Graphene oxide: An efficient recyclable solid acid for the synthesis of bis(indolyl)methanes from aldehydes and indoles in water

Article abstract of DOI:10.1016/j.catcom.2016.09.027

An efficient synthesis of bis(indolyl)methanes from aldehydes with indoles through graphene oxide -catalyzed Friedel-Crafts alkylation is developed. The reaction proceeds in water by using graphene oxide as the single catalyst to provide the desired products in good to excellent yields. Also, this methodology has a broad substrate scope, and is environment friendly and cost economic.

Full text of DOI:10.1016/j.catcom.2016.09.027

Graphene oxide: An efficient recyclable solid acid for the synthesis of
bis(indolyl)methanes from aldehydes and indoles in water
Yihong Wang, Rui Sang, Yang Zheng, Li Guo, Mei Guan, Yong Wu
PII:
DOI:
Reference:
S1566-7367(16)30347-8
doi:10.1016/j.catcom.2016.09.027
CATCOM 4796
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Catalysis Communications
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Revised date:
Accepted date:
23 June 2016
27 August 2016
17 September 2016
Please cite this article as: Yihong Wang, Rui Sang, Yang Zheng, Li Guo, Mei Guan,
Yong Wu, Graphene oxide: An efficient recyclable solid acid for the synthesis of
bis(indolyl)methanes from aldehydes and indoles in water, Catalysis Communications
(2016), doi:10.1016/j.catcom.2016.09.027
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Graphene oxide: an efficient recyclable solid acid for the synthesis of
bis(indolyl)methanes from aldehydes and indoles in water
Yihong Wang a, Rui Sang a, Yang Zheng a, Li Guo a, Mei Guanb *, Yong Wu a *
a. Key Laboratory of Drug-Targeting of Education Ministry and Department of Medicinal
Chemistry, West China School of Pharmacy, Sichuan University, Chengdu, 610041, P. R. of China.
b. West China Hospital, Sichuan University, No. 37. GuoXue road, Chengdu, Chengdu 610041, P. R.
China
e-mail: meiguan92@163.com; wyong@scu.edu.cn
Abstract An efficient synthesis of bis(indolyl)methanes from aldehydes with indoles through
graphene oxide -catalyzed Friedel-Crafts alkylation is developed. The reaction proceeds in water
by using graphene oxide as the single catalyst to provide the desired products in good to
excellent yields. Also, this methodology has a broad substrate scope, and is environment friendly
and cost economic.
Key words graphene oxide, Bis(indolyl)methanes, Friedel-Crafts reaction, recyclable, water
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1. Introduction
Bis(indolyl)methanes (BIMs),which are widely presented in various terrestrial
and marine origin bioactive metabolites [1], are important intermediates in synthetic
organic and medicinal chemistry [2]. They are finding applications as highly selective
colorimetric, fluorescent molecular chemosensors for Cu2+cation [3] and also well
known to possess various pharmacological effects such as hypolipidemic [4],
antiobesity [5], β-glucuronidase inhibitors [6], anti-microbial [7] and anti-cancer
activities [8].
Due to their biological and medicinal activities, great deals of new effective and
powerful synthesis routes have been established within the past ten years. Most of
synthesis strategies of BIMs are indoles respond to aldehydes or ketones through
Friedel-Crafts alkylation reaction route with the presented of Lewis acids [9], brønsted
acids [10], solid acids [11], ionic liquids [12] or coordination catalyst [13]. In spite of
these catalysts have different structures, all of them have similar reaction mechanism.
The reaction process is the acidic ions of catalysts promote the Friedel-Crafts
alkylation reaction of indoles with carbonyl compounds to get BIMs. Even if these
protocols have proved their efficiency in BIMs synthesis, they also suffered from
several drawbacks, such as the toxic metal ions and solvents, high costs, limitations of
catalyst recovery and harsh conditions. Consequently, development of milder,
convenient, environment friendly method to access BIMs is still highly valuable.
In recent years, high molecular materials are gaining much attention in organic
synthesis owe to their easy separation, mild reaction conditions, ease in recovery and
low-toxic nature [14]. Among these materials, graphene oxide (GO) interestingly
exhibits excellent activity due to its privileged lamellar flexible structure with a wide
range of functional groups, such as epoxy (C-O-C), hydroxyl (OH), and carboxyl
(COOH) [15]. Because of their high specific surface areas as well as excellent
stabilities, GO has become a favorable material to support a wide range of ions or
biomolecules, and GO supported catalysts have been applied to many kinds of
chemistry reactions [16]. But many literatures ignored that the carboxyl on the surface
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of GO played an important role in organic reactions which can be used as solid acids
to catalyze Friedel–Crafts reaction. To the best of our knowledge, only very limited
ways about using GO as catalyst has been found and the usage of GO served as the
single catalyst in the synthesis of BIMs from aldehydes has not been reported before.
Apart from that, we decided to explore the viability of using GO as the single catalyst
to prepare BIMs.
Figure 1. The synthesis of BIMs catalyed by Go
In this paper, we report GO, which can be used as solid acids to promote
Friedel-Crafts reaction. Compared with the traditionally applications, we developed a
new area of GO which is not only a support material, but also a powerful catalyst in
the synthesis of BIMs (as shown in Figure 1).
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2. Experimental
2.1 Synthesis of GO
Graphene oxide (GO) used in this work was synthesized from graphite according
to the modified Hummers method as reported [17]. To begin, 3.0 g of graphite and 1.5
g of NaNO3 were placed in a 500 ml beaker. After adding 69 ml of 98% sulfuric acid,
the mixture was stirred until cooled to 0 oC in an ice-water bath. KMnO4 (9.0 g, 99%)
was gradually added to the mixture and control the temperature below 20 oC. After
complete the adding, the ice-bath was exchanged for an oil-bath and the mixture was
heat up to 35 oC and maintain this temperature for 30 min. Then, 138 ml deionized
water was added gradually to the reaction and the resulting mixture was heated at 98
oC for 15 min. As the reaction progressed, the reaction mixture was cooled to room
temperature and diluted with 420 ml deionized water and 3 ml H2O2 (30%) was also
added to the reaction. The suspension was filtered and washed with 200 ml of 5%
hydrochloric acid solution. Next, the suspension was washed with deionized water
three times until the pH turn nature. The final precipitated GO was dried on vacuum at
60 oC for 24 hours for further use.
2.2 General experiment for the synthesis of bis(indolyl)methanes (3a as an
example)
A mixture of benzaldehyde 1a (0.5 mmol), indole 2a (1.5 mmol) and GO 150 mg
were added in 10 mL water with a condenser and then stirred under air at 40 oC for 3h.
After the completion of the reaction (monitored by TLC), the reaction mixture was
cooled to room temperature, extracted with ethyl acetate. The organic layer was
washed with saturated brine, dried over anhydrous sodium sulfate and the solvent was
evaporated to dryness. The crude residue was purified by flash chromatography on
silica to afford pure 3,3'-(phenylmethylene)bis(1H-indole) 3a as a pink solid (92%
yield).
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3. Results and discussion
3.1 Catalyst characterization
Fourier transform infrared (FTIR) spectra were recorded using a Nicolet 6700
FI-IR spectrometer (Nicolet). The GO powder was mixed with potassium bromide to
form the pellets in order to scan the FTIR spectra.
100
80
60
1225.4
40
1727.1
1054.2
1619.4
20
0
3385.9
4000
3500
3000
2500
2000
1500
1000
wavenumber (cm-1)
Fig 2. FTIR spectra of GO
The FTIR spectra of GO was shown in Fig 2. The wide peak at 3385.9 cm-1 in
the GO is attributed to the stretching mode of the O–H bond. Stretching vibration of
the C=O bond of carboxy on the surface of GO was observed as the band present at
1727.1 cm-1. The other intense band at 1619.4, 1225.4, 1054.2 cm-1 are attributed to
the v (C=C) of skeletal vibrations from unoxidized graphitic domains, C–OH and
C–O (epoxy) groups in the GO respectively [18].
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Figure 3. Point of zero charge of GO using 0.1 M KNO3.
The pHpzc (point of zero charge) of GO was determined by plottingΔpH against
initial pH (Figure 3). GO was added to 50 ml of 0.1 M of KNO3 solutions at various
solution pH (0.58–3.02) as per solid addition method. The curve crosses the
horizontal line at pH 2.32, suggesting that the surface charge is zero at pH 2.32. If pH
< pHpzc, the surface of the adsorbent becomes more positively charged. In contrast,
when pH > pHpzc, it is negatively charged.
3.2. Catalyst reaction activity
At the beginning of our investigation to synthesize BIMs, experiments were
carried out using benzaldehyde 1a and indole 2a as prototypical substrate.
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Table 1 Optimization of the reaction conditionsa
Entry
1
GO(mg)
100
100
100
100
100
100
50
Solvent
DCM
EA
Temp.(oC)
1a : 2a
1:3
1:3
1:3
1:3
1:3
1:3
1:3
1:3
1:3
1:3
1:3
1:3
1:3
1:2
1:4
Yieldb (%)
r.t
r.t
r.t
r.t
r.t
r.t
r.t
r.t
r.t
r.t
40
60
80
40
40
5
2
68
50
80
66
82
77
85
85
0
3
CH3CN
EtOH
THF
H2O
4
5
6
7
H2O
8
150
200
0
H2O
9
H2O
10
11
12
13
14c
15d
H2O
150
150
150
150
150
H2O
92
80
75
76
91
H2O
H2O
H2O
H2O
a Reaction conditions: 1a (0.5 mmol), 2a (1.5 mmol), catalyst (as indicated), solvent (10mL) for 3h
under air. b Isolated yield. c 1a (0.5 mmol), 2a (1.0 mmol), d 1a (0.5 mmol), 2a (2.0 mmol).
Firstly, a series of solvents, such as DCM, EA, CH3CN, EtOH, THF and H2O
were screened for this reaction under air. The results showed that H2O was the best
solvent for the ambient temperature employed (Table 1, entries 1-6), presumably due
to its favorable dispersion ability to GO. Next, we varied the amount of catalyst and
found that 150 mg of GO gave the best result (Table 1, entries 6-9), and no products
were detected without the presence of GO (Table 1, entry 10). In order to get even
o
higher yield, the reaction was performed at different temperatures. At 40 C, the
highest yield of 3a (92%) was obtained and when the temperature was carried out at
o
o
60 C and 80 C only led to a decrease in the yield (Table 1, entries 11-13). Finally,
we searched the optimal ratio of the reaction substrate in this reaction and 1:3
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equivalent weights of 1a and 2a was the superlative proportion to prepare BIMs
(Table 1, entries 14-15). Consequently, the optimal reaction conditions to get BIMs
tend to be: benzaldehyde 1a (0.5 mmol), indole 2a (1.5 mmol) and GO 150 mg in
water at 40 oC for 3h.
With the optimal reaction condition in hand, a range of reactions was carried out
to expand the scope of substituted indoles and aldehydes, the yields and reaction time
were shown in Figure 4. Firstly, when electron-withdrawing and electron-donating
groups were employed as the substituent on benzaldehyde, BIMs were obtained in
good to excellent yields (Figure 3, 3a-3l) and the results showed that substrates with
electron-withdrawing groups were more reactive. Additionally, other aromatic
aldehydes such as furan, thiophene, pyridine, pyrrole as well as naphthalene were well
tolerated in this reaction (Figure 3, 3m-3q) and this condition can also applied to
aliphatic aldehyde (Figure 3, 3r). Different substituted indoles were investigated too.
The results showed that methyl, halogen and cyano substituted indoles are compatible
and good yields were obtained (Figure 3, 3s-3w).
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Figure 4. The synthesis of BIMs (3) from aldehydes (1) and indoles (2).
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Reaction conditions: aldehydes (1, 0.5 mmol), indoles (2, 1.5 mmol), GO (150 mg) in water
(10 mL) at 40 oC for indicated time.a Isolated yield.
The further studying to check the recovering and reusing of GO was also
performed (Figure 5). After completion of the reaction, GO was separated by
filtration, and wash with ethyl acetate until all the organic residuals were completely
removed. The catalysis was recovered directly in the new reaction, and almost no loss
of activity occurs even after being reused ten times.
3a
Yield %
95
92
92
91
91
90
90
90
90
89
89
89
90
85
80
75
70
0
1
2
3
4
5
6
7
8
9
10
Runs
Figure 5. Reuse of GO in the synthesis of 3a.
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A plausible mechanism for this reaction is shown in Scheme 1. Promoted by
carboxylic acid in the surface of GO, the electrophilicity of the carbonyl carbon
increased and which in turn facilitates the reactivity of indole molecules. After the
Friedel-Crafts reaction, aldehydes and indoles were successful transformed into
BIMs.
Scheme 1. Plausible mechanism for this reaction.
4. Conclusion
In summary, we have successfully developed a highly efficient, environment
friendly and metal-free synthesis of BIMs. This green synthesis offers the
corresponding products with good yields and excellent functional group tolerance. In
addition, compared with the traditionally applications, we found that GO is not only a
support material, but also a powerful catalyst to synthesis BIMs. Further applications
of this method to other substrates are in progress.
Acknowledgment
We are grateful financial support from the National Natural Science Foundation of
China (NSFC) (grant number 81573286 & 21472130).
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Graphical abstract
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Highlights
The synthesis of bis(indolyl)methanes catalyzed by graphene oxide is developed.
Graphene oxide could be used as solid acids to catalyze Friedel–Crafts reaction
The reaction was performing in water and the catalyst could be reused ten times.
This methodology has a broad substrate scope and good to excellent yields.
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