Immobilized palladium nanoparticles on a cyclodextrin-polyurethane nanosponge (Pd-CD-PU-NS): An efficient catalyst for cyanation reaction in aqueous media

Article abstract of DOI:10.1016/j.ica.2019.05.021

Immobilized palladium nanoparticles on a cyclodextrin-polyurethane nanosponge (Pd-CD-PU-NS) were found to be an efficient heterogeneous catalyst in the cyanation reaction of aryl halides in aqueous media. This catalyst system is containing palladium nanoparticles with a size of ～7 nm. Moreover, the CD-PU-NS support formed microsphere-shaped structures with a size of ～100–200 nm. The TEM images show that Pd nanoparticles were formed in near spherical shape morphology and were immobilized in the structure of the CD-PU-NS support. Under our optimized reaction conditions, aryl cyanides were obtained in high yields in the presence of the Pd-CD-PU-NS catalyst. Our results demonstrated that the Pd-CD-PU-NS catalyst is highly effective in the cyanation reaction in aqueous media. Furthermore, the catalyst could be simply extracted from the reaction mixture, providing an efficient methodology for the synthesis of aryl cyanides. The Pd-CD-PU-NS catalyst could be recycled four times with almost consistent catalytic efficiency.

Full text of DOI:10.1016/j.ica.2019.05.021

Accepted Manuscript
Research paper
Immobilized Palladium Nanoparticles on a Cyclodextrin-polyurethane Nano-
sponge (Pd-CD-PU-NS): An efficient catalyst for Cyanation Reaction in Aque-
ous Media
Soheila Khajeh Dangolani, Sara Sharifat, Farhad Panahi, Ali Khalafi-Nezhad
PII:
S0020-1693(19)30262-2
https://doi.org/10.1016/j.ica.2019.05.021
ICA 18922
DOI:
Reference:
Inorganica Chimica Acta
To appear in:
Received Date:
Revised Date:
Accepted Date:
26 February 2019
11 May 2019
12 May 2019
Please cite this article as: S.K. Dangolani, S. Sharifat, F. Panahi, A. Khalafi-Nezhad, Immobilized Palladium
Nanoparticles on a Cyclodextrin-polyurethane Nanosponge (Pd-CD-PU-NS): An efficient catalyst for Cyanation
Reaction in Aqueous Media, Inorganica Chimica Acta (2019), doi: https://doi.org/10.1016/j.ica.2019.05.021
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Immobilized Palladium Nanoparticles on a Cyclodextrin-polyurethane
Nanosponge (Pd-CD-PU-NS): An efficient catalyst for Cyanation
Reaction in Aqueous Media
Soheila Khajeh Dangolani,a Sara Sharifat,b Farhad Panahi,*,a,b and Ali Khalafi-Nezhad*,a
a Department of Chemistry, College of Sciences, Shiraz University, Shiraz 71454, Iran
b Department of Chemical Engineering, Amirkabir University of Technology (Tehran Polytechnic), Mahshahr Campus, Mahshahr, Iran
Email: Panahi@shirazu.ac.ir
Email: khalafi@chem.susc.ac.ir
Supporting Information Placeholder
Abstract: Immobilized palladium nanoparticles on a cyclodextrin-polyurethane nanosponge (Pd-CD-PU-NS) were found to be
an efficient heterogeneous catalyst in the cyanation reaction of aryl halides in aqueous media. This catalyst system is containing
palladium nanoparticles with a size of ~7 nm. Moreover, the CD-PU-NS support formed microsphere-shaped structures with a size
of ~100-200 nm. The TEM images show that Pd nanoparticles were formed in near spherical shape morphology and were
immobilized in the structure of the CD-PU-NS support. Under our optimized reaction conditions, aryl cyanides were obtained in
high yields in the presence of the Pd-CD-PU-NS catalyst. Our results demonstrated that the Pd-CD-PU-NS catalyst is highly
effective in the cyanation reaction in aqueous media. Furthermore, the catalyst could be simply extracted from the reaction mixture,
providing an efficient methodology for the synthesis of aryl cyanides. The Pd-CD-PU-NS catalyst could be recycled four times with
almost consistent catalytic efficiency.
Keywords
Palladium Nanoparticles, Cyclodextrin-polyurethane Nanosponge, Cyanation Reaction, Aqueous Media, Heterogeneous Catalysis
1

Introduction
There are several drugs, advanced materials, pharmaceuticals and biologically important compounds containing a nitrile group
which in their preparation require a cyanation reaction step.1 The chemical structures of some biologically active molecules
containing a nitrile group are shown in Figure 1.2 On the other hand, the nitrile moiety could be converted to a variety of functional
groups and this is very important from a viewpoint of organic synthesis.3
S
N
Me
N
N
H
N
N
N
Me
N
O
NC
N
CN
N
Me
N
NC
CN
Me Me
CN
Me Me Me Me
N
F
A
D
C
B
Figure 1. The chemical structures of some drugs containing one or more nitrile groups. A: cyamemazine is a typical antipsychotic
drug. B: topiroxostat is a drug for the treatment of gout and hyperuricemia. C: periciazine is an antipsychotic agent. D: is a drug
for the treatments of breast cancer.
Transition metal-catalyzed cyanation of aryl halides using metals such as palladium, nickel and copper is one of the most widely
used methods in aryl nitrile synthesis.4 There is considerable interest to develop palladium catalyst systems for cyanation reactions,
because a variety of functional groups are tolerated compared to other metals.5
The key problem in the cyanation reaction using palladium catalyst systems is the inhibition of reaction catalytic cycles when the
palladium catalyst is exposed to a high concentration of cyanide ions, resulting in low yields. Some experiments showed that this
limitation is probably due to the formation of inactive palladium cyanide species. The formed palladium cyanide species cannot
easily undergo the reductive elimination, thus the catalytically active Pd(0) species cannot regenerated.6 To overcome this problem,
a slow cyanide delivery approach is needed which could be achieved by a careful choice of solvents and cyanide sources. For
example, by use of K4[Fe(CN)6] as cyanide source some of the problems associated with the cyanation reaction in the presence of
Pd catalysts can be resolved.7 In the structure of the K4[Fe(CN)6] complex the cyanide ion is strongly bonded to the Fe ion, so that it
substantially releases cyanide ions slowly, preventing the inactivation of the catalyst during reaction progress. In addition to the
slow cyanide delivery of the K4[Fe(CN)6] reagent it also has many advantages including low cost and little toxicity.
Since the solubility of K4[Fe(CN)6] is low in organic solvents and this affects reaction yields remarkably, the addition of water to
the reaction mixture sometimes improves the reaction yield. However, the cyanation reaction in the pure water was not successful
2

yet, and the addition of a fraction of water is effective on the reaction progress. NMR experiments confirm that water effectively
deactivates the Pd catalyst in the cyanation reaction due to the formation of HCN, ultimately leading to the formation of inactive Pd
species.8 There are several methods to avoid catalyst poisoning, including the use of low solubility cyanide sources in organic
solvents, the use of a sterically bulky phosphine ligand and the addition of reducing agents such as zinc, isopropanol and
polymethylhydrosiloxane (PMHS).9 Each of these approaches has its problems, for example, addition of reducing agents
complicates workup operations, use of zinc dust leads to the release of heavy metal waste and the addition of PMHS results in the
formation of an unacceptable amount of byproducts.
One of the promising ways to overcome these problems would be the use of supported nano-catalyst systems. Metal
nanoparticles (MNPs) with high surface-to-volume ratio have a large number of available active catalytic sites per unit area, which
is believed to be responsible for their high catalytic performance.10 Moreover due to the large number of active sites, the catalytic
poisoning and formation of palladium black is less important in nanocatalyst systems compared to homogeneous catalyst systems.
Nanosponges are a novel class of hyper cross-linked polymer-based structures with cavities in the range of nanometers.11
Nanosponges have gained attention for being tiny sponges which have the capacity to incorporate a large variety of substances
within their core.12 One of the interesting types of this category of compounds are cyclodextrin-polyurethane nanosponges (CD-PU-
NS). This network of nanosponges significantly enhances the stability constant of an inclusion complex compared to natural
cyclodextrins, representing an ideal candidate for the controlled synthesis of nanoparticles.
In continuation of our program on the synthesis of Pd nanoparticles (PNPs) and their application in Pd-catalyzed reactions under
green conditions13 we would like to introduce a new Pd catalyst system based on cyclodextrin-polyurethane nanosponges (CD-PU-
NS) for a catalytic application in aqueous media. Being aware of the importance of nitriles1,2 and the excellent catalytic capability
of PNPs, we investigated whether immobilized PNPs on CD-PU-NS can be used as efficient catalysts to promote the cyanation of
aryl halides in aqueous media. To the best of our knowledge there are only a few reports in the literature on the Pd-catalyzed
cyanation reaction in aqueous media (Scheme 1).9c,14 Hence, we have developed a ligand and an additive-free procedure for the
cyanation of aryl halides in aqueous media under aerobic conditions using a recyclable heterogeneous nanocatalyst system.
3

I
PdX2(L1)2
CN
CN
P
L1:
Shim et al.
Zou et al.
Ar
Ar
Ar
Ar
Zn(CN)2 or KCN, ZnCl2
SO3K
n-heptane/H2O
100 o
C
O
O
N
N
Br
Pd2(dba)3, L2
P
N
L2:
K4Fe(CN)6
t-BuOH/H2O
O
K2CO3, 85 o
C
P(Cy)2
X
i-Pr
i-Pr
Pd(OAc)2, L3
Zhang et al.
CN
L3:
Ar
Ar
K4Fe(CN)6
SO3Na
1,4-dioxane/H2O
X = Cl, OTs
K2CO3, 120 o
C
X
K4Fe(CN)6
PEG-4000/H2O
Pd/C
CN
CN
Chen et al.
Ar
Ar
Ar
NaF, 100-160 o
C
X = I, Br, Cl
X
This work
Pd-CD-PU-NS
Ar
K4Fe(CN)6
DMF/H2O
X = I, Br, Cl
Na2CO3, 120 o
C
Scheme 1. Some of the available Pd-catalyzed aryl cyanation methodologies in aqueous media
Results and Discussion
Synthesis and characterization of the Pd-CD-PU-NS catalyst system
In this study, a CD-PU-NS was synthesized using the reaction of α-cyclodextrin with methylene diphenyldiisocyanate (MDI).
The CD-PU-NS was prepared using commercially available starting materials. The hydroxyl groups of CDs react with the
isocyanate functionalities of MDI and form a urethane linkage between two or more CD units (Figure 2).15
O
O
OH
HO
O
OH
HO
O
a)
O
O
O
b)
O
O
O
O
O
O
O
OH
O
O
OH
HO
OH
OH
HO
HO
OH
OH
HO
HO
OH
OH
HO
O
O
HO
O
OH
OH
O
O
H
N
O
OH
O
O
H
N
OH
H
N
O
O
O
O
OH
H
N
O
O
OH
O
O
OH
OH
O
O
HO
OH
OH
O
OH
O
OH
O
OH
O
OH
HO
O
OH
HO
O
OH
O
OH
OH
O
O
HO
OH
O
OH
OH
O
O
HO
OH
O
O
HO
OH
O
O
HO
OH
OH
OH
OH
OH
O
O
O
O
O
O
O
O
O
O
O
O
O
HO
O
O
O
O
O
O
HN
HO
N
HO
NH
H
N
H
H
HN
N
NH
O
N
O
O
O
O
O
H
O
O
HO
HO
O
O
O
O
O
HO
O
O
O
O
O
O
OH
OH
O
OH
OH
OH
HO
OH
HO
OH
OH
HO
HO
OH
HO
OH
HO
O
O
OH
O
OH
O
O
O
O
O
O
O
O
O
OH
O
O
O
OH
O
HO
OH
NH
O
O
HO
OH
N
HN
O
OH
O
OH
N
O
OH
O
O
OH
O
OH
O
OH
H
O
OH
O
OH
H
O
O
HO
OH
O
OH
O
O
HO
OH
OH
HO
OH
O
O
OH
HO
OH
OH
OH
OH
OH
OH
O
O
O
O
O
O
O
O
O
O
OH
O
O
OH
O
O
HO
HO
HO
HO
Figure 2. Schematic representation of the chemical units of the PU-CD-NS substrate (a) and a plausible interaction between PU-
CD-NS functionalities with palladium nanoparticles (b)
4

The CD-PU-NS substrate was characterized using FT-IR spectroscopy. The C=O bond of the urethane units is clearly observable
in the FT-IR spectrum at 1659 cm-1 (See Supporting Information, Figure 1S).16The frequency of this bond changed (1648 cm-1)
when the Pd species was immobilized on the surface of CD-PU-NS, demonstrating the strong interaction of the amide bonds with
the Pd metal. Thus, the amide subunits of the CD-PU-NS substrate play a significant role in the stabilization of the Pd species in the
Pd-CD-PU-NS catalyst. The stabilization of the Pd nanoparticles by amide bonds has been previously reported.17,18 The peaks
around 3300-3400 cm-1 refer to the hydroxyl groups, confirming that there are a lot of free hydroxyl groups in the structure of CD-
PU-NS which are important in the stabilization of the Pd species on the surface of the material.19 The vibration of the -CH and -
CH2- groups appears in the 2923 cm-1 region.20 These peaks remained unchanged in the FT-IR of both CD-PU-NS support and Pd-
CD-PU-NS catalyst. Also, the C-O stretching frequency related to the ether bonds in the structure of cyclodextrin occurs at 1034
cm-1.21
By treatment of CD-PU-NS with Pd(OAc)2 in the presence of ethanol (as a green reducing agent) at room temperature,13b
palladium nanoparticles are produced and immobilized on the surface of the nanosponge substrate (Pd-CD-PU-NS). The
transmission electron microscopy (TEM) images of this material are shown in Figure 3.
5

Figure 3. TEM images of the Pd-CD-PU-NS catalyst (a-c). The histogram representing size distribution of Pd nanoparticles
immobilized on CD-PU-NS substrate (d).
The TEM images of the catalyst revealed the presence of microspheres with a size of 150-200 nm which are containing
palladium nanoparticles (Figure 3a-c). The images obviously illustrate that large numbers of Pd nanoparticles are immobilized on
the surface of the CD-PU-NS microspheres. Some of the CD-PU-NS sponges have an excess of Pd nanoparticles, while some are
more sparsely decorated, which may be due to the fact that ethanol reduced some of the Pd(OAc)2 well before it was uniformly
distributed on the CD-PU-NS microspheres. The average size of the Pd nanoparticles is about 7 nm (Figure 3d).
The surface morphology of CD-PU-NS and Pd-CD-PU-NS was investigated by scanning electron microscopy (SEM) and is
shown in Figure 4. The presence of microspheres in the range of 100-200 nm is clearly observable in the SEM images. Nonetheless,
they are not uniform and after immobilization of the Pd nanoparticles on the surface of CD-PU-NS, the morphology of the substrate
did not change remarkably.
Figure 4. SEM images of CD-PU-NS (a-c) and Pd-CD-PU-NS (d-f)
The energy-dispersive X-ray (EDX) spectra of CD-PU-NS show the presence of the elements C, N and O in the structure of this
material (Figure 5).
6

Figure 5. Energy-dispersive X-ray (EDX) spectra of CD-PU-NS (left) and Pd-CD-PU-NS (right)
The amount of nitrogen is 12.5% which shows the presence of 4.5 mmol.g-1 of MDI in the structure of CD-PU-NS. The content
of Pd based on the EDX analysis for Pd-CD-PU-NS is 4.0% (Figure 5). Based on this percentage, it is possible to calculate the
amount of the immobilized Pd species on the surface of CD-PU-NS, which is equal to 0.37 mmol.g-1 of the material. Also, in order
to confirm the Pd content, the supported catalyst was treated with concentrated hydrochloric acid and nitric acid to digest the Pd
species and to allow an analysis by ICP. The Pd content was determined to be 0.318 mmol.g-1, which is in good agreement with
EDX analysis.
The nitrogen gas adsorption/desorption isotherms for both CD-PU-NS and Pd-CD-PU-NS were recorded. The BET surface areas
of CD-PU-NS and Pd-CD-PU-NS were determined to be 11.9 and 29.6 m2g-1, respectively (ESI, Figure 2S&3S). After
immobilization of the Pd nanoparticles, the BET surface area enhanced 2.5 fold, demonstrating the presence of Pd nanostructures,
because they are containing high surface area (Table 1).22
Table 1. Results of the BET study of CD-PU-NS and of the Pd-CD-PU-NS catalyst
Material
Vm [cm3(STP) g-1]
as,BET[m2 g-1]
Total pore volume [cm3
g-1]
C
Mean
pore
diameter [nm]
CD-PU-NS
2.75
6.81
11.9
29.6
0.11
0.22
41.4
69.1
35.9
30.2
Pd-CD-PU-NS
The X-ray powder diffraction (XRD) patterns of Pd-CD-PU-NS shows characteristic peaks at 2θ = 40.2°, 45.8°, and 67.4°,
revealing the formation of Pd nanoparticles, as they refer to the (111), (200) and (220) planes in the crystal structure of Pd
nanoparticles, respectively (Figure 6).22
7

Figure 6. XRD pattern of the Pd-CD-PU-NS catalyst
In the XRD pattern (Figure 6), a sharp peak is observed at 2 θ of around 40°, indicating the presence of PNPs. The size of the
PNPs was determined using the X-ray line-broadening via the Debye−Scherrer equation [D = 0.9 L/β cos (θ)].13bAccording to this
formula, D is the average crystalline size, L is the X-ray wavelength used, β is the angular line width at half-maximum intensity,
and θ is Bragg’s angle. Thus, for θ = 20°, L = 1.06 Å and the obtained β value (~1.5 mm), the average size of the PNPs on the SCD
substrates was estimated to be ~6.8 nm. This value is in good agreement with the data obtained from the TEM study.
The thermal gravimetric analysis (TGA) of CD-PU-NS shows a main weight loss at 280–410 °C which is associated with the
decomposition of the polymer structure (Figure 7). According to the TGA analysis, the CD-PU-NS material has a high thermal
stability. Also, the TGA analysis of Pd-CD-PU-NS shows a main weight loss between 290 and 400 °C, which is essentially the
same as for CD-PU-NS. The TGA analysis of CD-PU-NS and Pd-CD-PU-NS obviously indicates the high thermal stability of the
substrate required for catalysis at high temperatures.
Figure 7. Comparison between the TGA analysis of CD-PU-NS and the Pd-CD-PU-NS catalyst
8

The chemical state of the Pd species and the surface element composition of the catalyst were further investigated by X-ray
photoelectron spectroscopy (XPS) analysis (Figure 8). The binding energy observed around 289.0, 286.1, 285.0 and 284.4 eV
corresponds to C species (C 1S) in C=O, C-O, C-H and C-C bonds, respectively. These carbon atoms clearly confirm the carbon
structure of the CD-PU-NS substrate. The binding energy observed at 400.6 eV is related to the N atom in the urethane bond. The
binding energy at 531.1 eV corresponds to O atoms in hydroxyl groups and ether bonds of cyclodextrin in the CD-PU-NS substrate.
Interestingly, the peak related to the oxygen atom in the C=O bond in the urethane linkage is observed at 533.1 eV.17 The doublet
with a binding energy at 335.8 (Pd, 3d5/2) and 341.1 eV (Pd, 3d3/2) can be indexed to the Pd(0) state. The other set of peaks at
336.8 (Pd, 3d5/2) and 342.4 eV (Pd, 3d3/2) are ascribed to the Pd(II) oxidation state.18 The integration areas of these two doublets
demonstrate that Pd(0) was formed as the major phase on the catalyst surface (63%).
Figure 8. XPS spectra for elements carbon, palladium, nitrogen and oxygen in the Pd-CD-PU-NS catalyst
Cyanation reaction of aryl halides with the Pd-CD-PU-NS catalyst
After the synthesis and characterization of the Pd-CD-PU-NS catalyst, its activity was evaluated in the cyanation reaction. The
reaction between 4-bromoacetophenone and K4[Fe(CN)6] as a nontoxic cyanide source was selected as a model reaction. Different
conditions were checked and the results are summarized in Table 2.
9

Table 2. Optimization of the reaction conditions for the cyanation of aryl halides with K4[Fe(CN)6] using the Pd-CD-PU-NS
catalysta
CN
O
CN
Pd-CD-PU-NS (x mol%)
NC
NC
CN
CN
Fe
K4
CH3
+
H3C
base, Solvent,
Temperature, 12h
CN
Br
O
2a
1a
Entry
1
Catalyst (x mol%)
-
Base
Solvent
DMF
DMF
H2O
Temp (h)
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
100
90
Yield (%)b
0
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Cs2CO3
K2CO3
2
Pd-CD-PU-NS (1.7)
Pd-CD-PU-NS (1.7)
Pd-CD-PU-NS (1.7)
Pd-CD-PU-NS (1.7)
Pd-CD-PU-NS (1.7)
Pd-CD-PU-NS (1.7)
Pd-CD-PU-NS (1.7)
Pd-CD-PU-NS (1.7)
Pd-CD-PU-NS (1.7)
Pd-CD-PU-NS (1.7)
Pd-CD-PU-NS (1.7)
Pd-CD-PU-NS (1.7)
Pd-CD-PU-NS (1.7)
Pd-CD-PU-NS (1.7)
Pd-CD-PU-NS (0.7)
Pd-CD-PU-NS (2.7)
Pd-CD-PU-NS (3.4)
Pd-CD-PU-NS (1.7)
Pd-CD-PU-NS (1.7)
Pd/C (1.7)
93
3
trace
91
4
DMF:H2O (1:1)
DMF:H2O (1:2)
t-BuOH:H2O (1:1)
Dioxane:H2O (1:1)
DMSO
5
70
6
37
7
32
8
40
9
NMP
52
10
11
12
13
14
15
16
17
18
19
20
21
DMAc
42
CH3CN
20
DMF:H2O (1:1)
DMF:H2O (1:1)
DMF:H2O (1:1)
DMF:H2O (1:1)
DMF:H2O (1:1)
DMF:H2O (1:1)
DMF:H2O (1:1)
DMF:H2O (1:1)
DMF:H2O (1:1)
DMF:H2O (1:1)
92
78
Et3N
64
DABCO
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
81
65
92
93
85
37
120
40
10

22
23
24
25
26
Pd/Alumina (1.7)
PNP-SSS (1.7)
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
DMF:H2O (1:1)
DMF:H2O (1:1)
DMF:H2O (1:1)
DMF:H2O (1:1)
DMF:H2O (1:1)
120
120
120
120
120
51
65
60
30
25c
PdNP-SCD (1.7)
Pd(OAc) (1.7)/α-CD
Pd(OAc) (1.7)/PU
a)
Reaction conditions: aryl halide (1.5 mmol), K4[Fe(CN)6] (0.6 mmol), Pd-CD-PU-NS (1.7 mol%), Na2CO3 (1.8 mmol), solvent
(5.0 mL). b All the yields refer to those of the isolated products. c Polyurethane diol solution. 88 wt. % in H2O.
As shown in Table 2, in the presence of base and in DMF solvent at 120 °C no product was obtained (Table 2, entry 1). In
contrast, using the Pd-CD-PU-NS catalyst system in DMF solvent at 120 °C about 93% of product was detected (Table 2, entry 2).
Then, we checked the cyanation reaction in pure water and a trace amount of product was observed (Table 2, entry 3). By use of
DMF:H2O (1:1) as reaction medium, about 91% of product was produced (Table 2, entry 4). Then we changed the ratio of
DMF:H2O to 1:2, but no improvement in the reaction yield was observed (Table 2, entry 5). Using other mixed solvents no
enhancement in the reaction yield was observed either (Table 2, entries 6&7). Additional solvents were also tested in the reaction
and the reaction yield was not comparable to that in DMF (Table 2, entries 8-11). Thus, DMF:H2O (1:1) was selected as the
medium of choice for the cyanation reaction in the presence of the Pd-CD-PU-NS catalyst.
The type of base was also modified, but no superiority was observed with respect to sodium carbonate (Table 2, entries 12-15).
Then, the catalyst loading was optimized and 5.0 mg of catalyst, which is equal to 1.7 mol% of Pd, was recognized as optimum
(Table 2, entries 16-18). The reaction temperature was also checked and at lower temperatures the reaction yield was decreased.
Thus, the temperature of 120 °C was selected as the optimum temperature (Table 2, entries 19&20). In order to show the superiority
of this catalyst system in the cyanation reaction in aqueous media, some other catalyst systems were also checked under the same
conditions. The reaction yields in the presence of Pd/C and Pd/alumina were between 40-50% (Table 2, entries 21&22). Two other
catalyst systems which had previously been reported by our group were tested in the cyanation reaction in aqueous media, too. In
the case of Pd nanoparticles on silica-starch substrate (PNP-SSS)13b only 65% of product and for Pd nanoparticles on silica-
cyclodextrin substrate13a about 60% was obtained (Table 2, entries 23&24).
Two other experiments were also performed to show that Pd-CD-PU-NS represent a unique structure to facilitate the
accomplishment of the cyanation reaction in aqueous media and that each of its components cannot do this separately. The
11

cyanation reaction in the presence of only alpha-cyclodextrin afforded 30% of product (Table 2, entry 25). Also a polyurethane
substrate was used as ligand besides Pd(OAc)2 as catalyst instead of Pd-CD-PU-NS and only 25% of product was observed (Table
2, entry 26). These experiments show that Pd-CD-PU-NS is a suitable catalyst for the cyanation reaction of aryl halides in aqueous
media and that this may be related to its structures, as it contains nano-cavities, providing an appropriate environment for the
cyanation process in aqueous media.
According to the optimization study, the best conditions for an efficient cyanation of 4-bromoacetophenone is shown in Scheme
2.
O
CN
O
CH3
Pd-CD-PU-NS (1.7 mol%)
NC
NC
CN
CN
Fe
K4
CH3
+
Na2CO3 (1.8 mmol)
DMF:H2O (1:1)
120 oC, 10h
NC
CN
Br
2a
: 96%
1.5 mmol
0.60 mmol
Scheme 2. Optimized reaction condition for the synthesis of 4-acetylbenzonitrile (2a) using Pd-CD-PU-NS catalyst
Having optimized reaction conditions in hand, we tested different substrates to investigate the generality and scope of the
reaction (Scheme 3). As shown in Scheme 3, different types of aryl halides could be used in this protocol. Aryl halides bearing
electron-rich and electron-poor substituents were both tolerated, and good to excellent yields of the products were isolated.
When an aniline derivative was used, the reaction occurred readily to give compound 2d in good yield. Functional groups such as
nitro (2e,i,k,u,2ae), cyano (2w,z), trifluoromethyl (2l), aldehyde (2c), keto (2a,m), amino (2d,p,t,z), hydroxy (2f), alkoxy
(2n,x,2ac), sulfonate (2y) and amide (2z) were compatible with these reaction conditions.
12

CN
Fe
X
Pd-CD-PU-NS (1.7 mol %)
CN
NC
NC
CN
CN
Ar
K4
Ar
+
Na2CO3 (1.8 mmol)
DMF:H2O (1:1)
CN
120 o
C
1.5 mmol
0.60 mmol
CN
CN
CN
CN
CN
HO
OHC
H2N
O2N
2d
2e
2b
2c
X = I, 15h, 90%
X = Br, 15h, 88%
X = Cl, 15h, 80%
X = I, 10h, 92%
X = Br, 10h, 89%
X = Cl, 12h, 75%
X = I, 15h, 70%
X = Br, 15h, 60%
2f
X = Br, 15h, 91%
X = Cl, 18h, 55%
X = Br, 20h, 50%
CH3
CN
CN
CN
CN
O2N
CN
O2N
NO2
2k
F3C
Cl
Br
2i
2h
X = Br, 10h, 95%
X = Cl, 12h, 89%
2l
2g
X = I, 18h, 69%
X = Br, 18h, 50%
X = Br, 10h, 90%
X = I, 18h, 68%
O
CN
CN
CN
CN
Me
N
MeO
2n
NC
2q
2o
2p
2m
X = Br, 12h, 90%
X = Br, 15h, 82%
X = Br, 15h, 80%
X = Br, 15h, 85%
X = Cl, 10h, 85%
CN
Cl
CN
H2N
CN
NC
CN
N
NC
NO2
NH2
2v
2u
2s
2t
2r
X = Br, 18h, 73%
X = Cl, 18h, 74%
X = Br, 15h, 84%
X = Br, 15h, 87%
X = Br, 12h, 86%
CN
CN
MeO
CN
N
CN
NC
O
O
N
N
2w
O
S
X = Cl-Cl, 18h, 68%a,b
X = Br-Br, 12h, 84%a
X = Br, 15h, 86%c
MeO
CN
OMe
HN
2y
O
N
O
NH2
X = Br, 20h, 69%b
2x
H
X = Cl, 18h, 73%d
2z
X = Br, 20h, 58%b
CN
Br
CN
CN
NC
N
H
O
2aa
2ab
2ac
X = Br, 18h, 73%
2ad
X = Br, 20h, 64%
X = Br, 20h, 82%
X = Br, 24h, 76%
Scheme 3. Pd-CD-PU-NS-catalyzed cyanation of aryl halides with K4[Fe(CN)6]. Reaction conditions: aryl halide (1.5 mmol),
K4[Fe(CN)6] (0.6 mmol), Pd-CD-PU-NS (1.7 mol%), Na2CO3 (1.8 mmol), solvent (5.0 mL). All the yields refer to those of the
isolated products.
13

1-Bromo-4-iodobenzene and 1-bromo-4-chlorobenzene were examined as bis-halogen substrates, and good yields of the mono-
substituted products were obtained (2g&2h). Compounds 2i and 2k were obtained from sterically hindered substrate in good
isolated yield. When phenanthrene, anthracene and naphthalene derivatives were used, the corresponding nitriles 2q, 2r and 2ab
were obtained in 90, 86 and 82% isolated yields, respectively. Good yields of the hetro(aryl) nitriles were obtained using
heterocyclic substrates, demonstrating that this catalyst system is also suitable for the cyanation of hetro(aryl) halides (2v,x,z,2ad).
Bis-cyanation of aryl halides containing two halogen groups is possible using this method (2v,w). As demonstrated in Scheme 3,
this methodology is applicable in the synthesis of diverse aryl nitrile derivatives in good to excellent yields.
The potential utility of this method in organic synthesis was tested for the synthesis of letrozole as a non-steroidal aromatase
inhibitor.23 Using the Pd-CD-PU-NS catalyst system under optimized reaction conditions, the letrozole product was obtained in
87% isolated yield (Scheme 4).
N
N
N
O
OH
N
N
N
a)
b)
c)
Br
Br
Br
Br
Br
Br
92%
NC
CN
80%
87%
1ae
letrozole
Scheme 4. Synthesis of letrozole starting from bis(4-bromophenyl)methanone and using the Pd-CD-PU-NS catalyst in the
o
o
cyanation step. a) NaBH4, MeOH, rt. b) SOCl2, CH2Cl2, 0 C for 2h and then 1,2,4-triazole, K2CO3, DMF, 80 C, 24h. c) 1ae,
K4[Fe(CN)6], Pd-CD-PU-NS, Na2CO3, DMF:H2O (1:1)
A reaction mechanism is proposed in agreement with the literature.24-26 Accordingly, oxidative addition of aryl halides to Pd
species is followed by an anion exchange. Finally, reductive elimination affords the product. However, what is important here is the
role of the CD-PU-NS cavities in the stabilization of the Pd intermediates in the presence of water to enable the cyanation reaction
effectively in aqueous media. This structure has the ability to trap the released HCN in aqueous media and to prevent it from
poisoning the Pd catalyst through the formation of inactive [Pd(CN)m]n- complexes.8
14

Ar
X
Pd
Ar CN
Ar
Ar
Pd
CN
Pd
X
CN
NC
NC
CN
Fe
CN
CN
Ar
X
X
NC
CN
CN
Pd
Fe
CN
N
NC
NC
NC
CN
CN
Fe
CN
MDI unit
alpha-CD unit
Scheme 5. Proposed reaction mechanism for the cyanation reaction of aryl halides using the Pd-CD-PU-NS catalyst. It suggested
that the cyanation process is taking place in the cavities/microspheres in the structure of the CD-PU-NS substrate.
The reusability of the Pd-CD-PU-NS catalyst was also evaluated. The model reaction (Scheme 2) was selected and after
completion of the reaction, the catalyst was separated from the reaction mixture using simple filtration and was then washed with
water and dichloromethane. The catalyst could be reused for 5 times (run yields in order: 95, 93, 92, 91, 90%) without remarkable
decrease in its activity.
After 5 cycles of reusability, the Pd content of the Pd-CD-PU-NS catalyst was checked using ICP analysis, and the data showed
that about 0.9% of the total stabilized Pd species had leached from the CD-PU-NS substrate.
These experiments confirm that this substrate is highly efficient to prevent leaching of the metal species. It is likely that this
capability is related to the ability of the cyclodextrin unit(s) and urethane bonds in binding the metals.
To demonstrate the advantages of the introduced catalyst in the cyanation reaction of aryl halides with K4Fe(CN)6 compared to
other reported catalysts systems, a table of comparison is provided (Table 3). As shown in Table 3, the cyanation reaction with the
Pd-CD-PU-NS catalyst is acceptable with respect to reaction condition, time and yield in comparison with some of the previously
reported catalyst systems.28
15

Table 3. Comparison of the Pd-CD-PU-NS catalyst with other catalyst systems in the cyanation of 4-bromoacetophenone using
K4Fe(CN)6·3H2O as cyanide source
Entry
Cat. & Cat. amount
Pd-LHMS-3, 0.03g
Pd(OAC)2, 0.5 mol%
Pd NPs, 0. 5 mol%
Solvent
DMAc
Conditions
Time (h)
Yield (%)
Ref
24
1
2
3
4
5
6
7
110 °C, Sealed tube heating
120 °C, under nitrogen
120 °C
16
5
75
86
88
85
9
DMAc
DMF
3b
12
13
0.5
15
10
25
ZnO-Pd NPs, 0.015g (0.2 mol% Pd) DMF
130 °C, under argon
175 °C, microwave irradiation
140 °C, under nitrogen
120 °C, under air
26
CuI , 15 mol %
H2O
27
Pd@CC2r, 0.017 g (4 mol % Pd)
Pd-CD-PU-NS, 1.7 mol %
DMF
90
96
28
DMF:H2O
(1:1)
this
work
Conclusions
In conclusion, a new type of polymer-supported catalyst based on immobilized palladium nanoparticles on a nanosponge
cyclodextrin polyurethane has been illustrated. The TEM images of the catalyst show the formation of microspheres with a size of
100-200 nm. The microspheres are containing Pd nanoparticles with a size of less than 10 nm which are highly considerable for
catalysis. The Pd-CD-PU-NS catalyst showed high catalytic activity in the cyanation reaction of aryl halides with K4[Fe(CN)6] as a
nontoxic cyanide source in aqueous environment under aerobic conditions. This catalyst system is reusable several times and a
range of aryl cyanides could be synthesized using this catalyst system under optimized reaction conditions. Moreover, the CD-PU-
NS substrate and the Pd-CD-PU-NS catalyst provide great promise for further useful applications in organic synthesis and in the
absorption of metals in the future.
16

Experimental section
General
Chemicals were purchased from Sigma-Aldrich chemical company and used as received. FT-IR spectroscopy (Shimadzu FT-IR
8300 spectrophotometer) was employed for characterization of the catalyst and synthesized compounds. The scanning electron
micrography (SEM) images of the catalyst were obtained by SEM instrumentation (SEM, XL-30 FEG SEM, Philips, at 20 kV).
Transmission electron microscopy (TEM) images were obtained using a TEM apparatus (CM-10-Philips, 100 kV) for the
1
characterization of the Pd-CD-PU-NS catalyst. For recording H and 13C NMR spectra, we used a Bruker (250 and 300 MHz)
Advance DRX in pure deuterated DMSO-d6 and CDCl3 solvents with tetramethylsilane (TMS) as the internal standard. Melting
points were determined in open capillary tubes in a Barnstead Electrothermal 9100 BZ circulating-oil melting-point apparatus. The
reaction monitoring was accomplished by TLC on silica gel PolyGram SILG/UV254 plates. Column chromatography was carried
out on columns of silica gel 60 (70–230 mesh).
Procedure for the synthesis cyclodextrin polyurethane nanosponge (CD-PU-NS)
A 100 mL three-necked flask equipped with a thermometer, a dropping funnel, and a nitrogen inlet was charged with 5.0 mL of
dry DMF, and then was degassed by nitrogen for 30 min at room temperature. Then of α-cyclodextrin (CD; 0.50 mmol, 0.486 g) is
gradually added to reaction container. Subsequently, dry triethylamine (0.010 mmol, 0.0014 mL) was injected, and then a solution
of vigorously the methylene diphenyldiisocyanate (MDI; 5.0 mmol, 1.250 g) in DMF (1.0 mL) was added dropwise to the reaction
flask within 30 min. The reaction mixture was stirred seriously (1000 rpm) for 30 min at ambient temperature. Eventually, the
temperature was raised to 70 °C and maintained for 2 h. After this time, the white suspension was poured into 250 mL of acetone to
precipitate the polymer. The sediment was filtered, washed with water and acetone several times. Further purification was carried
out by soxhlet extraction with ethanol. The white powder was dried overnight at 35 °C in a vacuum oven.
Procedure for the synthesis of Pd nanoparticles on cyclodextrin polyurethane nanosponge (Pd-CD-PU-NS)
A mixture of polymer (0.50 g) in absolute ethanol was sonicated for 10 min and then palladium acetate (0.050 g, 0.22 mmol) was
added and stirred for 24 h at room temperature to form a black precipitate. Then, the mixture was filtered and washed with ethanol
(3 × 10 mL) and diethyl ether (2 × 10). Then the solid was dried in a vacuum oven to obtain the Pd-CD-PU-NS catalyst. Inductively
coupled plasma (ICP) analysis of the catalyst displayed that the Pd weight percentage on polymer substrate was 3.4%.
17

Procedure for cyanation aryl halide using Pd-CD-PU-NS catalyst
A round-bottomed flask (10 mL) was charged with aryl halide derivatives (1.5 mmol), Na2CO3 (1.8 mmol, 0.190 g), the catalyst
(7.5 mg, 1.7 mol% pd) and DMF/H2O (1:1; 5 mL) as solvent. The reaction mixture was heated to 120 °C and K4[Fe(CN)6].3H2O
(0.60 mmol, 0.253 g) was then added. The final mixture was stirred for the required period of time at 120 ºC to complete the
reaction, as monitored by TLC. The reaction mixture cool down to room temperature and the catalyst was filtrated. Then H2O (15.0
mL) was added to the mixture and the product was extracted with ethyl acetate (3 × 10.0 mL). The organic extracts were collected
and dried over anhydrous Na2SO4. Evaporation of the solvent afforded the crude product, which was purified by column
chromatography on silica gel using n-hexane or different mixtures of n-hexane–ethyl acetate as the eluents to afford the highly pure
products in 50-96% yields.
ACKNOWLEDGMENT
Financial support from the research councils of Shiraz University is gratefully acknowledged.
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Aryl Halide Cyanation and Hiyama Cross-Coupling Reaction Under Ligand Free Conditions. Catalysis Letters, 1-17. DOI:
10.1007/s10562-018-2369-5.
(26) Chatterjee, T., Dey, R., &Ranu, B. C. (2014). ZnO-Supported Pd Nanoparticle-Catalyzed Ligand-and Additive-Free Cyanation of
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(27) DeBlase, C., &Leadbeater, N. E. (2010). Ligand-free CuI-catalyzed cyanation of aryl halides using K4 [Fe(CN)6] as cyanide source and
water as solvent. Tetrahedron, 66(5), 1098-1101. DOI:10.1016/j.tet.2009.11.016.
(28) Mondal, B., Acharyya, K., Howlader, P., & Mukherjee, P. S. (2016). Molecular cage impregnated palladium nanoparticles: efficient,
additive-free heterogeneous catalysts for cyanation of aryl halides. Journal of the American Chemical Society, 138(5), 1709-
1716.DOI: 10.1021/jacs.5b13307.
20

Graphical Abstract
X
CN
R
R
K4[Fe(CN)6]
120 o
C
X = Cl, Br, I
X = Cl, Br, I
O
O
O
O
H
O
O
O
HO
H2O
O
H2O
H2O
H
O
N
OH
O
H
N
HO
HO
H2O
H2O
OH
HO
OH
O
O
N
OH
OH
OH
O
OH
O
OH
OH
HO
OH
HO
OH
O
O
O
OH
O
O
O
O
O
O
OH
OH
O
O
H2O
HO
OH
OH
HO
O
O
O
O
N
H
N
O
O
O
O
H2O
HO
OH
H
OH
O
OH
OH
O
N
N
O
HO
OH
O
O
OH
OH
O
H
H
O
O
O
O
O
H2O
OH
O
OH
H2O
O
HO
H2O
H2O
O
O
O
O
H
N
O
HO
O
HO
HN
O
O
O
OH
OH
O
O
HO
O
OH
HN
O
O
H2O
H2O
O
O
H
N
H
N
HO
O
NH
H
N
H
N
H2O
H2O
HN
O
H
N
O
H2O
O
HN
O
O
H2O
O
H2O
H2O
O
O
H2O
HO
O
HO
H2O
H
N
OH
NH
O
HO
OH
HO
OH
O
HO
O
O
OH
OH
O
OH
OH
O
OH
HO
O
O
O
O
HO
OH
O
O
O
O
O
OH
OH
O
O
OH
OH
HO
H2O
OH
HO
OH
O
O
O
O
N
N
O
O
O
OH
O
O
H
H
O
OH
O
HO
OH
N
H
N
O
OH
OH
O
H
HO
O
O
O
O
O
OH
O
O
OH
OH
O
O
OH
H2O
O
O
O
O
O
HO
OH
O
H2O
O
O
OH
OH
H
N
H
N
HO
OH
O
O
H2O
O
H
N
H2O
PNPs
HO
21

Highlight
► Synthesis of a cyclodextrin-polyurethane nanosponge as support in nano-catalysis
► Immobilization of palladium nanoparticles with a size of ~7 nm on CD-PU-NS surface
► Catalytic application of Pd-CD-PU-NS in the cyanation reaction of aryl halides in aqueous media
► The Pd-CD-PU-NS catalyst is a heterogeneous catalyst with 5 times reusability
22