Nickel oxide nanoparticles: A green and recyclable catalytic system for the synthesis of diindolyloxindole derivatives in aqueous medium

Article abstract of DOI:10.1039/c4ra14551h

This study focuses on the use of nano-NiO particles as green and inexpensive nanocatalysts for the synthesis of diindolyl oxindoles, an important class of potentially bioactive compounds. The oxindole derivatives were prepared by the condensation of indole and isatin compounds in water, an excellent solvent in terms of environmental impact and reduction of waste production. This journal is

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Nickel oxide nanoparticle: A green and recyclable
catalytic system for the synthesis of diindolyloxindole
derivatives in aqueous medium
Cite this: DOI: 10.1039/x0xx00000x
Mohammad Ali Nasseri,* Faezeh Ahrari and Batol Zakerinasab
Received 00th January 2012,
Accepted 00th January 2012
Department of Chemistry, College of Sciences, University of Birjand, Birjand 97175ꢀ615, Iran
Eꢀmail: manaseri@birjand.ac.ir
DOI: 10.1039/x0xx00000x
www.rsc.org/
Abstract
This study focuses on nanoꢀNiO particles as a green and inexpensive nanocatalyst for the synthesis
of diindolyl oxindoles, an important class of potentially bioactive compounds. The oxindole
derivatives were prepared by the condensation of indole and isatin compounds in water, an
excellent solvent in terms of environmental impact and reduction waste production.
.
Keywords: Nano particle; NanoꢀNiO; Green chemistry; Diindolyloxindole
and environmental concern. Sometimes it shows higher reactivity
and selectivity compared to other conventional organic solvents due
to its strong hydrogen bonding ability. 6,7
1. Introduction
On a different note, oxindole derivatives often appear as important
Recently, great attention has been focused from both environmental
and economical points on the use of heterogeneous solid acid
catalysts for various organic transformations.1,2 Heterogeneous
catalysts are always superior to their homogeneous counterparts in
terms of many aspects such as operational simplicity, reusability,
environmental compatibility and high selectivity. With the
advancement of nanoscience and nanotechnology, nanoparticulate
heterogeneous catalysts have received notable attention in organic
transformations on the ground of their ability to enhance faster rates
of organic reactions, high catalytic activity and higher yield of
products which is due to their ability to afford high particle sizeꢀtoꢀ
volume ratio along with greater surface area.3 During recent years,
nickel oxide nanoparticle has attracted much attention as an
inexpensive and nonhazardous catalyst or an effective promoter that
can enhance the reactivity and selectivity of various organic
reactions. 4,5
structural components in biologically active and natural compounds.
Among oxindole systems, spirooxindoles have received considerable
attention due to their wide range of useful biological properties,
which include antibacterial, antiprotozoal, antiꢀinflammatory
8ꢀ13
activities and progesterone receptors (PR) agonists.
Due to the
pharmacological properties of oxindoles, development of synthetic
methods enabling easy access to these compounds are desirable. In
continuation of our work on the synthesis of biologically important
compounds using simple, efficient and nontoxic catalysts,14ꢀ17 in this
paper we report synthesis of diindolyloxindole derivatives by the
coupling of indole and isatin derivatives in the presence of nanoꢀNiO
as an inexpensive and green catalyst in aqueous medium.
2. Results and discussion
In many cases, organic solvents which are used in huge amounts for
many different applications have a negative impact on the health and
the environment. One of the key areas of green chemistry is the
elimination of solvents in chemical processes or the replacement of
hazardous solvents with environmentally benign solvents. Water
emerged as a useful alternative solvent for several organic reactions
owing to many of its potential advantages such as safety, economy
Initially, nickel oxide nanoparticles was synthesized by the reaction
of nickel nitrate hexahydrate with urea in deionized water and was
heated at 115 °C for 1.5 h in an oil bath. Resulting compound was
dried and was calcined in at 400 °C for 1 h. Then Nano NiO were
characterized by XRD, DLS, BET and TEM. XRD patterns of the
products obtained after the precursors were calcined at 400 oC. All of
these diffraction peaks in Figure 1, not only the peak positions
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appearing at 2θ = 37.37, 43.43, 62.97, 75.52, and 79.48 but also their
lattice parameters, were quite consistent with those of the standard
JCPDS Card No. 04ꢀ0835 for the standard spectrum of the pure NiO.
The average size of the NiO particles was estimated to be about 9
nm by the Debye–Scherrer equation.
Fig. 4 Size dispersion by number NiO befor calcinition
Fig. 1 XRD pattern of NiO nanoparticle
TEM analysis of NiO nanoparticle (Fig. 2) provided information on
the size of NiO nanoparticles. the mean particle size determined by
TEM is very close to the average particle size calculated by Debye–
Scherer formula from the XRD pattern. The particle size distribution
of NiO showed that the average diameter of the particles was 11 nm
(Fig 3).
Fig. 5 Size dispersion by number NiO after calcinition
In order to show the merit of synthesized heterogeneous catalyst in
organic reactions, Nano NiO was used as an efficient and
inexpensive catalyst for synthesis of a series of analogues of
oxindole using various isatins and indoles. Indole and isatin were
selected as the model substrates and reacted under different
experimental variants (Scheme 1).
HN
O
O
O
N
N
N
H
H
H
N
H
Scheme 1. Synthesis of 3,3ꢀdiindolyloxindole
To obtain the optimized reaction conditions, we changed the amount
of catalyst. The results are summarized in Table 1. Consequently,
among the tested temperature and the amount of catalyst, the
condensation of indole and isatin was best catalyzed by 0.004 gr of
Nano NiO at 70 oC as the reaction was completed within a high
yield. In the presence of 0.0004 gr of catalyst, the model reaction
was not completed for 30 min and only 50% of the product was
obtained. Further increases in the amount of Nano NiO (0.008 gr) in
mentioned reaction did not show any significant effect on the
product yield.
Fig. 2 TEM pattern of NiO nanoparticle
14
12
10
8
6
4
2
0
Table 1 Effect of the amount of catalyst on the synthesis of
13
9
10 11 12 15 30
oxindole catalyzed by nanoꢀNiOa
Particle size (nm)
Entry Cat.(gr)
Time(min) Yield(%)
1
2
3
4
0.008
15
92
87
88
83
0.004
15
0.0008
0.0004
120
120
Fig. 3 particle size distribution of NiO nanoparticle
The average hydrodynamic size of NiO NPs in water determined by
dynamic light scattering (DLS). Size dispersion by number patterns
obtained befor and after the precursors were calcined at 400 oC (Fig
4 and 5). When NiO NPs were calcined number of nanoparticle
with higher size decreased.
aReaction conditions: isatin (1 mmol), indole (2 mmol) and water (2
mL) at 70 oC
b The yield refers to pure isolated product
To evaluate catalytic activity of nanoꢀNiO, the model reaction was
carried out in water (2 mL) at 70 C for 30 min in the presence of
o
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different catalytic systems (0.004 gr), separately. The results are Table 4 Synthesis of 2,2ꢀdiindolyloxindole derivativesa
CH3
shown in Table 2. As it is evident from the results, nanoꢀNiO was
the most effective catalyst in terms of yield of the oxindole (98%)
while other catalysts formed the product with the yields of 33ꢀ68%
(Table 2, Entries 2ꢀ6). To establish the catalytic role of Nano NiO,
indole was treated with isatin in the absence of catalyst. In this case,
the reaction proceeded in low yield over model reaction times (30
min) (Table 2, Entry 9).
H3C
CH3
O
R2
NanoꢀNiO
H2O, 70oc
N
N
H
O
H
N
N
R1
O
H
R2
N
R1
Table 2 Synthesis of 3,3ꢀdiindolyloxindole in the presence of
various catalytic systems
Entry R1
R2
H
Br
Br
H
Time(h)
1
0.5
0.5
1
1.5
1.5
Yield(%)
80
85
90
98
80
82
1
2
3
4
5
6
H
PhCH2
H
PhCH2
Me
PhCH2
Entry
Catalyst
Yield(%)
1
2
3
4
5
6
7
8
9
NanoNiO
NiO
CdO
PbO
As2O3
CuO
CaO
Al2O3
None
98
45
52
65
67
68
38
33
10
H
NO2
aReaction conditions: isatin compounds (1 mmol), 3ꢀ methyl indole
(2 mmol), Nano NiO (0.004 gr) and water (2 mL) at 70 oC
b The yield refers to pure isolated product
In Table 5, the efficiency of our method for the synthesis of
diindolyloxindole is compared with some other compared with some
other published works in literature. Each of these methods have their
own advantages, but they often suffer from some troubles including
the use of organic solvent (entries 2ꢀ4), long reaction time (entries 2,
aReaction conditions: isatin (1 mmol), indole (2 mmol), catalyst
(0.004 gr) and water (2 mL) at 70 oC for 30 min
b The yield refers to pure isolated product
Further explore the scope and limitation of this protocol under the 4 and 5) and employ of nonꢀrecyclable catalyst (entry 5).
optimized conditions (0.004 gr catalyst in H2O at 70 oC), particularly Table 5 Comparison of results using Nano NiO with results
in regard to library construction, was evaluated using various isatin obtained by other works for the synthesis of diindolyloxindole
and indole compounds (Table 3). In all cases, the reaction proceeded
Entry
Catalyst
Yield
(%)
Time
(h)
Condition
Solvent
Ref
readily to afford the corresponding oxindoles in good to excellent
yields (60ꢀ 98%) in very short reaction times (0.5ꢀ 1.5 h).
Table 3 Preparation of 3,3ꢀdiindolyloxindole derivativesa
R3
1
2
3
4
Currrnt
Bi(OTf)3
RuꢀY
98
92
93
93
0.5
3.0
0.5
2.5
70
H2O
ꢀ
r.t.
CH3CN
C2H4Cl2
CH3CN
18
19
20
N
R4
O
reflux
r.t.
O
R4
R2
R2
R2
NanoꢀNiO
H2O, 70oc
PEGꢀ
O
R1
R1
R1
N
N
N
N
OSO3H
H
H
H
R3
5
CAN
95
3.0
U.S.
EtOH
21
At the end of the reaction, the catalyst could be recovered by
centrifuge. The recycled catalyst was washed with dichloromethane
and subjected to another reaction process. The results show that the
yield of product after five runs was only slightly reduced (Fig. 6).
Reactant
Indole
Entry
Time(h) Yield
(%)b
Isatin
R3
H
H
H
Me
Me
Me
PhCH2
PhCH2
PhCH2
H
PhCH2
H
H
R1
R2
R4
H
NO2
Br
NO2
H
Br
Br
H
NO2
H
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
0.5
0.5
0.5
0.5
1.5
1.5
1.5
1.5
1.5
1
98
95
92
95
90
80
93
60
75
90
85
95
80
90
88
86
85
83
100
50
80
30
30
30
30
4
30
0
Yield(%)
Time(min)
9
H
1
2
3
10
11
12
13
14
Me
Me
Me
Me
Me
5
H
Br
OMe
Br
1.5
1
Recycle
1.5
1.5
Et
Fig 6.Recyclability of nanoꢀNiO as a catalyst in the synthesis of
aReaction conditions: isatin compounds (1 mmol), indole compounds
(2 mmol), Nano NiO (0.004 gr) and water (2 mL) at 70 oC
b The yield refers to pure isolated product
These reactions also proceeded with 3ꢀmethyl indole (Table 4). In
these cases, the reaction times are longer than 2ꢀmethyl indole/
indole.
oxindoles
A reasonable pathway for the reaction of indole with isatin
compounds conducted in the presence of Nano NiO is presented by
Scheme 2. The first step involves the formation of activated isatin
(1) followed by its reaction with indole to generate compound 2 that
subsequently undergoes elimination reaction to produce the
compound 4. Intermediate 4 undergoes further addition with the
second indole molecule to afford oxindole derivatives.
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DOI: 10.1039/C4RA14551H
A mixture of indole (2 mmol), isatin (1 mmol), nanoꢀNiO (0.004 gr)
and water (2 mL) was stirred for the appropriate time at 70 C, as
H
N
o
O
H
N
shown in Tables 3 and 4. Completion of the reaction was indicated
by TLC monitoring. After completion of the reaction, the reaction
mixture was dissolved in acetone and catalyst was isolated by
centrifuged. The product was afforded by evaporation of solvent and
was recrystallized from EtOH to afforded the pure products in high
purity and yield. Structural assignments of the products are based on
their 1H NMR, 13C NMR and IR spectra.
H
ONi
O
O
NiO
N
O
+
N
H
H
O
1
2
O
N
H
N
H
O
2.4.Spectral data for selected products:
3,3-Diindolyloxindole (compound 1, Table 3). White Solid, m.p>
NiO
1
250oC; H NMR (250 MHz, DMSOꢀd6) 6.79 (2H, m, ArH), 6.84
O
..
N
(2H, m, ArH), 6.92 (1H, m, ArH), 6.97–7.02 (3H, m, ArH), 7.22
(4H, m, ArH), 7.35 (2H, m, ArH), 10.58 (1H, s, N–H), 10.94 (2H, br
s, N–H); 13C NMR (62.9 MHz, DMSO) 53.4, 110.4, 112.4, 115.2,
119.1, 121.6, 121.8, 122.3, 125.1, 125.8, 126.6, 128.7, 135.5, 137.8,
142.2, 179.6; IR (KBr, cmꢀ1) 3420, 3300, 1704, 1610, 1105, 737 cmꢀ
1; Anal. Calcd for C24H17N3O: C, 79.32; H, 4.72; N, 11.56. Found:
C, 79.39; H, 4.68; N, 11.63.
NiO
H
HN
O
3
N
N
H
H
H
+
N
HN
O
H
3,3-Diindolyl-5-bromooxindole (compound 3, Table 3). White Solid,
O
o
1
mp> 250 C; H NMR (DMSOꢀd6) 6.81 (2H, t, ArH), 6.88 (2H, s,
ArH), 6.96 (1H, m, ArH), 7.03 (2H, m, ArH), 7.21 (2H, m, ArH),
7.30 (1H, s, ArH), 7.38 (2H, m, ArH), 7.43 (1H, m, ArH), 10.77
(1H, s, NH), 11.03 (2H, s, NH) ppm; 13C NMR (DMSOꢀd6) 53.64,
112.65, 114.00, 114.35, 119.23, 119.35, 121.35, 121.94, 125.21,
125.35, 126.34, 128.22, 137.79, 137.84, 141.53, 179.11 ppm; IR
(KBr, cmꢀ1): 3340, 3120, 1699 cmꢀ1; Anal. Calcd for C24 H16BrN3O:
C, 65.17; H, 3.65; N, 9.50. Found: C, 65.11; H, 3.49; N, 9.62.
N
N
NH
4
H
HN
NiO
Scheme 2. The proposed mechanism for the synthesis of diindolyl
oxindole in the
presence of Nano NiO.
3. Experimental
2.1. General Methods
3,3-Bis(2-methylindolyl)oxindole (compound 9, Table 3). White
o
1
Solid, m.p> 250 C; H NMR (DMSOꢀd6) 1.95 (3H, s, Me), 2.09
(3H, s, Me), 6.47 (1H, m, ArH), 6.61–6.66 (2H, m, ArH), 6.71 (1H,
m, ArH), 6.85–6.92 (3H, m, ArH), 6.96 (1H, m, ArH), 7.16 (1H, m,
ArH), 7.21–7.24 (3H, m, ArH), 10.57 (1H, s, NH), 10.87 (1H, s,
NH), 10.90 (1H, s, NH) ppm; 13C NMR (DMSOꢀd6) 13.87, 14.05,
53.28, 110.21, 110.29, 111.21, 111.27, 118.78, 118.84, 120.15,
120.21, 120.46, 120.63, 122.13, 126.32, 127.90, 128.54, 128.68,
132.84, 134.81, 135.76, 135.83, 136.44, 142.06, 180.21 ppm; IR
(KBr, cmꢀ1) 3400, 3250, 1700 cmꢀ1; Anal. Calcd for C26H21N3O: C,
79.77; H, 5.41; N, 10.73. Found: C, 79.85; H, 5.32; N, 10.64.
Indole and isatin derivatives were purchased from Merck
Chemical Company. Purity determination of the products were
accomplished by TLC on silicaꢀgel polygram SILG/UV 254
plates. Melting points were measured on an Electro thermal
9100 apparatus. IR spectra were taken on a Perkin Elmer 781
spectrometer in KBr pellets and reported in cmꢀ1. H NMR and
1
13C NMR spectra were measured on a Bruker DPXꢀ250 Avance
instrument at 250 MHz and 62.9 MHz in CDCl3 or DMSOꢀd6
with chemical shift given in ppm relative to TMS as internal
standard. The morphology of the products was determined by
using CMPhilips10 model Transmission Electron Microscopy
(TEM) at accelerating voltage of 100 KV. Power Xꢀray
diffraction (XRD) was performed on a Bruker D8ꢀadvance Xꢀ
ray diffractometer with Cu Kα (λ = 0.154 nm) radiation.
2.2.Preparation of nano NiO
Conclusions
In summary, an efficient protocol for the preparation of
diindolyloxindole derivatives was described. The procedure offers
several advantages including the cheapness and the availability of
the catalyst, mild reaction conditions and high yields of the products
as well as simple experimental and isolation procedures. All these,
make this protocol a useful and an attractive procedure for the
synthesis of oxindole derivatives.
Nickel oxide nanoparticles were prepared through the following
process. The molar ratio of nickel nitrate hexahydrate to urea at 1:4,
a
stoichiometric amount of Ni(NO3)2.·6H2O (0.08 mol) and
Acknowledgements
We gratefully acknowledge the support of this work by the Birjand
University Research Council.
CO(NH2)2 (0.32 mol) was accurately weighed and dissolved into 60
mL of deionized water, respectively. The two solutions were mixed
in a beaker and stirred with a magnetic stirrer at room temperature
until a homogeneous solution obtained. Thereafter, the mixture was
transferred into a round bottom flask, sealed and maintained heating
at 115 °C for 1.5 h in an oil bath. In this process, a kind of light
green sediment (i.e., the precursor) was formed. After the reaction
was completed, the precipitated powders were filtered and washed
with demonized water to neutral and colorless. This was to remove
the possibly adsorbed ions and chemicals to reduce the potential of
agglomeration. After being dried in an oven at 90 °C for 6 h, the
precursors were calcined in a muffle furnace at 400 °C for 1 h to
obtain the products in dark color (i.e., NiO nanoparticles). The
calcined products were then collected for further analyses. 5
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