Fe3O4@SiO2 nanoparticle supported ionic liquid for green synthesis of antibacterially active 1-carbamoyl-1-phenylureas in water

Article abstract of DOI:10.1039/c8ra04368j

In the present work, we have designed a novel, heterogeneous and recyclable magnetic Br?nsted acidic ionic liquid based on 5-phenyl-1H-tetrazole. The {Fe₃O₄@SiO₂@CH₂)₃5-phenyl-1H-tetrazole-SO₃H/Cl} ([FSTet-SO₃H]Cl) was prepared via the immobilization of 5-phenyl-1H-tetrazole-bonded sulfonic acid onto the surface of silica-coated magnetic nanoparticles using 3-chloropropyltriethoxysilane as a linker. The catalyst was characterized by XRD, TEM, FESEM, EDS, TG-DTA, and FT-IR. The ability and high activity of this catalyst were demonstrated in the synthesis of 1-carbamoyl-1-phenylureas with good to excellent yields via a new, simple and one-pot procedure in aqueous media under reflux conditions. This procedure has advantages such as high yields, short reaction times, a simple methodology and work-up process, green reaction conditions, high stability, catalytic activity, and easy preparation, separation and reusability of the catalyst. The synthesis of these compounds was confirmed by FT-IR, ¹H NMR, ¹³C NMR and CHN. In addition, we investigated the biological properties of the 1-carbamoyl-1-phenylureas as newly synthesized compounds. The described catalyst could be easily separated from the reaction mixture by additional magnetic force and reused several times without a remarkable loss of its catalytic activity and any considerable changes in the product yield and the reaction time.

Full text of DOI:10.1039/c8ra04368j

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Fe3O4@SiO2 nanoparticle supported ionic liquid for
green synthesis of antibacterially active
1-carbamoyl-1-phenylureas in water
Cite this: RSC Adv., 2018, 8, 27631
a
Zahra Issaabadia and S. Mohammad Sajadib
*
Mahmoud Nasrollahzadeh,
In the present work, we have designed a novel, heterogeneous and recyclable magnetic Brønsted acidic
ionic liquid based on 5-phenyl-1H-tetrazole. The {Fe3O4@SiO2@(CH2)35-phenyl-1H-tetrazole-SO3H/Cl}
([FSTet-SO3H]Cl) was prepared via the immobilization of 5-phenyl-1H-tetrazole-bonded sulfonic acid
onto the surface of silica-coated magnetic nanoparticles using 3-chloropropyltriethoxysilane as a linker.
The catalyst was characterized by XRD, TEM, FESEM, EDS, TG-DTA, and FT-IR. The ability and high
activity of this catalyst were demonstrated in the synthesis of 1-carbamoyl-1-phenylureas with good to
excellent yields via a new, simple and one-pot procedure in aqueous media under reflux conditions. This
procedure has advantages such as high yields, short reaction times, a simple methodology and work-up
process, green reaction conditions, high stability, catalytic activity, and easy preparation, separation and
reusability of the catalyst. The synthesis of these compounds was confirmed by FT-IR, H NMR, 13C NMR
1
Received 22nd May 2018
Accepted 7th July 2018
and CHN. In addition, we investigated the biological properties of the 1-carbamoyl-1-phenylureas as
newly synthesized compounds. The described catalyst could be easily separated from the reaction
mixture by additional magnetic force and reused several times without a remarkable loss of its catalytic
activity and any considerable changes in the product yield and the reaction time.
DOI: 10.1039/c8ra04368j
rsc.li/rsc-advances
Recently, solid acid catalysts have attracted a lot of attention
in the eld of organic reactions.8 In this regard, many Brønsted
Introduction
Ionic liquids (IL) are a class of liquids that contain only ions.1 In
general, ionic liquids contain molten salts at a temperature above
800 C, however today, ionic liquids are known as salts that are
acids such as thiourea, TADDOL, amidinium and phosphate
can be used as green and free-of-metal catalysts.9 If an alkane
sulfonic acid group is covalently tethered to the IL cation, the IL
is converted into a strong Brønsted acid.10 These SO3H-
functionalized ionic liquids can act as good alternatives for
homogenous and heterogeneous acidic catalysts due to their
advantages such as being non-corrosive, nonvolatile and
immiscible with many organic solvents.11
From the past to present, the synthesis of organic
compounds has attracted the attention of many chemists due to
their special importance in biological and medical studies.
Among the organic compounds, 1-carbamoyl-1-phenylureas are
an important class of compounds. However, there is no report
on the synthesis of 1-carbamoyl-1-phenylureas in literature
so far.
Over the past few years, the hydration of cyanamides has
attracted a lot of attention as one of the most important ways of
synthesizing N-monosubstituted ureas.12 However, the hydra-
tion of cyanamides suffers from several disadvantages
including the use of corrosive bases or acids, low yields, the use
of toxic organic solvents, long reaction times and tedious work-
up.13 Therefore, the development of a new, easy and efficient
method for the hydration of cyanamides is one of the most
important challenges.
ꢀ
liquid at temperatures below 100 ꢀC.2 Over the past few years,
ionic liquids have attracted the attention of many scientists due
to their capabilities as catalysts, reaction media, reagents and
solvents.3 Ionic liquids have advantages such as a high thermal
stability, being non-ammable, having a low vapor pressure,
being recyclable and having excellent solvation properties.4
However, ionic liquids have limited applications due to their
toxic nature.5 Recently, extensive studies have been conducted to
eliminate the disadvantages associated with ionic liquids and
replace them with safer and more productive ones. One of the
best techniques is the combination of ionic liquids and magnetic
nanoparticles (MNPs). MNPs act as a good support for the
immobilization of the ionic liquids.6 Magnetic ionic liquids have
certain specications such as a large specic surface area, high
stability, facile separation and recovery from the reaction
mixture, good magnetic permeability and low toxicity and price.7
aDepartment of Chemistry, Faculty of Science, University of Qom, Qom 3716146611,
Iran. E-mail: mahmoudnasr81@gmail.com; Fax: +98 25 32103595; Tel: +98 25
32850953
bDepartment of Petroleum Geoscience, Faculty of Science, Soran University, PO Box
624, Soran, Kurdistan Regional Government, Iraq
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Scheme 1 Synthesis of 1-carbamoyl-1-phenylureas.
1-Carbamoyl-1-phenylureas are the parent compounds of Design MPMS XL). Melting points were taken in open capillaries
a large and interesting class of organic substances. It is prob- using BUCHI 510 melting point apparatus and are uncorrected.
able that the presence of three nitrogen atoms in their structure
has led to greater biological properties, but still nobody has
succeeded in synthesizing this important compound. In addi-
tion, they are important compounds which can be used as
starting materials in coordination chemistry and organic
synthesis in the future.
In this research, we have designed a heterogeneous and
recyclable magnetic Brønsted acidic ionic liquid catalyst by
General protocol for the synthesis of the
{Fe3O4@SiO2@(CH2)35-phenyl-1H-tetrazole-SO3H/Cl}
Firstly, in a 250 mL ask, 1.0 g of Fe3O4, 20.0 mL of H2O, 3.0 mL
of NH3, 80.0 mL of EtOH and 3.0 mL of tetraethylorthosilicate
(TEOS) were mixed and reuxed to afford silica-coated Fe3O4
(Fe3O4@SiO2). In the next step, 3.0 g of Fe3O4@SiO2, 10.0 mmol
of (3-chloropropyl)trimethoxysilane and 80.0 mL of dry toluene
were reuxed under nitrogen for 12 h. The as-prepared Fe3-
using 5-phenyl-1H-tetrazole. Although many ionic liquid based
imidazoles are known, only very few ionic liquid based tetra-
O4@SiO2@(CH2)3Cl was separated with an external magnet,
zoles have been described.14 However, it is noteworthy that
washed with dry toluene and anhydrous diethyl ether, and dried
at 80 ꢀC for 6 h under vacuum. Then 5-phenyl-1H-tetrazole
there is no report on the synthesis of magnetic ionic liquid
based tetrazoles. Therefore, this report could create a new
(0.73 g, 5.0 mmol) and K2CO3 (0.69 g, 5.0 mmol) in 50.0 mL of
approach for the production of magnetic ionic liquid based
DMF were added to the Fe3O4@SiO2@(CH2)3Cl and the mixture
tetrazoles. Next, we investigated the catalytic activity of [FSTet-
was reuxed for 24 h. The resulting solid was ltered, washed
with ethanol and distilled water and dried at 80 ꢀC for 6 h under
SO3H]Cl in the synthesis of 1-carbamoyl-1-phenylureas via
a one-pot procedure in aqueous media under reux conditions
vacuum. Finally, chlorosulfonic acid (1.165 g, 10.0 mmol)
(Scheme 1). The results show that the catalyst has excellent
was added dropwise to the Fe3O4@SiO2@(CH2)35-phenyl-1H-
catalytic activity in this reaction. The products were prepared in
1
tetrazole in dry dichloromethane and the mixture was
stirred for 3 h. Then with similar steps of ltering, washing and
drying, {Fe3O4@SiO2@(CH2)35-phenyl-1H-tetrazole-SO3H/HCl}
as a magnetically recoverable catalyst was obtained.
good to excellent yields and characterized by FT-IR, H NMR,
13C NMR, CHN and melting point determination.
Experimental
Reagents and methods
General protocol for the one-pot synthesis of 1-carbamoyl-1-
phenylureas
All materials of commercial reagent grade were purchased from
the Merck and Aldrich companies and used without further
purication. FT-IR spectra were recorded on a Nicolet 370 FT/IR
spectrometer (Thermo Nicolet, USA) using pressed KBr pellets.
X-ray diffraction (XRD) measurements were carried out with
a Philips powder diffractometer type PW 1373 goniometer. It
was equipped with a graphite monochromator crystal. The X-ray
In a typical procedure, to a mixture of arylcyanamide (1.0 mmol)
and sodium cyanate (0.065 g, 1.0 mmol) 0.2 g of the {Fe3O4@-
SiO2@(CH2)35-phenyl-1H-tetrazole-SO3H/Cl} catalyst in 10.0 mL
of H2O was added and stirred under reux conditions for an
ꢀ
wavelength was 1.5405 A and the diffraction patterns were
recorded in the 2q range (10–80) with a scanning speed of
2ꢀ minꢁ1. TEM images were taken using a Philips EM208
transmission electron microscope with an accelerating voltage
of 90 kV. Scanning electron microscopy (SEM) of the {Fe3O4@-
SiO2@(CH2)35-phenyl-1H-tetrazole-SO3H/HCl} was performed
on a Cam scan MV2300. The chemical compositions of the
synthesized catalyst were determined by EDS (energy dispersive
X-ray spectroscopy) performed in SEM. Thermal analysis (TG-
DTG) was carried out using an STA 1500 Rheometric Scientic
(England). The ow rate of air was 120 mL minꢁ1 and the
ramping rate of the sample was 2 ꢀC minꢁ1. VSM measurements
Scheme 2 Preparation of arylcyanamides (A) and 5-phenyl-1H-tet-
were recorded using a SQUID magnetometer at 298 K (Quantum razole (B).
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Scheme 3 Synthesis of {Fe3O4@SiO2@(CH2)35-phenyl-1H-tetrazole-SO3H/Cl}.
Fig. 1 The EDS spectra of Fe3O4@SiO2 (A), Fe3O4@SiO2@(CH2)3-Cl (B), Fe3O4@SiO2@(CH2)35-phenyl-1H-tetrazole (C) and [FSTet-SO3H]Cl (D).
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appropriate amount of time. The reaction progress was moni- 98.6, 55.7, 55.5; anal. calcd for C10H13N3O4: C, 50.21; H, 5.48; N,
tored using TLC. Aer completion of the reaction, the catalyst 17.56. Found: C, 50.28; H, 5.53; N, 17.64.
was recovered magnetically and the mixture was cooled for the
2-(4-(1-Carbamoylureido)phenyl)malonamide (7). Mp ¼ 303–
product to precipitate. All of the products were puried via 306 C; FT-IR (KBr, cmꢁ1) 3301, 3169, 3081, 1662, 1571, 1513,
recrystallization from EtOAC–n-hexane. The products were ob- 1453, 1402, 1368, 1318, 1038, 1007, 960, 834, 749, 604, 591, 521;
ꢀ
1
tained in high yields and characterized by FT-IR, H NMR, 13C 1H NMR (400 MHz, DMSO-d6) dH ¼ 9.86 (s, br, 8H), 7.46 (s, 4H);
NMR, CHN and melting points.
1-Carbamoyl-1-(3-bromophenyl)urea (1). FT-IR (KBr, cmꢁ1
)
3294, 3249, 3112, 3181, 3077, 1686, 1665, 1592, 1542, 1474,
1418, 1372, 1334, 1311, 1281, 1258, 1225, 1167, 1092, 1067, 996,
1
964, 889, 873, 746, 680, 657, 608, 535, 435; H NMR (400 MHz,
CDCl3) d 7.79 (s, 1H), 7.50 (s, br, 4H), 7.43 (d, J ¼ 7.6 Hz, 1H),
7.26 (d, J ¼ 8.0 Hz, 1H), 7.19 (t, J ¼ 7.8 Hz, 1H); 13C NMR (100
MHz, CDCl3) d 168.5, 139.1, 130.3, 127.3, 122.8, 122.6, 118.3;
anal. calcd for C8H8BrN3O2: C, 37.23; H, 3.12; N, 16.28. Found:
C, 37.31; H, 3.20; N, 16.36.
1-Carbamoyl-1-(4-chlorophenyl)urea (2). Mp ¼ 178–180 ꢀC;
FT-IR (KBr, cmꢁ1) 3304, 3193, 3127, 1665, 1068, 1539, 1490,
1394, 1371, 1291, 1260, 1170, 1090, 1009, 968, 830, 750, 708,
607, 506, 450; 1H NMR (400 MHz, CDCl3) dH ¼ 7.48 (d, J ¼
8.0 Hz, 2H), 7.39 (s, br, 4H), 7.30 (d, J ¼ 8.0 Hz, 2H); 13C NMR
(100 MHz, CDCl3) dC ¼ 168.3, 136.4, 129.3, 129.0, 121.1; anal.
calcd for C8H8N3O2Cl: C, 44.98; H, 3.77; N, 19.67. Found: C,
44.91; H, 3.69; N, 19.72.
ꢀ
1-Carbamoyl-1-(4-methylphenyl)urea (3). Mp ¼ 154–156 C;
FT-IR (KBr, cmꢁ1) 3291, 3188, 3123, 3067, 1662, 1603, 1551,
1510, 1455, 1402, 1365, 1321, 1264, 1114, 1040, 1013, 820, 753,
619, 605, 510; 1H NMR (400 MHz, CDCl3) dH ¼ 7.71 (s, br, 4H),
7.40 (d, J ¼ 8.2 Hz, 2H), 7.13 (d, J ¼ 8.2 Hz, 2H), 2.33 (s, 3H); 13
C
NMR (100 MHz, CDCl3) dC ¼ 168.3, 136.4, 129.3, 129.0, 121.1;
anal. calcd for C9H11N3O2: C, 55.95; H, 5.74; N, 21.75. Found: C,
56.02; H, 5.80; N, 21.82.
1-Carbamoyl-1-(4-methoxylphenyl)urea (4). Mp
¼
130–
132 C; FT-IR (KBr, cmꢁ1) 3277, 3243, 3191, 3131, 3068, 1647,
1606, 1561, 1512, 1465, 1455, 1440, 1411, 1369, 1320, 1303,
1246, 1175, 1113, 1031, 970, 838, 820, 767, 650, 619, 607, 520,
463; 1H NMR (400 MHz, CDCl3) dH ¼ 7.80 (s, br, 4H), 7.42 (d, J ¼
8.4 Hz, 2H), 6.85 (d, J ¼ 8.4 Hz, 2H), 3.79 (s, 3H); 13C NMR (100
MHz, CDCl3) dC ¼ 168.3, 136.4, 129.3, 129.0, 121.1; anal. calcd
for C9H11N3O3: C, 51.67; H, 5.30; N, 20.09. Found: C, 51.76; H,
5.37; N, 20.15; MS: m/z ¼ 203 (M+).
ꢀ
1-Carbamoyl-1-(2,4-dimethylphenyl)urea (5). Mp ¼ 127–
129 C; FT-IR (KBr, cmꢁ1) 3277, 3192, 3010, 1652, 1615, 1598,
ꢀ
1531, 1365, 1299, 1281, 1017, 973, 875, 813, 708, 625, 610, 505,
1
448; H NMR (400 MHz, CDCl3) dH ¼ 7.52 (d, J ¼ 8.8 Hz, 1H),
7.11 (br, 4H), 7.04–7.01 (m, 2H), 2.31 (s, 3H), 2.23 (s, 3H); 13C
NMR (100 MHz, CDCl3) dC ¼ 168.6, 135.3, 132.9, 131.2, 130.2,
127.2, 124.1, 20.9, 17.8; anal. calcd for C10H13N3O2: C, 57.96; H,
6.32; N, 20.28. Found: C, 58.08; H, 6.41; N, 20.36.
1-Carbamoyl-1-(2,4-dimethoxylphenyl)urea (6). Mp ¼ 128–
130 C; FT-IR (KBr, cmꢁ1) 3285, 3192, 3131, 2999, 2964, 2839,
ꢀ
1663, 1614, 1539, 1504, 1467, 1437, 1417, 1375, 1282, 1258,
1220, 1184, 1127, 1042, 1024, 968, 916, 839, 801, 675, 607, 511;
1H NMR (400 MHz, CDCl3) dH ¼ 8.23 (d, J ¼ 6.0 Hz, 1H), 7.57 (s,
br, 4H), 6.50–6.47 (m, 2H), 3.87 (s, 3H), 3.81 (s, 3H); 13C NMR
(100 MHz, CDCl3) dC ¼ 167.9, 156.3, 149.1, 121.3, 120.8, 103.7,
Fig. 2 FESEM images of Fe3O4@SiO2 (A), Fe3O4@SiO2@(CH2)3Cl (B),
Fe3O4@SiO2@(CH2)35-phenyl-1H-tetrazole (C) and [FSTet-SO3H]Cl (D).
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13C NMR (100 MHz, DMSO-d6) dC ¼ 168.3, 134.9, 119.8; anal. method. To the best of our knowledge, this is the rst report
calcd for C10H12N6O4: C, 42.86; H, 4.32; N, 29.99. Found: C, wherein an ionic liquid based tetrazole has been immobilized
42.91; H, 4.41; N, 30.08.
on the Fe3O4@SiO2 surface as a powerful catalytic support.
Results and discussion
Characterization of the [FSTet-SO3H]Cl
Our recent studies have shown that arylcyanamides and tetra- As shown in Scheme 3, the [FSTet-SO3H]Cl was prepared in four
zoles could be used as highly active compounds in organic steps: (1) coating the Fe3O4 with the silica (Fe3O4@SiO2), (2)
synthesis.8,15 However, a lack of convenient methods for the linking the Fe3O4@SiO2 with the 3-chloropropyltriethoxysilane,
preparation of the arylcyanamides and ionic liquid based tet- (3) graing the Fe3O4@SiO2@(CH2)3Cl with 5-phenyl-1H-tetra-
razoles strongly restricts their potential application in organic zole and (4) converting the Fe3O4@SiO2@(CH2)35-phenyl-1H-
synthesis. In this work, the arylcyanamides and 5-phenyl-1H- tetrazole to an ionic liquid by chlorosulfonic acid. The synthe-
tetrazole were prepared according to our recent work on aryl sized catalyst was characterized using FT-IR, XRD, TEM, FE-
amines15c and benzonitrile15d (Scheme 2).
SEM, EDS, VSM, TGA and DTG.
Due to our interest in green protocols, in the present work,
The chemical composition of Fe3O4@SiO2, Fe3O4@SiO2@-
for the rst time we have reported the synthesis of 1-carbamoyl- (CH2)3Cl,
1-phenylureas using [FSTet-SO3H]Cl as a magnetic Brønsted [FSTet-SO3H]Cl was analyzed by Energy Dispersive X-ray Spec-
acidic ionic liquid catalyst in water as a green solvent. troscopy (EDS). The EDS spectra of these materials indicate the
Fe3O4@SiO2@(CH2)35-phenyl-1H-tetrazole,
and
In this work, by combining the advantages of a Brønsted presence of the corresponding elements in their structure. The
acidic ionic liquid as a H+ source and silica-coated magnetic EDS spectrum of [FSTet-SO3H]Cl conrmed that it was
nanoparticles (Fe3O4@SiO2) with high surface area, excellent composed of Fe, Si, N, C, O and S (Fig. 1). Fig. 1 conrmed that
thermal stability, low toxicity, and easy synthesis and separation Fe, Si, N, C, and O were the main components present in both
from the reaction mixture by an external magnet, a [FSTet- Fe3O4@SiO2@(CH2)35-phenyl-1H-tetrazole and [FSTet-SO3H]Cl
SO3H]Cl nanocomposite has been produced using a simple along with the S element which is present only in [FSTet-SO3H]
Fig. 3 TEM images of [FSTet-SO3H]Cl.
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Fig. 4 TG-DTA analysis of [FSTet-SO3H]Cl.
Cl further demonstrating the formation of an ionic liquid in the
case of [FSTet-SO3H]Cl.
The thermal stability of [FSTet-SO3H]Cl was also analyzed by
TGA (thermogravimetric analysis) and DTA (differential thermal
Fig. 2 shows the FESEM images of Fe3O4@SiO2, Fe3O4@- analysis) experiments in air ow (120 mL minꢁ1) at a heating rate
SiO2@(CH2)3Cl, Fe3O4@SiO2@(CH2)35-phenyl-1H-tetrazole and of 2 ꢀC minꢁ1 on an autonomic TG-DTA. As shown in Fig. 4, three
[FSTet-SO3H]Cl. These materials show a spherical morphology weight loss stages were observed in air ow for [FSTet-SO3H]Cl.
with an average particle size in the range 23–39 nm. The The rst weight-loss step mainly happened at 120–190 ꢀC and is
morphology of [FSTet-SO3H]Cl was also studied from TEM associated with desorbed water or other organic solvents which
images at different magnications (Fig. 3). The morphology were employed during the preparation steps of the catalyst. In the
calculated from the FESEM images was in agreement with TEM second stage at 218–300 ꢀC, a weight loss is observed which can
images in the case of [FSTet-SO3H]Cl. However, the average be attributed to the thermal decomposition of 5-phenyl-1H-tet-
particle size was found to be smaller in the TEM images.
razole functionalized with chlorosulfonic acid on the surface of
Fig. 5 The FT-IR spectra of 5-phenyl-1H-tetrazole (A), Fe3O4@SiO2 (B), Fe3O4@SiO2@(CH2)3Cl (C), Fe3O4@SiO2@(CH2)35-phenyl-1H-tetrazole
(D) and [FSTet-SO3H]Cl (E).
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Fig. 6 The XRD patterns of Fe3O4@SiO2 (A), Fe3O4@SiO2@(CH2)3Cl (B), Fe3O4@SiO2@(CH2)35-phenyl-1H-tetrazole (C) and [FSTet-SO3H]Cl (D).
the silica coating. Finally, the weight loss observed at 650–750 ꢀC formation of Fe3O4. The absorption peak at 570 cmꢁ1 is
is due to the decomposition of the catalyst.
attributed to Fe–O vibration of the Fe3O4 MNPs. The formation
FT-IR analysis was carried out to conrm the structure and of Fe3O4@SiO2 was conrmed by the appearance of peaks at
the formation of [FSTet-SO3H]Cl. Fig. 5 shows the FT-IR spectra 450, 801, 955 and 1097 cmꢁ1 which are assigned to the Si–O–Si
of 5-phenyl-1H-tetrazole (A), Fe3O4@SiO2 (B), Fe3O4@SiO2@ bending, Si–O bending, Si–OH stretching and Si–O–Si stretch-
(CH2)3Cl (C), Fe3O4@SiO2@(CH2)35-phenyl-1H-tetrazole (D) and ing, respectively (Fig. 5B). The peak at 1619 cmꢁ1 may be
[FSTet-SO3H]Cl (E). The structure of 5-phenyl-1H-tetrazole was attributed to C]C and C]N vibrations of the tetrazolium
in agreement with the FT-IR spectra data. The disappearance of moiety of the ionic liquid (Fig. 5E).
one strong and sharp absorption band (CN stretching band) in
To determine the crystallographic structure of Fe3O4@SiO2,
benzonitrile, and the appearance of an NH stretching band in Fe3O4@SiO2@(CH2)3Cl, Fe3O4@SiO2@(CH2)35-phenyl-1H-tetra-
the FT-IR spectroscopy, was evidence for the formation of 5- zole and [FSTet-SO3H]Cl, XRD analysis was carried out (Fig. 6).
phenyl-1H-tetrazole (Fig. 5A). In Fig. 5B–E, the peak at 3600– As shown in Fig. 6, peaks of 2q at 30.00ꢀ, 35.30ꢀ, 42.80ꢀ, 53.00ꢀ,
3100 cmꢁ1 is due to the O–H stretching mode. The appearance 56.80ꢀ and 62.50ꢀ can be indexed as (hkl) to the (220), (311),
of two peaks at 570 cmꢁ1 and 617 cmꢁ1 (Fig. 5B) supports the (400), (422), (511) and (440) planes of cubic iron oxide.
Fig. 7 Magnetization curve for [FSTet-SO3H]Cl.
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reported where NaOCN is used as an effective salt in the
synthesis of the 1-carbamoyl-1-phenylureas.
We applied our catalyst to the synthesis of 1-carbamoyl-1-
phenylureas under reux conditions and 3-bromophenylcya-
namide was chosen as a model substrate. Various reaction
conditions including the amount of the [FSTet-SO3H]Cl catalyst
and temperature were varied to examine the inuence on the
compositions in the reaction mixture (Table 1). We observed
that 1-(3-bromophenyl)-1-carbamoylurea (1) was not produced
without using the [FSTet-SO3H]Cl catalyst (Table 1, entry 1).
However, with the presence of a 3-bromophenylcyanamide,
NaOCN, [FSTet-SO3H]Cl catalyst and H2O mixture at room
temperature, product (1) was obtained in 23% yield. We found
that the yield and reaction rate were improved signicantly by
increasing the reaction temperature. In general, the best result
was obtained with 0.2 g of the [FSTet-SO3H]Cl catalyst under
Scheme 4 Preparation of primary carbamates.
In order to study the magnetic properties of [FSTet-SO3H]Cl,
a vibrating sample magnetometer (VSM) was used to charac-
terize the as-prepared catalyst with a magnetometer at 298 K
and with eld sweeping from ꢁ10 000 to +10 000 Oe. Fig. 7
shows a typical room temperature magnetization curve of
[FSTet-SO3H]Cl. As demonstrated in Fig. 7, the magnetization
curves of the as-prepared ionic liquid display no hysteresis loop
which demonstrates its superparamagnetic characteristics.
Therefore, at the end of the reaction, [FSTet-SO3H]Cl could
simply be collected from the reaction mixture using an external
magnet.
Table 2 Substrate scopea
Following the synthesis of 1-arylureas8 and in a further study
on the preparation of nitrogen-containing compounds, we
focussed on the synthesis of 1-carbamoyl-1-phenylureas as
nitrogen-rich compounds from arylcyanamides and sodium
cyanate (NaOCN) as starting materials. In 2008, our research
group reported the synthesis of primary carbamates from the
reaction between phenol or alcohols with NaOCN in the pres-
ence of HClO4–SiO2 at room temperature or 55–65 ꢀC for an
appropriate time in high yields and under solvent-free condi-
tions (Scheme 4).16
Herein, in the course of our research on the synthesis of the
nitrogen-containing compounds,15 we now wish to report the
preparation of novel 1-carbamoyl-1-phenylureas by the reaction
of NaOCN with arylcyanamides in the presence of a [FSTet-
SO3H]Cl catalyst in water under reux conditions. Apparently,
to the best of our knowledge, so far no methodology has been
Table 1 Synthesis of the 1-(3-bromophenyl)-1-carbamoylurea (1):
reaction condition optimizationa
Entry
Cat. (g)
Temperature (ꢀC)
Time (h)
Yieldb (%)
1
2
3
4
5
6
0.0
0.05
0.1
0.2
0.3
0.2
Reux
Reux
Reux
Reux
Reux
R.T.
5
10
7
5
5
0.0
43
70
90
90
23
10
a
a
The reactions were performed with 1.0 mmol of 3-
The reactions were performed with 1.0 mmol arylcyanamide,
b
bromophenylcyanamide and 1.0 mmol NaOCN in H2O (10 mL). Yield
1.0 mmol NaOCN and 0.2 g [FSTet-SO3H]Cl catalyst in H2O (10 mL)
under reux conditions. Yield refers to the pure isolated product.
refers to the pure isolated product.
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Fig. 8 FT-IR spectrum of 1-carbamoyl-1-(3-bromophenyl)urea (1).
reux conditions (Table 1, entry 4), whereas no signicant OMe and Me groups were compatible, and achieved a yield up to
improvements in the reaction yield and time were observed by 90% (1–7). Both electron-withdrawing and electron-donating
further increasing the amount of the [FSTet-SO3H]Cl catalyst groups in the cyanamides were compatible. As shown in Table
from 0.1 g to 0.3 g (Table 1, entry 5).
2, the arylcyanamides with electron-donating groups were
With the optimized conditions in hand, we next tested the completed under reux conditions aer 3 h and the corre-
substrate scope of this transformation. Excellent yields could be sponding products were obtained in shorter reaction times
achieved regardless of the substituents associated with the because of their greater ability to attack the NaOCN. However,
arylcyanamides (Table 2). Different substituents such as Br, Cl, the species bearing electron withdrawing groups required
Fig. 9 Expanded 1H NMR spectrum (400 MHz, CDCl3) of 1-carbamoyl-1-(3-bromophenyl)urea (1).
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Fig. 10 13C NMR spectrum (100 MHz, CDCl3) of 1-carbamoyl-1-(3-bromophenyl)urea (1).
higher reaction times. As shown in Table 2, 1,4-phenyl- appeared corresponding to C]O and NH2 groups absorption
enecyanamide interestingly afforded the double-addition vibrations and the CN peak had disappeared (Fig. 8). The 1H
product (7), due to presence of two CN groups. The products NMR spectra showed one characteristic peak belonging to the
1
were characterized by IR, H NMR and 13C NMR spectroscopy, NH2 group (Fig. 9). The appearance of a carbon signal corre-
elemental analysis and melting point determination.
The structures of the 1-carbamoyl-1-phenylureas were in of the formation of 1-carbamoyl-1-phenylureas (Fig. 10).
agreement with their FT-IR and NMR spectra. In the FT-IR The possible mechanism for the synthesis of 1-carbamoyl-1-
spectra of the 1-carbamoyl-1-phenylureas, three new peaks phenylureas under reux conditions is shown in Scheme 5. The
sponding to a carbonyl group in the 13C NMR spectra is evidence
Scheme 5 Possible mechanism for the synthesis of 1-carbamoyl-1-phenylureas.
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Fig. 11 Chemical structures of many bioactive arylureas.
Table 3 The antibacterial activity of 2-(4-(1-carbamoylureido)phenyl)malonamide (7) on E. colia
Compound name
20 mg mLꢁ1
15% mg mLꢁ1
10% mg mLꢁ1
5% mg mLꢁ1
1% mg mLꢁ1
2-(4-(1-Carbamoylureido)phenyl)malonamide
t1: 11 mm
t2: 9 mm
t3: 9 mm
C+: 12 mm
t1: 9 mm
t1: no result
t2: no result
t3: no result
C+: 12 mm
t1: no result
t2: no result
t3: no result
C+: 12 mm
t1: no result
t2: no result
t3: no result
C+: 12 mm
t2: 11 mm
t3: 14 mm
C+: 12 mm
a
C+: chloramphenicol disc diameter (positive control), t: test frequency.
[FSTet-SO3H]Cl catalyst as a Brønsted acidic ionic liquid has an through a pair of nitrogen electrons. Eventually, due to the
important role in the synthesis of 1-carbamoyl-1-phenylureas. presence of the [FSTet-SO3H]Cl catalyst and water in the reac-
[FSTet-SO3H]Cl is supposed to convert the ꢁN]C]O to tion medium, 1-aryl-1-cyanourea was hydrolyzed and the nal
a
+H2N]C]O electrophile and enhance its reactivity with product was produced.
cyanamide as a nucleophile. In the rst step, the presence of the
They are important structural motifs for many arylurea
[FSTet-SO3H]Cl catalyst leads to the protonation of sodium analogs as broad-spectrum antibacterial agents (Fig. 11).17
cyanate. Next, arylcyanamides attack the protonated cyanate Nevertheless, there are no reports on the synthesis of 1-
Fig. 12 Antibacterial activity of 2-(4-(1-carbamoylureido)phenyl)malonamide (7) against E. coli.
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The antibacterial activity of the sample was studied against
Escherichia coli bacteria by disk diffusion method using a Muller
Hinton agar culture. The concentrations used for investigations
of the sample were 1% (10 mg mLꢁ1), 5% (50 mg mLꢁ1), 10%
(100 mg mLꢁ1), 15% (150 mg mLꢁ1) and 20% (200 mg mLꢁ1
)
respectively. The results were compared with chloramphenicol
as a positive control. For reporting the results of the antibio-
gram test the minimum protection zone per millimeter (mm)
was reported for each test. Furthermore, the frequency of the
test was in triplicate for each concentration of the sample.
According to Table 3 and Fig. 12, the sample demonstrated no
antibacterial activity against E. coli in concentrations lower than
15% but showed an antibacterial activity with good potential for
concentrations equal and greater than 15%.
Fig. 13 Reusability of [FSTet-SO3H]Cl for the synthesis of 1-carba-
moyl-1-(4-methoxylphenyl)urea.
As shown from Fig. 12, for both concentrations of 15% and
20% the sample showed a suitable antibacterial activity but in
concentrations lower than 15% no antibacterial results were
carbamoyl-1-phenylureas and investigations of their antibacte- detected. Therefore, the study conrmed that the concentration
rial properties. In the present study, for the rst time, we report of the compound is an important factor concerning its biological
the antibacterial properties of 2-(4-(1-carbamoylureido)phenyl) activity against E. coli, and in concentrations greater than 15%
malonamide (7) as a model substrate.
Escherichia coli is a common inhabitant of the intestinal mentioned bacteria compared to the positive control.
tract of humans and warm-blooded animals. Most strains of E.
One of the most important points in the area of nano-
the sample demonstrated a good antibacterial activity against the
coli are harmless and are a part of the normal intestinal catalysis is the stability and recyclability of heterogeneous
microora. These strains serve a useful function in the body by catalysts. In order to show the effectiveness of [FSTet-SO3H]Cl,
suppressing the growth of harmful bacteria and by synthe- catalyst recycling experiments were carried out using 1-(4-
sizing appreciable amounts of vitamins. However, several methoxyphenyl)urea as the model substrate under optimized
pathogenic E. coli strains have emerged which cause disease in conditions. Aer each cycle, [FSTet-SO3H]Cl was separated with
humans. Pathogenic E. coli can be divided into intestinal an external magnet, washed with ethanol, dried and then
pathogens causing diarrhoea, and extra intestinal E. coli reused at least ve times without signicant loss of catalytic
causing a variety of infections in both humans and animals.18 activity (Fig. 13). Easy separation and reusability of the catalysts
Through this report we investigated the antibacterial activity is one of the most important benets. As shown in FE-SEM and
of synthesized 2-(4-(1-carbamoylureido)phenyl)malonamide TEM images of the recycled catalyst (Fig. 14 and 15), no obvious
(7) against pathogenic E. coli as following.
change in the morphology of [FSTet-SO3H]Cl was observed.
Fig. 14 FESEM images of recovered [FSTet-SO3H]Cl.
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Fig. 15 TEM images of recovered [FSTet-SO3H]Cl.
Conclusion
Conflicts of interest
In conclusion, we have developed a novel and highly efficient There are no conicts to declare.
protocol for the preparation of a heterogeneous and recyclable
magnetic Brønsted acidic ionic liquid catalyst using 5-phenyl-
1H-tetrazole. To the best of our knowledge, this is the rst
report on the synthesis of a tetrazole-based ionic liquid stabi-
Acknowledgements
We gratefully acknowledge the Iranian Nano Council and
University of Qom for the support of this work.
lized on the surface of silica-coated magnetic nanoparticles
using 3-chloropropyltriethoxysilane as a linker. In this work, we
have developed a new strategy for the synthesis of 1-carbamoyl-
1-phenylureas from arylcyanamides via a one-pot procedure in
aqueous media under reux conditions. A wide range of
substituted arylcyanamides as substrates were employed and
afforded the desired products in excellent yields. The high yield
of products, the efficiency, generality, short reaction time, clean
reaction prole, the use of water as a green solvent, the use of
a relatively inexpensive catalyst, simplicity and easy work-up
procedure, recyclability and reusability of the catalyst, and the
straightforward isolation of the products are the advantages of
this protocol. The wide substrate scope, green reaction condi-
tions, high yield of products and recovery and recyclability of
the catalyst offer the potential for scale-up in pharmaceutical
applications. Further studies and the development of other
methodologies for the arylcyanamides’ and 1-carbamoyl-1-
phenylureas’ reactivities are in progress.
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