Magnetically separable ZnFe2O4 nanoparticles: A low cost and sustainable catalyst for propargyl amine and NH-triazole synthesis

Article abstract of DOI:10.1016/j.apcata.2021.118338

The multicomponent reaction (MCR) strategy for the construction of important molecular scaffolds is in trending nowadays and among them, A³-coupling stands in a significant position. Aldehyde, amine and alkynes are coupled in this particular reaction via C-H activation process. Herein, we have reported zinc ferrite nanoparticles as magnetically separable heterogeneous catalyst for A³-coupling reaction with attractive attributes like excellent productivity, selectivity and better reusability. Moreover, the catalyst can also be effectively applied for the synthesis of various NH-triazoles with quantitative yields of the products. A plausible mechanism has been proposed for the synthesis of NH-triazoles followed by validation with computational study.

Full text of DOI:10.1016/j.apcata.2021.118338

Applied Catalysis A, General 625 (2021) 118338
Contents lists available at ScienceDirect
Applied Catalysis A, General
journal homepage: www.elsevier.com/locate/apcata
Magnetically separable ZnFe2O4 nanoparticles: A low cost and sustainable
catalyst for propargyl amine and NH-triazole synthesis
Roktopol Hazarikaa, Anirban Garga, Swadhin Chetiaa, Parmita Phukana, Akshay Kulshresthab,
,
*
Arvind Kumarb, Ankur Bordoloic, Amlan Jyoti Kalitad, Ankur Kanti Guhad, Diganta Sarmaa
a Department of Chemistry, Dibrugarh University, Dibrugarh 786004, Assam, India
b AcSIR, Salt and Marine Chemicals Division, CSIR-Central Salt and Marine Chemicals Research Institute, Bhavnagar 364002, India
c Nano Catalysis, Catalytic Conversion and Process Division, CSIR -Indian Institute of Petroleum, Mohkampur, Dehradun 248005, India
d Department of Chemistry, Cotton University, Panbazar, Guwahati, Assam, 781001
A R T I C L E I N F O
A B S T R A C T
Keywords:
The multicomponent reaction (MCR) strategy for the construction of important molecular scaffolds is in trending
nowadays and among them, A3-coupling stands in a significant position. Aldehyde, amine and alkynes are
coupled in this particular reaction via C-H activation process. Herein, we have reported zinc ferrite nanoparticles
as magnetically separable heterogeneous catalyst for A3-coupling reaction with attractive attributes like excellent
productivity, selectivity and better reusability. Moreover, the catalyst can also be effectively applied for the
synthesis of various NH-triazoles with quantitative yields of the products. A plausible mechanism has been
proposed for the synthesis of NH-triazoles followed by validation with computational study.
A3-coupling
Multicomponent reaction
Magnetically separable catalyst
Propargyl amine
NH-triazole
Computational study
1. Introduction
process [3]. Gholinejad et al. reported several gold and copper catalyzed
A3 coupling reactions [4]. Propargyl amines are very interesting mo-
Designing novel reaction strategies with high yield and negligible by-
product formation are of great importance in this present era from the
environmental as well as physiological point of view. MCRs stand high
as one of the principal tactics in this aspect as these reaction strategies
are atom economic in nature and very much strict in by-product for-
mation that significantly contributes towards “Green Chemistry”. The
MCR technique emerges as a powerful tool to build up a library of
structurally complexed molecules with diverse elements in a single
synthetic step [1]. Recently, such strategies have been widely applied in
numerous organic transformations such as triazole formation, propargyl
amine formation etc. The MCR strategy for propargyl amine synthesis
consists of coupling of aldehyde, alkyne and amine respectively and is
commonly accepted as A3-coupling reaction. Classically, the prop-
argylamine derivatives have been synthesized via nucleophilic addition
of Grignard reagents with enamines or by addition of lithium acetylides
with imines [2]. However, the multistep preparative methods and
storage issue due to sensitivity towards moisture or water make these
reagents inappropriate for organic transformations. As an alternative,
low cost, nontoxic transition metal catalysts have been employed for the
construction of the propargyl amine derivatives via C-H activation
lecular entities which open up new ways to access versatile synthetic
molecular scaffolds. Propargyl amines serve as intermediate to the
synthesis of many biologically active compounds as well as natural
products such as β-lactams, herbicides, fungicides etc. [5]. Moreover,
some of them have been tested and approved as drug molecules against
neurological diseases in the likes of Parkinson’s and Alzheimer’s dis-
eases [6,7].
Literature indicates that a good number of reports are available
regarding the synthesis of propargyl amine which are predominantly
based on copper and silver [8]. However, adverse cytotoxicity effect or
the high cost of these coinage metals demand replacement with inex-
pensive yet efficient metal catalyst. In this context, Zn is considered as a
suitable alternative with very few examples citing its use in catalysis [9].
Therefore, Zn is chosen as the first preference for the aforesaid reaction.
In recent years, magnetic nanoparticles (MNPs) have established
themselves as a material of prodigious significance in different fields
especially in ferrofluids, magnetic drug transportation, magnetic data
storage devices, magnetic separations, magnetic resonance imaging
(MRI) and magnetic fluid hyperthermia treatment for malicious growth
[10]. Moreover, applying MNPs as catalyst can afford simple separation
* Corresponding author.
E-mail addresses: dsarma22@gmail.com, dsarma22@dibru.ac.in (D. Sarma).
https://doi.org/10.1016/j.apcata.2021.118338
Received 26 July 2021; Received in revised form 25 August 2021; Accepted 25 August 2021
Available online 1 September 2021
0926-860X/© 2021 Elsevier B.V. All rights reserved.

R. Hazarika et al.
Applied Catalysis A, General 625 (2021) 118338
Fig. 1. (A) and (B): SEM images for the zinc ferrite nanoparticles.
Fig. 2. TEM (a and b) and HRTEM (c and d) images for ZnFe2O4.
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R. Hazarika et al.
Applied Catalysis A, General 625 (2021) 118338
Fig. 4. FTIR spectrum of ZnFe2O4.
Fig. 3. SAED pattern of ZnFe2O4.
of the catalyst from the reaction mixture by the application of an
external magnet genuinely enhancing reusability with minimal loss in
the catalyst loading. In this regards, spinel compounds especially ferrite
system plays vital role. Different ferrite systems based on transition
metals as well as different metal organic frameworks were successfully
applied in various organic reactions [11]. Facile synthetic procedures,
inexpensive nature, economic efficiency, availability of high percentage
of surface area, insolubility in reaction media, easy recovery and supe-
rior catalytic activity make these mixed metal oxide nanoparticles
(MMONs) more advantageous to the individual component oxides in
diverse catalysis [12].
Owing to these attractive characteristics, magnetically separable
catalysts are very much trending in modern applications. Therefore, we
thought of applying such catalytic system for our desired
transformations.
In recent years, literature reveals that ZnFe2O4 nanoparticles have
been efficaciously screened in various catalytic transformations into
pyrano pyrimidines [12], isatinylidenethiazol-4-one [13], 1,4-dihydro-
pyridines [14], 2-amino-3-cyano-4H-pyran [15] etc. as these nano-
particles are inexpensive, very much effective with high catalytic
efficiency, safe, easily recyclable and contribute towards the production
of high yields of products in shorter duration of reaction time. Therefore,
in our work, zinc ferrite nanoparticles have been chosen as the catalyst
for the one pot synthesis of propargyl amine derivatives via A3- coupling
reaction. Further, the same catalyst is successfully employed for syn-
thesis of NH-1,2,3-triazoles.
Fig. 5. XRD pattern of ZnFe2O4.
mixture was carefully heated to boiling and the yellow granular pre-
cipitate formed was allowed to settle. The supernatant liquid was dec-
anted and the precipitate was washed with hot water for several times
and oven dried overnight.
The zinc ferrite nanoparticles were then prepared by heating zinc
oxalate, ferrous oxalate and PEG600 in weight ratio 1:1:5 under Bunsen
burner in open air. After complete burning, the carbon residue from PEG
got removed from the mixture as carbon dioxide and the residue left was
obtained as zinc ferrite nanoparticles. The final product was then
characterized by Scanning Electron Microscopy (SEM), Transmission
Electron Microscopy (TEM) and X–Ray Diffraction (XRD) analyses and
for the magnetic hysteresis, Vibrating Sample Magnetometer (VSM) was
performed.
2. Preparation of the catalyst and characterization
ZnFe2O4 nanoparticles were prepared by following a literature
report [16]. Initially, the precursors zinc oxalate and ferrous oxalate
were synthesized. For the synthesis of zinc oxalate, equimolar amount of
ZnSO4.7 H2O (2.87 g, 10 mmol) and oxalic acid (1.26 g, 10 mmol) were
separately dissolved in distilled water and the homogeneous solutions of
these two were mixed through vigorous stirring to form white precipi-
tate of zinc oxalate dihydrate. The mixture was filtered to separate the
mother liquor and the precipitate was dried in an oven. On the other
hand, ferrous oxalate was prepared by initially mixing equimolar
aqueous solution of ferrous ammonium sulphate hexahydrate (3.77 g in
12.5 ml) with aqueous solution of oxalic acid (1.67 g in 16.75 ml). The
3. Results and discussion
The surface morphology of the catalyst was studied by SEM analysis
and some flake like structures of the particles were obtained as shown in
Fig. 1(A) and (B).
TEM analysis confirmed the formation of zinc ferrite nanoparticles
(Fig. 2(a) and (b)). The sizes of the nanocrystals were obtained by size
counting from the relevant TEM images and it was found that the size of
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R. Hazarika et al.
Applied Catalysis A, General 625 (2021) 118338
sample magnetometer (VSM) analysis was performed for preliminary
magnetic measurements. The nature of the magnetic hysteresis (MH)
graph confirmed the formation of the ferrite particles with ferromag-
netic properties (Fig. 6). The MH graph was measured at 25 ℃ in the
range of H = ± 10 kOe for the fresh catalyst. The saturation magneti-
zation (Ms) at room temperature was found to be 4.5295 emu/g,
retentivity (Mr) was equal to 0.35136 emu/g and coercivity (Hci) was
61.175 Oe.
ICP-MS analysis of the catalyst revealed that 7 mg of the fresh
catalyst contains 2.78 mol% of Zn which was quite comparable with the
theoretical results (2.89 mol% in 7 mg fresh catalyst). Herein, 5 mol% of
zinc ferrite (12 mg of the catalyst) was used which contains 4.77 mol%
of elemental Zn.
After characterization of the catalyst, it was applied in A3-coupling
reaction as well as NH-triazole synthesis. The study was initiated by
following the multicomponent synthetic procedure with benzaldehyde
(1 mmol), morpholine (1.2 mmol) and phenyl acetylene (1.5 mmol) as
the model substrates for A3 coupling. The reaction was set up in a reflux
condenser at 110 ℃ using toluene as the reaction medium and different
zinc catalysts along with the precursors of the zinc ferrite were inves-
tigated as the catalytic system. With 10 mol% of catalyst loading, it was
found that best result was obtained in case of ZnFe2O4 compared to
other examined catalysts. The precursors of zinc ferrite namely zinc
oxalate and iron oxalate gave 77% and 27% of product yields respec-
tively (Table 1, entries 5–6). ZnFe2O4 was chosen over them owing to
the possession of magnetic properties, better reusability and better
productivity.
Fig. 6. MH spectrum of fresh catalyst.
the nanoparticles falls in the range of 10–20 nm. HRTEM images (Fig. 2c
and d) and SAED pattern (Fig. 3) for the corresponding ferrite nano-
crystals portrayed highly crystalline characteristics. The lattice in the
image is indexed to the projected (220) plane of the cubic spinel struc-
ture of zinc ferrite [17].
Fourier transform infrared (FTIR) analysis of the catalyst was also
performed for the prepared catalyst (Fig. 4). The peaks at 624 and
550 cm–1 correspond to the vibrational modes of Fe–O stretching and
corroborate the spinel structure characteristics of zinc ferrite [16,18].
The peaks at 3391 and 1629 cm–1 correspond to water of hydration. The
peaks at 1319 and 825 are due to Zn–O–Fe stretching vibrations [19].
The absorption band at 1103 cm–1 is due to overtone.
The amount of the catalyst was optimized (Table 1, entries 7–8,
10–12) and found that 5 mol% of the catalyst loading was enough to
carry out the reaction very smoothly.
To find out the best solvent, different types of solvents such as polar,
non-polar and green solvents were employed but promising results were
obtained only in non-polar solvents especially in toluene which is indeed
considered as an excellent organic solvent [20]. Toluene is less toxic
than benzene and xylene and only a long time exposure can lead to
unhealthy situation. Under reflux condition, in toluene; the model re-
action afforded up to 95% product yield in a time duration of 5 h.
(Table 2).
The powder XRD analysis of the synthesized catalyst was also per-
formed (Fig. 5). The reflection at 2θ values 30.1◦, 35.1◦, 43.4◦, 57.3◦,
62.5◦ correspond to the Bragg’s planes (220), (311), (400), (333) and
(440) which established the formation of FCC cubic spinel structure with
the space group of Fd3m (227) of zinc ferrite nanoparticles.
As our concern was to prepare magnetic nanoparticles, the vibrating
Table 1
Optimization of catalysta.
Sl. No.
Catalyst
Amount (mol%)
(%)Yieldb
1
Zn dust
10
10
10
10
10
10
10
5
64
58
30
65
77
27
96
95
66
70
79
95
2
Fe powder
SiO2-Fe(ac)
Clay zinc
3
4
5
Zinc oxalate
Fe oxalate
Zinc ferrite
Zinc ferrite
Zinc ferrite
Zinc ferrite
Zinc ferrite
Zinc ferrite
6
7
8
9c
10
11
12
5
2
3
7
a
Reaction conditions: Benzaldehyde (0.106 g, 1 mmol), morpholine (0.104 g, 1.2 mmol) and phenyl acetylene (0.159 g, 1.5 mmol) were refluxed in toluene (2 ml)
for 5 h with different catalysts.
b
c
Isolated yield.
Neat condition. (10 mol% = 0.024 g, 7 mol% = 0.016 g, 5 mol% = 0.012 g, 3 mol% = 0.0072 g, 2 mol% = 0.0048 g).
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Applied Catalysis A, General 625 (2021) 118338
Table 2
Solvent optimizationa.
Sl. No.
Solvent
Temperature (◦ C)
Yieldb (%)
1
PEG400
Water
100
100
70
–
2
–
3
Ethyl acetate
Ethanol
Acetonitrile
THF
–
4
70
–
5
80
–
6
65
–
7
DMSO
100
68
–
8
Hexane
42
38
–
9
1,4-Dioxane
DMF
100
100
110
60
10
11
12
Toluene
Chloroform
95
78
a
Reaction conditions: Benzaldehyde (0.106 g, 1 mmol), morpholine (0.104 g, 1.2 mmol) and phenyl acetylene (0.159 g, 1.5 mmol) were refluxed in the respective
boiling temperature (except DMF, DMSO, PEG) of the solvents (2 ml) for 5 h.
b
Isolated yield.
Table 3
Temperature optimizationa.
Sl. No.
Temperature
Yieldb (%)
1
2
110
100
90
95
90
85
78
87
3
4
85
5c
90
a
Reaction conditions: Benzaldehyde (0.106 g, 1 mmol), morpholine (0.104 g, 1.2 mmol) and phenyl acetylene (0.159 g, 1.5 mmol) were refluxed in toluene (2 ml)
for 5 h.
b
c
Isolated yield.
Catalyst loading is 5 mol%.
Scheme 1. Optimized reaction condition for propargyl amine synthesis.
With the optimized catalyst and solvent, we tried to improve the
than 110 ℃ did not add any further improvement in product yields.
Therefore, 110 ℃ was set as the ideal temperature to carry out A3-
coupling reaction. (Table 3).
reaction condition by optimizing the reaction temperature. Variation of
the temperature indicated that decrease in the reaction temperature
declined the product yield. While employing higher temperature more
Finally we got the best reaction condition as depicted in Scheme 1.
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R. Hazarika et al.
Applied Catalysis A, General 625 (2021) 118338
Fig. 7. Substrate scope for propargyl amine derivativesa.
aReaction conditions: Aldehyde (1 mmol), amine (1.2 mmol) and alkyne (1.5 mmol) were refluxed in toluene for 5 h. All yields are reported as isolated yields. TON:
mmol of product per mmol of catalyst.
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Applied Catalysis A, General 625 (2021) 118338
Fig. 8. Plausible mechanistic pathway of the reaction.
Table 4
Gram scale synthesisa.
Sl. No.:
Aldehyde
Amine
Alkyne
%Yieldb
1
2
3
Benzaldehyde (1 g, 9.42 mmol)
Morpholine (0.984 g, 11.30 mmol)
Morpholine (0.854 g, 9.81 mmol
Morpholine (0.841 g, 9.66 mmol)
Phenyl acetylene (1.499 g, 14.13 mmol)
76
52
78
3--Hydroxybenzaldehyde (1 g, 8.18 mmol)
4--Fluorobenzaldehyde (1 g, 8.05 mmol)
Phenyl acetylene (1.254 g, 12.27 mmol)
Phenyl acetylene (1.232 g, 12.07 mmol)
a
Reaction conditions: Aldehyde (1 equiv), morpholine (1.2 equiv) and phenyl acetylene (1.5 equiv) were refluxed in toluene at 110 ℃ for 5 h with 5 mol% ZnFe2O4.
b
Isolated yields.
To justify the optimized reaction protocol, we extended our study by
aldehyde (Fig. 7, entry 4d) which may be due to the steric crowding in
the desired product. The reaction condition also showed excellent
tolerance towards heterocyclic aldehydes. To extend the applicability of
the protocol, variation in amine as well as alkyne components was also
performed. Morpholine, piperidine and naphthyl amine were employed
in this regard and quantitative yields were obtained. The feasibility of
the reaction is found to be low only in case of aliphatic alkynes, aliphatic
aldehydes and simple amines like diethyl amine and ethyl amine.
the variation of different starting materials and results are summarized
in Fig. 7. From the results, it is quite noticeable that the presence of
halogen in the aldehyde counterpart facilitates the reaction very
smoothly (Fig. 7, entries 4b-4-c, 4 h-4-i, 4 l-4-m, 4o-4-p), whereas the
aldehydes with electron donating group slow down the kinetics of the
reaction (Fig. 7, entries 4e, 4 f, 4 g, 4 n, 4q). Unlike previous literatures,
we observed quite a decent yield of 82% with 4--methyl benzaldehyde
(Fig. 7, entry 4e). The yield of the product is low in case of disubstituted
Scheme 2. Schematic representation of the gram scale synthesis of propargyl amine.
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R. Hazarika et al.
Applied Catalysis A, General 625 (2021) 118338
Fig. 9. Reusability of the catalyst: schematic as well as graphical representationsa.
aReaction conditions: Benzaldehyde (1 equiv), morpholine (1.2 equiv) and phenyl acetylene (1.5 equiv) were refluxed in toluene at 110 ℃ for 5 h with 5 mol%
ZnFe2O4. Isolated yields are reported.
Fig. 10. MH spectra of the reused catalyst.
Fig. 11. X-ray diffraction pattern of the reused catalyst.
3.1. Reaction pathway
3.2. Reusability
In this protocol, initially discrete formation of acetylide (II) and
imine (VII) takes place from their respective starting materials (Fig. 8).
For further determination of the catalytic efficiency, we thought of
The lone pair on nitrogen attacks the electrophilic carbon atom of the
reusing the catalyst by recovering it from the reaction mixture and it was
aldehyde to get the intermediate V followed by intramolecular proton
observed that the catalyst can successfully be applied up to 5th catalytic
transfer to obtain intermediate VI. This intermediate loses a hydroxyl
cycle with negligible loss in the product yield. In doing so, we have
group to form the imine intermediate VII. The acetylide then attacks the
chosen benzaldehyde, morpholine and phenyl acetylene as the model
electrophilic carbon atom of the imine intermediate VII to give the
substrates. After the fresh batch of reaction, the catalyst was separated
desired product VIII. The catalyst is regenerated in the final step and is
by means of magnetic separation followed by centrifugation to ensure
ready for the next cycle [9(b),21].
maximum possible recovery of the catalyst. The catalyst was dried and
Further, to demonstrate the synthetic utility of this protocol, three
again applied to another cycle by maintaining the same stoichiometry of
gram-scale reactions were carried out by using three different combi-
the reaction. This process was repeated for five consecutive cycles. Both
nations as shown in Table 4.
schematic and graphical representations of this process are presented in
The schematic representations of the results are shown in Scheme 2.
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Applied Catalysis A, General 625 (2021) 118338
Fig. 12. NH-triazole containing biologically active molecules.
Table 5
Optimization of reaction parametersa.
Sl. NO.:
Temperature (℃)
Solvent
% Yieldb
1
70
70
H2O
trace
trace
trace
–
2
Ethyl acetate
Ethanol
3
70
4
70
Toluene
5
70
THF
–
6
70
Ethyl-L-Lactate
PEG
34
50
93
93
–
40
76
79
81
68
71
73
78
94
33
86
93
7
70
8
100
110
100
70
PEG
9
PEG
10
11
12
13
14
15
16
17
18c
19d
20e
21f
22g
Neat
H2O + PEG (1:1)
H2O + PEG (1:1)
H2O + PEG (1:1)
H2O + PEG (1:1)
H2O + PEG (50 µL)
H2O + PEG (100 µL)
H2O + PEG (200 µL)
PEG
90
100
110
100
100
100
100
100
100
100
100
PEG
PEG
PEG
PEG
a
Reaction conditions: Benzaldehyde(1 mmol), nitromethane (1.5 mmol) and NaN3 (2 mmol) were heated in PEG400 for 4 h with zinc ferrite (5 mol%), Solvent
(2 ml).
b
c
d
e
f
Isolated yield.
2 mol% of the catalyst was used.
10 mol% of the catalyst was used.
Reaction was performed in absence of the catalyst.
3 mol% of the catalyst was used.
7 mol% of the catalyst was used.
g
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Applied Catalysis A, General 625 (2021) 118338
Fig. 13. Schematic representation of PEG400 acting as crown ether.
Fig. 9.
(Table 5, entries 11–17) at different temperatures but these combina-
tions also failed to display superior reactivity to PEG400 alone. It may be
due to the polymeric nature of PEG400, it can enhance the solubility of
the organic compounds. Moreover, PEG400 can act as a crown ether
[30] as well as a phase transfer agent [31] which in turn enhances the
solubility of metal-based salts such as sodium azide (Fig. 13). Due to all
these factors, the reaction might occur in the same phase which in turn
facilitated the reaction. Thereafter the catalyst loading was changed to
2 mol% (Table 5, entry 18) and 10 mol% (Table 5, entry 19) respec-
tively but none of them exhibited superior activity to the results ob-
tained when 5 mol% of the catalyst was used. Further, we have also
performed two more reactions with 3 mol% (Table 5, entry 21) and
7 mol% (Table 5, entry 22) catalyst loading. No further improvement in
yield was observed with 7 mol% catalyst and a decrease in yield was
observed with 3 mol% catalyst. Another reaction without catalyst was
also performed. The uncatalyzed reaction afforded 33% product yield
which is believed to be due to the presence of thermal energy. Hence
5 mol% of the catalyst was considered optimum for catalytic action.
After obtaining best condition, different aryl aldehydes were tested with
nitromethane/nitroethane and NaN3 to generate NH-1,2,3-triazoles in
good to excellent yields. The results are summarized in Table 6.
After reusing up to 5th times, VSM analysis was again performed for
the reused catalyst (Fig. 10) and almost similar values were obtained
which is an indication that the prepared catalyst retained its magnetism
after reuse. The values found for the reused catalyst were 68.148 Oe,
4.0036 emu/g, 0.39648 emu/g as coercivity (Hci), magnetization (Ms)
and retentivity (Mr) respectively.
XRD analysis was also performed to the reused catalyst and almost
identical pattern was observed which suggests that the catalyst
remained unaltered during the reaction (Fig. 11).
3.3. Application of zinc ferrite in NH-1,2,3-triazole synthesis
4-Aryl-NH-1,2,3-triazoles are recognized as important class of 1,2,3-
triazoles and receive tremendous attention for years due to their
numerous biological properties [22]. The bio-isosteric nature of the
triazole molecules with the amide bond makes them privileged molec-
ular entity for successful exploitation in medicinal chemistry such as
anticancer drugs [23], antibacterial and antibiotic agents along with as a
suitable probe for the biosynthesis of endocannabinoid [24] (Fig. 12).
Compared to the N-substituted triazoles, the synthesis of N-unsub-
stituted triazoles is fairly challenging, with few methods available which
are based on metal catalysis [25], 1,3-dipolar cycloaddition [26],
multicomponent reaction [27], organocascade process [28] and het-
erogeneous catalyst. Despite of having prevailing importance, these
methods own several demerits like limited substrate scope, inaccessible
starting materials and harsh reaction conditions. Therefore, there is
scope for development of improved method for NH-triazole synthesis
and hence in this work, along with the A3 coupling reaction; we have
tried to synthesize the NH-triazoles by applying zinc ferrite as the cat-
alytic system. With this catalyst NH-triazole synthesis proceeded
smoothly from the starting materials aldehyde, nitroalkane and NaN3
again via one pot strategy.
4.1. Synthesis of biologically active NH-triazole molecule in large scale
As our method was able to tolerate a wide range of substrate scope,
we thought of applying our method for the synthesis of medicinally
established NH-triazole molecules in larger scale and fruitful results
were obtained thereby making our method as an efficient one. The
observation are incorporated in Table 7.
4.2. Mechanism of action
The reaction proceeds with the formation of nitroalkene (III) from
aldehyde and nitroalkane (Fig. 14). Due to the Lewis acidic nature of Zn
(II), zinc ferrite attacks the nucleophilic oxygen atom of the nitro group
(IV). Then NaN3 attacks the electrophilic double bond of the interme-
diate V followed by subsequent cyclization. Zinc ferrite is then detached
followed by expulsion of nitro group providing aromaticity to the
compound which may act as the driving force for the forward reaction to
obtain intermediate VIII. Protonation to this intermediate finally gives
the desired molecule IX [33].
4. Results and discussion
For the optimization of NH-triazole synthesis, different solvent sys-
tems were examined with 5 mol% of zinc ferrite as the catalyst at
different temperatures. Water being an inexpensive, cheap and non-
toxic medium [29], was screened as the first choice for the reaction
but no positive outcome was observed (Table 5, entry 1). Some polar
(Table 5, entries 2–3) and non-polar (Table 5, entries 4–5) solvents were
also part of this investigation but neither of them stood high in this
context. After obtaining disappointing results with these solvent sys-
tems, green solvent ethyl-L-lactate was used which also showed inef-
fectiveness towards triazoles synthesis (Table 5, entry 6). Further, we
opted for PEG 400 and surprisingly 93% of product yield was obtained in
PEG 400 within 4 h at 100 ℃ (Table 5, entry 8). After getting optimistic
results in PEG400, the study was extended by using various solvent
mixtures comprising of PEG 400 and water in different proportion
Further, to validate the plausible mechanism, we have performed
computational study. To the best of our knowledge, it is the first report
on the theoretical study on the mechanism of NH-1,2,3-Triazole. The
details of the study are stated below:
All the structures were fully optimized without any symmetry con-
straints in the gas phase and at 298 K using M06–2X/Def2-TZVP level of
theory [34]. Harmonic frequency calculations were also performed at
the same level of theory to understand the nature of the stationary states.
All intermediates and products were found to be at their local minima
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Applied Catalysis A, General 625 (2021) 118338
Table 6
Substrate scopea.
Entry
1
Aldehyde
Nitroalkane
Product
Yield
TON
CH3NO2
93%
18979
CH3NO2
CH3NO2
88%
68%
17959
2
3
13877
17755
CH3NO2
CH3NO2
87%
92%
4
5
18775
CH3NO2
CH3NO2
90%
89%
18367
18163
6
7
CH3NO2
CH3NO2
79%
78%
88%
16122
15918
17959
8
9
CH3CH2NO2
10
CH3CH2NO2
88%
17959
11
a
Reaction conditions: Aldehyde (1 mmol), nitroalkane (1.5 mmol) and NaN3 (2 mmol) were heated in 2 ml PEG400 for 4 h with Zinc ferrite (5 mol%). All the yields
reported here are isolated yields.
11

R. Hazarika et al.
Applied Catalysis A, General 625 (2021) 118338
Table 7
Synthesis of previously existing biological molecule.
Sl. No.:
1
Aldehyde
Product
%Yieldb
Activity
Benzaldehyde (1 g, 9.42 mmol)
82
78
79
IDO1 inhibitor[32(a)]
2
3
2--Chlorobenzaldehyde 1 g, 8.18 mmol
3--Bromobenzaldehyde (1 g, 8.05 mmol)
IDO1 inhibitor[32(a)]
hMETAP2 inhibitor[32(b)]
aReaction conditions: Aldehyde (1 equiv), nitromethane (1.5 equiv) and NaN3 (1.5 equiv) were heated in PEG400 at 100 ℃ for 4 h with 5 mol% ZnFe2O4.
b
Isolated yields.
Fig. 14. Plausible mechanistic steps of formation of NH-1,2,3-Triazole.
-
with all real frequencies while the transition state was found to have one
imaginary value of the frequency corresponding to the movement of the
terminal N-atom of the N3- group to the terminal acyclic carbon atom.
Further, the transition state was verified with intrinsic reaction coordi-
nate analysis. All energies are zero point and thermally corrected. All
calculations were performed using GAUSSIAN16 suite of program [35].
In the first step of the mechanism (Fig. 15), ZnFe2O4 attaches to the
–NO2 group of A through one of the O-atoms to generate B. This step is
calculated to be exergonic by 3.2 kcal/mol. In the next step, azide ion,
N3 attacks the olefenic carbon atom which bears a positive natural
charge of 0.45 |e|. The formation of C through this step is also found to
be exergonic by 1.3 kcal/mol. C then loses ZnFe2O4 to generate the final
N-heterocyclic product D through the transition state TSCD. The acti-
vation barrier involved in this process is moderate, only 8.7 kcal/mol at
this level of theory. The C… N distance in TSCD is 1.913 Å. The loss of NO2
and a proton yields the final product D. This process is again exergonic
by 4.5 kcal/mol. The overall exergonic nature of the process with a
moderate activation barrier is expected to help the formation of the N-
12

R. Hazarika et al.
Applied Catalysis A, General 625 (2021) 118338
Fig. 15. Energetic of the reaction profile. All relative energies are in kcal/mol and are zero point and thermally corrected. Bond length is in Å.
methodology. To the best of our knowledge, only a few reports are
available citing use of zinc catalyst in A3-coupling as well as NH-triazole
Table 8
Comparison of the present protocol of A3 coupling with some literature reports.
synthesis and none describes use of zinc ferrite. We therefore, hope our
catalytic system can be used as an effective alternative for propargyl
amine as well as NH-triazole synthesis.
Entry
Conditions
Yield (%)
References
1
2
CuFe2O4 (6.5 mol%), toluene, 80 ℃, N2, 4–15 h
Fe3O4 MNPs (20 mol%), toluene, 80–110 ℃,
16 h
65–91%
40–92%
[36(a)]
[36(b)]
Supporting Information
3
Fe3O4@SBA-15 (5 mol%), toluene, 110 ℃,
6–8 h
45–93%
[36(c)]
General Information, Experimental and Analytical data, 1H and 13
C
4
5
MNP@PILAu (5 mg), 10–20 h
Fe3O4@Au NPs (10 mol%), toluene, 100 ℃,
48 h
86–98%
7–95%
[36(d)]
[36(e)]
NMR spectra and characterization data all are found in the “Supple-
mentary Content” section of this article’s webpage.
6
ZnFe2O4, toluene, 100 ℃, 5 h
68–96%
This work
CRediT authorship contribution statement
heterocyclic product both thermodynamically and kinetically.
Roktopol Hazarika: Conceptualization, Visualization, Formal
analysis, Data curation, Writing – original draft. Anirban Garg: Data
curation, Visualization. Swadhin Chetia: Formal analysis. Parmita
Phukan: Formal analysis. Akshay Kulshrestha: Formal analysis, Data
curation. Arvind Kumar: Formal analysis. Ankur Bordoloi: Formal
analysis, Data curation. Amlan Jyoti Kalita: Formal analysis, Data
curation. Ankur Kanti Guha: Formal analysis, Data curation. Diganta
Sarma: Conceptualization, Supervision, Writing – review & editing,
Visualization.
4.3. Brief comparison
Herein, we have reported two separate synthetic procedures to ac-
cess propargyl amine as well as NH-triazole catalysed by the same
catalyst zinc ferrite. Both these class of compounds possess their own
importance regarding chemical, medicinal and industrial fields. Prop-
argyl amines can be exceptionally useful as intermediates to the syn-
thesis of various heterocyclic compounds. Moreover, some of their
derivatives can be used as effective remedies for Parkinson’s as well as
Alzeimer diseases. On the other hand, NH-triazoles offer a variety of
important compounds having various pharmacophoric attributes e.g.
anti-inflammatory, antiviral, antibacterial etc. Here, in our approach,
both the reactions provided exciting results in their respective devel-
oped methodologies. In case of propargyl amine synthesis, toluene
provided the suitable medium whereas in case of NH-triazoles, this job
was done by PEG400. As discussed earlier, along with the organic
compounds metal based salts are easily soluble in PEG due to its ability
to act as crown ether. The presence of NaN3 as one of the starting ma-
terials has better solubility in PEG400 by the formation of crown ether.
However, we believe that lack of similar salt like starting material for the
synthesis of propargyl amine restricts the aforementioned reaction in
PEG400. Moreover, In order to highlight the efficiency of the present
protocol of A3 coupling, our results are compared with some literature
reports in Table 8.
Declaration of Competing Interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
Acknowledgements
D.S. is thankful to DST, New Delhi, India for a research grant [No.
EMR/2016/002345]. Authors thank the Department of Science and
Technology for financial assistance under DST-FIST programme and
UGC, New Delhi for Special Assistance Programme (UGC-SAP) to the
Department of Chemistry, Dibrugarh University.
Appendix A. Supporting information
5. Conclusions
Supplementary data associated with this article can be found in the
online version at doi:10.1016/j.apcata.2021.118338.
In this work, we have demonstrated an efficient methodology for
both A3-coupling as well as NH-1,2,3-triazole synthesis. The afford-
ability of the starting materials as well as precursors of the catalyst, the
inertness of the catalyst to the environment, magnetic separation and
chemical reactivity are the positive outcomes of the described
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