Graphene oxide nanosheets promoted regioselective and green synthesis of new dicoumarols

Article abstract of DOI:10.1039/c4ra00508b

Graphene oxide (GO) was obtained by modified Hummers oxidation of graphite and used as a highly efficient, metal-free, non-oxidative, and recyclable catalyst to promote the condensation of 4-hydroxycoumarin and aryl glyoxals for synthesis of new dicoumarols. This method is completely in accord with green chemistry. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4ra00508b

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Graphene oxide nanosheets promoted
regioselective and green synthesis of new
Cite this: RSC Adv., 2014, 4, 17891
dicoumarols†
a
a
Saeed Khodabakhshi, Bahador Karami, Khalil Eskandari,a S. Jafar Hoseinia
*
*
and Alimorad Rashidib
Received 17th January 2014
Accepted 3rd April 2014
Graphene oxide (GO) was obtained by modified Hummers oxidation of graphite and used as a highly efficient,
metal-free, non-oxidative, and recyclable catalyst to promote the condensation of 4-hydroxycoumarin and
aryl glyoxals for synthesis of new dicoumarols. This method is completely in accord with green chemistry.
DOI: 10.1039/c4ra00508b
www.rsc.org/advances
experiments as an inhibitor of reductases.8 According to the
importance of some compounds containing coumarin nucleus
Introduction
in pharmaceutical research, the chemistry of this compounds
have recently received special attention of chemists.9,10 Although
dicoumarol was rstly discovered in mouldy wet sweet-clover
hay, several methods have been described in the literature for
synthesis of dicoumarol derivatives. As a background, the total
synthesis of dicoumarols starting from salicylaldehyde and
formaldehyde,11 biosynthesis of dicoumarol employing micro-
organisms such as Penicillium jenseni,12 and Knoevenagel
condensation of 4-hydroxycoumarins with carbonyls using
several catalysts13–16 are some of them.
Organic synthesis on water has been well reviewed by
Chanda and Fokin describing the heterogeneous reactions on
the surface of water.17 Water possesses many unique properties
including safety and cheapness, thus, using water instead of
organic solvents can efficiently help to nish the concerns
about economic and environmental problems to the chemical
reactions.18 Besides, employing safe and recyclable catalytic
systems is an important factor in the context of sustainable
Green chemistry by nanocatalysis has emerged as a sustainable
alternative to the conventional methods.1–3 Although various
catalysts are used in chemical reactions, metal-free and
heterogeneous catalysts have attracted considerable attention
in recent years.4,5 Among metal-free catalysts, graphene and
graphene oxide (GO) are emerging as a new class of carbocata-
lysts.6 Until now, however, the catalytic application of graphene
and reduced-GO has focused primarily on the use of these
materials as supports for catalytically active transition metals.
Simplied structure of a single layer of graphene oxide (GO) was
proposed (Fig. 1).7
The acidic and oxidative nature of the oxygen functionalities
allows it to function as a solid acid or green oxidant. From a
broader perspective, the unique properties inherent to well-
dened nanosheets such as graphene and GO are suitable for
facilitating a wide range of transformations and may offer
extraordinary potential in the design of novel catalytic systems.
GO and its related materials have advantages over many
common catalysts. For example, stability, safety, insolubility in
common solvents, and recyclability make them green catalysts
for chemical reactions. However, the application of GO and
other reduced-GO as catalysts in synthetic chemistry remains
essentially unexplored.
Pharmaceutically, dicoumarol is a naturally occurring anti-
coagulant that functions like warfarin as a vitamin K antagonist.
Dicoumarol is the bridge substituted dimers of 4-hydroxy-
coumarin which has been employed for the prevention and
treatment of thrombosis. It is also used in biochemical
aDepartment of Chemistry, Yasouj University, P. O. Box 353, Yasouj, 75918-74831,
Iran. E-mail: karami@mail.yu.ac.ir; Fax: +98 7412242167; Tel: +98 7412223048
bNanotechnology Research Center, Research Institute of Petroleum Industry, Tehran,
Iran
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c4ra00508b
Fig. 1 Structural model of graphene oxide (GO).
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chemistry.19,20 Accordingly, in this paper, we report the use of 300 MHz): d ¼ 11.15 (s, 2H), 7.89 (dd, 2H, J1 ¼ 8.2, J2 ¼ 1.6 Hz),
GO as a metal-free, eco-friendly and recyclable catalyst for the 7.79–7.75 (m, 2H), 7.56–7.50 (m, 2H), 7.33–7.24 (m, 4H), 6.94
convenient synthesis of some dicoumarols containing aryloyl (t, 2H, J ¼ 8.6 Hz); 13C NMR (CDCl3, 75 MHz): d ¼ 192.91, 165.40,
group in aqueous media.
152.41, 133.27, 132.00, 130.77, 130.65, 125.08, 124.56, 116.75,
116.35, 115.97, 115.68, 42.80; anal. calcd for C26H15FO7: C,
68.12; H, 3.30. Found: C, 68.30; H, 3.22.
Experimental
4-Methoxy-benzoyl[bis(4-hydroxycoumarin-3-yl)]methane(3e).
M.p. 265–267 ꢀC; IR (KBr) ~n ¼ 3500–3300, 3076, 2978, 1684, 1650,
All chemicals were purchased from Merck and Aldrich. GO was
prepared using modied Hummers method from ake graphite
(Merck Company).21 Aryl glyoxals were synthesized in accord
with our previously reported method.22 The reaction progresses
were monitored by thin layer chromatography (TLC; silica-gel 60
1
1620, 1601, 1571, 1263 cmꢁ1; H NMR (CDCl3, 300 MHz): d ¼
11.22 (s, 2H), 8.00 (dd, 2H, J ¼ 8.2, 1.6 Hz), 7.77–7.72 (m, 2H),
7.55–7.49 (m, 2H), 7.32–7.24 (m, 4H), 6.77–6.72 (m, 2H), 6.00
(s, 1H), 3.71 (s, 3H); 13C NMR (CDCl3, 75 MHz): d ¼ 193.13,
165.22, 163.55, 152.40, 133.08, 130.48, 128.30, 124.94, 124.57,
116.68, 116.48, 113.88, 55.46, 42.62; anal. calcd for C27H18O8: C,
68.94; H, 3.86. Found: C, 69.10; H, 3.69.
F254, n-hexane: AcOEt). IR spectra were recorded on a FT-IR
JASCO-680 and the 1H NMR spectra were obtained on a Bruker-
Instrument DPX-400 and 300 MHz Avance 2 model. X-ray
photoelectron spectroscopy (XPS) data were obtained with an
ESCALab220i-XL electron spectrometer from VG Scientic using
300 W AlKa radiation. The varioEl CHNS was also used for
elemental analysis. Scanning electron micrographs (SEM) were
obtained using a Cambridge S-360 instrument with an accel-
erating voltage of 20 kV. The powder X-ray diffraction (XRD)
pattern was obtained by a Bruker AXS (D8, Avance) instrument
employing the reection Bragg–Brentano geometry with CuKa
radiation. The structure of the products was conrmed on the
basis of IR, NMR spectroscopic data, and elemental analysis.
3-Methoxy-benzoyl[bis(4-hydroxycoumarin-3-yl)]methane (3f).
M.p. 205–207 ꢀC; IR (KBr) ~n ¼ 3500–3300, 1693, 1655, 1619, 1602,
1
1567, 1273, 1427 cmꢁ1; H NMR (CDCl3, 300 MHz): d ¼ 11.16
(s, 1H), 8.00 (dd, 2H, J ¼ 8.2, 1.6 Hz), 7.55–7.49 (m, 2H), 7.34–7.24
(m, 6H), 7.12 (t, 1H, J ¼ 8.2 Hz), 6.94–6.90 (m, 1H), 6.00 (s, 1H),
3.69 (s, 3H); 13C NMR (CDCl3, 75 MHz): d ¼ 194.21, 165.28,
159.72, 152.40, 136.93, 133.17, 129.42, 125.03, 124.52, 120.26,
120.15, 116.73, 116.42, 112.46, 42.91; anal. calcd for C27H18O8: C,
68.94; H, 3.86. Found: C, 69.06; H, 3.65.
4-Chloro-benzoyl[bis(4-hydroxycoumarin-3-yl)]methane (3g).
M.p. 250–252 ꢀC; IR (KBr) ~n ¼ 3500–3300, 3080, 2884, 1713,
1665, 1650, 1614, 1564, 1266, 1090, 767 cmꢁ1; 1H NMR (DMSO-
d6, 400 MHz): d ¼ 11.10 (s, 2H), 7.85 (d, 2H, J ¼ 6.0 Hz), 7.72
(d, 2H, J ¼ 5.2 Hz), 7.62–7.52 (m, 4H), 7.31–7.25 (m, 4H), 6.28
(s, 1H); 13C NMR (DMSO-d6, 100 MHz): d ¼ 196.16, 165.92,
163.33, 152.27, 135.90, 131.66, 131.24, 129.32, 125.94, 123.83,
123.45, 118.09, 115.87, 101.64, 42.92; anal. calcd for
Preparation of GO
A ask containing graphite (1 g) and of NaNO3 (0.75 g) was
placed in the ice-water bath. H2SO4 (75 ml) was added with
stirring and then KMnO4 (4.5 g) was slowly added over about 1
h. Aer vigorously stirring for 5 days at room temperature, 5%
H2SO4 (140 ml) aqueous solution was added over about 1 h with
C
26H15ClO7: C, 65.76; H, 3.18. Found: C, 65.91; H, 3.03.
ꢀ
stirring, and the temperature was kept at 98 C. The tempera-
2-Naphthoyl[bis(4-hydroxycoumarin-3-yl)]methane (3h). M.p.
ture was reduced to 60 ꢀC, 3 ml of H2O2 (30 wt% aqueous
solution) was added, and the mixture was stirred for 2 h at room
temperature. As-prepared GO was suspended in ultra-pure
water to give a brown dispersion, which was subjected to dial-
ysis to completely remove residual salts and acids. Resulting
puried GO powders were collected by centrifugation and air-
dried. GO powders were dispersed in water to create 0.05 wt%
dispersion. Then, the dispersion was exfoliated through ultra-
sonication for 1 h, which the bulk GO powders were trans-
formed into GO nanoplatelets.
255–257 ꢀC; IR (KBr) ~n ¼ 3550–3300, 1694, 1653, 1617, 1565,
1454, 1280 cmꢁ1; 1H NMR (CDCl3, 300 MHz): d ¼ 11.24 (s, 2H),
8.27 (s, 1H), 8.01 (dd, 2H, J1 ¼ 8.2, J2 ¼ 1.6 Hz), 7.83–7.72 (m, 4H),
7.54–7.43 (m, 4H), 7.33–7.23 (m, 4H), 6.19 (s, 1H); 13C NMR
(DMSO-d6, 75 MHz): d ¼ 177.38, 166.60, 163.65, 152.32, 134.48,
134.38, 131.82, 131.50, 129.13, 127.95, 127.54, 126.70, 124.15,
123.90, 123.33, 118.50, 115.78, 101.67, 43.14; anal. calcd for
C30H18O7: C, 73.47; H, 3.70. Found: C, 73.68; H, 3.75.
Results and discussion
Synthesis of dicoumarols 3 (mentioned in Table 2)
GO sheets were synthesized by a modied Hummers method
A mixture of 4-hydroxycoumarin 1 (2 mmol), aryl glyoxals 2 (* please see from Exp. section). Fig. 2 shows the XRD pattern of
(1 mmol) and GO (0.005 g) in H2O (10 ml) was reuxed for an the bulk GO in dry state of GO. In the XRD pattern, the clear
appropriate time mentioned in Table 2. The progress of the diffraction bands centered at 2q ꢂ 10ꢀ correspond to the (002)
reaction was monitored by TLC. Upon completion of reaction, plane of the GO with an interlayer spacing about 0.87 nm. With
the mixture was poured on ice. Aer formation of precipitate, respect to that the pure graphite shows a diffraction peak at 2q
the solid was ltered off, dried, and dissolved in hot EtOH–THF ¼ 26.3ꢀ (inset in Fig. 2), corresponding to an interlayer spacing
(2 : 1) to separate the catalyst. Finally, the product 3 was affor- of about 0.335 nm, therefore, the elimination of the peak at
ded aer recrystallization from EtOH–THF (2 : 1).
26.3ꢀ and the appearance of the peak at 10ꢀ conrm that GO has
4-Flouro-benzoyl[bis(4-hydroxycoumarin-3-yl)]methane (3b). been completely oxidized.23
ꢀ
M.p. 235–237 C; IR (KBr) ~n ¼ 3500–3300, 3066.26, 2887, 1695,
Scanning electron microscopy was used to observe the
1650, 1619, 1600, 1567, 1271, 1225, 1107 cmꢁ1; 1H NMR (CDCl3, morphology of graphene oxide nanoplatelets. Fig. 3 is SEM
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Fig. 2 XRD pattern of GO (inset shows XRD of graphite).
Fig. 4 Overall XPS spectra of GO.
images of as-prepared GO nanoplatelets that shows crumpled
thin layers with wrinkles and folds on the surface of GO. The
upturned crinkly GO nanosheets can be attributed to a high-
power ultrasound or a partial high-temperature environment
created by the intense oxidization during the preparing process.
X-ray photoelectron spectroscopy (XPS) was also used to char-
acterize the functional groups present in GO.
As shown in Fig. 4, the overall XPS spectrum of the GO shows
the typical peaks of C 1s and O 1s.
Fig. 5 also shows the C 1s signal of the prepared graphene
oxide sheets that was tted by four components at C]C (284.5
eV), C–O (286.4 eV), C]O (287.5 eV) and O]C–O (288.6 eV). In
addition, the estimated C/O atomic ratio is 2.5, in agreement
with the previous studies.24
Following our continuous interest to introduce new and safe
methods in the eld of organic synthesis,25 we turned our
attention towards the condensation of 4-hydroxycoumarin (1)
and aryl glyoxals 2 in the presence of catalytic amounts of gra-
phene oxide nanosheets (GO NSs) to produce dicoumarol
derivatives 3 (Scheme 1).
Fig. 5 C 1s XPS spectra of GO.
To achieve this aim, several experiments were preliminary
performed in order to nd the simple reaction conditions for
the synthesis of 3. Therefore, the synthesis of 3a was selected as
a model.
As can be seen in Table 1, we found that the reaction
proceeds slowly and cannot be completed aer 120 min in the
Scheme 1 Synthesis of dicoumarols catalyzed by GO.
absence of the catalyst. Also, higher loadings of the catalyst did
not show a marked inuence on the product yield or reaction
rate. In the next experiment, to demonstrate the effect of solvent
or media on the reaction progress, we used several solvents
which the results have been shown in Table 1. It should be also
noted that 4-hydroxycoumarin is soluble in alcohol, acetone
Fig. 3 SEM image of GO.
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Table 1 Effect of several conditions in synthesis of 3a under reflux
Table 2 Synthesis of dicoumarols using GO (0.005 g) under reflux in
H2Oa
Entry Catalyst
Solvent
Time (min) Yield (%)
Entry
Ar
Time (min)
Yield (%)
M.p. (ꢀC)
1
2
3
4
5
6
7
8
Catalyst-free
H2O
H2O
H2O
H2O
Solvent-free
MeOH
EtOH
THF
CH2Cl2
EtOH–H2O (1/1)
120
45
10
10
120
15
10
20
120
10
10
10
10
10
10
Trace
77
83
82
Trace
80
80
75
50
83
GO NSs (0.003 g)
GO NSs (0.005 g)
GO NSs (0.010 g)
GO NSs (0.005 g)
GO NSs (0.005 g)
GO NSs (0.005 g)
GO NSs (0.005 g)
GO NSs (0.005 g)
GO NSs (0.005 g)
Fe3O4 NPs (0.005 g) H2O
ZnO NPs (0.005 g) H2O
ZnO NWs (0.005 g) H2O
TiO2 NPs (0.005 g) H2O
TiO2 NWs (0.005 g) H2O
3a
3b
3c
3d
3e
3f
C6H5
4-F-C6H4
10
10
12
10
8
12
15
5
83
75
80
80
77
73
80
85
177–175
273–235
262–264
270–272
265–267
205–207
250–252
255–257
4-Br-C6H4
4-NO2-C6H4
4-MeO-C6H4
3-MeO-C6H4
4-Cl-C6H4
2-Naphthyl
3g
3h
9
10
11
12
13
14
15
a
Isolated yields.
25
30
25
10
the produced a,b-unsaturated ketone and subsequent enoliza-
tion promoted by GO gives nal products.
10
To strengthen the speculative mechanism, the effect of the
catalyst on the reaction rate through using several samples with
different concentrations of acid groups was investigated for
synthesis of 3a. In the rst case, the reaction was conducted in
the presence of pure graphite (0.005 g) and it was found that the
reaction is not completed aer 30 min. Using a sample with less
acidic groups in which graphite has not been completely
oxidized, led to an increase of production rate (completion: 17
min) in compression with pure graphite. By employing the
completely oxidized graphite (0.005 g), the reaction proceeded
well and the desired product was obtained in good yield and
short reaction time (Table 1, entry 10). In another variation, to
demonstrate the effect of acidic group on the rate of the reac-
tion, the NaOH was used as catalyst, but the reaction did not
proceed aer 30 min.
Green chemistry principles emphasizes on the development
of new methods for chemical transformations which are
resource and energy efficient, practically simple and environ-
mentally safe. The use of water instead of organic solvents is
more reasonable because of its safety and cheapness. To
investigate the reusability of GO in synthesis of dicoumarols 3,
the recyclability of GO was also investigated (Fig. 6).
and ether, but it has low solubility in water. Nevertheless,
considerable rate acceleration is mostly observed in reactions
performed using protic solvents, such as EtOH, MeOH, and H2O
when compared to those in aprotic ones. However, water can be
perfectly used, without hindering the yield. In addition, the
reaction did not proceed under solvent-free conditions, so, it
can show the importance of aqueous media for this type of
reactions. Through screening, we found that this reaction was
efficiently completed using GO (0.005 g) under reux in H2O
about 10 min.
In another variation, to show the merit of GO with other
catalysts, we surveyed the effect of some commonly nano-sized
catalysts in the synthesis of model compounds. Despite the
merits of nano Fe3O4, ZnO, and TiO2, using them suffers from
some disadvantages such as long reaction times and low yields.
By using ZnO NPs, the reaction proceeded slowly. However, ZnO
nanoparticles (NPs) seem to be better than nano Fe3O4 and
TiO2. Considering the results, it is clear that GO acts better
rather than other ones from the aspect of productivity and
reaction time.
The results show that the GO is usable for 4 times without
appreciable loss in catalytic activity. Avoidance of organic
In addition, from the environmental point of view, GO is a
metal-free solid acid and using it is more reasonable than
abovementioned catalysts which act as Lewis acids.
The scope of this unique synthesis was investigated aer
optimization. As can be seen in Table 2, the reaction proceeded
effectively with different substitution on aryl glyoxal and it was
not found to be dependent upon the electronic properties of the
substituents.
It should be noted that the exact mechanism for this reaction
is unclear, as there are not sufficient insights into the mecha-
nistic aspects of the GO. In regard of recently published review
explaining the possible mechanistic pathways for GO in organic
reactions,6 we think the probable active sites of the catalyst, in
the present reaction, are acidic groups.
A simple plan for the GO catalyzed synthesis of 3 is suggested
in Scheme 2. It seems that the reaction takes a place in three
steps. It is reasonable to assume that the initial event involves
the Knoevenagel condensation of the aryl glyoxal and
4-hydroxycoumarin. In the next steps, a Michael type addition to Scheme 2 Suggested mechanism for synthesis of 3 using GO.
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Conclusions
To sum up, we have established an environmentally benign
procedure to synthesize dicoumarols containing aryloyl group
starting from 4-hydroxycoumarin with aryl glyoxals in H2O. The
reactions have been dramatically promoted by GO as a metal-
free catalyst leading to good yield of desired products in short
reaction times. Use of a safe and recyclable catalyst in water is
completely compatible with sustainable chemistry. The
simplicity of the protocol will be also benecial to the sustain-
able synthesis of dicoumarols in the laboratory and in industry.
Acknowledgements
We thank the Yasouj University Research Council for nancial
support. Also, we would like to thank the Iranian Nanotech-
nology Initiative Council for their support.
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