Practical scale up synthesis of carboxylic acids and their bioisosteres 5-substituted-1H-tetrazoles catalyzed by a graphene oxide-based solid acid carbocatalyst

Article abstract of DOI:10.1039/d1ra01053k

Herein, catalytic application of a metal-free sulfonic acid functionalized reduced graphene oxide (SA-rGO) material is reported for the synthesis of both carboxylic acids and their bioisosteres, 5-substituted-1H-tetrazoles. SA-rGO as a catalytic material incorporates the intriguing properties of graphene oxide material with additional benefits of highly acidic sites due to sulfonic acid groups. The oxidation of aldehydes to carboxylic acids could be efficiently achieved using H₂O₂as a green oxidant with high TOF values (9.06-9.89 h^?1). The 5-substituted-1H-tetrazoles could also be effectively synthesized with high TOF values (12.08-16.96 h^?1). The synthesis of 5-substituted-1H-tetrazoles was corroborated by single crystal X-ray analysis and computational calculations of the proposed reaction mechanism which correlated well with experimental findings. Both of the reactions could be performed efficiently at gram scale (10 g) using the SA-rGO catalyst. SA-rGO displays eminent reusability up to eight runs without significant decrease in its productivity. Thus, these features make SA-rGO riveting from an industrial perspective.

Full text of DOI:10.1039/d1ra01053k

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Practical scale up synthesis of carboxylic acids and
their bioisosteres 5-substituted-1H-tetrazoles
catalyzed by a graphene oxide-based solid acid
carbocatalyst†
Cite this: RSC Adv., 2021, 11, 11166
a
b
and Satish Kumar Awasthi *a
Rupali Mittal,
Amit Kumar
Herein, catalytic application of a metal-free sulfonic acid functionalized reduced graphene oxide (SA-rGO)
material is reported for the synthesis of both carboxylic acids and their bioisosteres, 5-substituted-1H-
tetrazoles. SA-rGO as a catalytic material incorporates the intriguing properties of graphene oxide
material with additional benefits of highly acidic sites due to sulfonic acid groups. The oxidation of
aldehydes to carboxylic acids could be efficiently achieved using H
O
2 2
as a green oxidant with high TOF
ꢀ1
values (9.06–9.89 h ). The 5-substituted-1H-tetrazoles could also be effectively synthesized with high
ꢀ1
TOF values (12.08–16.96 h ). The synthesis of 5-substituted-1H-tetrazoles was corroborated by single
crystal X-ray analysis and computational calculations of the proposed reaction mechanism which
correlated well with experimental findings. Both of the reactions could be performed efficiently at gram
scale (10 g) using the SA-rGO catalyst. SA-rGO displays eminent reusability up to eight runs without
significant decrease in its productivity. Thus, these features make SA-rGO riveting from an industrial
perspective.
Received 8th February 2021
Accepted 26th February 2021
DOI: 10.1039/d1ra01053k
rsc.li/rsc-advances
Tetrazoles are a privileged class of ve-membered synthetic
heterocyclic rings composed of one carbon and four nitrogen atoms.
1
. Introduction
Oxidation reactions are one of the most fundamental areas of The interesting biological characteristics of these nitrogen abundant
research in chemistry because of their persistent utilization in heterocycles have triggered immense research, specically 5-
the chemical and pharmaceutical industries as well as in substituted-1H-tetrazoles in medicinal chemistry because they can be
1
10
academic research. Among these, oxidation of aldehydes to used as bioisosteric replacement of carboxylic acids. The presence
carboxylic acids is highly desirable because of the common of multiple nitrogen atoms in their structure renders them phar-
occurrence of the carboxylic acid moiety in the manufacturing macophore property. The drugs containing tetrazole ring belong to
11
12
13
of ne chemicals, drugs, soaps and detergents, cosmetics and antibacterial, antifungal, anticancer, antitubercular and anti-
protective coatings. In the previously available literature, the malarial category. Several commercial drugs like losartan, valsartan,
oxidation of aldehydes to carboxylic acids was either facilitated cefazolin, azosemide, etc. contain tetrazole moiety. Over the years,
2
14
15
by using stoichiometric quantities of oxidants like potassium several attempts have been made for the preparation of 5-
3
–5
permanganate, chromium trioxide, periodate reagent, etc. or substituted-1H-tetrazoles via [3 + 2] cycloaddition reaction between
15
by a metal containing catalyst (Ag, Rh, Cu and Fe) in the pres- nitriles and sodium azide using diversied catalysts like Lewis
6
–9
16,17
18–20
ence of a ligand or a base. Thus, looking at the setbacks acids, inorganic salts,
etc. but regardless of the efficiency, their
related to the utilization of hazardous oxidants, toxic metal homogeneous nature posed difficulty in separation, recovery and
catalysts, ligands, etc. in the previous reports, it is crucial to reusability. Thereaer, to circumvent these issues, heterogeneous
develop a sustainable, cost-effective and metal-free catalytic catalytic systems emerged but they have been mostly performed
approach for the oxidation of aldehydes to carboxylic acids.
using metal-based catalysts which have drawbacks like metal toxicity
15,21–26
and leaching of metal into the reaction medium.
The reports of
metal-free catalysis in this eld are scarce and need attention for the
development of sustainable and cost-effective methods.
Solid acid catalysts have emerged as viable alternatives to the
conventional liquid acid catalysts that are susceptible to
corrosion, toxicity, non-separability from the reaction mixture
a
Chemical Biology Laboratory, Department of Chemistry, University of Delhi,
Delhi-110007, India. E-mail: satishpna@gmail.com
b
Department of Chemistry, Jamia Millia Islamia, Jamia Nagar, New Delhi-110025,
India
†
Electronic supplementary information (ESI) available. CCDC 1953617. For ESI and the production of harmful wastes post reaction which
and crystallographic data in CIF or other electronic format see DOI:
27
require additional neutralization step. The development of solid
1
0.1039/d1ra01053k
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ꢂ
acid catalysts by regulating the surface characteristics of a support
H
2
O (2 mL). The reaction mixture was stirred for 6 h at 100 C.
material with acid functionalities results in improved catalytic Aer the completion of the reaction as indicated by TLC, the
performance due to the inherit attributes of the support material reaction mixture was allowed to cool to RT and vacuum ltered
in addition to the graed acidic groups. Graphene oxide is an to separate out SA-rGO. Then, the obtained ltrate was washed
2 3
attractive candidate as a support material because of its fascinating with Na CO solution and extracted with dichloromethane. The
properties like hydrophilicity, large specic surface area, high combined organic layers were dried over anhydrous Na
thermal and mechanical stability, moisture insensitivity, easy and concentrated in vacuo to yield the product.
abundant availability and cost-effectiveness.
2 4
SO and
28–30
In the current work, we report sulfonic acid functionalized
reduced graphene oxide (SA-rGO) as a low-cost and efficient
metal-free solid acid carbocatalyst for the oxidation of alde-
hydes to carboxylic acids using hydrogen peroxide as the green
oxidant and for the synthesis of 5-substituted-1H-tetrazoles via
2
.3. General procedure for the synthesis of 5-substituted-1H-
tetrazoles
In a 10 mL RB ask, SA-rGO (10 mg) was added into the reaction
mixture containing nitrile (1 mmol) in DMSO (3 mL) and NaN
97.5 mg, 1.5 mmol). The reaction mixture was then stirred for
3
(
[
3 + 2] cycloaddition reaction between nitriles and inorganic
sodium azide. The fascinating application of a common catalyst
SA-rGO) for the synthesis of carboxylic acid derivatives and
their bioisosteres 5-substituted-1H-tetrazoles is unprecedented.
ꢂ
the required time (Table 2) at 120 C. Aer the completion of the
reaction as indicated by TLC, the reaction mixture was allowed
to cool to RT and vacuum ltered to separate out SA-rGO. Then,
the pH of the obtained ltrate was adjusted to 2 by addition of
(
5
N HCl and extracted with ethyl acetate. The combined organic
2
. Experimental section
layers were dried over anhydrous Na SO and concentrated in
vacuo to yield the product.
2
4
2.1. Preparation of SA-rGO
Firstly, graphene oxide (GO-H) was prepared using Hummers
3
1
method. Thereaer, SA-rGO was prepared with modications
3
. Results and discussion
30,32
in the previously reported methods.
Briey, the GO-H
In this report, we have prepared sulfonic acid functionalized
reduced graphene oxide (SA-rGO) as a low-cost and efficient
metal-free solid acid carbocatalyst. Initially, graphene oxide
(GO-H) was prepared from graphite using Hummers method.
Then, GO-H was chemically reduced using non-toxic L-ascorbic
acid as a mild reducing agent to obtain reduced graphene oxide
which was subsequently graed with sulfonic acid containing
aryl radicals prepared from the diazonium salt of sulfanilic acid,
to attain SA-rGO. A systematic representation of the preparation
of SA-rGO from GO-H is provided in Scheme 1. The graphene
oxide acts as an ideal support material to anchor large number
of acidic functionalities onto its surface with easy to access
powder was ultrasonicated in double distilled water for
ꢀ1
30 min to achieve a dispersion of 0.5 mg mL . To 500 mL of this
dispersion, 2.5 g of L-ascorbic acid was added under vigorous stirring.
ꢂ
The reaction mixture was stirred at room temperature (ꢁ35 C) for 12 h.
The reduced product was separated through centrifugation and washed
ꢀ1
thrice with double distilled water. Thereaer, 0.5 mg mL dispersion
of this reduced graphene oxide was prepared in double distilled water
through ultrasonication for 30 min. A separately prepared diazonium
salt solution of sulfanilic acid (ESI†) was directly added to this disper-
ꢂ
sion at 0 C and stirred for 1 h. The solution was then stirred at room
temperature for 18 h. The resulting black solution was centrifuged at
7000 rpm for 10 min, washed three times with double distilled water
33
3
active sites. In SA-rGO, the presence of highly acidic –SO H
groups on the surface render it with Brønsted acid sites that are
capable of furnishing organic transformations.
and nally with absolute ethanol. The precipitate was dried in an air
ꢂ
oven at 80 C for 4 h and coded as SA-rGO.
The functional group modications from GO-H to SA-rGO
were understood through FTIR spectroscopy (Fig. 1a). The
2.2. General procedure for the synthesis of carboxylic acids
In a 10 mL RB ask, SA-rGO (10 mg) was added into the reaction FTIR spectrum of GO-H shows peaks at 3432, 1738, 1642 and
ꢀ
1
mixture containing aldehyde (1 mmol), 30% H O (1 equiv.) and 1090 cm . These peaks can be ascribed to the existence of O–H,
2
2
Scheme 1 Schematic representation for the preparation of sulfonic acid functionalized reduced graphene oxide (SA-rGO).
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Fig. 1 (a) FTIR spectra of GO-H and SA-rGO. (b) Raman spectra of GO-H and SA-rGO. (c) XRD patterns of GO-H and SA-rGO. (d) Nitrogen
adsorption–desorption isotherm of SA-rGO. Inset: pore size distribution curve.
C]O for carbonyl and carboxylic acid, C]C and C–O (epoxy) GO-H depicts an absorption peak at 232 nm with a shoulder at
31
ꢀ1
groups, respectively. In GO-H, peak at 1403 cm
can be 304 nm, which can be assigned to p–p* transitions due to C]C
attributed to the O–H bending mode of carboxylic acid. Further, bonds of the conjugated aromatic network and n–p* transitions
31
in the SA-rGO spectrum, the severe attenuation of peaks at due to C]O bonds, respectively. Further, on partial reduction
ꢀ
1
ꢀ1
1
738 cm and 1642 cm aer the sulfonation process suggest of GO-H with subsequent graing of sulfonic acid groups onto
the partial reduction of GO-H and the partial restoration of the its surface as indicated by FTIR and Raman spectroscopy, the
aromatic network of GO-H, respectively. Moreover, the appear- absorption peak of GO-H at 232 nm red shis to 260 nm while
ꢀ
1
ance of peaks at 1383 and 1172 cm
attributed to S]O the shoulder at 304 nm completely disappears in the UV-vis
34
stretching modes, respectively corroborate the graing of spectrum of SA-rGO.
sulfonic acid groups onto the surface of SA-rGO.
30
To understand the crystallographic ne structure of GO-H
The Raman spectra of GO-H and SA-rGO were recorded to and SA-rGO, their PXRD patterns were recorded (Fig. 1c). For
ꢂ
understand their lattice structure and distortions (Fig. 1b). The GO-H, the diffraction peak at 2q ¼ 10.8 (d ¼ 0.81 nm) corre-
ꢀ
1
two characteristic peaks around 1345 and 1597 cm for GO-H and sponding to (001) plane of the hexagonal system was observed.
ꢀ
1
1
346 and 1602 cm for SA-rGO corresponding to defects insti- This indicates the successful formation of graphene oxide due
2
gated D band and vibration of sp carbon atoms in graphitic to the introduction of oxygen-containing functionalities and
hexagonal lattices (G band), respectively were observed. The intercalation of water molecules between stacked sheets. The
modications in the structure aer the sulfonation process were water molecules trapped within the interlayer spacing are
assessed via the comparison of intensity ratio (I /I ) values for GO- responsible for the exfoliation of graphite oxide into individual
D
G
35
H and SA-rGO. The I /I ratio for SA-rGO (1.17) > GO-H (1.01) due graphene oxide sheets upon sonication. Moreover, a very low
D
G
ꢂ
to the introduction of acidic –SO
network. The blue shi of ca. 5 cm in the G band aer sulfo- consistent with the hexagonal structure of carbon. For SA-rGO,
3
ꢀ1
H groups into the aromatic intensity peak at 42.2 (d ¼ 0.21 nm) belongs to the (100) plane
ꢂ
nation can be imputed to (a) doping which exposed the graphene the diffraction peak at 2q ¼ 10.8 disappeared and a broad peak
ꢂ
oxide structure to large number of aryl radicals and (b) alterations at 2q ¼ 25.6 (d ¼ 0.35 nm) indexed to (002) plane of hexagonal
in the conjugated double bond system of graphene oxide structure structure of carbon was observed as a result of partial reduction
33
aer sulfonation.
of graphene oxide using L-ascorbic acid followed by introduc-
The aqueous dispersions of GO-H and SA-rGO were sub- tion of sulfonic acid containing aryl radicals, insinuating
36
jected to UV-visible spectroscopy (Fig. S1†). UV-vis spectrum of restacking of sheets through p–p interactions.
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To elucidate the textural and surface properties of SA-rGO,
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To determine the elemental composition and concentration
Brunauer–Emmett–Teller (BET) surface analysis was performed of –SO H groups in SA-rGO, CHNS elemental analysis was per-
3
(Fig. 1d). The nitrogen adsorption–desorption isotherm of SA-rGO formed (Table S1†). The sulfur content (%) was found to be 5.16,
exhibits type IV isotherm with H3 type of hysteresis loop. The BET using which the concentration of –SO H groups in SA-rGO was
3
2
ꢀ1
ꢀ1
surface area of SA-rGO was found to be 26 m g . The inset of calculated to be 1.60 mmol g (Table S2†). Further, to calculate
Fig. 3b displays the pore size distribution curve ascertained by BJH the total acidic sites present in SA-rGO, back acid–base titration
method, with maximum mesoporous distribution at 4.32 nm pore was performed (Section S1†). The total acidic sites in SA-rGO
3
ꢀ1
ꢀ1
diameter and 0.014 cm g pore volume.
were found to be 2.40 mmol g (Table S2†).
The morphological attributes of GO-H and SA-rGO were
Aer successful synthesis and characterization of SA-rGO,
studied using electron microscopy. The two-dimensional the catalytic potential of the as-synthesized SA-rGO was
morphology of GO-H and SA-rGO was studied using TEM assessed for the oxidation of aldehydes to carboxylic acids and
analysis. Fig. 2a depicts the TEM image of GO-H which mani- for the synthesis of 5-substituted-1H-tetrazoles. Moreover, the
fests transparent crumpled sheet-like morphology. The TEM catalytic efficacy of SA-rGO was further evaluated in the light of
image of SA-rGO shows a similar corrugated sheet-like structure turnover frequency (TOF) values. Benzaldehyde and benzoni-
but with reduced transparency, suggesting restacking of sheets trile were selected as the model substrates for the oxidation
as also indicated by XRD results (Fig. 2b). Moreover, the SAED reaction and synthesis of 5-substituted-1H-tetrazoles,
pattern of SA-rGO suggests semi-crystalline nature and random respectively.
37
stacking of sheets (inset, Fig. 2b).
As shown in Table 1, the oxidation of benzaldehyde carried
Thereaer, to apprehend three-dimensional morphology, out at 1 mmol scale using 30% H O (1.1 equiv.) as the oxidant
2
2
ꢂ
SEM analysis of GO-H and SA-rGO was performed (Fig. 2c and and H O (2 mL) as the solvent at 100 C in the absence of any
2
d). The SEM images of both GO-H and SA-rGO depict wrinkled catalyst did not proceed towards product formation even aer
sheet-like morphology. Thus, the TEM and SEM analyses of GO- 24 h of reaction (entry 1, Table 1). The completion of the reac-
H and SA-rGO depict similar microstructures, implying resto- tion was discerned by thin-layer chromatography indicated by
ration of morphology aer the sulfonation process. Further- the complete consumption of benzaldehyde. Subsequently, the
more, SEM-EDS analysis of SA-rGO was carried out to determine importance of SA-rGO catalyst was explored for the oxidation of
the composition of elements in SA-rGO which depicts the stoi- benzaldehyde to benzoic acid. The reaction was performed
chiometric ratios of C, O and S elements. The sulfur content was using O balloon and 30% H O (1.1 equiv.) as the oxidant in the
2
2 2
found to be 5.11 wt% in SA-rGO (Fig. S2†).
presence of SA-rGO (5 mg) as the catalyst and H O (2 mL) as the
2
Fig. 2 (a and b) TEM images of GO-H and SA-rGO, respectively. Inset of (b) SAED pattern of SA-rGO. (c and d) SEM images of GO-H and SA-rGO,
respectively.
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solvent at 100 C which produced the desired product in 72% radar plot in Fig. 3 show the closeness of the calculated values
and 88% yield in 16 h and 6 h, respectively (entries 2 and 3, for the current protocol to the ideal values of the green chem-
Table 1). Clearly, H O was better oxidant for the present istry parameters. This manifests the sustainability of the
2
2
protocol, therefore, the amount of H O oxidant was optimized. present method.
2
2
The highest yield of the desired product was achieved using 1.1
To decipher the reaction pathway, oxidation reaction was
equiv. of H (entries 3–5, Table 1). The best solvent for the carried out in the presence of a free radical scavenger, hydro-
2 2
O
present protocol was selected by performing the reaction in 1,4- quinone. The addition of hydroquinone to the reaction mixture
dioxane, ethanol (EtOH) and neat conditions which resulted in did not affect the oxidation reaction suggesting that a non-
71%, 73% and 79% yield of the desired product, respectively radical pathway is followed. Therefore, in Fig. 4, a plausible
aer 8 h of reaction (entries 6–8, Table 1). This displayed that mechanism demonstrating the role of SA-rGO for the oxidation
H O is the optimum solvent for the current protocol. Next, the of aldehydes to carboxylic acids is depicted using benzaldehyde
2
reaction temperature was optimized by performing the reaction as the representative substrate. The interaction between SA-rGO
ꢂ
at room temperature and 80 C which resulted in trace amount and H
2
O
2
leads to the formation of peroxysulfuric acid inter-
and 75% yield of the product, respectively (entries 9 and 10, mediate (I) which on further reaction with the aldehyde results
Table 1). The amount of SA-rGO catalyst required for the reac- in the peroxyacetal intermediate (II). Finally, the decomposition
tion was optimized which showed that 10 mg of SA-rGO of peroxyacetal intermediate (II) generates the carboxylic acid
produces the highest yield (entries 11–13, Table 1). Finally, and SA-rGO.
under the optimized reaction conditions, GO-H was scrutinized
as catalyst which could furnish the desired product in only 63% between benzonitrile and sodium azide for the preparation of 5-
yield aer 16 h of the reaction (entry 14, Table 1). phenyl-1H-tetrazole was performed at 1 mmol scale without any
As depicted in Table 3, the [3 + 2] cycloaddition reaction
Aer achieving the optimal reaction conditions, substrate catalyst using DMF and DMSO as solvents which resulted in
scope for SA-rGO catalyzed oxidation reaction was evaluated. very low yield (20–22%) of the desired product aer 24 h of
Table 2 summarizes the substrate scope results displaying good reaction (entries 1 and 2, Table 3). The completion of the
to excellent yields (87–95%) of carboxylic acids. Aromatic alde- reaction was discerned by thin-layer chromatography indicated
hydes substituted with electron-withdrawing groups produced by the complete consumption of benzonitrile. Subsequently, the
higher yields of the corresponding carboxylic acids as compared importance of SA-rGO catalyst was explored for the synthesis of
to those substituted with electron-donating groups. Tereph- 5-phenyl-1H-tetrazole. The efficacy of SA-rGO (5 mg) as a catalyst
thalaldehyde could also be oxidized to disubstituted tereph- was evaluated in the presence of various solvents (DMF, DMSO,
2 2 3 2
thalic acid using 2.2 equiv. H O (entry 2 g, Table 2). The CH CN, EtOH and H O) at varying temperatures (entries 3–7,
aliphatic long chain aldehyde also produced the corresponding Table 3). Among these, the highest yield of 5-phenyl-1H-tetra-
carboxylic acid in good yield (entry 2 h, Table 2). Further, the zole (89%) was achieved when DMSO was used as solvent at
ꢂ
catalytic activity of SA-rGO was assessed by determining the TOF 120 C (entry 4, Table 3). Further, the amount of SA-rGO
values for the synthesized carboxylic acid derivatives which were required for the catalysis was optimized. The amount of SA-
ꢀ1
found to be between 9.06–9.89 h . The details regarding the rGO was varied from 2.5–15 mg in the presence of DMSO as
ꢂ
calculation of TOF values of SA-rGO is given in Section S2.†
solvent at 120 C (entries 8–10, Table 3). Thus, the optimized
Further, the green chemistry metrics for the oxidation reac- reaction conditions were established to be SA-rGO (10 mg) as
ꢂ
tion of benzaldehyde to benzoic acid 2a were calculated. The catalyst in the presence of DMSO (3 mL) at 120 C (entry 9, Table
calculations tabulated in Table S3† and the results depicted as 3). Under these conditions, the product 5-phenyl-1H-tetrazole
a
Table 1 Optimization of reaction conditions for the oxidation of benzaldehyde to benzoic acid
ꢂ
b
c
Entry
Catalyst amount (mg)
Oxidant (equiv.)
Solvent
Temp. ( C)
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
—
H
2
O
2
(1.1)
H
H
H
H
H
2
2
2
2
2
O
O
O
O
O
100
100
100
100
100
100
100
100
RT
24
16
6
7
6
8
8
8
24
6
N.R.
72
88
84
89
71
73
79
Trace
75
SA-rGO (5 mg)
SA-rGO (5 mg)
SA-rGO (5 mg)
SA-rGO (5 mg)
SA-rGO (5 mg)
SA-rGO (5 mg)
SA-rGO (5 mg)
SA-rGO (5 mg)
SA-rGO (5 mg)
SA-rGO (2.5 mg)
SA-rGO (10 mg)
SA-rGO (15 mg)
GO-H (10 mg)
O balloon
2
H
H
H
H
H
H
H
H
H
H
H
H
2
O
2
O
2
O
2
O
2
O
2
O
2
O
2
O
2
O
2
O
2
O
2
O
2
2
2
2
2
2
2
2
2
2
2
2
(1.1)
(1.0)
(1.5)
(1.1)
(1.1)
(1.1)
(1.1)
(1.1)
(1.1)
(1.1)
(1.1)
(1.1)
1,4-Dioxane
CH CN
Neat
H
H
H
H
H
H
3
2
2
2
2
2
2
O
O
O
O
O
O
1
1
1
1
1
0
1
2
3
4
80
100
100
100
100
8
6
6
16
80
94
94
63
a
c
b
Reaction conditions: benzaldehyde (1 mmol), oxidant (equiv.), solvent (2 mL) and catalyst (mg). Complete consumption of benzaldehyde.
Isolated yields. N.R. ¼ no reaction. RT ¼ room temperature.
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a,c
Table 2 Substrate scope for SA-rGO catalyzed oxidation of aldehydes to carboxylic acids.
a
b
c
Reaction conditions: aldehyde (1 mmol), 30% H
2
O
2
(1.1 equiv.), H
2
O (2 mL) and SA-rGO (10 mg). Isolated yields. Products were characterized
1
13
d
using H and C NMR spectroscopy.
2 2
H O (2.2 equiv.).
was isolated in 94% yield aer 4 h of the reaction. Finally, under was extended to aromatic, heteroaromatic and aliphatic nitriles.
the optimized reaction conditions, GO-H was scrutinized as Table 4 summarizes the substrate scope results displaying good
catalyst which could furnish the desired product in only 42% to excellent yields (82–95%) of 5-substituted-1H-tetrazoles.
yield aer 12 h of the reaction (entry 11, Table 3).
Aromatic nitriles substituted with electron-withdrawing groups
Aer achieving the optimal reaction conditions, substrate produced higher yields of the corresponding 5-substituted-1H-
scope for SA-rGO catalyzed 5-substituted-1H-tetrazole synthesis tetrazoles as compared to those substituted with electron-
donating groups. The heteroaromatic and aliphatic nitriles
also produced the corresponding 5-substituted-1H-tetrazoles in
good yields (entry 5f and 5k, Table 4, respectively). The benzyl
carbamate substituted nitrile produced the corresponding 5-
substituted-1H-tetrazole in moderate yield (entry 5m, Table 4).
Further, the catalytic activity of SA-rGO was assessed by deter-
mining the TOF values for the synthesized 5-substituted-1H-
tetrazole derivatives which were found to be between 12.08–
ꢀ
1
1
6.96 h . The details regarding the calculation of TOF values of
SA-rGO is given in Section S2.†
Further, the current approach for the synthesis of 5-
substituted-1H-tetrazoles was authenticated using single crystal
X-ray analysis of compound 5k. The X-ray quality crystals were
grown in 50% ethyl acetate in hexane using slow evaporation of
solution growth method. Fig. 5 depicts the ORTEP diagram of
compound 5k which was crystallized in monoclinic cell and
P21/n space group having following lattice parameters: a ¼
Fig. 3 Radar plot depicting Green chemistry metrics for the synthesis
of benzoic acid 2a.
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Fig. 4 Plausible mechanism for the oxidation of aldehydes to carboxylic acids using SA-rGO.
ꢀ
ꢀ
ꢀ
ꢂ
4
1
1
.8058 (5) A, b ¼ 26.6823 (19) A, c ¼ 7.1899 (7) A, a ¼ 90 , b ¼ synthesis of 5-substituted-1H-tetrazoles. Fig. 7 depicts the
ꢂ
ꢂ
ꢀ
3
06.575 (14), g ¼ 90 , V ¼ 883.65 (15) A and r (calculated) ¼ energy prole diagram for the reaction between benzonitrile
ꢀ
3
.463 g cm . The other single crystal X-ray crystallographic and azide ion via an uncatalyzed (blue line) and SA-rGO cata-
lyzed (pink line) reaction pathway. The computational calcula-
details of compound 5k are given in Table S4.†
In Fig. 6, the plausible mechanism demonstrating the role of tions suggest that both uncatalyzed (blue line) and SA-rGO
SA-rGO for the synthesis of 5-substituted-1H-tetrazoles is catalyzed (pink line) reaction pathway involve the addition of
depicted using benzonitrile as the representative substrate. azide ion to nitrile group followed by cyclization step which
Initially, the coordination of nitrogen atom of benzonitrile to nally results into 5-substituted-1H-tetrazole product. It is also
the sulfonic acid group (acidic sites) of SA-rGO results in step I. predicted that the formation of 5-substituted-1H-tetrazole
The activation of nitrogen atom of benzonitrile by the acidic occurs through two transition states, viz. TS-1A and TS-2A for
sites of SA-rGO facilitates the [3 + 2] cycloaddition reaction uncatalyzed reaction while TS-1B and TS-2B for SA-rGO cata-
between the nitrile group (–C^N) and the azide ion smoothly, lyzed reaction. The energy difference between TS-1A and TS-1B
ꢀ
1
resulting in the step II. Finally, SA-rGO is separated out through was found to be 7.5 kJ mol while that between TS-2A and TS-
ꢀ1
vacuum ltration and the pH of the solution is adjusted to 2 to 2B was found to be 11.7 kJ mol . Thus, the computational
yield 5-phenyl-1H-tetrazole. calculation outlined in Fig. 7 clearly indicates that the forma-
Further, the computational calculations were performed to tion of 5-substituted-1H-tetrazole is faster for SA-rGO catalyzed
get a better insight into the proposed reaction mechanism and reaction pathway compared to that of the uncatalyzed reaction
to comprehend the importance of SA-rGO catalyst for the pathway, which is in correlation with our experimental ndings.
a
Table 3 Optimization of reaction conditions for the synthesis of 5-phenyl-1H-tetrazole
ꢂ
b
c
Entry
Catalyst amount (mg)
Solvent
Temp. ( C)
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
—
—
DMF
DMSO
DMF
140
120
140
120
80
78
90
120
120
120
120
24
24
8
20
22
88
89
38
51
42
76
94
95
42
SA-rGO (5 mg)
SA-rGO (5 mg)
SA-rGO (5 mg)
SA-rGO (5 mg)
SA-rGO (5 mg)
SA-rGO (2.5 mg)
SA-rGO (10 mg)
SA-rGO (15 mg)
GO-H (10 mg)
DMSO
8
CH
3
CN
12
12
12
12
4
EtOH
H
2
O
DMSO
DMSO
DMSO
DMSO
1
1
0
1
4
12
a
c
b
Reaction conditions: benzonitrile (1 mmol), NaN
Isolated yields.
3
(1.5 mmol), solvent (3 mL) and catalyst (mg). Complete consumption of benzonitrile.
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a,c
Table 4 Substrate scope for SA-rGO catalyzed synthesis of 5-substituted-1H-tetrazoles.
a
b
c
Reaction conditions: nitrile (1 mmol), NaN
H NMR, C NMR, IR spectroscopy and HRMS.
3
(1.5 mmol), DMSO (3 mL) and SA-rGO (10 mg). Isolated yields. Products were characterized using
1
13
This data is in agreement with the proposed reaction mecha- phenyl-1H-tetrazole and reaction time (h) is represented in
nism within the thermodynamic limitations.
Fig. 8a and b, respectively.
The practicality of the oxidation reaction and 5-substituted-
The prowess of a heterogeneous catalyst to show easy
1H-tetrazoles synthesis for the potential industrial application recoverability and effective reusability are necessary for their
were studied. Keeping the reaction stoichiometry unaltered, worthwhile industrial application. In the current study, the
gram scale synthesis of benzoic acid and 5-phenyl-1H-tetrazole recoverability and reusability of SA-rGO was investigated for the
was carried out at 100 mmol scale (10 g). The results are synthesis of benzoic acid and 5-phenyl-1H-tetrazole under the
summarized in Tables S5 and S6† for benzoic acid and 5-phenyl- optimized reaction conditions. Aer the completion of each
1H-tetrazole, respectively. The reaction occurred steadily and cycle, SA-rGO could be easily recovered by vacuum ltration,
encouraging yields were obtained. A plot showing the effect of washed with ethanol and subsequently dried in an air oven at
ꢂ
scale (mmol) on the isolated yield (%) of benzoic acid and 5- 70 C for 3 h which was then reused for the next cycle. SA-rGO
was reused for eight consecutive catalytic cycles without
signicant depreciation in its activity. The isolated yield (%) for
the eight catalytic cycles for both the reactions is plotted in
Fig. 8c and tabulated in Tables S7 and S8,† respectively.
The stability of SA-rGO reused over eight consecutive cata-
lytic cycles was examined through FTIR, PXRD and Raman
studies (Fig. S3a–c†). The peaks in FTIR and Raman spectra
match well with that of fresh SA-rGO sample insinuating
structural integrity even aer eight consecutive catalytic cycles.
Fig. 5 ORTEP diagram of compound 5k.
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Fig. 6 Plausible mechanism for the synthesis of 5-substituted-1H-tetrazoles using SA-rGO.
The resemblance of PXRD pattern with fresh SA-rGO sample
implies phase purity. Further, SEM image of the SA-rGO reused
over eight cycles was collected which did not display any note-
worthy changes indicating morphology preservation (Fig. S3d†).
To rationalize the use of SA-rGO for the synthesis of 5-
substituted-1H-tetrazoles, the present work was compared with
the available literature. The comprehensive literature survey
suggested that the use of SA-rGO as a catalyst for the oxidation
reaction and the synthesis of 5-substituted-1H-tetrazoles has
several advantages over earlier work (Tables S9 and S10†). The
present catalyst was synthesized keeping in mind the low-cost,
easy preparation of graphene oxide-based materials and the
usefulness of solid acid catalysts. It is evident from Tables S9
and S10,† that SA-rGO produces carboxylic acid derivatives and
5-substituted-1H-tetrazoles in high yields with short reaction
time using low amount of catalyst. Specically, the comparison
with previously reported sulfonated carbon analogues also
Fig. 7 The free energy profiles for the synthesis of 5-substituted-1H-
tetrazoles via an uncatalyzed (blue line) and SA-rGO catalyzed (pink reveal better catalytic output of the current SA-rGO catalyst in
line) reaction pathway.
terms of better reaction conditions with higher yields in shorter
reaction times (entry 3, Table S9 and entry 10, Table S10†). Also,
Fig. 8 (a) Plot representing the effect of substrate scale (mmol) on isolated yield (%) of benzoic acid 2a and 5-phenyl-1H-tetrazole 5a. (b) Plot
representing the effect of substrate scale (mmol) on reaction time (h) for the synthesis of benzoic acid 2a and 5-phenyl-1H-tetrazole 5a. (c) Plot
representing the reusability of SA-rGO for the synthesis of benzoic acid 2a and 5-phenyl-1H-tetrazole 5a over eight catalytic cycles.
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the previous sulfonated carbon analogues were prepared using
harmful and highly corrosive concentrated sulfuric acid while
SA-rGO was prepared via diazonium salt solution of sulfanilic
acid. Moreover, both the reactions in the current work could be
performed at gram scale with high efficiency, which makes the
current methodology using SA-rGO catalyst interesting from
industrial viewpoint.
2 L. Sancineto, C. Tidei, L. Bagnoli, F. Marini, E. J. Lenard ˜a o
and C. Santi, Molecules, 2015, 20, 10496.
3 A. Mahmood, G. E. Robinson and L. Powell, Org. Proc. Res.
Dev., 1999, 3, 363.
4 J. K. Thottathil, J. L. Moniot, R. H. Mueller, M. K. Y. Wong
and T. P. Kissick, J. Org. Chem., 1986, 51, 3140.
5 M. Hunsen, Synthesis, 2005, 15, 2487.
6
M. Liu, H. Wang, H. Zeng and C.-J. Li, Sci. Adv., 2015, 1,
e1500020.
4
. Conclusions
7
X. Wang, C. Wang, Y. Liu and J. Xiao, Green Chem., 2016, 18,
In conclusion, we have successfully developed a methodology
using metal-free sulfonic acid functionalized reduced graphene
oxide (SA-rGO). SA-rGO was implemented as solid acid carbo-
catalyst for the oxidation of aldehydes to carboxylic acids and
4605.
8 M. Liu and C.-J. Li, Angew. Chem., Int. Ed., 2016, 55, 10806.
9 H. Yu, S. Ru, G. Dai, Y. Zhai, H. Lin, S. Han and Y. Wei,
Angew. Chem., Int. Ed., 2017, 56, 3867.
for the synthesis of 5-substituted-1H-tetrazoles. The amalgam- 10 H. Singh, A. S. Chawla, V. K. Kapoor, D. Paul and
ation of fascinating properties, easy and low-cost preparation of R. K. Malhotra, Prog. Med. Chem., 1980, 17, 151.
graphene oxide-based materials with additional benets of 11 Y. M ´e ndez, G. D. Armas, I. P ´e rez, T. Rojas, M. E. Vald ´e s-
´
highly acidic sites due to the graing of sulfonic acid groups
was found quite valuable. The oxidation of substituted aromatic
and aliphatic aldehydes to their corresponding carboxylic acids
could be efficiently achieved using H O as green oxidant and
Tresanco, M. Izquierdo, M. A. Rivero, Y. M. Alvarez-
Ginarte, P. A. Valiente, C. Soto, L. Le ´o n, A. V. Vasco,
W. L. Scott, B. Westermann, J. Gonz ´a lez-Bacerio and
D. G. Rivera, Eur. J. Med. Chem., 2019, 163, 481.
2
2
ꢀ1
H
2
O as green solvent with high TOF values (9.06–9.89 h ). The 12 S.-Q. Wang, Y.-F. Wang and Z. Xu, Eur. J. Med. Chem., 2019,
calculation of their green chemistry metrics displayed an E- 170, 225.
factor value of 0.24 which is very close to ideal value. Further, 13 Z. Yan, S. Chong, H. Lin, Q. Yang, X. Wang, W. Zhang,
the 5-substituted-1H-tetrazoles could be effectively synthesized
X. Zhang, Z. Zeng and Y. Su, Eur. J. Med. Chem., 2019, 164,
from their corresponding substituted aromatic, heteroaromatic
562.
and aliphatic nitrile substrates with high TOF values (12.08– 14 C. Gao, L. Chang, Z. Xu, X.-F. Yan, C. Ding, F. Zhao, X. Wu
ꢀ
1
1
6.96 h ). The current approach for the synthesis of 5-
and L.-S. Feng, Eur. J. Med. Chem., 2019, 163, 404.
substituted-1H-tetrazoles was corroborated by computational 15 R. Mittal and S. K. Awasthi, Synthesis, 2019, 51, 3765.
calculations of the proposed reaction mechanism which was 16 Z. P. Demko and K. B. Sharpless, J. Org. Chem., 2001, 66,
found to be in agreement with the experimental ndings.
Moreover, both the reactions could be performed at gram scale 17 S. D. Guggilapu, S. K. Prajapti, A. Nagarsenkar, K. K. Gupta
with high efficiency. Thus, low-cost, easy recovery, eminent and B. N. Babu, Synlett, 2016, 27, 1241.
reusability and ability to perform gram scale reactions makes 18 L. Bosch and J. Vilarrasa, Angew. Chem., Int. Ed., 2007, 46,
7945.
this metal-free solid acid carbocatalyst riveting for industrial
applications.
3926.
19 F. Himo, Z. P. Demko, L. Noodleman and K. B. Sharpless, J.
Am. Chem. Soc., 2003, 125, 9983.
2
0 P. Mani, A. K. Singh and S. K. Awasthi, Tetrahedron Lett.,
Conflicts of interest
2014, 55, 1879.
There are no conicts to declare.
21 P. Mani, C. Sharma, S. Kumar and S. K. Awasthi, J. Mol.
Catal. A Chem., 2014, 392, 150.
2
2 S. Kumar, A. Kumar, A. Agarwal and S. K. Awasthi, RSC Adv.,
Acknowledgements
2015, 5, 21651.
RM is grateful to UGC, New Delhi, India for providing senior 23 M. L. Kantam, K. B. S. Kumar and C. Sridhar, Adv. Synth.
research fellowship. SKA acknowledges the nancial support Catal., 2005, 347, 1212.
Tamoradi, A.
M. Ghadermazi, New J. Chem., 2017, 41, 11714.
from Institution of Eminence, University of Delhi (IoE/FRP/ 24 T.
PCMS/2020/27) and University of Delhi, Delhi, India. Authors
Ghorbani-Choghamarani
and
are sincerely thankful to University Science Instrumentation 25 D. Khalili and M. Rezaee, Appl. Organomet. Chem., 2019, 33,
Centre (USIC) and Department of Chemistry, University of e5219.
Delhi, Delhi, India for providing instrumentation facilities. We 26 H.
Sharghi,
S.
Ebrahimpourmoghaddam
and
are also grateful to Sophisticated Analytical Instrument Facility
M. M. Doroodmand, J. Organomet. Chem., 2013, 738, 41.
(SAIF)-AIIMS, New Delhi, India for providing TEM facility.
27 B. Majumdar, S. Mandani, T. Bhattacharya, D. Sarma and
T. K. Sarma, J. Org. Chem., 2017, 82, 2097.
2
8 X. Fan, G. Zhang and F. Zhang, Chem. Soc. Rev., 2015, 44,
023.
Y. Zhang, Y. Cheng, H. Cai, S. He, Q. Shan, H. Zhao, Y. Chen 29 A. Bahuguna, A. Kumar and V. Krishnan, Asian J. Org. Chem.,
References
3
1
and B. Wang, Green Chem., 2017, 19, 5708.
2019, 8, 1263.
©
2021 The Author(s). Published by the Royal Society of Chemistry
RSC Adv., 2021, 11, 11166–11176 | 11175

View Article Online
RSC Advances
Paper
3
0 R. Mittal, A. Mishra and S. K. Awasthi, Synthesis, 2020, 52, 34 L. Q. Xu, Y. B. Liao, N. N. Li, Y. J. Li, J. Y. Zhang, Y. B. Wang,
91. X. F. Hu and C. M. Li, J. Colloid Interf. Sci., 2018, 514, 733.
5
31 D. C. Marcano, D. V. Kosynkin, J. M. Berlin, A. Sinitskii, 35 O. C. Compton and S. T. Nguyen, Small, 2010, 6, 711.
Z. Sun, A. Slesarev, L. B. Alemany, W. Lu and J. M. Tour, 36 M. Brahmayya, S. A. Dai and S.-Y. Suen, Sci. Rep., 2017, 7,
ACS Nano, 2010, 4, 4806.
4675.
3
3
2 J. Zhang, H. Yang, G. Shen, P. Cheng, J. Zhang and S. Guo, 37 W. Zhang, W. He and X. Jing, J. Phys. Chem. B, 2010, 114,
Chem. Commun., 2010, 46, 1112.
10368.
3 J. Ji, G. Zhang, H. Chen, S. Wang, G. Zhang, F. Zhang and
X. Fan, Chem. Sci., 2011, 2, 484.
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