Chitosan nanoparticles as a green and renewable catalyst in the synthesis of 1,4-dihydropyridine under solvent-free conditions

Article abstract of DOI:10.1039/c4nj01730g

In the present study, chitosan nanoparticles were obtained by the gelation of chitosan by heptamolybdate anions and dried with dry CO₂ for 30 minutes. Chitosan nanoparticles efficiently proceeded the Hantzsch reaction at 80 °C under metal and solvent free conditions. The present method offers several advantages such as a simple procedure, green conditions, excellent yields and short reaction time.

Full text of DOI:10.1039/c4nj01730g

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Chitosan nanoparticles as a green and renewable
catalyst in synthesis of 1,4-dihydropyridine under
solvent-free conditions
Cite this: DOI: 10.1039/x0xx00000x
Received 00th January 2012,
Accepted 00th January 2012
Javad Safari, Fatemeh Azizi and Masoud Sadeghi
DOI: 10.1039/x0xx00000x
In the present study Chitosan nanoparticles were obtained based on the gelation of Chitosan by
heptamolybdate anions and dried with dry CO2 for 30 minutes. Chitosan nanoparticles
efficiently proceeded Hantzsch reaction in 80 °C under metal and solvent free condition. The
present method offers several advantages such as simple procedure, green condition, excellent
yields and short reaction time.
www.rsc.org/
1. Introduction
chemically into many forms and can participate more
effectively in different types of chemical reactions as a suitable
support for different catalytic species [16]. The OH and NH2
groups can activate the nucleophilic and electrophilic
These are exciting times for renewable chemicals. Throughout
history, humans have enlisted biological polymers especially
proteins and polysaccharides to meet their needs for food, fuel,
clothing and shelter. The development of renewable chemicals components of the reactions by hydrogen bonding and lone
and polymers will significantly benefit from the previous
advances in industrial chemistry. There is also increasing
interest in obtaining chemicals from renewable resources and
this has spurred a myriad of commercial activities. Chitin is the
second most abundant natural polysaccharide on earth after
pairs, respectively. These requirements are fully exist in the
multi component Strecker reaction of carbonyl compounds and
amines with trimethylsilyl cyanide (TMSCN) [16]. The Hantzsch
reaction is one of the most straightforward methods for the
synthesis of 1,4ꢀDihydropyridines (DHPs). 1,4ꢀ DHPs, first
synthesized by Arthur Hantzsch in 1882 [17]. DHPs are an
cellulose [1]. Chitosan, a random copolymer of
N
ꢀacetylꢀ
4), is obtained
ꢀdeacetylation of chitin (Scheme 1). Literature
βꢀDꢀ
glucosamine and
after partial
βꢀDꢀglucosamine linked (1ꢀ
[2]
N
important class of Nꢀheterocyclic ring. Many DHPs are already
[19]
commercial products such as: amlodipine [18], felodipine
,
,
survey shows that a wide range of applications have been
reported for chitosan in different fields such as medicinal, drug
[23]
isradipine [20], lacidipine [21], nicardipine [22], nitrendipine
delivery [3], food packaging [4], cosmetics [5], water treatment [6]
,
[24]
nifedipine
and nemadipine B [25], of which nitrendipine and
membranes [7], fuel cells [8], hydrogels [9], adhesives [10], and
surface conditioner [11]
nemadipine
B exhibit potent calcium channel blocking
.
activities [26]. Realizing the importance of 1,4ꢀdihydropyridine
derivatives, several synthesis methods have been reported, like
Scheme 1. Chemical structure of chitosan
FeF3[27], ionic liquid [28], organocatalysts [29], Microwave
assisted [30], Cellulose sulfuric acid [31], nanoꢀZnO
[32]
and
Heteropolyacid catalyst [33]. Although some reactions are
satisfactory in terms of yield, the use of high temperatures,
expensive metal precursors, catalysts that are harmful to the
environment, and long reaction times, limits the use of these
methods. This study investigates the role that chitosan and
chitosan nanoparticles can play in the Hantszch reaction. herein
we wish to report commercially available chitosan NPs, as a
renewable and recoverable bifunctional heterogeneous catalyst,
for the oneꢀpot threeꢀcomponent Hantzsch reaction of
aldehydes and ethyl acetoacetate and ammonium acetate under
solventꢀfree conditions at 40 ºC temperature (Scheme 2).
Chitosan is an antibacterial, biocompatible, environment
friendly, biodegradable material and has great potential for
surface modification due to amino and hydroxyl groups in its
chemical structure [12]. chitosan is soluble in most mineral and
organic acids and it’s insoluble in the most of organic
compounds and pure water [13]. Nano materials are expected to
be a fruitful area for green catalysis due the increasing ability to
design in the nano scales and the high surface areas found in
nano materials.[14] Chitosan nanoparticles were first prepared by
Alonso et al. that were based on the ionic gelation of chitosan
with sodium tripolyphosphate (TPP) anions [15]. The number of
active hydroxyl and amino groups existing on chitosan
nanoparticles are more than chitosan and it can be modified
Scheme 2. The Hantzsch reaction of carbonyl compounds and ammonium
acetate catalyzed by chitosan NPs
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2. Exprimental method
SEM micrograph of synthesized Chitosan NPs is shown in Fig. 2
As can be seen in Fig. 2 the particles are nearly spherical with an
average diameter 50 nm.
2.1. General
All chemicals were purchased from Merck or Aldrich. Melting
points were determined using an Electrothermal 9100 apparatus and
are uncorrected. FTꢀIR spectra were recorded as KBr pellets on a
2.4. Procedure for preparation of 1,4-dihydropyridin by
chitosan NPs
1
Shimadzu FT IRꢀ8400S spectrometer. H NMR (400 MHz) spectra
In a 25 ml round bottom flask equipped with a magnetic bar, a
mixture of aldehyde (1 mmol), ethyl acetoacetate (2 mmol),
ammonium acetate (1 mmol) and 0.05 g Chitosan NPs was
stirred under solventꢀfree conditions at 80 °C. After completion
of the reaction (monitored by TLC, Petroleum: Ethyl acetate,
3:2), 5 ml EtOH 96% was added to mixture reaction and was
heated to 60 ˚C. The products were solved in EtOH and isolated
from Chitosan NPs and in crystalline form by cooling in an iceꢀ
bath and need no further crystallization.
were obtained using a Bruker DRXꢀ400 AVANCE spectrometer.
Analytical thinꢀlayer chromatography (TLC) was accomplished on
0.2ꢀmm precoated plates of silica gel 60 Fꢀ254 (Merck) or neutral
alumina oxide gel 60F 254 (Merck). Morphological characteristics
of the nanoꢀconjugates were observed by scanning electron
microscope (SEM, EVO LS 10, Zeiss, Carl Zeiss Inc., Germany)
operating at an accelerating voltage of 20 KV under high vacuum.
Freshly prepared nanoꢀconjugate sample was fixed to aluminum
stubs with doubleꢀsided carbon adhesive tape, sputterꢀcoated with
conductive gold–palladium and observed using SEM.
Figure 2. FTꢀIR spectra of Chitosan (red line) and Chitosan NPs (blue
line)
2.2. Procedure for preparation of chitosan NPs
Chitosan was modified to nanoꢀChitosan by an ionicꢀgelation
method with Ammonium heptamolybdate. 0.5 g Chitosan was
dissolved in 2% acetic acid solution under constant magnetic stirring
at room temperature and dropwise 5 ml Ammonium heptamolybdate
tetrahydrate with the concentration of 2 g/l to 50 ml of Chitosan
solution. The product were extensively rinsed with distilled water to
remove any ammonium heptamolybdate and then Chitosan NPs were
obtained by centrifugation at 16,000 rpm after dried with dried CO2
for 30 min.
2.3. Morphology and structure characterization of chitosan
NPs
FTꢀIR of Chitosan and Chitosan NPs were taken with KBr pellets
(Figure 1). The characterization peaks in the Chitosan spectrum are
3000ꢀ3800 cmꢀ1 (–OH and –NH2 stretching), 2877 cm−1 (CꢀH
stretching) 1656 cmꢀ1 (amide I band), 1640 cmꢀ1 (N–H deformation)
and 1079 cmꢀ1 (C–O stretching). The FTꢀIR spectrum of Chitosan
NPs shows the characteristic absorption peak of OH and NH2 at
3000–3800 cm−1. The characteristic absorption peaks of N– H, –CH3
and the second hydroxyl (OH) absorption peak (bending) appear at
1631, 1382 and 1337 cm−1 respectively. The OH bending appears as
a broad and weak peak and here obscured by the CH3 bendings. The
absorption bands at 1080 cm−1 (asymmetric stretching of the C–O–C
bridge) was characteristic absorption bands of the polysaccharide
structure of Chitosan.
Figure 2. SEM micrograph of synthesized chitosan NPs
In Fig. 3 the Xꢀray diffraction(XRD) patterns of Chitosan NPs
were shown. Original Chitosan (see Electronic Supplementary
Information (ESI)) gives two characteristic peaks at and 2θ=10°
(weak diffraction peak) and 20° (strong diffraction peak) indicating
the high degree of crystallinity of chitosan. However, there are not
Comparable peak in the diffractograms of chitosan NPs. The reason
for broad peaks is attributed to the increased amorphous nature of
Chitosan NPs. The XRD of chitosan NPs is characteristic of an
amorphous polymer.
3. Results and discussion
In order to compare Chitosan and Chitosan NPs catalytic
properties, a reaction model was carried out. The results were
indicated, Chitosan NPs have better efficiency than bulk
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Chitosan (Table 1, Entry 9). Hence, Chitosan NPs were selected Table 1. Optimization of the Reaction Conditions
as main catalyst and all reactions were carried out using Chitosan
NPs. According to our studies, the Hantzsch reaction has a poor
Yield
(%)*
Entry
Catalyst (g)
Solvent Time
yield in organic solvents and water. To achieve the best
conditions, various solvents and amount of catalyst were
employed and results listed in Table 1. The results were proposed
that the solventꢀfree condition is more efficient than solvents
such as EtOH or CCl4. The varying amounts of Chitosan NPs
were tested and 0.1 g was used as optimized catalyst amount
under the reaction conditions (Table 1, Entry 9).
1
2
3
4
5
6
7
8
ꢀ
ꢀ
18 h
3 h
3 h
3 h
4 h
4 h
4 h
1 h
Trace
65
Chitosan NPs (0.05)
Chitosan NPs (0.1)
Chitosan NPs (0.15)
Chitosan NPs (0.05)
Chitosan NPs (0.1)
Chitosan NPs (0.15)
Chitosan NPs (0.05)
EtOH
EtOH
EtOH
CCl4
CCl4
CCl4
ꢀ
70
70
55
55
55
Figure 3. Xꢀray diffraction patterns of Chitosan NPs
80
9
Chitosan NPs (0.1)
-
20 m
90
10
Chitosan (0.1)
ꢀ
3 h
90
Sulfonated Chitosan
(0.1)
11
12
ꢀ
2 h
90
90
Chitosan NPs (0.15)
ꢀ
40 m
*Reaction condition: benzaldehyde (1 mmol), ethylacetoacetate
(2 mmol), ammonium acetate (1 mmol) and catalyst stirred at
80 °C.
Scheme 3. Chitosan NPs catalyzed synthesis of 1,4ꢀdihydropyridines
R
O
EtO2C
H3C
CO2Et
CH3
O
O
H
Chitosan NPs (0.1 g)
80 °C, 15-40 min.
R
NH OAc
+
+
4
H3C
OEt
N
H
Table 3. Chitosan NPs catalyzed synthesis of 1,4ꢀdihydropyridines
Entry
Aldehyde
Product
Time (min)
Yield (%)
M. p.
M. p.ref
EtO2C
CH3
NH
O
1
20
90
157ꢀ158
157ꢀ159
H
EtO2C
EtO2C
CH3
O2N
CH3
O
O2N
NH
2
3
15
40
95
80
162ꢀ164
147ꢀ148
162ꢀ164
146ꢀ149
H
EtO2C
CH3
H3CO
O
EtO2C
CH3
H3CO
H3CO
H3CO
NH
H
EtO2C
CH3
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EtO2C
CH3
NH
O
H
H3CO
4
40
30
30
80
80
90
157ꢀ159
145ꢀ146
144ꢀ146
156ꢀ159
147ꢀ149
146ꢀ148
H3CO
EtO2C
CH3
EtO2C
CH3
O
NH
5
6
H
CH3
CH3
EtO2C
EtO2C
O
Cl
NH
H
Cl
EtO2C
CH3
EtO2C
N
CH3
O
O
NH
7
8
30
30
20
20
40
95
95
95
98
80
192ꢀ194
192ꢀ194
149ꢀ152
169ꢀ171
210ꢀ212
190ꢀ192
190ꢀ192
148ꢀ150
172ꢀ174
205ꢀ212
H
N
EtO2C
EtO2C
CH3
CH3
N
NH
H
O
EtO2C
EtO2C
CH3
CH3
N
O
NH
9
O
EtO2C
H
CH3
CH3
EtO2C
O
O
NH
10
11
S
S
H
EtO2C
CH3
EtO2C
CH3
HO
NH
H
EtO2C
CH3
HO
*Reaction condition: benzaldehyde (1 mmol), ethylacetoacetate (2 mmol), ammonium acetate (1 mmol), catalyst (0.1 g) stirred at 80 °
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and leads to improved products yields by easy work up
procedures at room temperature.
By considering the optimal conditions we further investigated
for more substrate derivatives, satisfactory results were
observed that the results are summarized in Table 3. The
reaction time for the Hantzsch reaction catalyzed by Chitosan
NPs is generally shorter compared to previous methodologies
that require a Bronsted or Lewis acid center in the structure of
their catalysts. As we expect the aldehyde substrate containing
electron donor groups (like OMe and OH, Entries 3, 4, 11),
showed weaker results than cases containing electron
withdrawing groups (like NO2, Cl and Py. Entries 2, 6, 7, 8).
The cases like furanꢀ2ꢀcarbaldehyde and thiopheneꢀ2ꢀ
carbaldehyde (Entry 9, 10) showed an excellent yield that
probably could relate with less steric hindrance.
Acknowledgements
We gratefully acknowledge the financial support from the
Research Council of the University of Kashan for supporting
this work by Grant No. 256722/XI.
Scheme 4. Proposed mechanism for Chitosan NPs catalyzed Hantzsch
synthesis
The proposed mechanism for the formation of the 1,4ꢀ
dihydropyridines is shown in Scheme 3. As is clear from the
structure of chitosan, it has many hydroxyl group and amine (or
amide) groups. These OH and NH2 groups in the structure of
chitosan can activate the electrophilic components of the
reactions like carbonyl group by hydrogen bonding. The
hydrogen bonding between hydroxyl and amine groups and the
substrates is key factor in Hantzsch reaction catalyzed by
chitosan.
Figure 4. Recyclability study
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