially applicable in practice. The obtained
results are discussed below.
Figure 1. Modified -cyclodextrins for the Suzuki-Miyaura coupling reaction.
2 Experimental section
2.1 Reagents and Instrumentation
7

All chemicals and reagents were of commercial grade, and were used without any
further purification unless otherwise noted. The reactions were monitored by thin
layer chromatography (TLC) using silica gel GF254. Column chromatography was
performed with 200-300 mesh silica gel. All yields refer to isolated products after
purification unless otherwise noted. The NMR spectra were recorded on a Bruker
13
13
DRX-400 (1H: 400 MHz, C: 105 MHz), DRX-500 (1H: 500 MHz, C: 125 MHz)
and DRX-600 (1H: 600 MHz, 13C: 150 MHz) using CDCl3, D2O and DMSO-d6 as
solvents. Chemical shifts (δ) are expressed in parts per million (ppm) and J values are
given in hertz (Hz). IR spectra were recorded on an FT-IR Thermo Nicolet Avatar
360 using a KBr pellet. HRMS was performed on an Agilent LC/MSD TOF
instrument. X-ray powder diffraction (XRD) patterns were examined using Rigaku
D/max-2400 X-ray diffractometer (Cu Kα, λ=1.5406 Å, 40 kV, 200 mA). Chemical
characterization of the sample surface was recorded with X-ray photoelectron
spectroscopy (XPS ULVAC-PHI, Quantera). The charge effect was calibrated using
the binding energy of C 1s. The content of TiO2 nanoparticles in TGH hydrogels were
determined by TGA/DSC (Mettler Toledo TGA/DSC 1) in air with a heating rate of
o
10 C/min. HRTEM images were obtained with a JEM 2100F field emission gun
transmission electron microscope operated at an accelerating voltage of 200 kV.
2.2 Preparation of Catalysts
The detailed preparation for the picolinamide-modified β-cyclodextrin/Pd(II) complex
(Pd(II)@PCA-β-CD) is illustrated in Scheme 1. First, mono-6-tosyl β-cyclodextrin (1,
8

Tos-β-CD) was obtained by the method of Khan etc (Khan & Pitchumani, 2016).
Then, Tos-β-CD was reacted with NaN3 to form 6-monodeoxy-6-monoazido-β-CD (2,
N3-β-CD), which was further reduced by triphenylphosphine to give a key
intermediate: 6-monodeoxy-6-amino-β-CD (3). PCA-β-CD (4) was prepared by
condensation of PCA (2-pyridinecarboxylic acid) with NH2-β-CD using
N,N’-dicyclohexylcarbo-diimide (DCC) and 1-hydroxy-1H-benzotriazole (HOBt) in
N,N’-dimethylformamide (DMF). The synthesis of PCA-(CH2)nNH-β-CD (6) was
achieved in two simple steps: nucleophilic substitution (from 1 to 5) and amidation
(from 5 to 6). Finally, all the obtained ligands were stirred with Pd(OAc)2 at room
temperature for 24 hours in toluene, and the target complexes Pd(II)@PCA-β-CDs
(C1-C3) were obtained as light yellow powders. The water solubility of the 4, 6
ligands and C1, C2, C3 complexes in different temperatures were studied. The results
showed the complexes have high solubility in the aqueous solution (see Table 1S in
SI).
Scheme 1. Synthesis of Pd(II)@PCA-β-CDs.
Reaction conditions: (a) TsCl, NaOH, CH3CN, H2O, rt, 2 h, 15% yield; (b) NaN3, DMF, 80 oC, 12
o
h, 93% yield; (c) PPh3, DMF, rt, 10 h, 91% yield; (d) DCC, HOBt, DMF, 4 h at 0 C, 18 h at rt,
72-83% yield; (e) Pd(OAc)2, toluene, rt, 24 h, 60-70% yield; (f) diamine, 80 oC, 12 h, 30% yield.
9

2.3 General procedure for Suzuki coupling reaction.
Aryl, benzyl or allyl halides (1.0 mmol), arylboronic acid (1.2 mmol), K2CO3 (1.5
mmol), C1 (5 × 10−6 mol%) and H2O (2.0 mL) were added into a sealed tube and the
o
mixture was stirred at 60 C for a few hours. After the reaction, the aqueous phase
was extracted with ethyl acetate for 3 times (3×7 mL). Then the combined organic
layers were dried over anhydrous Na2SO4, concentrated under vacuum and purified by
column chromatography.
2.4 Computational methods
QM/MM calculations in water as solvent were used to investigate the energetics of
our proposed mechanism. The structure of molecules was divided into QM and MM
subsystems. For the QM subsystem, including the picolinamide, Pd(II)(OAc)2,
phenyl-boronic acid and 4-bromo-acetophenone moieties, was treated by the B3LYP
functional with 6-31+G(*) basis set for C, H, N, O, B, Br atoms and LanL2DZ with
relativistic effective core potentials for palladium. This B3LYP(SDD, 6-31 G*) level
of QM treatment has been previously tested and employed successfully to describe
metal coordination shell. Single point calculations were performed at the M06 level
with a mixed basis set of SDD for palladium and 6-311+G(*) for all other atoms. All
calculations were performed with Gaussian 09 program packages. All transition states
were confirmed by intrinsic reaction coordinate (IRC) toward a set of pre- and
postreaction complexes. Computed structures are displayed with CYLview.
3 Results and Discussion
3.1 Characterization of Catalysts
1
PCA-β-CD (4) and PCA-(CH2)2NH-β-CD (6) were confirmed by H nuclear
magnetic resonance (NMR), electrospray ionization-high resolution mass
spectrometry (ESI-HRMS), and Fourier transform infrared spectroscopy (FT-IR) (see
10

SI†, Figure 1S-6S). Pd(II)@PCA-β-CD (C1 and C2) were also characterized by
transmission electron microscopy (TEM) and electron-dispersive X-ray spectroscopy
(EDS). In addition, thermogravimetric analysis (TGA), X-ray diffraction (XRD), and
X-ray photoelectron spectroscopy (XPS) were used to study the presence of palladium
in the complex Pd(II)@PCA-β-CD.
From the ROESY NMR spectrum (two-dimensional rotating frame overhauser
effect spectroscopy) of C1 (Figure 2), obvious correlation peaks between the H atoms
in the pyridine ring and the H5 in the cavity of the β-CD can be observed. This result
confirmed the picolinamide moiety have been linked with β-CD. Additionally, clear
nuclear overhauser effect (NOE) interactions between the acetyl protons of the
Pd(OAc)2 and the H5 protons of β-CD were also observed. This illustrated that Pd(II)
have been complexed with PCA-β-CD. In order to speculate the possible structure of
C1, we propused an optimal conformation of C1 by molecular simulation (see ESI,
section 1.6).
11

Figure 2. 2D ROESY NMR spectrum of C1 in D2O (25 oC).
To explore the change from PCA-β-CD (4) to Pd(II)@PCA-β-CD (C1), the FT-IR
spectra of both of them are shown in Figure 9S (see S1†). For PCA-β-CD (4), a broad
band centered at 3416 cm−1 and 2926 cm−1 was assigned to –OH stretching vibration
and –CH2 asymmetric stretching vibration, respectively. And the bands at 1536 cm−1
and 1637 cm−1 can be attributed to the –NH and C=O bending vibrations of –NH–
CO–. As for catalyst C1, the –OH stretching of the complex, and vibration and –NH–
CO– vibration shift to 3397 and 1590 cm−1, respectively, indicates that Pd(II) has
successfully complexed with ligand (4).
The stability of the catalyst Pd(II)@PCA-β-CD (C1) and ligand PCA-β-CD (4) was
also investigated by TGA (see S1†, Figure 12S). For the C1, a sharp weight loss of
o
approximately 33% mainly occurred from 260 to 320 C, which is related to the
decomposition of the palladium complex. For the PCA-β-CD (4), a weight loss of
45% occurred at approximately 270 oC due to the heat decomposition of grafted CD.
The morphology and distribution of the synthesized catalyst C1 were further
characterized using high-resolution transmission electron microscopy (HRTEM). As
shown in Figure 3a, we found some metallic aggregate were existed, this might be
partial palladium(II) acetate were decomposed to Pd(0) metal clusters when preparing
C1. The lattice fringes of Pd were also detected and are shown in Figure 3b. The
interplanar distance was approximately 0.22 nm, which closely corresponds with the
(111) lattice plane of Pd. Then, the mapping image of the C1 shows that the
homogeneous distribution of Pd atoms is clearly observed in the supramolecular
12

ligand as demonstrated in Figure 3 (c–d). Moreover, the EDS spectrum exhibited the
presence of carbon, nitrogen, oxygen, and especially palladium in the structure of
catalyst C1, which confirmed that the catalyst was successfully prepared (see S1†,
Figure 13S).
Figure 3. HRTEM and Mapping of Pd(II)@PCA-β-CD (C1).
In order to obtain further insight into the changes from PCA-β-CD (4) to the
Pd(II)@PCA-β-CD (C1) complex, the XPS spectra of the catalyst and ligand were
obtained (Figure 4). In the C1, the binding energy of the doublet peaks at 337 eV and
343 eV was observed in Figure 4a, which can be attributed to Pd3d5/2 and Pd3d3/2 of
PdII, respectively. The sharp N peaks at 400 eV in Figure 4b (red curve) reveal the
presence of Pd(OAc)2 in the supramolecular ligand PCA-β-CD (4). Additionally, the
N1s binding energy was found to be higher compared to PCA-β-CD (4), and the
corresponding electron density of N-Pd in the C1 obviously increased. These results
further indicate that a coordinative conformation was formed between Pd(II) and
PCA-β-CD (4).
13

Figure 4. XPS spectra of PCA-β-CD (4) and Pd(II)@PCA-β-CD (C1). Blue, cyan, green and
yellow lines are fitting curves for Pd(0) and Pd(II) peaks, respectively.
3.2 The Performance of Catalysts in C-C Coupling
To explore the catalytic activity, picolinamide-modified cyclodextrin/Pd(II)
complexes (C1-C3) were employed for C-C coupling reactions in aqueous solution
(see Table 1a). Three representative halide compounds, 4-bromo-acetophenone,
cinnamyl bromide, and benzyl bromide, as well as 4-methylphenylboronic acid, were
chosen to establish a model reaction for the optimization of the reaction conditions.
As shown in Table 1a, using C1 gives excellent yields for the three model reactions
(entries 1, 4, and 7, Table 1a). However, with the length of methylene linker
increased, the efficiency of the catalyst (C2 or C3) was sharply decreased. The reason
is probably related to the mismatch between the catalytic metal center and CD’s
hydrophobic cavity. In addition, compared to the catalyst C1, using the native
β-CD/Pd(OAc)2 inclusion complex results in a poor yield (entries 16, 17, and 18,
Table 1a). Pd(OAc)2 on its own without the presence of the ligand (entries 19, 20,
and 21, Table 1a) also leads to a poor yield, highlighting the positive influence of the
14

picolinamide ligand. Notably, there is no yield obtained with only PCA-β-CD as
catalyst (entries 22, Table 1a).
Table 1a. Optimization of catalysts in C-C cross-coupling reactions a,b
b
Yield
[%]
97
55
34
95
57
32
90
53
43
96
53
30
45
12
11
31
27
24
17
15
15
0
Entry
Cat
R’
R”
Cat. [%]
T. [oC]
1
2
3
4
5
6
7
8
C1
C2
C3
C1
C2
C3
C1
C2
C3
C1
C2
C3
C1
C2
C3
4-COCH3
4-COCH3
4-COCH3
H
H
H
H
H
H
4-COCH3
4-COCH3
4-COCH3
4-COCH3
4-COCH3
4-COCH3
4-COCH3
H
Br
Br
Br
1×10-3
1×10-3
1×10-3
1×10-3
1×10-3
1×10-3
1×10-3
1×10-3
1×10-3
1×10-4
1×10-4
1×10-4
1×10-3
1×10-3
1×10-3
1×10-3
1×10-3
1×10-3
1×10-3
1×10-3
1×10-3
1×10-3
80
80
80
80
80
80
80
80
80
80
80
80
r.t
-CH=CHCH2Br
-CH=CHCH2Br
-CH=CHCH2Br
-CH2Br
-CH2Br
-CH2Br
Br
Br
Br
Br
Br
Br
9
10
11
12
13
14
15
16
17
18
19
20
21
r.t
r.t
β-CD+Pd(OAc)2
β-CD+Pd(OAc)2
β-CD+Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PCA-β-CD
Br
80
80
80
80
80
80
80
-CH=CHCH2Br
-CH2Br
Br
-CH=CHCH2Br
-CH2Br
Br
H
4-COCH3
H
H
22
4-COCH3
a
Reaction conditions: 4-bromo-acetophenone (0.5 mmol), cinnamyl bromide (0.5 mmol), benzyl bromide (0.5
mmol), 4-methylphenyl-boronic acid (0.6 mmol), base (1.0 mmol), catalyst (1×10-4–1×10-3 mol%) and H2O (1 mL)
were stirred under air for 12 h at r.t. or 80 °C, respectively. b NMR yield.
1b. Optimization of the reaction conditions a,b
Entry
Base
Base [eq]
Cat. [%]
T. [oC]
Yield b [%]
1
2
3
4
5
6c
7
8
Na2CO3
KOH
Et3N
K3PO4
Cs2CO3
K2CO3
NaHCO3
LiOH
2
2
2
2
2
1.5 c
2
1×10-4
1×10-4
1×10-4
1×10-4
1×10-4
1×10-4
1×10-4
1×10-4
80
80
80
80
80
80
80
80
60
5
23
45
75
94, 97, 97, 90
87
NR
2
15

9d
K2CO3
K2CO3
1.5
1.5
5×10-6 d
80
60 e
95, 97, 97, 96, 95, 95
45, 65, 84, 97, 97, 97, 93
10e
1×10-4
a Reaction conditions: 4-bromo-acetophenone (0.5 mmol), 4-methylphenyl-boronic acid (0.6 mmol), base (0.75
mmol), catalyst, C1 (1×10-4 mol%) and H2O (1 mL) were stirred under air for 0.5 h at 80 °C. b NMR yield.
c
Carried out with 1.25, 1.5, 1.75, and 2.0 eq of base K2CO3. Carried out with 1×10-6, 5×10-6, 1×10-4, 1×10-3,
d
5×10-3, and 1×10-2 mol% catalyst C1. e Carried out at rt, 40, 50, 60, 70, 80, and 100 °C.
With the best catalyst, C1, further optimization of the reaction conditions was
conducted (see, Table 1b). Initially, eight commonly utilized bases were tested with
o
1×10-4 mol% of the catalyst in water at 80 C for 12 hours (entries 1-8, Table 1b).
K2CO3 provided the highest coupling yield (entry 6, Table 1b), while using other
bases gave low to moderate yields for the reaction. Subsequently, we found that a
higher yield could still be maintained if the amount of K2CO3 was reduced to 1.5 eq.
(entry 6, Table 1b). Next, we screened the effect of loading amount of the catalyst on
the yield of the reaction. The results showed that even under 5×10-6 mol% loading,
high catalytic activity was maintained (entry 9, Table 1b). Finally, different
o
temperatures were also confirmed, and 60 C was selected as the most suitable (entry
10, Table 1b). Therefore, K2CO3 as a base in water and 5×10-6 mol% catalyst C1 at 60
oC was selected as an optimal reaction condition.
3.3 Application of Pd(II)@PCA-β-CD (C1) catalyzed Suzuki-Miyaura reactions
Initially, we investigated the catalytic activity of C1 with different aryl halides and
arylboronic acids (Table 2a). As expected, various substituted aryl halides and
arylboronic acids, bearing electron-rich and electron-deficient groups, such as -CH3,
-OCH3, -NO2, -CN, -COCH3, and F, were found to produce high yields (entries 3, 6,
10, 11, and 13, Table 2a). Remarkably, the TONs and TOFs of Pd(II)@PCA-β-CD
reached up to 2.0 × 107 and 2.0 × 108, respectively. The treatment of substituted aryl
16

iodide with 4-methoxy boronic acid gave the corresponding biaryl with excellent
yields (over 90%) in short reaction times (entries 10-13, Table 2a), and a high TOF
up to 1.1-2.0 × 108. The substituted bromobenzenes also gave satisfactory yields
(entries 1-9 and 20-22, Table 2a). Meanwhile, most of the substituted chlorobenzenes
also generated excellent yields (entries 15-19 and 24-26, Table 2a). Heterocyclic
thiophene boronic gave a low yield (entry 23, Table 2a). ortho-Substituted aryl
halides produced the corresponding products in a lower yield for a longer time than
meta- or para-positions (entries 1-9, 11-13 and 24-26, Table 2a), this may be because
increasing the steric hindrance in the aryl halides could decrease the reactivity and
make substrates inclusion with catalyst C1 difficult.
a
Table 2a. Suzuki-Miyaura coupling reactions between aryl halides and arylboronic acid using C1
Time
[h]
Yieldb
[%]
88
93
98
83
88
95
81
87
90
96
92
95
99
83
83
87
81
85
82
83
87
86
74
TOF
Entry R1
X
R2
TONc
Product
[h-1] d
1
2
3
2-COCH3 Br
3-COCH3 Br
4-COCH3 Br
4-CH3
4-CH3
4-CH3
4-CH3
4-CH3
4-CH3
4-CH3
4-CH3
4-CH3
4-CH3
4-OCH3
4-OCH3
4-OCH3
4-CH3
4-OCH3
4-OCH3
4-OCH3
4-OCH3
4-OCH3
3-CH3
3-F
1.0
1.0
0.5
1.0
1.0
1.0
1.5
1.0
0.5
0.1
0.1
0.1
0.1
1.0
5.0
3.5
4.5
3.0
3.0
0.5
0.5
0.5
1.8×107
1.9×107
2.0×107
1.7×107
1.8×107
1.9×107
1.6×107
1.7×107
1.8×107
1.9×107
1.8×107
1.9×107
2.0×107
1.6×107
1.6×107
1.7×107
1.6×107
1.7×107
1.6×107
1.7×107
1.7×107
1.7×107
1.5×107
1.8×107
1.9×107
4.0×107
1.7×107
1.8×107
1.9×107
1.1×107
1.7×107
3.6×107
1.9×108
1.8×108
1.1×108
2.0×108
1.6×107
3.3×106
5.0×106
3.6×106
5.7×106
5.5×106
3.3×107
3.5×107
3.4×107
4.9×106
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
1q
1r
1s
4
2-NO2
Br
Br
Br
Br
Br
Br
I
I
I
I
Br
Cl
Cl
Cl
Cl
Cl
5
3-NO2
6
4-NO2
7
8
9
2-OCH3
3-OCH3
4-OCH3
4-NO2
2-COCH3
3-COCH3
4-COCH3
2-CN
3-CH3
4-CH3
3-CN
4-CN
10
11
12
13
14
15
16
17
18
19
20
21
22
23
4-NO2
4-COCH3 Br
4-COCH3 Br
4-COCH3 Br
4-COCH3 Br
1t
1u
1v
1w
4-F
3-Thiopheneboronic acid 3.00
17

24
25
26
2-COCH3 Cl
3-COCH3 Cl
4-COCH3 Cl
4-OCH3
4-OCH3
4-OCH3
6.00
4.00
3.00
77
85
89
1.5×107
1.7×107
1.8×107
2.6×106
4.3×106
6.0×106
1x
1y
1z
a Reaction conditions: aryl halide (1.0 mmol), arylboronic acid (1.2 mmol), catalyst C1 (5x10-6 mol%), K2CO3 (1.5
mmol), H2O (2 mL), and 60 °C. b Isolated by column chromatography. Turnover number (TON) based on the
number of moles of isolated product. d TOF is defined as mol product molPd-1 h-1.
c
a
2b. C(sp3)-C(sp2) coupling reactions between cinnamyl halide and arylboronic acid using C1
b
Yield
[%]
82
88
93
83
85
82
91
86
92
95
88
83
85
81
86
93
80
86
89
87
87
88
84
TOF [h-1]
Entry
R3
X
R2
Time [h]
TON c
Product
d
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
H
H
H
H
Br
Br
Br
Br
Br
Br
Br
Cl
Cl
Cl
Cl
Cl
Cl
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
2-OCH3
3-OCH3
4-OCH3
3-F
0.5
0.5
0.5
0.5
0.5
1.6×107
1.8×107
1.9×107
1.7×107
1.7×107
1.6×107
1.8×107
1.7×107
1.8×107
1.9×107
1.8×107
1.7×107
1.7×107
1.6×107
1.7×107
1.9×107
1.6×107
1.7×107
1.8×107
1.7×107
1.7×107
1.8×107
1.7×107
3.3×107
3.5×107
3.7×107
3.3×107
3.4×107
6.3×107
3.6×107
3.4×107
3.7×107
3.8×107
3.5×107
3.3×107
3.4×107
5.4×106
6.9×106
7.4×106
6.4×106
6.8×106
5.9×106
5.8×106
8.7×106
7.0×106
3.4×106
2a
1b
1c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
2r
2s
4-F
3-Thienylboronic acid 0.5
4-CH3
3-CH3
4-CH3
4-OCH3
4-F
2-OCF3
H
2-OCH3
3-OCH3
4-OCH3
2-CN
0.5
0.5
0.5
0.5
0.5
0.5
0.5
3.0
2.5
2.5
2.5
2.5
3.0
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
H
2-NO2
2-NO2
2-NO2
2-NO2
2-NO2
2-NO2
2-NO2
2-NO2
2-NO2
2-NO2
3-CN
4-CN
3-Thienylboronic acid 3.0
H
3-CH3
2,3-CH3
2t
2.0
2.5
5.0
2u
2v
2w
a Reaction conditions: cinnamyl halide (1.0 mmol), arylboronic acid (1.2 mmol), catalyst C1 (5x10-6 mol%), KF (1.5
mmol), H2O (2 mL), 60 °C. b Isolated by column chromatography. c Turnover number (TON) based on the number of
moles of isolated product. d TOF was defined as mol product molPd-1 h-1.
a
2c. C(sp3)-C(sp2) coupling reactions between benzyl halides and arylboronic acid using C1
Entry
R4
R2
Time [h]
Yield b [%] TON c
TOF [h-1] d Product
1
2
3
4
5
6
7
8
9
H
H
H
2-OCH3
3-OCH3
4-OCH3
4-OCH3
4-OCH3
2-OCH3
4-OCH3
4-OCH3
4-CH3
0.5
0.5
0.5
0.5
1.0
1.0
0.5
5.0
5.0
79
83
87
89
88
81
86
78
81
1.6×107
1.7×107
1.7×107
1.8×107
1.8×107
1.6×107
1.7×107
1.6×107
1.6×107
3.2×107
3.3×107
3.5×107
3.6×107
1.8×107
1.6×107
3.4×107
3.1×106
3.2×106
3a
3b
3c
3d
3e
3f
3g
3h
3i
3-CH3
4-C(CH3)3
3-OCF3
3-OCF3
4-NO2
3-NO2
18

10
11
12
13
14
15
3-CH3
3-NO2
C(CH3)3
4-NO2
H
3-Thienylboronic acid 0.5
3-OCH3 5.0
3-Thienylboronic acid 1.5
3-Thienylboronic acid 5.0
89
83
85
79
71
73
1.8×107
1.7×107
1.7×107
1.6×107
1.4×107
1.5×107
3.6×107
3.3×106
1.1×107
3.2×106
2.8×106
2.9×106
3j
3k
3l
3m
3n
3o
3-CN
4-CN
5.0
5.0
H
a Reaction conditions: benzyl halides (1.0 mmol), arylboronic acid (1.2 mmol), catalyst C1 (5x10-6 mol%), K2CO3
(1.5 mmol), H2O:EtOH = 5:1 (2 mL), 60 °C. b Isolated by column chromatography. c Turnover number (TON) based
on the number of moles of isolated product. d TOF is defined as mol product molPd-1 h-1.
Next, we explored the performance of catalyst C1 used with allyl halides and
arylboronic acids for C-C coupling (see, Table 2b). As shown in Table 2b, all
substrates reacted smoothly to afford the corresponding cross-coupling products (E
isomer) in moderate to high yields, and isomerization of the products was not detected
in any of the cases. Notably, the reaction of unsubstituted cinnamyl halides (Cl, Br)
with most arylboronic acids proceeded with the desired products in excellent yields
with high TONs and TOFs (entries 3, 7, 9, and 10, Table 2b), while the introduction
of a nitro substituent on cinnamyl halides led to an obvious decrease in the reactivity
and extended reaction time (entries 14-23, Table 2b). When treating 2-substituted and
multi-substituted arylboronic acids with cinnamyl halides, satisfactory yields were not
obtained (entries 1, 12, 14, 17, and 23, Table 2b), which probably was due to the
steric hindrance of the substituent group, reinforcement of the carbon-boron bond, and
disadvantage in the trans-metallation step.
To further extend the scope of the catalyst system for the C(sp3)-C(sp2) coupling,
the reaction of benzyl halides with arylboronic acids was investigated using catalytic
amount of C1 (5×10-6 mol%), 1.5 mmol K2CO3, and 2 ml of mixed solvent
o
(H2O:EtOH = 5:1) at 60 C for 0.5-5 hours (see, Table 2c). From Table 2c,
19

electron-donating or electron-withdrawing groups of the aromatic ring of benzyl
halides did significantly influence the yield of targeted products. For the benzyl
halides bearing an electron-donating group, yields up to 89% were obtained in a very
short reaction time (entries 4, 5, and 10, Table 2c). However, for benzyl halides
bearing electron-withdrawing groups, a maximum of 83% yield was obtained after 5
hours (entries 11, Table 2c). It is noteworthy that the average yields (75-89%)
obtained in this reaction was lower than that of the above-mentioned reactions. In
addition, the introduction of a cyano substituent (entries 14 and 15, Table 2c) on the
phenylboronic acid resulted in a 71-73% yield of the corresponding product.
3.4 Putative Mechanism for C1 Catalyzed Suzuki-Miyaura Reactions
In order to establish a chemical reaction mechanism for the C1 catalyzed
Suzuki-Miyaura reaction, firstly, the ROESY NMR of a freeze-dried mixture of
4-bromo-acetophenone (1 mmol), 4-methylphenylboronic acid (1 mmol) and C1 (0.1
mmol) in D2O was recorded (Figure 5a). There were obvious NOE interactions
between protons of 4-bromo-acetophenone and H5 of C1, which indicated that C1
carried out an adsorption inclusion with 4-bromo-acetophenone in the cavity.
On the other hand, in general, the intrinsic feature of the Pd-catalyzed
cross-coupling reactions is the Pd(0)/Pd(II) catalytic cycle. We explored
Suzuki-Miyaura C-C coupling reactions catalyzed by Pd(II)(OAc)2 or Pd(0)(PPh3)4
with PCA-β-CD under N2 (O2-free) (see, Figure 5b). The former resulted in obtaining
the product with an excellent yield of 96%, but the latter only resulted in a trace of the
product. This suggests that the reaction may have occurred at the Pd(II)/Pd(IV) center.
20

Figure 5. a). ROESY of the mixture of 4-bromo-acetophenone, (4-Methylphenyl)-boronic acid
and C1 in D2O. b). Pd(OAc)2 or Pd(PPh3)4 with PCA-β-CD catalyzed Suzuki-Miyaura C-C
coupling reactions under N2 (O2-free), respectively.
Indeed, some previous studies (Hickman & Sanford, 2012; Xu, Li, Yang, & Shi,
2010) have reported a C-C bond that formed based on organopalladium(IV). However,
the application of the Pd(II)/Pd(IV) catalytic cycle to the Suzuki reaction is very rare.
On the basis of the above results, a putative mechanism for the C1 catalyzed
Suzuki-Miyaura reaction is depicted in Fig. 1B. Firstly, C1 conducted an
adsorption-inclusion with benzene derivative. The inclusion complexes were
advantageous to the oxidative insertion at the Pd(IV) center. In succession, under the
attacks of the boron reagent, diaryl/Pd(IV) complex intermediates could be produced
21

by transmetallation. Lastly, the C-C coupling of aryl-aryl could be formed by
reductive elimination, and the product could be dissociated by desorption from the
cavity of PCA-β-CD. Additionally, it needs to be discussed here, in the real case, aryl
boric acid, aryl halide, and even coupling products should be in competition for the
inclusion with cyclodextrin C1. The competitive affinity of different substrates will
affect the rate and equilibrium constant of the coupling reaction. Meanwhile, the
position of palladium can be not only on top of the cavity, but also outside the cavity,
the substrate could approach palladium inside or outside the cavity of C1. There is
probably a competitive pathway. Taking into account the effects of these factors,
more experiments are needed to explore the exact relationship between substrate
affinity and reaction mechanism. In Fig. 1B, the above is just a putative mechanism
that we assumed.
To explore the possibility of the outlined mechanism, we performed QM/MM and
density functional theory (DFT) calculations in water to investigate the energetics of
the proposed mechanism (Figure 6, detailed methods are in the Supporting
Information). We began the calculations from C1, 1-(4-bromophenyl) ethan-1-one,
and p-tolylboronic acid. Firstly, inclusion between substrate and catalyst C1 reduced
the energy of the mixture system and produced Pd(II)@PCA-β-CD/aryl halide
complexes (Figure 6, M2), which then underwent oxidative addition with a low
-1
activation barrier of 4.2 kcal·mol from TS1. Additionally, the free energy of
intermediate M3 is much lower (Figure 6), by 37.1 kcal·mol-1) than that of M2,
which makes oxidative addition a very favorable process. Next, the transmetallation
22

step proceeded with the nucleophilic addition of boron reagent through its
coordination and formation of boron-ate adduct. Two stages of the reaction included
substitution of the bromine atom, and elimination of boric acid molecules was carried
out through the transition states TS2 and TS3. The last reductive elimination stage
could take place via the TS4 transition state and required an activation barrier that is
-1
equal to 27.3 kcal·mol . In summary, thermodynamical analysis showed the
equilibrium of reaction catalyzed by inclusion complexes C1 was irreversible shift
towards the product, as free enthalpy of the system decreased by over 77.4 kcal·mol -1
as a result of this C-C coupling reaction. Noteworthy, the product of TS4 was
calculated again in the vacuum, then the product of TS4 is the included product but
not M6, an uphill energy will be encountered to desorb and obtain target product M6.
But in the water condition, as the result of solvent, the product of TS4 will be M6.
The specific role of solvent may require further study. Moreover, a kinetic experiment
was carried out to determine the rate of this catalytic reaction. The results confirmed
the reaction following a Michaelis Menten type of kinetics. (see ESI, section 1.10)
23

Figure 6. Computed free-energy (kcal/mol) profile for the reaction of Suzuki-Miyaura C-C
coupling with the catalyst C1.
3.5 Recyclability of Pd(II)@PCA-β-CD (C1) Catalyst
Recently, the assessment of catalyst recycling ability is a serious indicator in practical
application (Molnar, 2011; Molnar, etc., 2017). Because of the high price and toxicity
of precious metals, recycling of the Pd catalyst is attractive from the economic,
environmental, and industrial points of view. The recyclability and reusability of
catalyst were investigated using the model reaction of 4-bromo-acetophenone,
4-methylphenylboronic acid and C1. When the reaction completed, the aqueous
reaction mixture was extracted by ethyl acetate to remove the product and then the
remaining aqueous phase was charged again and another fresh substrate and K2CO3
(1.5 eq.) were added to the aqueous phase for the next reaction cycle. A detailed
schematic representation is given in Figure 7a. In this recycling experiment, there are
24

steadily decreasing activities from 98% to 90% with 8 runs (Figure 7b). Since
Pd(II)@PCA-β-CD (C1) belongs to homogeneous catalyst and, inevitably, a small
amount of C1 remains in the organic phase for each extraction operation, thus we
think the reduction of its activity mainly may be attributed to the loss in the extraction
process. Additionally, catalytic reaction process needs heating, which may also lead to
unstable decomposition of catalyst. These require more experimental data to explain,
such as kinetic analysis and TEM images. We will further explore the recycling
characteristics of C1 in the application of other reactions.
Figure 7. a). Recycling procedure for C1 catalyzed C-C coupling reactions. b). Recycling for C1
in the eight runs.
4 Conclusions
25

In conclusion, we have successfully designed and prepared three novel
picolinamide-modified -cyclodextrin/Pd(II) complexes. The length of linker between
picolinamide and CDs affects the catalytic activity of the Suzuki-Miyaura coupling
reaction. It may be that the metal ion is far away from the cavity of CDs, resulting in
the reduction of catalytic efficiency. Among these catalysts, the supramolecular
catalyst C1 afforded the best catalytic performance and exhibited extremely high
TONs and TOFs for the C-C cross-coupling reaction in water. Additionally, it can be
easily separated after the reaction and reused several times without a significant loss
of activity. Meanwhile, a putative Mechanism for C1 catalyzed Suzuki-Miyaura
coupling was suggested that the reaction may have occurred at the Pd(II)/Pd(IV)
center by controlled experiment and quantum chemical calculation. This research
addresses a number of sustainability issues within homogeneous catalysis, which
further builds bridges between green chemistry and organometallic catalysis.
Acknowledgements
The authors gratefully acknowledge the Program for Changjiang Scholars and
Innovative Research Team in University (IRT17094), the NSFC (Nos. 81760621,
21662044 and U1202221) and the Foundation of “Yunling Scholar” Program of
Yunnan Province (C6153001) for financial support, and thank the High-Performance
Computing Center at Yunnan University for use of the high-performance computing
platform.
26

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