A green and facile approach for the synthesis of N-monosubstituted ureas in water: Pd catalyzed reaction of arylcyanamides (an unexpected behavior of electron withdrawing groups)

Article abstract of DOI:10.1016/j.poly.2018.05.049

The Fe₃O₄ magnetic nano-particles were prepared, coated with tetraethyl orthosilicate (TEOS), functionalized with 3-chloropropyltrimethoxysilane (CPTMS), further functionalized with 2,2′-(piperazine-1,4-diylbis(methylene) dianiline (PDMD) and the corresponding Pd complex synthesized as a novel nano-magnetic heterogeneous catalyst (Fe₃O₄@SiO₂@CPTMS@PDMD@Pd) to be used for the synthesis of various N-monosubstituted ureas in water. Also, in another attempt to see the effect of HCOOH, the hydration reaction of arylcyanamide was carried out in the presence of HCOOH (water + 98% HCOOH) which had two effects: it decreased the amount of the Pd catalyst from 40 to 30 mg, and the reaction condition was changed from the reflux condition to room temperature. Interestingly, the arylcyanamides with electron withdrawing groups influence the course of the reaction and need more reaction times for completion which is an unexpected behavior, probably due to the high electron density around the central carbon atom of the nitrile group.

Full text of DOI:10.1016/j.poly.2018.05.049

Accepted Manuscript
A green and facile approach for the synthesis of N-monosubstituted ureas in
water: Pd catalyzed reaction of arylcyanamides (an unexpected behavior of
electron withdrawing groups)
Davood Habibi, Somayyeh Heydari, Alireza Faraji, Hasan Keypour, Masoumeh
Mahmoudabadi
PII:
S0277-5387(18)30294-8
https://doi.org/10.1016/j.poly.2018.05.049
POLY 13196
DOI:
Reference:
Polyhedron
To appear in:
Received Date:
Revised Date:
Accepted Date:
10 March 2018
19 May 2018
20 May 2018
Please cite this article as: D. Habibi, S. Heydari, A. Faraji, H. Keypour, M. Mahmoudabadi, A green and facile
approach for the synthesis of N-monosubstituted ureas in water: Pd catalyzed reaction of arylcyanamides (an
unexpected behavior of electron withdrawing groups), Polyhedron (2018), doi: https://doi.org/10.1016/j.poly.
2018.05.049
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A green and facile approach for the synthesis of N-monosubstituted ureas in water: Pd catalyzed
reaction of arylcyanamides (an unexpected behavior of electron withdrawing groups)
Davood Habibi*, Somayyeh Heydari, Alireza Faraji, Hasan Keypour, Masoumeh Mahmoudabadi
Department of Organic Chemistry, Faculty of Chemistry, Bu-Ali Sina University, Hamedan, 6517838683 Iran
* Corresponding author. Tel: +98 81 38380922; Fax: +98 81 38380709; e-mail: davood.habibi@gmail.com (D. Habibi)
ABSTRACT
The Fe3O4 magnetic nano-particles were prepared, coated with tetraethyl orthosilicate (TEOS), functionalized
with 3-chloropropyltrimethoxysilane (CPTMS), further functionalized with 2,2’-(piperazine-1,4-diylbis(methylene)
dianiline (PDMD) and the corresponding Pd complex synthesized as a novel nano-magnetic heterogeneous catalyst
(Fe3O4@SiO2@CPTMS@PDMD@Pd) to be used for the synthesis of various N-monosubstituted ureas in water.
Also, in another attempt to see the effect of HCOOH, the hydration reaction of arylcyanamide was carried out
in the presence of HCOOH (water + 98% HCOOH) which had two effects: it decreased the amount of the Pd catalyst
from 40 to 30 mg, and the reaction condition was changed from the reflux condition to room temperature.
Interestingly, the arylcyanamides with electron withdrawing groups influence the course of the reaction and
need more reaction times for completion which is an unexpected behavior, probably due to the high electron
density around the central carbon atom of the nitrile group.
Keywords: Pd nano-particle catalyst; Tetraethyl orthosilicate; 3-Chloropropyltrimethoxysilane; Monosubstituted
ureas; 2,2’-(Piperazine-1,4-diylbis(methylene))dianiline
1. Introduction
Urea derivatives have been synthesized by a number of methods and used for treatment of a range
of tumors [1-6]. Urea-based pro-drugs have been reported as candidates for melanocyte-directed
enzyme pro-drug therapy which the drug will be released upon exposure to tyrosinase [7]. Some
corresponding urea derivatives have been also reported as protein tyrosine kinases inhibitors to become
potential anticancer drugs [8]. For these reasons, the synthesis of urea and their functionalized
derivatives is of high interest. For instance, L. Fu and coworker designed and synthesized a novel series
of ureas containing pyrimidinyl group. Some of the prepared compounds showed potential cytotoxicity
against several human cancer cell lines. From the structure-activity relationships we may conclude that
introduction of a sulfide bridge between phenyl and pyrimidinyl rings would be critical for their
biological activities [9].
Also, aryl urea is an interesting entity for many medicinal chemists to explore its various biological
activities. For example Umadevi and coworkers synthesized few compounds by condensing urea, thio-
1

urea and thiosemicarbazide with phenol and substituted aromatic aldehyde (Scheme 1, compounds 1 to
5). These compounds were further evaluated for antibacterial activity in vivo against Bacillus subtilis,
Salmonella aureus, Salmonella typhi and Shigella dysentry. Ampicillin was taken as standard drug. These
compounds show significant antibacterial activity [10].
Scheme 1. Synthesis of some medicinal ureas
The hydrolysis of cyanamide to urea by different catalysts has been investigated for a long time [11-
16], since the N-monosubstituted ureas are found in many natural products and were used in
pharmaceutical and agrochemical industry, biological chemistry, and agrochemical industry [17-22].
Some researchers have devoted their careers to find the better procedure for the synthesis of ureas. For
example, D. P. Fairlie and coworkers synthesized the guanidine and urea Ligands through amination and
hydration of a cyanamide ligand bound to Pt(II), Os(III), and Co(III) [23]. F. Briganti and coworkers
prepared urea from the hydration reaction of cyanamide by the use of carbonic anhydrase catalyst [24].
P.-L. Fabre and coworkers prepared the [Pd(en)(3,4-(NC(O)NH2)sq)]-0.5H2O complex and observed the
2

unusual hydration of the cyanamido ligand [25]. The three-dimensional structure of a possible
intermediate in the hydration reaction of cyanamide to urea catalyzed by human carbonic anhydrase II
(hCAII) has been determined by S. Mangani and coworkers via the cryocrystallographic techniques [26].
However, hydration of cyanamides suffers from various disadvantages such as low yields, long
reaction times, the use of corrosive base or acids, the use of the toxic organic solvents, application of
the expensive, toxic and dangerous reagents or catalysts and tedious work-up [27-31]. Therefore, it is
desirable to develop an efficient and green method for the preparation of N-monosubstituted ureas that
reduce or eliminate the problems.
The use of magnetic nanoparticle catalysts has a significant growth during the past decade since
nanoparticles have a large surface-to-volume ratio compared to bulk materials [32-34]. Also, their use
are in accord with the principles of green chemistry due to their minimum chemical wastes, energy
efficiency, improved economy and easy separation since the system is heterogeneous. Among the
various magnetic nanoparticles, Fe3O4 is the most widely used magnetic substance for catalyst
supported which is less toxic than their metallic counterparts [35]. For example, a magnetic nanoparticle
conjugated mesoporous nanocatalyst (Fe3O4@SBA-15) with a high surface area was synthesized by A.
Bhaumik and co-workers via the chemical conjugation of Fe3O4 nanoparticles with functionalized
mesoporous SBA-15. The Fe3O4@SBA-15 catalyst has surface carboxyl and amino groups and was
synthesized by the thiol-ene click reaction of cysteine hydrochloride and vinyl functionalized SBA-15. The
catalytic activity was evaluated in the Biginelli reaction under mild conditions for the synthesis of a
diverse range of 3,4-dihydropyrimidin-2(1H)-ones. The separation and reuse of the Fe3O4@mesoporous
SBA-15 nanocatalyst were simple, effective and economical [36].
Due to the potential application of the urea derivatives as anti-cancer and anti-tumor drugs, we
report the synthesis of a range of N-monosubstituted ureas from the hydration reaction of
arylcyanamide in water in the absence or presence of 98% formic acid by the Pd nano-particle catalyst at
room temperature (Scheme 2).
Scheme 2. Synthesis of the N-monosubstituted ureas
3

Also, we would like to report preparation of the Pd nano-particle catalyst (Fe3O4@SiO2@CPTMS@
PDMD@Pd) via synthesis of the Fe3O4 magnetic nanoparticles, its coating with TEOS, functionalization
with CPTMS and PDMD ligands, and complexation with PdCl2, to be used as an efficient heterogeneous
nano-particle catalyst for the synthesis of N-monosubstituted ureas (Scheme 3).
Scheme 3. Synthesis of the Pd nano-particle catalyst
2. Results and discussion
2.1. Synthesis of the Pd catalyst
The Pd nano-particle catalyst (Fe3O4@SiO2@CPTMS@PDMD@Pd) was prepared via synthesis of the
Fe3O4 magnetic nanoparticles, its coating with TEOS, functionalization with CPTMS and PDMD ligands,
and complexation with PdCl2.
2.1. Characterization of the Pd catalyst
Formation of the Pd nano-catalyst was verified by FT-IR, X-ray diffraction (XRD), dispersive X-ray
spectroscopy (EDX), scanning electron microscope (SEM), transmission electron microscope (TEM),
thermo-gravimetry-differential thermal analysis (TG-DTA), X-ray photoelectron spectroscopy (XPS) and
vibrating sample magnetometer (VSM).
2.1.1. Characterization of the catalyst by the IR spectroscopy
Figure 1 shows the four FT-IR spectra of: Fe3O4@SiO2 (A), Fe3O4@SiO2@CPTMS (B), Fe3O4@SiO2@
CPTMS@PDMD (C) and the Fe3O4 @SiO2@CPTMS@PDMD@Pd nano-catalyst (D).
Curve A exhibits two basic characteristic peaks at about 583 and 1082 cm-1 which are attributed to
the presence of the Fe–O and Si-O vibrations, respectively to indicate the silica coated magnetite
nanoparticles. Curve B shows a new peak at about 635 cm-1 indicating presence of the C-Cl bond. Curve
C shows two new peaks at 1375 and 3443 cm−1 which are attributed to the C-N and N-H bonds,
4

respectively to indicate anchoring of the 2,2’-(piperazine-1,4-diylbis(methylene))dianiline ligand to
Fe3O4@SiO2@CPTMS. And finally, the curve D shows shifts from 3443 to 3478 and from 1623.9 to
1632.5 cm−1 which are related to the new interactions of Pd with the nitrogen containing ligand.
Consequently, comparison of the IR spectra confirms the successful stages of the Pd nano-catalyst.
Fig. 1. The IR spectra of Fe3O4@SiO2 (A), Fe3O4@SiO2@CPTMS (B), Fe3O4@SiO2@CPTMS@PDMD (C) and the Fe3O4
@SiO2@CPTMS@PDMD@Pd nano-catalyst (D)
2.1.2. Characterization of the catalyst by the XRD patterns
Figure 2 shows the XRD patterns of Fe3O4@SiO2 (blue), Fe3O4@SiO2@CPTMS (red), Fe3O4@SiO2@
CPTMS@PDMD (green) and Fe3O4@SiO2@CPTMS@PDMD@Pd nano-catalyst (purple). The XRD pattern
exhibited peaks at 2θ of 10, 15-20, 30, 35, 43, 53, 57 and 63 correspond to the spinal structure of Fe3O4
MNPs. The XRD pattern of the Fe3O4@SiO2@CPTMS@PDMD@Pd nano-catalyst exhibited broadened
pattern due to its non-crystalline nature at 17, 27, 29, 38, 50, 52, 80, 83 and 87.
5

Fig. 2. The XRD patterns of Fe3O4@SiO2 (blue), Fe3O4@SiO2@CPTMS (red), Fe3O4@SiO2@ CPTMS@PDMD (green)
and Fe3O4@SiO2@CPTMS@PDMD@Pd nano-catalyst (purple)
2.1.3. Characterization of the catalyst by the EDX analysis
The chemical composition of the Fe3O4@ SiO2@CPTMS@PDMD@Pd catalyst was determined by the
EDX analysis (Fig. 3). The provided scans showed the presence of the anticipated elements in the
structure of the catalyst, namely carbon, oxygen, silicon, nitrogen, iron and palladium.
5000
PdL
4000
3000
PdL
2000
1000
FeL
O K
N K
SiK
FeK
FeK
keV
15
0
0
5
10
Fig. 3. The EDX analysis of Fe3O4@SiO2@CPTMS@PDMD@Pd
2.1.4. Characterization of the catalyst by the SEM and the TEM images
The morphology and the particle size distribution of the Pd nano-catalyst were determined by the
SEM and TEM images (Figs. 4 and 5). According to these figures, the nanoparticles appearance and their
sizes are similar, indicating that the Pd nano-catalyst adequately coated to have good mechanical
stability during the whole modification. Also, the SEM images of the Pd nano-catalyst showed that the
sizes of the catalysts are roughly between 20 to about 25 nm.
6

Fig. 4. The SEM images of Fe3O4@SiO2@CPTMS@PDMD@Pd
Fig. 5. The TEM images of the Fe3O4@SiO2@CPTMS@PDMD@Pd nano-catalyst
2.1.5. Characterization of the Pd nano-catalyst by the TG-DTA technique
The thermogravimetric analysis curves of the Fe3O4@SiO2@CPTMS@PDMD@Pd nano-catalyst show
the mass loss of the organic materials as they decompose upon heating (Fig. 6). It can be observed that
the nano-catalyst shows about five weight loss steps in the temperature range of about 125, 150, 250,
310 and 425 ᵒC, respectively. The initial two weight losses at 125 and 150 ᵒC are probably due to the
residual water, the third step at 250 ᵒC is attributed to the thermal decomposition of the complex, the
fourth step is probably due to the thermal decomposition of the CPTMS and PDMD ligands, and the fifth
7

step is probably due to the thermal decomposition of the SiO2 coating layers and Fe3O4.
On the basis of these results, the well grafting of ligand groups on the support is verified and
indicated that the nano catalyst has approximately a good thermal stability which is probably due to the
strong interaction between the CPTMS and PDMD ligands and Fe3O4 MNPs.
100.0
70.00
35.00
98.0
65.00
96.0
60.00
30.00
25.00
20.00
15.00
10.00
5.00
94.0
92.0
90.0
88.0
86.0
84.0
82.0
80.0
78.0
76.0
74.0
72.0
70.0
55.00
50.00
45.00
40.00
35.00
30.00
25.00
20.00
15.00
10.00
5.00
0.00
-5.00
-10.00
0.00
50.0
100.0
150.0
200.0
250.0
300.0
350.0
400.0
450.0
500.0
550.0
Temp Cel
Fig. 6. TG-DTA patterns of the Fe3O4@SiO2@CPTMS@PDMD@Pd nano-catalyst
2.1.6. Characterization of the Pd nano-catalyst by the VSM technique
The VSM analyses of Fe3O4@SiO2 (A), Fe3O4@SiO2@CPTMS (B) Fe3O4@SiO2@CPTMS@PDMD (C),
and the Fe3O4@SiO2@CPTMS@PDMD@Pd nano-catalyst (D) were performed in order to demonstrate
their magnetic properties (Fig. 7). As can be seen, all four compounds have magnetic properties;
however, magnetization of B (35 emu/g), C (27 emu/g) and D (12 emu/g) were decreased to some
extent in comparison with A (52 emu/g). This can be explained by considering the reduction in the
dipolar–dipolar interactions between the magnetic nanoparticles after their coating with SiO2,
functionalization with the CPTMS and PDMD ligands and complexation with the Pd ions which cause the
more coating of Fe3O4 MNPs.
8

65
52
42
35
28
21
14
7
39
26
13
0
0
-7
-13
-26
-39
-52
-65
-14
-21
-28
-35
-42
-10000 -8000 -6000 -4000 -2000
0
2000 4000 6000 8000 10000
-10000 -8000 -6000 -4000 -2000
0
2000
4000
6000
8000 10000
Applied Field(Oe)
Applied Field(Oe)
36
27
18
9
14
12
10
8
6
4
2
0
0
-2
-4
-6
-8
-10
-12
-14
-9
-18
-27
-36
-10000 -8000 -6000 -4000 -2000
0
2000 4000 6000 8000 10000
-10000 -8000 -6000 -4000 -2000
0
2000 4000 6000 8000 10000
Applied Field(Oe)
Applied Field(Oe)
Fig. 7. The VSM analyses of Fe3O4@SiO2 (A), Fe3O4@SiO2@CPTMS (B), Fe3O4@SiO2@CPTMS@ PDMD (C), and
Fe3O4@SiO2@CPTMS@PDMD@Pd (D)
2.1.7. Characterization of the catalyst by the XPS analysis
The XPS analysis is used to investigate the elemental compositions and the surface chemistry of the
Fe3O4@SiO2@CPTMS@PDMD@Pd nano-magnetic heterogeneous catalyst (Fig. 8). The overall XPS
spectrum of the Pd catalyst revealed that it is consisted of C, N, O, Si, Fe and Pd elements. The high-
resolution XPS spectrum of carbon peaks centered at 284.2, 285.3, and 399.8 eV, correspond to carbon
species of C=C, (C–N, and C-Si) and C-N, respectively. Also, the XPS spectrum of Pd peaks centered at
342.9, and 337.6 eV, correspond to Pd2+3d3/2 and Pd2+3d5/2, respectively. In addition, small amount of
Pd2+ was reduced in the course of reaction which the related peak was appeared at 336.0 (Pd03d5/2) [37-
39].
9

Fig 8. The XPS analysis of the Fe3O4@SiO2@CPTMS@PDMD@Pd catalyst
2.2 Synthesis of the N-monosubstituted ureas
Synthesis of the monosubstituted ureas by the Pd nano-particle catalyst was the next step to
optimize the reaction condition (Table 1). Therefore, the catalytic activity of the Fe3O4@SiO2@
10

CPTMS@PDMD@Pd nano-particle catalyst was investigated in the synthesis of 4-chlorophenylurea (2g)
as a model reaction in 24 different conditions of solvents (toluene, EtOH, H2O and H2O/HCOOH),
temperatures (room temperature and reflux) and amounts of the Pd catalyst (20, 30 and 40 mg).
Table 1. The hydration reaction optimization of 4-chlorophenylcyanamide (2g)* in different solvents and
temperatures by various amounts of Pd nanoparticles
Entry
Solvent
Temp Amount Time Yield Entry
Solvent
Temp Amount Time Yield
(°C)
rt
“
“
“
“
“
“
“
“
“
“
“
(mg)
20
20
20
20
30
30
30
30
40
40
40
40
(min)
109
98
90
20
89
100
85
20
88
(%)
49
51
65
35
65
61
70
93
68
72
73
85
(°C)
reflux
(mg)
20
20
20
20
30
30
30
30
40
40
40
40
(min)
90
80
80
-
70
65
65
25
57
45
30
-
(%)
60
65
67
-
73
85
87
85
72
89
93
-
1
2
3
4
5
6
7
8
9
toluene
EtOH
H2O
13
14
15
16
17
18
19
20
21
22
23
24
toluene
EtOH
H2O
“
“
“
“
“
“
“
“
“
“
“
H2O + HCOOH**
toluene
EtOH
H2O
H2O + HCOOH**
toluene
EtOH
H2O
H2O + HCOOH**
H2O + HCOOH**
toluene
EtOH
H2O
H2O + HCOOH**
toluene
EtOH
H2O
H2O + HCOOH**
10
11
12
82
80
25
* 1.0 mmol
** 2.0 mmol
By comparing the reaction times and yields, water was chosen as the best solvent and the two
following results were observed:

In the absence of HCOOH (water alone), the best result was obtained with 1.0 mmol of
arylcyanamide and 40 mg of the Pd nano-particle catalyst at reflux condition (entry 23, Table 1).
In the presence of formic acid (water + 98% HCOOH), the best result was obtained with 1.0
mmol of arylcyanamide, 2.0 mmol of HCOOH, and 30 mg of the Pd nano-particle catalyst at
room temperature (entry 8, Table 1). In several attempts, it was found that the best
concentration of HCOOH is 2.0 mmol.

Also, an increase on the reaction times with decreasing the yields were observed when we increased
the amount of the Pd catalyst from 30 to 40 mg in H2O/HOOH (entry 12, Table 1) or changing the
reaction condition from room temperature to reflux (entry 20, Table 1), which could be attributed to the
rate increase of the reverse reactions.
So, according to the optimized reaction conditions, synthesis of the various monosubstituted ureas
was carried out from the hydration reaction of arylcyanamide (1.0 mmol) in water in the absence or
presence of 98% formic acid (2.0 mmol) by the Fe3O4@SiO2@CPTMS@PDMD@Pd nano-particle catalyst
(Table 2). The results showed that the Pd nano-catalyst was effective for application of various
11

arylcyanamides with electron releasing or electron withdrawing groups in water or the mixture of water
+ 98% formic acid.
Table 2. The hydration reaction of arylcyanamides in water catalyzed by the Pd nano-particle catalyst
H2O
H2O + HCOOH (98%)
Entry
Arylcyanamide (1a-j)
Product (2a-j)
Time
(min)
Yield
%
Time
(min)
Yield
%
1
30
91
25
91
1a
2a
2c
2
3
30
93
30
93
1b
2b
35
93
40
91
1c
4
5
6
40
130
90
92
92
87
30
93
93
89
1d
2d
150
100
1e
2e
1f
2f
7
8
30
50
93
92
20
60
93
91
1g
2g
1h
1i
2h
2i
9
50
35
91
90
65
30
90
92
10
1j
2j
12

According to Scheme 3 and as far as we know due to our experiences so far, the withdrawing groups
usually facilitate the reaction rates in the nucleophilic substitution reactions, since they pull out the
electron density of the electrophilic centers inductively or by resonance, so the electrophilic centers will
become more positive, hence the nucleophilic attack will become easier [40,41].
Also, in this research project, we expected the same thing, but interestingly the arylcyanamides with
the withdrawing groups (entries 5 and 6, Table 2) need more reaction times for completion and
decreased the reaction rates in the observed phenomenon which was completely vice-versa and in our
opinion it is an unexpected behavior. This phenomenon is probably due to the high electron density
(bonding and unshared electron pair of the adjacent nitrogen atom) around the central carbon atom of
the nitrile group, which the nucleophilic attack by water becomes more difficult (Scheme 4).
Scheme 4. Difficulty of attacking water to the carbon of the nitrile group
2.3. Plausible mechanism of the reaction
The plausible mechanism for the synthesis of various N-monosubstituted ureas in water at room
temperature is shown in Scheme 5. The proposed mechanism is probably due to the Lewis acidity of the
Pd nano-catalyst by attaching to the nitrile group to facilitate the nucleophilic attack of the water to
form the intermediate with the subsequent formation of the final product.
Scheme 5. The plausible mechanism for the synthesis of varies of N-monosubstituted ureas
2.4. Recyclability of the Pd catalyst
The recyclability of the Fe3O4@SiO2@CPTMS@PDMD@Pd catalyst was investigated with the model
reaction (synthesis of 2g from the reaction of 1.0 mmol of 4-chlorophenylcyanamide, 2.0 mmol of
HCOOH, and 30 mg of the Pd nano-particle catalyst at room temperature in water), to find the capability
13

of the catalyst. After completion of the reaction as monitored by TLC, the catalyst was separated by the
strong magnet after the first run, washed with ethanol and dried under vacuum and then reused for the
next five successive runs under the same reaction conditions. Consequently, we found that the Pd
catalyst is a capable and reusable catalyst even after five runs; and the catalytic activity was almost as
same as the fresh one during the synthesis of various N-monosubstituted ureas in water (93, 91, 88, 84
and 81%, respectively).
2.5. Characterization of various monosubstituted ureas
All prepared compounds are known and were characterized by comparing their physical and
spectral data with those reported in the literature. The structures of the N-monosubstituted ureas were
in agreement with their IR and NMR spectra. In the IR spectra, the CN peaks at about 2200-2300 cm-1
were disappeared and one strong carbonyl band appeared instead (about 1700 cm-1). Also, a two bands
peak will appear at about 3300-3400 cm-1 which is attributed to the NH2 group.
N-Phenylurea (2a): M.p. 143-145 °C; FT-IR (KBr, cm-1) specific peaks: 3346, 3268, 3193, 3057, 1740,
1
13
1656; HNMR (300 MHz, DMSO-d6): δH = 8.55 (1H, NH), 6.86-7.39 (5H, aromatic), 5.84 (2H, NH2); C
NMR (75 MHz, DMSO-d6): δC = 156.51 (carbonyl C), 141-118.18 (aromatic C); Anal. calcd. for C7H8N2O: C,
61.75; H, 5.92; N, 20.58. Found: C, 61.65; H, 5.82; N, 20.49%.
N-(4-Methylphenyl)urea (2b): M.p. 182-184 °C; FT-IR (KBr, cm-1) specific peaks: 3431, 3311, 3218,
1
3041, 2920, 1655, 1651, 1620; H NMR (300 MHz, DMSO-d6): δH = 8.35 (1H, NH), 6.98-7.25 (4H,
aromatic), 5.73 (2H, NH2), 2.19 (3H, CH3); 13C NMR (75 MHz, DMSO-d6): δC = 156.47 (carbonyl C), 138.42-
118.25 (aromatic C), 40 (methyl C); Anal. calcd. for C8H10N2O: C, 63.98; H, 6.71; N, 18.65. Found: C, 63.35;
H, 6.65; N, 18.51%.
N-(2-Methylphenyl)urea (2c): M.p. 196-198 °C; FT-IR (KBr, cm-1) specific peaks: 3438, 3315, 3218,
1650, 1613, 1582, 1547; 1H NMR (250 MHz, DMSO-d6): δH = 7.79 (1H, NH), 7.69-6.88 (4H, aromatic), 6.03
13
(2H, NH2), 2.19 (3H, CH3); C NMR (62.5 MHz, DMSO-d6): δC = 156.6 (carbonyl C), 138.6, 130.5-121.4
(aromatic C), 18.36 (methyl C); Anal. calcd. for C8H10N2O: C, 63.98; H, 6.71; N, 18.65. Found: C, 63.85; H,
6.61; N, 18.52.
N-(4-Methoxyphenyl)urea (2d): M.p. 167-169 °C; FT-IR (KBr, cm-1) specific peaks: 3471, 3337, 3195,
1
2955, 1645, 1592, 1547, 1038; H NMR (300 MHz, DMSO-d6): δH = 8.27 (1H, NH), 7.24-6.77 (2H,
aromatic), 5.68 (2H, NH2), 3.31 (3H, OCH3); 13C NMR (75 MHz, DMSO-d6): δC = 154.36 (carbonyl C),
134.11-114.26 (aromatic C), 55.56 (methyl C); Anal. calcd. For C8H10N2O2: C, 57.82; H, 6.07; N, 16.86.
14

Found: C, 57.71; H, 5.94; N, 16.78.%
N-(4-Acethylphenyl)urea (2e): M.p. 297-298 °C; FT-IR (KBr, cm-1) specific peaks: 3407, 3307, 3215,
1
3066, 1672, 1613, 1584, 1536; H NMR (300 MHz, DMSO-d6): δH = 8.93 (1H, NH), 7.84-7.48 (4H,
13
aromatic), 6.02 (2H, NH2), 2.47 (3H, COCH3); C NMR (75 MHz, DMSO-d6): δC = 196.64 and 155.98 (two
carbonyl C), 145.68- 117.06 (aromatic C), 26.71 (methyl C); Anal. calcd. for C9H10N2O2: C, 60.66; H, 5.66;
N, 15.72. Found: C, 60.47; H, 5.45; N, 15.59.
N-(4-Nitrophenyl)urea (2f): M.p. 226-229 °C; FT-IR (KBr, cm-1) specific peaks: 3488, 3381, 3317, 3218,
2804, 1690, 1595, 1550; 1H NMR (300 MHz, DMSO-d6): δH = 9.29 (1H, NH), 8.11-7.59 (4H, aromatic), 6.18
13
(2H, NH2); C NMR (75 MHz, DMSO-d6): δC = 155.73 (carbonyl C), 147.71-117.3m (aromatic C); Anal.
calcd. for C7H7N3O3: C, 46.41; H, 3.89; N, 23.20. Found: C, 46.52; H, 3.80; N, 23.08%.
N-(4-Chlorophenyl)urea (2g): M.p. 208-210 °C; FT-IR (KBr, cm-1) specific peaks: 3426, 3314, 3209,
1
1654, 1611, 1587, 730.91; H NMR (250 MHz, DMSO-d6): δH = 8.65 (1H, NH), 7.41-6.72 (4H, aromatic),
5.90 (2H, NH2); 13C NMR (62.5 MHz, DMSO-d6): δC = 156.38 (carbonyl C), 139.9-119.71 (aromatic C); Anal.
calcd. for C7H7ClN2O: C,49.28; H, 4.14; N, 16.42. Found: C, 49.17; H, 4.05; N, 16.31%.
N-(2,5-Dichlorophenyl)urea (2h): M. p. 222-224 °C; FT-IR (KBr, cm-1) specific peaks: 3495, 3417,
1
3364, 2826, 1676, 1610, 1586, 764; H NMR (300 MHz, DMSO-d6): δH = 8.27 (1H, NH), 8.26-6.96 (3H,
aromatic), 6.58 (2H, NH2); 13C NMR (75 MHz, DMSO-d6): δC = 155.84 (carbonyl C), 138.51-119.91
(aromatic C); Anal. calcd. for C7H6N2OCl2: C, 41.00; H, 2.95; N, 13.66. Found: C, 39.84; H, 2.89; N, 13.80.
N-(3-Bromophenyl)urea (2i): M.p. 141-143 °C; FT-IR (KBr, cm-1) specific peaks: 3375, 3333, 3189,
1
1679, 1578, 599; H NMR (250 MHz, DMSO-d6): δH = 8.74 (1H, NH), 7.83-7.06 (4H, aromatic), 5.97 (2H,
13
NH2); C NMR (62.5 MHz, DMSO-d6): δC = 156.2 (carbonyl C), 142.7-116.8 aromatic C); Anal. calcd. for
C7H7N2OBr: C, 39.10; H, 3.28; N, 37.16. Found: C, 39.20; H, 3.34; N, 37.26%.
N-(1-Naphthyl)urea (2j): M.p. 221-222 °C; FT-IR (KBr, cm-1) specific peaks: 3444, 33055, 3206, 3052,
1
1651, 1608, 1555, 608; H NMR (250 MHz, DMSO-d6): δH = 8.70 (1H, NH), 8.15-7.38 (7H, aromatic
naphthyl), 6.18 (2H, NH2); 13C NMR (62.5 MHz, DMSO-d6): δC = 156.86 (carbonyl C), 135.7-117.11
(aromatic C); Anal. calcd. for C11H10N2O2: C, 70.95; H, 5.41; N, 15.04. Found: C, 70.82; H, 5.34; N, 14.91.
3. Experimental
3.1.Preparation of the Pd nano-catalyst
Novel Pd nano-catalyst was prepared in the following five successive stages:
15

Stage 1: Preparation of the Fe3O4 magnetic nanoparticles (Fe3O4 MNPs): The Fe3O4 MNPs was
prepared according to the literature [42]. Briefly, the mixture of FeCl3.6H2O (11.44 g) and FeCl2.4H2O (4.3
g) was dissolved in water (100 ml), and the solution stirred for 0.5 h in 80 ᵒC. The solution of 37%
ammonia was then added dropwise with vigorous stirring which a black solid product obtained when a
reaction media reached to pH 10. The mixture was heated for 0.5 h at 70 ᵒC and the black magnetite
solid product filtered, washed with water and dried at 80 ᵒC for 12 h.
Stage 2: Coating of the Fe3O4 magnetic nano-particles with TEOS (Fe3O4@SiO2). Fe3O4@SiO2 was
synthesized according to the literature [43]. Briefly, Fe3O4 MNPs (0.2 g, prepared in the Stage 1) were
dispersed into a solution containing ethanol and distilled water (250 ml, V/V = 4:1) and NH3.H2O (3 ml)
under ultrasonication. Then, tetraethyl orthosilicate (TEOS, 2 ml) was slowly added dropwise and the
mixture stirred for further 6 h. Fe3O4@SiO2 was obtained by centrifugation, washed with water and
ethanol for several times, and dried in vacuo.
Stage 3: Functionalization of the SiO2 coated Fe3O4 with the CPTMS ligand. (3-Chloropropyl)-
trimethoxysilane (CPTMS) (1.0 ml, 5 mmol) dissolved in dry toluene (100 ml) and Fe3O4@SiO2 (1.0 g,
prepared in the Stage 2) added and stirred for 18 h at 60 ᵒC. Then, the obtained product
(Fe3O4@SiO2@CPTMS) was separated with strong magnet, washed with toluene and dried in vacuo.
Stage 4: Further functionalization with the PDMD ligand. 2,2’-(Piperazine-1,4-diylbis(methylene)
dianiline (0.9 g, 3 mmol) and K2CO3 (0.414 g, 3 mmol) in toluene (50 ml) were added to
Fe3O4@SiO2@CPTMS (0.06 g, prepared from the Stage 3) and refluxed for 12 h. Then, the obtained
product (Fe3O4@SiO2@CPTMS@PDMD) was separated with strong magnet, washed repeatedly with
ethanol and water and dried in vacuo, and
Stage 5: Complexation of Fe3O4@SiO2@CPTMS@PDMD with PdCl2. Fe3O4@SiO2@CPTMS@PDMD
(0.2 g, prepared from the Stage 4) was added to a dispersed PdCl2 (0.52 g, 3 mmol) in toluene and stirred
vigorously for 24 h under nitrogen atmosphere at 70 ᵒC. Then, the resulting Pd catalyst (Fe3O4@SiO2@
CPTMS@PDMD@Pd) was separated with strong magnet, washed with ethanol and air-dried.
3.2.Typical procedure for the synthesis of N-monosubstituted ureas in water
In a typical procedure, a mixture of the appropriate arylcyanamide (1.0 mmol), palladium nano-
particle catalyst (40 mg) and water (10 ml) was stirred under reflux conditions for appropriate time
(Table 2). After completion of the reaction as monitored by TLC, the catalyst was separated by the
16

1
13
strong magnet. Pure products were obtained in high yields and characterized by FT-IR, H NMR, C
NMR, and melting points.
Also, to see the effect of HCOOH, the hydration reaction of arylcyanamide was carried out in the
presence of HCOOH. So, arylcyanamide (1.0 mmol), palladium nano-particle catalyst (30 mg), water (5.0
ml) and 98% formic acid (2.0 mmol) were added to a round-bottomed flask, and the reaction mixture
was stirred at room temperature for the appropriate time (Table 2). After completion of the reaction as
monitored by TLC, the catalyst was separated by the strong magnet, the aqueous layer extracted with
ethyl acetate, washed with water, dried over MgSO4, filtered and evaporated under reduced pressure,
and a crystallization step was performed using acetone/n-hexane to afford the pure product.
4. Conclusions
In conclusion, the Pd nano-catalyst was synthesized as a novel nano-magnetic heterogeneous
catalyst to be used for the synthesis of various N-monosubstituted ureas in water at reflux condition or
in the mixture of water/formic acid 98% at room temperature. Furthermore, this catalytic system has
some advantages such as simplicity of the procedure, inexpensive raw material, commercially available
and non-toxic reagents, and simple magnetically work-up.
ACKNOWLEDGEMENTS
The authors are grateful to the Bu-Ali Sina University, Hamedan Iran, for the financial support of this
work.
SUPPLEMENTARY DATA
Supporting information for this article is available online at http://dx.doi.org/.....
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19

A green and facile approach for the synthesis of monosubstituted ureas in water: Pd catalyzed
reaction of arylcyanamides (an unexpected behavior of electron withdrawing groups)
Davood Habibi*, Somayyeh Heydari, Hasan Keypour, Masoumeh Mahmoudabadi
Department of Organic Chemistry, Faculty of Chemistry, Bu-Ali Sina University, Hamedan 6517838683, Iran
Corresponding author email: davood.habibi@gmail.com, Tel: +98 81 38380922; Fax: +98 81 38380709
20

A green and facile approach for the synthesis of monosubstituted ureas in water: Pd catalyzed
reaction of arylcyanamides (an unexpected behavior of electron withdrawing groups)
Davood Habibi*, Somayyeh Heydari, Hasan Keypour, Masoumeh Mahmoudabadi
Department of Organic Chemistry, Faculty of Chemistry, Bu-Ali Sina University, Hamedan 6517838683, Iran
Corresponding author email: davood.habibi@gmail.com, Tel: +98 81 38380922; Fax: +98 81 38380709
21