Metal-Free Sustainable Synthesis of Amides via Oxidative Amidation Using Graphene Oxide as Carbocatalyst in Aqueous Medium

Article abstract of DOI:10.1007/s10562-019-02878-5

Abstract: We describe an efficient, clean and metal-free procedure for the synthesis of amides via oxidative amidation of aldehydes with anilines using graphene oxide (GO) as a recyclable catalyst and KBrO₃ as a mild oxidant in aqueous medium under microwave irradiation. GO nanosheets were prepared and characterized by XRD, TEM, SEM, and FT-IR, analyses. GO showed high compatibility with KBrO₃ in water and offered high TOF value (1.30 × 10^?3 mol?g^?1 min^?1). GO oxygen functionalities catalyze the oxidative amidation effectively in mild condition with high recyclability. A plausible mechanism was proposed by the isolating the intermediate. Graphic Abstract: [Figure not available: see fulltext. ]

Full text of DOI:10.1007/s10562-019-02878-5

Catalysis Letters
https://doi.org/10.1007/s10562-019-02878-5
Metal‑Free Sustainable Synthesis of Amides via Oxidative Amidation
Using Graphene Oxide as Carbocatalyst in Aqueous Medium
Anshu Dandia1 · Sonam Parihar1 · Pratibha Saini1 · Kuldeep S. Rathore2 · Vijay Parewa1
Received: 9 August 2018 / Accepted: 22 June 2019
© Springer Science+Business Media, LLC, part of Springer Nature 2019
Abstract
We describe an efcient, clean and metal-free procedure for the synthesis of amides via oxidative amidation of aldehydes
with anilines using graphene oxide (GO) as a recyclable catalyst and KBrO3 as a mild oxidant in aqueous medium under
microwave irradiation. GO nanosheets were prepared and characterized by XRD, TEM, SEM, and FT-IR, analyses. GO
showed high compatibility with KBrO3 in water and ofered high TOF value (1.30×10−3 mol g−1 min−1). GO oxygen func-
tionalities catalyze the oxidative amidation efectively in mild condition with high recyclability. A plausible mechanism was
proposed by the isolating the intermediate.
Graphic Abstract
O
O
R2
GO, KBrO3,
H2O
H
N
H
R1
R1
+
NH2
R2
Microwave irradiation
Keywords Carbocatalyst · Oxidative amidation · Metal-free synthesis
1 Introduction
Amide bond linkage has attracted a fair amount of inter-
est on account of their efcacy in pharmaceuticals, agro-
chemicals, natural products and organic materials [1–3].
The vital importance of amides has led to them being
encountered through the advancement of diverse synthetic
protocols. Traditionally used protocol involves the direct
reaction of amines with activated carboxylic acid deriva-
tives [4]. Although these methods are suitable for certain
synthetic applications but many of these procedures are
associated with one (or more) disadvantages such as stoi-
chiometric amount of high molecular weight of by prod-
ucts, low functional group tolerance and poor atom econ-
omy. The oxidative amidation of aldehydes with amines is
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s10562-019-02878-5) contains
supplementary material, which is available to authorized users.
* Anshu Dandia
dranshudandia@yahoo.co.in
* Vijay Parewa
parewavijay.parewa@gmail.com
Kuldeep S. Rathore
kuldeep_ssr@yahoo.com
1
Department of Chemistry, Centre of Advanced Studies,
University of Rajasthan, Jaipur 302004, India
2
Department of Physics, Arya College of Engineering and IT,
Jaipur, India
Vol.:(0123456789)
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A. Dandia et al.
one of the most efcient and expedient alternative strategy
due to abundant starting materials [5–11].
2 Results and Discussion
A guarded study would necessitate that this alterna-
tive path tolerate some obstructs owing to their limited
utility due to the exploitation of metal as catalysts, use
excess amount of oxidants, non-compatible solvent, long
reaction time, tedious workup and low selectivity. Fur-
ther, the afanced catalytic systems are non-recoverable,
hence tumbling the turn over frequency (TOF) observed,
which is vital from the industrial vision. While some metal
free modifcations have been accredited for upliftment of
the reaction condition [12], but somewhere down the line
it still require the broad adaptability. Therefore, further
development of the catalytic system will require advanced
materials that can facilitate straight access to amides by
metal-free oxidative amidation employing mild oxidant is
of high genuine interest.
GO were synthesized by simple one-pot chemical route
[29] and well characterized by XRD, TEM, SEM and FT-IR
analyses. XRD patterns of GO are given in Fig. 1. For GO,
a sharp characteristic peak is observed due to (001) refec-
tion [34].
In SEM analyses, GO nanosheets displayed a crumpled
and wrinkled surface (Fig. 2). The nanosheets stacked
together to form a typical multi-layer structure due to pres-
ence of p–p interaction. Further, the wrinkled structure of
GO nanosheets afords a huge surface area.
TEM analyses of GO also augment the results obtain by
SEM (Fig. 3). From the FT-IR spectrum of GO (Fig. 4), the
peaks at 3465, 1721, 1368 and 1030 cm−1 of GO could be
Carbon materials at nanoscale have been made an
intense impact. It is the chemical genius of carbon that
it can create diferent nanostructures with entirely difer-
ent properties [13, 14]. Particularly, graphene oxide (GO)
nanosheets illustrated ubiquitous concern due to high sur-
face area, presence of oxy functionalities like hydroxyl
(–OH), carboxylic (–COOH), carbonyl (C=O), epoxide
groups (C–O–C) on both accessible sides, easy availabil-
ity, chemical functionalization, good water-dispersion and
high cell compatibility. These advantages lead to advance
magnetic, optoelectronic and catalytic materials [15–17].
Among them graphene oxide (GO) nanosheets widely
acceptable metal-free carbocatalyst in various organic
transformations such as oxidation, hydration, alkylation
reaction, redaction etc. [18–22]. Additionally, prologue
of water [23] carbon based materials [24–28] and in this
metal free oxidative amidation added imperative endeavor
in this vicinity.
Inspired by our previous work on catalytic applica-
tion of carbon-based nanostructures and development of
sustainable protocols [29–33], herein, we describe metal-
free oxidative amidation of aldehydes with amines using
GO as a recyclable catalyst and KBrO3 as a mild oxidant
in water with some fascinating mechanistic deliberation
under microwave irradiation. (Scheme 1).
Fig. 1 XRD patterns of GO
O
R2
O
GO, KBrO3
H2O, MW
N
H
NH2
R1
H
R2
+
R1
Scheme 1 Metal-free oxidative amidation
Fig. 2 SEM image of GO
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Metal-Free Sustainable Synthesis of Amides via Oxidative Amidation Using Graphene Oxide as…
produced low yield of desired product in the presence of 10
wt% PTSA. Further, moderate yields were observed in the
presence of other metal-free catalyst. In order to develop
sustainable metal-free catalyst, the study of catalytic aptitude
of GO and rGO were studied. The best result in terms of
turnover frequency (TOF: number of moles of product pro-
duced per gram of catalyst used per min [29, 31]) attained by
GO nanosheets catalyst (10 wt% loading, TOF=1.30×10−3
mol g−1 min−1). Inferior yield was observed in the presence
of rGO as compared to GO due to the presence of lower
functional site, which confrmed the active role of GO’s
oxygen functional groups in the reaction. It was evidently
designated from Table 1 that 10 wt% of catalyst loading was
adequate to catalyze the reaction, excessive amount of cata-
lyst did not afect the yield remarkably. The use of diverse
oxidant illustrated that KBrO3 was found to be the most ef-
cient oxidant to generate desired product 3a with good selec-
tivity. The model reaction was also studied with diferent
equivalent of KBrO3 (2 equiv., 4 equiv. and 6 equiv.). Best
results were found with four equiv. of KBrO3. Evidently, in
the absence of any oxidant poor yield of the product was
observed. The reaction was also investigated in various sol-
vents, such as H2O, MeOH, DMSO, THF, DCM and CHCl3.
As shown in Table 1, water was superior solvent as con-
trast to other organic solvents. It appears that a large amount
of oxygen-containing groups on GO nanosheets can improve
its dispersion in aqueous media. Due to this higher catalytic
sites were available for the reaction and gave high yield of
products compared to many other catalytic systems. Moreo-
ver, KBrO3 act as an admirable oxidant in water due to its
high extent of solvolysis in water with respect to other sol-
vents [36].
Fig. 3 TEM image of GO
The catalytic activity of GO was found fourfold higher
than the conventional method (Table 1). Due to diference in
dielectric properties of materials and by volumetric dielec-
tric heating nanomaterials selectively absorbs MW in the
reaction mixture [37]. Thus, they can works as a catalyst as
well as susceptor [38] and serve as an internal heat source
for the reactions which enhance overall catalytic activity
of nanomaterials in MW. During the optimization of the
reaction condition, the model reaction was also studied by
varying microwave power (300, 400, and 500 W) and tem-
perature. It was concluded that 400 W power output at 80 °C
was required to accomplish maximum conversion to prod-
uct. To exclude the possibility of radical reaction pathway,
TEMPO (2,2,6,6-tetramethylpipridine-N-oxyl) was added to
the reaction as a radical inhibitor. No Inhibition of reaction
was observed by adding TEMPO which ruled out the radical
process nature of the reaction.
Fig. 4 FT-IR of GO
assigned to the –OH stretching, C=O stretching, O–H defor-
mation and C–O stretching vibrations respectively. A broad
peak at around 1209 cm−1 corresponds to C–O–C vibra-
tion. Further, four absorption peaks ranging from 1438 to
1568 cm−1 observed due to the aromatic C=C stretching of
GO nanosheet [35].
Now we have employ as prepared GO as a metal-free
catalyst for oxidative amidation of aldehydes. For that
purpose reaction of benzaldehyde (2.0 mmol) and aniline
(2.0 mmol) was chosen as a model reaction using KBrO3 as
a mild oxidant in water under microwave irradiation. When
the reaction was carried out in the absence of the catalyst,
no desired product was formed as determined. Thus the pre-
liminary attempts were focused on the competent assessment
of diferent catalyst systems. As shown in Table 1, reaction
Next we examined the scope of the reaction with respect
to diverse aldehydes and anilines under the optimized con-
ditions. The results are summarized in Table 2. However,
aldehydes were liable to be oxidized to acids, no amount
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A. Dandia et al.
Table 1 Comparison of catalytic activity of GO with other catalytic systems for the oxidative amidation (3a)
S. no.
Catalyst
Solvent
Oxidant
Time (min)
Yield (%)a
TOF (×10−3
mol g−1
min−1 b
)
1.
2.
3.
4.
5.
6.
7.
8.
–
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
MeOH
DMSO
THF
DCM
CHCl3
H2O
H2O
KBrO3
KBrO3
KBrO3
KBrO3
KBrO3
KBrO3
KBrO3
KBrO3
KBrO3
KBrO3
H2O2
TBHP
NaClO3
NaBrO3
–
KBrO3
KBrO3
KBrO3
KBrO3
KBrO3
KBrO3
KBrO3
40
40
40
40
40
40
30
40
40
30
30
30
30
30
30
30
30
30
30
30
12 h
40
–
n.c.
PTSA (p-Toluenesulfonic acid) (10 wt%)
MeSA (Methanesulfonic acid) (10 wt%)
I2 (10 wt%)
KI (10 wt%)
NaI (10 wt%)
GO (10 wt%)
rGO (reduced graphene oxide) (10 wt%)
GO (5 wt%)
GO (20 wt%)
GO (10 wt%)
GO (10 wt%)
GO (10 wt%)
GO (10 wt%)
GO (10 wt%)
GO (10 wt%)
GO (10 wt%)
GO (10 wt%)
GO (10 wt%)
37
49
46
41
39
86
48
47
86
Trace
43
Trace
47
14
27
21
18
16
14
56
26
0.420
0.556
0.522
0.464
0.444
1.30
0.545
1.11
0.579
n.c.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
0.650
n.c.
0.711
0.131
0.408
0.319
0.273
0.242
0.212
0.354
0.028
GO (10 wt%)
GO (10 wt%)c
GO (10 wt%)c
n.c. Not calculated
Reactions are performed on benzaldehyde (2.0 mmol) and aniline (2.0 mmol) in water with diferent catalysts and oxidant under microwave irra-
diation
aIsolated yield
bTOF is defned as the number of moles of product produced per gram of catalyst used per min
cConventional method, reaction at 120 °C
of acids were examined in our method, which shows that
KBrO3 chemoselectively oxidized imines rather than the
aldehydes. Additionally, replacing the aldehydes with
corresponding carboxylic acids did not give the desired
amides. Therefore, the possibility of oxidation of alde-
hydes to carboxylic acids in this oxidative amidation was
also being ruled out. A series of aromatic aldehydes and
anilines with both electron donating and electron with-
drawing substituents such as halo, methoxy, methyl,
hydroxy, etc. were successfully produced corresponding
product in excellent yields. We found as compared elec-
tron donating substituted aldehydes, electron withdrawing
substituted aldehydes gave better yield. However, Ortho
substitute aldehydes and anilines gave moderate yields due
to the steric hindrance. Further, at the expense of time
up to 60 min, heterocyclic aldehydes also aforded good
yields. Probably due to the electronic factors, unpublish-
able results were obtained with the aliphatic counter parts
of the reactants.
Although the accurate mechanism of this transformation
is uncertain, but on the bases of literature survey and con-
sidering our whole experimental fnding a plausible mecha-
nistic pathway for oxidative amidation of aldehydes with
amines was outlined in Scheme 2. The reaction may pro-
ceed via any of the two possible pathways as represented in
Scheme 2. GO nanosheets can serve as an acidic catalyst for
the two possible pathways (Path A and B). In path A, GO
served as a acid catalyst for the reaction of benzaldehyde
with aniline through acid sites coordinated to the oxygen
of carbonyl groups to form imine intermediate A. Then,
intermediate A oxidize by KBrO3 in further step afording
the oxaziridine intermediate B. Thermal rearrangement of
oxaziridine [39–42] intermediate gave amides 3a as a desired
product. In path B, GO facilitate the formation of hemiami-
nal intermediate C via direct coupling of benzaldehyde with
aniline, which was afterward oxidized by KBrO3 to form
corresponding amide 3a. Although, we isolate the imine
intermediate A in controlled conditions (See ESI), but the
1 3

Metal-Free Sustainable Synthesis of Amides via Oxidative Amidation Using Graphene Oxide as…
Table 2 Oxidative amidation of
OMe
O
O
O
aldehydes with anilines
Cl
O
N
H
N
H
N
H
N
H
3a, 86%
O
3b, 70%
3c, 74%
3d, 74%
OMe
NO2
O
F
O
O
N
H
N
H
N
H
N
H
Cl
Cl
Cl
3e, 76%
3f, 80%
O
3g, 81%
3h, 82%
Cl
O
O
NO2
O
N
H
N
H
N
H
N
H
NO2
3k, 67%
OPh
3i, 75%
3j, 78%
3l, 62%
Br
O
O
S
O
N
H
NH
N
H
Cl
OH
Cl
3n, 85%
3m, 69%
3o, 58%
Reactions are performed on benzaldehydes (2 mmol), anilines (2 mmol), KBrO3 (4 eq.) and 10 wt% GO
in water under microwave irradiation
exact mechanism of this reaction remains uncertain and both
pathways could be possible.
NH2
O
To confrm the heterogeneous nature of GO nanosheet in
the reaction, the model reaction was carried out again under
similar reaction conditions with the catalyst procured from
a previous cycle. After 15 min, the catalyst was separated
from the reaction mixture. The reaction was continued with
the fltrate for another 60 min and the reaction conversion
was monitored for every 5 min. It was observed that fur-
ther increment in conversion was not observed even after
60 min. These results revealed that the oxidative amidation
was occurring only due to the solid GO catalyst.
+
H
Path A
2
1a
Path B
OH
N
A
N
H
KBrO3
[O]
GO nanosheets
C
O
N
[O]
KBrO3
O
Recycling experiments were performed by choosing the
benzaldehyde (2.0 mmol) and aniline (2.0 mmol) as a model
reaction in water under microwave irradiation using GO as
a solid catalyst. The reaction was started with the addition
of KBrO3 as a mild oxidant. When the reaction was com-
pleted, the reaction mixture was fltered and the solid mass
(product+catalyst) was dried. Then, the solid mass was dis-
solved in ethanol and the dispersed catalyst was recovered by
fltration. The recovered catalyst was washed with water and
ethanol and reused in succeeding 8 reaction cycles without
B
N
H
3a
Scheme 2 Plausible mechanism for oxidative amidation
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A. Dandia et al.
4 Conclusion
In conclusion, we illustrated GO as a competent metal-free
carbocatalyst for oxidative amidation of aldehydes with
amines using KBrO3 as a mild oxidant in aqueous medium
under microwave irradiation. No other oxidative side prod-
ucts like acids were produced in this process with amides.
This atom-economical protocol, includes a much milder
procedure, does not involve any tedious work-up for purif-
cation, avoids hazardous reagents/byproducts and the target
molecules were obtained in good to excellent yields. The
protocol will promote newer area of environmental research,
based on innovation, aimed at developing environmen-
tally sound catalysts and techniques and would be useful
in introduction of newer, cleaner and economical synthetic
procedures.
Fig. 5 Recyclability of GO nanosheet
any signifcant loss in its catalytic activity (Fig. 5). The rea-
son is that the characteristics obtained from SEM and TEM
of fresh and used catalysts are similar (Fig. S3 and S4; see
ESI), which suggest the retention of structure and morphol-
ogy of GO after repeated use as catalyst.
Acknowledgements Financial assistance from the DST-SERB, CSIR,
and UGC New Delhi is gratefully acknowledged. We are thankful to
the Malaviya National Institute of Technology, Jaipur for the spectral
analyses.
Compliance with Ethical Standards
Conflict of interest The authors declare that they have no confict of
interest.
3 Experimental Section
3.1 General
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