Nano copper and cobalt ferrites as heterogeneous catalysts for the one-pot synthesis of 2,4,5-tri substituted imidazoles

Article abstract of DOI:10.1007/s12039-014-0729-2

A simple one-pot synthesis has been developed for the synthesis of 2,4,5-trisubstituted imidazoles using magnetic recyclable spinel nano copper and cobalt ferrites by the condensation of benzil, aromatic aldehyde and ammonium acetate in ethanol as solvent

Full text of DOI:10.1007/s12039-014-0729-2

J. Chem. Sci. Vol. 126, No. 6, November 2014, pp. 1715–1720. ꢀc Indian Academy of Sciences.
Nano copper and cobalt ferrites as heterogeneous catalysts
for the one-pot synthesis of 2,4,5-tri substituted imidazoles
∗
PAUL DOUGLAS SANASI , D SANTHIPRIYA, Y RAMESH, M RAVI KUMAR, B SWATHI
and K JAYA RAO
Department of Engineering Chemistry, A.U. College of Engineering (A), Andhra University,
Visakhapatnam 530 003, Andhra Pradesh, India
e-mail: pauldouglas12@gmail.com
MS received 18 March 2014; revised 26 May 2014; accepted 04 June 2014
Abstract. A simple one-pot synthesis has been developed for the synthesis of 2,4,5-trisubstituted imidazoles
using magnetic recyclable spinel nano copper and cobalt ferrites by the condensation of benzil, aromatic alde-
hyde and ammonium acetate in ethanol as solvent. The reaction, with these catalysts was carried out under mild
reaction conditions with very good yields of substituted imidazoles. These catalysts can be recycled very easily
and reused, which makes this methodology environmentally benign.
Keywords. Heterogeneous catalysts; nano copper and cobalt ferrites; one-pot synthesis; 2,4,5-tri substituted
imidazoles.
1
. Introduction
In continuation to our efforts to explore the cat-
alytic activity of magnetically separable substituted
nanoferrites for various organic transformations, it is
observed that the efficacy of copper and cobalt nano-
ferrite catalysts for the synthesis of trisubstituted imi-
dazoles has not been explored before. Hence, the influ-
ence of nanoferrite catalyst in the one-pot synthesis
of 2,4,5,-trisubstitued imidazoles by cyclocondensa-
tion of benzil, benzaldehyde and ammonium acetate
Multi-component reactions carried out in one-pot pro-
cess are of interest as they form a single product with
1
,2
high yields. These reactions are convenient and pow-
erful tools for the preparation of a few biologically and
pharmaceutically active organic compounds. Many bio-
logically active natural products were found to contain
substituted imidazole structures. Tri aryl imidazole is
the main structural unit in some widely used drugs such
(scheme 1) has been attempted. Previously, copper and
3
4
as ketoconazole, proton pump inhibitors omeprazole,
cimetidine, clotrimazole and metronidazole, poten-
cobalt nanoferrites were synthesized and used for var-
5
6
7
21 –27
ious organic transformations.
Now a one-pot syn-
3
8
8
9
tial inhibitor of P mapkinase, therapeutic agents and
thesis of 2,4,5,-trisubstituedimidazoles has been carried
out using cobalt and copper substituted nanoferrites and
the results are reported.
anti HIV-I protease.10
Numerous methods have been developed for the
synthesis of substituted imidazoles. 2,4,5-trisubstituted
imidazoles can be prepared by a three-component cyclo
11
condensation in the presence of acetic acid, silica sup- 2. Experimental
12
13
ported sulphuric acid, InCl .3H O, ceric ammonium
nitrate, iodine, trichloroisocyanuric acid (TCCA),
NiCl .6H O/Al O , ionic liquids, zeoliteHY/silica
3
2
14
15
16
2.1 Catalyst preparation
17
18
2
2
2
3
19
20
Solvents and reagents were of AR grade acquired from
the commercial sources and used without purifica-
tion. Magnetic spinel nanoferrite catalysts with com-
position MFe O [M = Cu/Co] were chosen for this
gel and ZrCl4 under reflux conditions. Although
these methods have a lot of potential, the reactions suf-
fer from low yields, longer reaction times, use of expen-
sive reagents, associated with a mixture of products and
lack of generalization. Thus, they were not appropriate
for synthesis of structurally diverse imidazoles. Devel-
opment of clean and high yielding and environmentally
benignapproaches is still desirable and much in demand.
2
4
study. For the preparation of catalysts, aqueous solu-
tions of stoichiometric amounts of copper and cobalt
nitrates along with ferric citrate were reacted with cit-
ric acid in 1:1 molar ratio. pH of the solution was
increased to 7 by addition of ammonia to complete the
reaction and ethane diol was added. The solution was
∗
For correspondence
1
715

1
716
Paul Douglas Sanasi et al.
O
O
Ferrite
Catalyst
H
N
2
+
Ar-CHO
+ +
H4N-O
CH3
Ar
O
Ethanol
N
Ar = (a) C H (b) 4-OMe C H (c) 4-Br C H
4
6
5
6
4
6
4a-4c
Scheme 1. One-pot synthesis of 2,4,5,-trisubstituted imidazoles.
evaporated very slowly over a period of ten to twelve XRD pattern for copper and cobalt nanoferrite sam-
◦
hours to dryness. Viscosity and colour changed as the ples respectively, which were sintered at 500 C. The
solution turned into a puffy and porous dry gel. As pattern shows all the characteristic peaks of a spinal
soon as the solvent removal completed, dried precur- structure and confirms the phase formation indicating
sor underwent a self-ignition reaction to form a very the absence of other impurity phases. The XRD param-
fine powder known as as-synthesized powder. The as- eters of various peaks were compared with the stan-
synthesized powders, thus obtained were calcined in a dard data of the cubic copper ferrites (JCPDS # 77-10)
◦
muffle furnace at 500 C for 2 h to remove the residual and found to be in cubic phase and cobalt ferrites nos.
carbon and furnace cooled.
(JCPDS3-864 and 22-1086). The particle size and other
characteristics of the copper and cobalt ferrite nano par-
ticles obtained from the XRD pattern using Scherer’s
2.2 Characterization
28–30
formula
was found to be 29 and 27 nm respectively
and reported in table 1. The peaks can be indexed to
111), (220), (311), (222), (400), (422), (511) and (440)
planes of a cubic unit cell.
For the characterization of the calcined as-synthesized
nanoferrites, the XRD spectra were recorded on
PANalytical-Xpertpro diffractometer and the average
crystallite size was determined from the corresponding
XRD data. The microstructural morphology was stud-
ied with a scanning electron microscope (SEM) model
JEOL–JSM 6610 LV. FTIR spectra were recorded on
BRUKER ALPHA FT-IR with Opus 6.1 version. Mag-
netization M(H) measurements were made using a com-
mercial vibrating sample magnetometer (VSM) model
BHV-50 of Riken Denshi Co. Ltd. Japan. Specific
surface area (SBET) of samples was determined by
BET surface area analyzer (Nova 2000 series, Quan-
tachrome Instruments, UK). Melting points were deter-
mined on a capillary melting point apparatus and are
uncorrected. HNMR and CNMR spectral data were
recorded on the Bruker-Avance 300-MHz spectrometer
in DMSO-d6. The chemical shift values were reported
on the δ scale in parts per million (ppm), downfield
from tetramethylsilane (TMS) as an internal standard.
The mass spectrum was recorded using a Perkin-Elmer
PE SCIEX-API 2000, equipped with ESI source used
online with a HPLC system after the ultraviolet (UV)
detector.
(
2.3b Infrared Spectroscopy: In order to confirm the
formation of the spinel phase and to understand the
nature of the residual carbon in the samples, the FT-
IR spectra of the as-synthesized powders and thermally
treated powder were recorded and shown in figures S3
and S4. The as-synthesized sample shows characteris-
tic absorptions of ferrite phase with a strong absorp-
−1
tion around 600 cm . Waldron studied the vibrational
spectra of ferrites and attributed the sharp absorption
−1
band around 580 cm to the intrinsic vibrations of the
tetrahedral groups and the other band of the octahe-
dral groups. There are two weak and broad absorptions
1
13
−1
around 1040, 1400, 1600, 3400 cm corresponding to
the presence of small amount of residual carbon in the
samples. These absorptions in the present case are very
weak which indicate that the residual carbon has mostly
burnt away during the sintering process.
2.3c Morphological and elemental analysis (SEM &
EDX): Figures S5 and S6 show the typical SEM image
of the nano copper and cobalt nanoferrites sintered at
◦
5
00 C. The crystallite size calculated from XRD is in
2.3 Characterization of nanoferrites
the range of below 30 nm which is in agreement with
.3a X-ray diffraction (XRD) analysis: Figures S1 the SEM image. The structural composition and crys-
2
and S2 (see supplementary information) show typical tallinity of the cobalt ferrite nano particles was further

Nano ferrite catalysed one-pot synthesis of tri-substituted imidazoles
Table 1. Particle size and other characteristics of copper and cobalt ferrites.
1717
S No
Sample
Lattice Parameter
Density (%)
FWHM
Porosity (%)
Grain size (D) (μm)
Particle Size
1
2
CuFe2O4
CoFe2O4
8.387
8.389
92.5
91.9
0.281
0.272
7.4
7.3
1.62
1.58
29
27
2
.5b 2-(4-methoxy phenyl)-4,5,diphenyl-1-H Imi-
examined by using SEM and TEM. The iron and cop-
per or cobalt ratio in the nano crystals as determined by
EDX analysis was very much close to the atomic ratio
in the formula CuFe2O4 and CoFe2O4.
◦
1
dazole (4b): M.p. 222–224 c; HNMR (Bruker)
(
CDCl /DMSO-d )δ = 3.85 (S, 3H), 6.97–6.95 (d, J
3
6
=
8.8Hz, 2H), 7.54–7.25(m, 10H), 7.84–7.82 (d, J =
3 6
13
8
.8Hz, 2H), CNMR (CDCl /DMSO-d ), 55.7, 113.4,
1
22.6, 126.3, 126.6, 128.0, 128.3, 133.4, 145.7, 159.6
2
.3d BET surface area analysis: The BET surface
−1
ppm; FTIR (KBr, cm ); 3450(N-H), 1612(C=C),
area of the CuFe O and CoFe O are found to be 127
+
2
4
2
4
1579(C=N), 1385(C-O), NCMS (m/z) 327 (M +1)
2
and 135 m /g respectively. The difference in the sur-
face area of the samples is attributed to the atomic
sizes of copper and cobalt. Further, copper ferrite shows
2.5c 2-(4-Bromo phenyl)-4,5,diphenyl-1-H
Imi-
◦
1
◦
dazole (4c): M.p. 260–262 C; HNMR (Bruker)
decrease in surface area during calcination at 500 C.
(
CDCl /DMSO-d ): δ = 7.76–7.05 (m,10H), 7.97–
3
6
This may be due to the completion of dehydration asso-
ciated with the completion of crystallization and growth
of crystallite size by sintering.
7
.92 (d,J = 8.0Hz, 2H), 6.71–6.67(d, J = 8.6Hz, 2H);
CNMR (CDCl /DMSO-d ); δ = 122.2, 125.4, 126.5,
13
3
6
−1
1
28.8, 129.9, 132.8, 144.3 ppm; FTIR (KBr,cm );
3
432(N-H), 1600(C=C), 1482(C=N), 729(C-Br),
+
2
.4 One pot synthesis of 2,4,5, trisubstituted
NCMS (m/z) 367 (M +1)
imidazoles
3
. Results and Discussion
The one-pot synthesis of substituted imadazoles was
carried out in a 50 mL round bottomed flask equipped
with a reflux condenser in an oil bath with tempera-
ture control and refluxed. About 500 mg of the catalyst
3.1 Catalytic Study
It can be understood from the similar studies reported in
◦
was taken and activated at 500 C for 2 h and cooled to
31
the literature, the plausible mechanism with the cop-
per and cobalt catalyst in the reaction may be shown
in scheme 2. The Aldehyde and 1,2-diketone are first
activated by ferrite nanoparticles (Fe ) to afford A and
B respectively. The imine intermediate (A), condenses
further with the carbonyl carbon or 1,2 diketone imine
room temperature before the experiment. 10 mmol each
of benzil, aromatic aldehyde and 20 mmol of ammo-
nium acetate were mixed together along with the cata-
lyst and 10 mL of ethanol as solvent and refluxed. The
completion of the reaction was checked with TLC (n-
hexane: ethyl acetate 4:1) and the products were iso-
lated by removing the catalyst magnetically from the
reaction mixture. All the products are known in the lit-
3+
(B) and formation of carbocation (C) followed by attack
of imine nitrogen to positive centre and dehydration to
afford the imo-imidazole (D), which rearranges via1
sigmatropic shift followed by deprotonation gives the
imidazole.
,5
1
13
erature and were identified by IR, HNMR, CNMR
and mass spectra of representative compounds and
compared.
3
.1a Comparison of effect of the present catalysts with
2
.5 Spectral data of substituted imidazole derivatives
other catalysts on synthesis of 2,4,5, tri-substituted imi-
dazoles: It is observed from table 2, that copper and
cobalt ferrites have shown similar effective yields when
compared to iodine and TCCA with minimum reaction
times, which is a significant contribution in this method.
(figures S7 and S15)
2.5a 2,4,5,triphenyl
1-H-Imidazole
(4a): M.p.
◦
1
273–275 C; HNMR (Bruker) (CDCl /DMSO-d )
3
6
13
δ = 7.97–7.34(m, 15H), 9.31(brs, N-H), CNMR
(CDCl /DMSO-d ); 122.5, 127.0, 128.7, 129.2, 136.4
3
6
−1
ppm; FTIR (KBr, cm ): 3450(N-H), 3062(C-H), 1658 3.1b Effect of solvent on synthesis of 2,4,5, trisub-
+
(C=C), 1578(C=N), NCMS (m/z) ; 297 (M +1)
stituted imidazoles: Investigation of reaction medium

1
718
Paul Douglas Sanasi et al.
2
NH OAC
2NH3
4
Fe+3
Ar
O
NH
A)
+
NH3
H
(
H
Ar
Fe+3
Ph
Ph
NH
O
+
NH3
O
O
B)
Ph
Ph
Ar
(
H
N+
Ph
Ph
N
HO
Ph
Ph
O
H
Ph
H
-
H O
2
HN
+
Ar
Ar
NH
(A)
NH
Ph
N+
(
B)
(C)
H
(
D)
-
H+
Ph
N
Ar
Ph
N
H
Scheme 2. Plausible mechanism for the formation of 2,4,5 tri-substituted imidazoles
for the process revealed that solvents played an impor- obtained when the catalyst was reused. We therefore
tant role in the reaction under investigation. The results selected ethanol as solvent.
are summarized in table 3. It was found that polar sol-
vents such as acetic acid, CH CN, and C H OH were 3.1c Effect of temperature on synthesis of 2,4,5-
3
2
5
much better than non-polar solvents. Trace amounts of trisubstituted imidazoles: The reaction temperature
yield observed when H O was used as solvent, presum- has a great influence on the model reaction. The
2
ably due to the aggregation of the hydrophobic cata- reactions were carried out in ethanol at different
◦
lyst. Although acetic acid was effective, low yield was temperatures ranging from 30 to 70 C. The results are
Table 2. Comparative catalytic activity of copper and cobalt ferrites with other catalysts.
◦
Sl. No.
Catalyst
Ar
Time (min)
Temp ( C)
Yield (%)
1
2
3
4
5
6
7
8
9
Iodine15
TCCA16
CuFe2O4
CoFe2O4
Iodine1
Ph
Ph
Ph
Ph
15
12hrs
10
10
25
12hrs
13
10
75
85
70
70
75
85
70
70
–
99
90
94
98(4a)
99
89
96
96(4b)
–
90
92
94(4c)
5
4-OMe C6H4
4-OMe C6H4
4-OMe C6H4
4-OMe C6H4
4-Br C6H4
4-Br C6H4
4-Br C6H4
4-Br C6H4
TCCA16
CuFe2O4
CoFe2O4
15
Iodine
–
1
1
1
0
1
2
TCCA16
CuFe2O4
CoFe2O4
12hrs
20
15
85
75
75

Nano ferrite catalysed one-pot synthesis of tri-substituted imidazoles
Table 3. Effect of solvent.
1719
Sl. No.
Catalyst
Ar
Solvent
Time (min)
Yield (%)a
1
2
3
4
5
CoFe2O4
CoFe2O4
CoFe2O4
CoFe2O4
CoFe2O4
Ph
Ph
Ph
Ph
Ph
H2O
CH2Cl2
CH3CN
CH3COOH
C2H5OH
60
60
45
25
10
trace
35
55
86, 57
98
b
All reactions were carried out under reflux conditions with 500 mg of catalyst.
a
b
Isolated yields Catalyst was reused
Table 4. Effect of temperature.
cobalt nanoferrites. This method offers several advan-
tages including high yield, short reaction time, ease of
separation and recyclability of the magnetic catalyst.
◦
a
S.No. Catalyst Ar Temperature ( C) Time (min) Yield (%)
1
2
3
4
CoFe2O4 Ph
CoFe2O4 Ph
CoFe2O4 Ph
CoFe2O4 Ph
R.T.
45
60
300
120
35
20
45
75
98
Supplementary Information
70
10
Supplementary information contains XRD, FTIR and
SEM images of copper and cobalt ferrites (S1–S6) and
FTIR, Mass and 1HNMR spectra of substituted imida-
zoles (S7–S15). For details, see www.ias.ac.in/chemsci.
All reactions are carried out using 500 mg of catalyst in
ethanol.
a
Isolated yields
presented in table 4. It is clear that at lower tempera-
tures, even if the times were prolonged to 8 h, only low
yields were observed. Consequently, we chose 70 C as
Acknowledgements
◦
The authors wish to thank the University Grants Com-
mission (UGC) for all the facilities received through
the major research project no. F. 41-371/2012 (SR) to
Paul Douglas Sanasi, UGC-FIP fellowship to D. Santhi
Priya, UGC-JRF to B Swathi, CSIR – JRF to M. Ravi
Kumar, TEQIP Fellowship to K. Jaya Rao.
the optimal temperature for our reaction.
3.2 Recycling of the catalyst
Catalyst reusability is of major concern in heteroge-
neous catalysis. The recovery and reusability of the cat-
alyst was investigated in this reaction with benzalde-
hyde (4a). Catalyst recycling was achieved by fixing
the catalyst magnetically at the bottom of the flask
with a strong magnet, after which the solution was
taken off with a pipette, the solid washed twice with
dichloromethane (DCM) and the fresh substrate dis-
solved in the same solvent was introduced into the flask,
allowing the reaction to proceed for the next run. The
catalyst was consecutively reused five times without
any noticeable loss of its catalytic activity. These cata-
lysts are highly magnetic and their saturation magneti-
zation values are found to be 32.45 and 35.56 emu/g,
which are much higher than other reported magnetic
catalysts. Therefore, they could be easily and almost
completely separated by an external magnet which is of
a great advantage for a heterogeneous catalyst.
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9
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