Synthesis of β-Amino Ketones using graphene oxide: a benign carbonaceous acid catalyst for Mannich reaction

Article abstract of DOI:10.1007/s11164-020-04324-3

Abstract: Simple and easily preparable graphene oxide (GO) is used as a straightforward carbocatalyst for the synthesis of β-amino ketones via a 3-component Mannich reaction under mild condition. The native GO is acting as a carbonaceous solid Br?nsted acid catalyst without any special functionalization, yielding a spectrum of β-amino ketones under metal-free conditions. The present catalytic method offers a benign and simple procedure without any hazardous workup, and chromatographic purification resulted in an excellent yield of β-amino ketones. The catalyst has shown good sustainability up to 6 consecutive catalytic cycles without any significant loss in its activity. The stability of the recovered catalyst is proved by analytical techniques such as FT-IR, PXRD, SEM, and TEM. This mild solid-acid catalyst offers an alternative and sustainable approach to get synthetically essential β-amino ketones under greener conditions. Graphical abstract: [Figure not available: see fulltext.].

Full text of DOI:10.1007/s11164-020-04324-3

Research on Chemical Intermediates (2021) 47:1197–1210
https://doi.org/10.1007/s11164-020-04324-3
Synthesis of β‑Amino Ketones using graphene oxide:
a benign carbonaceous acid catalyst for Mannich reaction
Nagappan Saravana Ganesan1 · Palaniswamy Suresh1
Received: 1 September 2020 / Accepted: 9 November 2020 / Published online: 5 January 2021
© Springer Nature B.V. 2020
Abstract
Simple and easily preparable graphene oxide (GO) is used as a straightforward car-
bocatalyst for the synthesis of β-amino ketones via a 3-component Mannich reac-
tion under mild condition. The native GO is acting as a carbonaceous solid Brønsted
acid catalyst without any special functionalization, yielding a spectrum of β-amino
ketones under metal-free conditions. The present catalytic method ofers a benign
and simple procedure without any hazardous workup, and chromatographic purifca-
tion resulted in an excellent yield of β-amino ketones. The catalyst has shown good
sustainability up to 6 consecutive catalytic cycles without any signifcant loss in its
activity. The stability of the recovered catalyst is proved by analytical techniques
such as FT-IR, PXRD, SEM, and TEM. This mild solid-acid catalyst ofers an alter-
native and sustainable approach to get synthetically essential β-amino ketones under
greener conditions.
Graphical abstract
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s1116
4-020-04324-3) contains supplementary material, which is available to authorized users.
*
Palaniswamy Suresh
ghemistry@gmail.com; suresh.chem@mkuniversity.ac.in
Extended author information available on the last page of the article
Vol.:(0123456789)
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N. Saravana Ganesan, P. Suresh
Keywords Graphene oxide · Mannich reaction · Multicomponent synthesis ·
β-amino ketones · Brønsted acid catalyst
Introduction
The ubiquity of C–C and C-N bonds extensively found in natural products, active
pharmaceutical ingredients, and agrochemicals, which enlighten their signifcance
to develop an elegant and straightforward method to construct them. Though dif-
ferent transition metal catalyst [1, 2] provided possible methodologies to construct
such bonds, Mannich reaction ofers a simple and efcient strategy for the syn-
chronized formation of C–C and C-N bonds. [3] The classical Mannich reactions
gave β-amino ketone through two-component [4] or three-component systems, [5]
which are acting as versatile synthetic building blocks for the preparation of amino
alcohols, peptides, and lactams to synthesize amino acids and biologically crucial
molecules containing nitrogens. Consequently, various synthetic and catalytic meth-
odologies have continuously explored in order to achieve a simplifed protocol for
the Mannich reaction. Notably, to establish a reliable method for the direct-Mannich
reaction through the one-pot three-component process, various synthetic and cata-
lytic pathways were reported. Most of the Lewis [6] and Brønsted acid catalysts, [7]
organocatalysts, [8] nanomaterials [9], and magnetically retrievable catalysts, [10]
were developed for the simplifed synthetic method of Mannich reaction. Though
diferent catalytic systems have already reported nevertheless, the hazardous reac-
tion condition, reduced yields, troublesome workup, and purifcation procedures still
limited their applications. Compared to the traditional methods, lately developed
catalysts, notably organocatalysts such as N-quaternized pyridoxal catalyst, [11] sil-
ver tartaric acid-derived phosphate, [9] ionic liquid-immobilized prolines, [12] sev-
eral squaramides-based bifunctional organocatalyst, [13–16] spiro phosphoric acids
[16] and metal salts like hafnium trifate [17] were ofered an excellent yield. How-
ever, indeed their complicated preparation, handling, environmental contaminants,
and loss of reactivity after a few recycles made dwindle the objective of such cata-
lysts. In this context, a high-performance, non-toxic, sustainable, and protective cat-
alyst is more desirable. Additionally, a straightforward and metal-free catalyst with
more environmental concern is an immediate necessity for the synthetically versatile
Mannich reaction.
Nowadays, the carbon-based metal-free catalytic active platforms have attracted
wide attention and pave a pathway for alternative catalytic methodologies. In the
constant efort on the development of greener catalytic systems, graphene oxide
(GO) and its derivatives have widely been studied both as a supporting material and
a catalyst. [18] The presence of high surface area, exceptional chemical and thermal
stability, high carbon and oxygen content, and the possibility for diverse function-
alization made GO an inevitable catalytic material in the development of greener
catalytic system, and it contributed extensive inspiring accomplishment in the syn-
thetic transformation as a carbocatalyst. [19] Though, to improvise the catalytic
behavior, functionalization and immobilization of active catalytic species on the sur-
face of the GO have been carried out; however, even without any cosmetic chemical
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Synthesis of β-Amino Ketones using graphene oxide: a benign…
1199
functionalization, the native graphene-oxide, itself being exhibit a superior catalytic
activity in the key organic transformations. [12] The presence of oxygen function-
alities on the surface of graphitic domains allows GO to behave as a mild oxidant,
soft Brønsted acid and showing the benefts of metal-free, cost-efective, recyclable
and heterogeneous nature in organic transformations which projecting it as a nota-
ble potential alternative to expensive organocatalyst and positioned as an economic
carbonaceous catalyst. Initially, GO has identifed as an oxidation catalyst, [20] and
now its catalytic potential has been explored in various synthetic transformations
such as functional group transformations, [21] coupling reactions, [22] heterocy-
clic syntheses, [23] Friedel–Crafts addition, [24] ipso-hydroxylation, [25] oxidation
and hydration reaction, [26] multicomponent reactions, [27] esterifcation reactions,
[28] and chemoselective thioacetalization of aldehydes, [29]. In the ongoing efort
to explore GO as a mild, metal-free reusable carbonaceous catalyst, in the present
work, we unlocked the catalytic utility of the native GO in the synthetically essential
Mannich reaction, where the GO facilitate both C–C and C-N formation simultane-
ously. Without any complicated catalyst preparations, we unveiled inexpensive and
native GO– as an eco-friendly carbonaceous solid-acid catalyst for the synthesis of
β-amino ketones through a metal-free tandem reaction in a one-pot protocol in a
renewable solvent medium.
Materials and methods
All reagents and starting materials were purchased commercially from Sigma-
Aldrich, Alfa Aesar, Merck, or Spectrochem and used as received without further
purifcation unless otherwise noted. The powder X-ray difraction was recorded
in the XPERT-PRO instrument using Cu Kα (λ=0.1542 nm) radiation operated
at a voltage of 40 kV and a current of 40 mA at room temperature. FT-IR spectra
were recorded in a Shimadzu instrument from 4000 cm−1 to 500 cm−1 with sam-
ples being dispersion using the KBr pellet technique. Raman spectra we,re recorded
in Shimadzu using laser 630 nm. SEM analysis was carried out in the TESCAN
VEGA3 instrument using SE detector and equipped with EDX (AMETEK EDAX,
Model Octane Prime with Active area=10 mm) detector. Samples for high-resolu-
tion transmission electron microscopy (HR-TEM) analysis were done by dispersing
the prepared samples in acetone using ultrasonication and then deposit a drop of that
dispersed solution on amorphous carbon-coated copper grids. Images were obtained
on TEF 20 TECNAI G2 200kv TEM (FEI) instrument. X-ray photoelectron spec-
troscopy (XPS) was collected on the Omicron Nanotechnology spectrometer with Al
Ka as the excitation source (hm=1486.6 eV). All 1H NMR and 13C NMR "A Bruker
Avance AV-300 MHz spectrometer" was employed for nuclear magnetic resonance
(NMR) experiments. NMR spectra were recorded at 300 MHz (1H) and 75 MHz
(13C) at 298 K using tetramethylsilane (0 ppm) as the internal reference. Chemical
shifts (δ) are given in ppm, and coupling constants (J) are given in Hz. The fol-
lowing abbreviations are used for multiplicities: s=singlet, d=doublet, t=triplet,
q=quartet, dd=doublet of doublets, and m=multiplet.
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N. Saravana Ganesan, P. Suresh
Synthesis of graphene oxide
Graphene oxide (GO) was synthesized from Pristine graphite using modifed Hum-
mer’s method. [30] In brief, 2.5 g of graphite powder and 2.5 g of sodium nitrate
were mixed together, followed by the addition of 115 mL of concentrated sulphu-
ric acid under constant stirring. After 1 h, 15 g of KMnO4 was added gradually to
the mixture containing graphite powder. During the addition, the temperature was
maintained under less than 20 °C. Because the addition of KMnO4 to sulphuric acid
is an exothermic reaction, to prevent the heating of the reaction mixture, the lower
temperature was maintained under an ice bath. After the addition of KMnO4, the
mixture was stirred at 35 °C for 24 h, and the resulting solution was diluted by add-
ing 200 mL of double-distilled water (DD water) (when the reaction mixture was
kept under an ice bath) under vigorous stirring. Then, the reaction mixture’s tem-
perature was raised to 98 °C in an oil bath and stirred for 24 h, then cooled to room
temperature. After reaching room temperature and ensuring reaction completion, the
suspension was further treated with 500 mL of double-distilled water followed by
50 mL of 30% H2O2 solution. The resulting mixture was washed with HCl (1 M)
to reach the neural pH and followed by double-distilled water. Then, it was fltered
and dried in an air-oven at 110 °C for 24 h. Finally, it was shifted to a glass oven and
dried under vacuum at 110 °C. Detailed characterization of the prepared graphene
oxide has given in supporting information.
GO catalyzed synthesis of β‑Amino ketones
In a dry reaction tube with a magnetic Tefon stir bar, a mixture of GO catalyst
(5 mg), benzaldehyde (1 mmol, 108 mg), acetophenone (1 mmol, 106 mg), and ani-
line (1 mmol, 98 mg) was added followed by the addition of 5 mL of ethanol. The
resulting mixture was stirred at room temperature for the appropriate time (5 h). The
progress of the reaction was monitored by thin-layer chromatography. After comple-
tion of the reaction, the ethanol was decanted by simple fltration. Where most of the
product was adsorbed on the surface of the GO, and the solid GO was extracted with
ethyl acetate. Parallelly, the fltrate ethanol was also extracted by ethyl acetate. The
combined ethyl acetate layer was dried with sodium sulfate and concentrated under
1
vacuum. The dried sample was analyzed by H and 13C NMR without chromato-
graphic purifcation. The recovered catalyst was washed with methanol followed by
DD water, then dried under vacuum in a glass oven at 110 °C and used for the next
reaction.
Results and discussion
Graphene oxide, the catalyst studied in the present Mannich reaction, was prepared
from the commercial graphite powder through chemical oxidation followed by exfo-
liation in DD water by adopting modifed Hummer’s method. [30] Resulting GO
repeatedly dialyzed in DD water using a membrane and confrmed free from metals
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Synthesis of β-Amino Ketones using graphene oxide: a benign…
1201
through EDX and ICP-OES analysis. The prepared GO was systematically charac-
terized using various analytical techniques such as elemental analysis, EDX, FT-IR,
PXRD, Raman spectroscopy, HR-XPS, and microscopical techniques such as SEM
and HR-TEM to determine its structural properties. All analytical characterizations
unambiguously confrmed the formation of GO and proved the presence of oxygen
functionalities such as hydroxyl, epoxide on the basal plane, and carboxylic acid
groups at the edges (SI in Fig. S1 and S2). Further, the pH of the as-prepared GO
was quantitatively measured in the aqueous dispersion of distilled water (0.1 mg in
1 mL), and it is shown in the range 4.83–4.92. It reveals the mild Brønsted acidic
nature of the synthesized GO, which has in good agreement with the reported value
[31, 32] The mild acidic and metal-free catalytic nature of the GO in organic trans-
formations triggered to study its potential in the synthesis of synthetically impor-
tant β-amino ketones. To study GO as a carbonaceous catalyst in the synthesis of
β-amino ketones through one-pot three-component condensation, other reaction
parameters which infuencing the catalytic behavior of the GO were optimized using
acetophenone (1a) (1 mmol, 106 mg), benzaldehyde (1b) (1 mmol, 108 mg) and
aniline (1c) (1 mmol, 98 mg) as a model substrate (Table 1). To identify a reliable
reaction condition, frst diferent solvents were screened. Due to the good dispers-
ibility nature of the GO in alcoholic medium, initially, reaction tested in diferent
alcohols such.
Table 1 Optimization of graphene oxide (GO) catalyzed by synthesis of β-amino ketones a
H
O
NH2
3a
NH
O
GO
O
+
+
Reaction
Conditions
1a
Solvent
4a
2a
Entry
Time (h)
Yield b (%)
1
2
3
4
5
6
7
8
Methanol
Ethanol
iso-propyl alcohol
toluene
CHCl3
THF
24
24
24
24
24
24
24
24
24
24
–
72
96
68
36
70
52
76
22
DMF
Water
9
EtOH: Water c
Neat
65
–
10
11
12
13
Ethanol
Ethanol
Ethanol
96d, 96e, 52f
96g, 96h, 63i
5
24
a
Reaction conditions: Benzaldehyde (1 mmol), acetophenone (1 mmol) and aniline (1 mmol), GO
25 mg, in 5 mL of solvent at RT stirring. 24 h, isolated yield.c 1:1 ratio, Reaction time: 12 h, 5 h,
b
d
e
f3 h, GO load: g 10 mg, h 5 mg, i 3 mg j without catalyst,
1 3

1202
N. Saravana Ganesan, P. Suresh
as methanol, ethanol, and isopropyl alcohol using 25 mg of the GO as a cata-
lyst and 24 h as reaction time. Among the used alcohols, in ethanol medium, GO
exhibited excellent reactivity with 96% of isolated yield (96%, entry 11 and 12,
Table 1). Further, to explore the better reactivity of the GO, other solvents such as
toluene, chloroform, and THF were also screened; however, moderate reactivity
only observed. Next, to study the role of high polar solvents, water and DMF were
screened. In which, the later one, DMF gave good yield, whereas, in water, though
GO has excellent dispersibility, but it resulted in poor yield. It might owe to the lack
of solubility of the substrate and poor mass transfer of substrates to the catalyst.
Though moderate reactivity was noted in water, further, to tune the reactivity, an
aqueous mixture of ethanol was tested; however, it also ended with an average yield.
Similarly, under solvent-free neat conditions, GO was highly inert. All the above
results concluded that ethanol is a suitable medium for the GO catalyzed synthesis
of β-amino ketones. Indeed, the use of ethanol as a reaction medium has attracted
much interest in the past few years remarkably, owing to the economic and environ-
mental advantages. Added to that, ethanol has considered as a renewable greener
solvent for diverse industrial applications, which is recommended by leading indus-
tries for medicinal chemistry purposes. It shows that the carbonaceous GO supports
a greener medium to get β-amino ketones. Furthermore, after ethanol was chosen as
a reaction medium, the exact reaction time and appropriate catalyst (GO) loading
were optimized. Screening studies showed that the complete conversion was reached
within 5 h, and only 5 mg (4.7 wt %) GO loading is adequate to get excellent yield
(96%, Table 1, entries 11 and 12). From the screening studies, it is concluded that
the as-prepared GO acts as a catalyst for the synthesis of β-amino ketones in an etha-
nol medium using 5 mg of the catalyst at ambient temperature in 5 h.
With the mild optimized reaction condition in hand, to explore the inherent poten-
tial of the GO as a catalyst in synthetic chemistry, the synthesis of β-amino ketones
was successfully extended using a spectrum of aromatic aldehydes with other substi-
tuted anilines and acetophenone, which aforded the respective products in good to
excellent yield (90–96%) without any by-products or impurities. The observed sub-
strate versatility has been depicted in Table 2. First, a series of aldehydes (2b–2p)
were studied; all aldehydes have efciently undergone the reaction under the opti-
mized condition and gave the corresponding products. Among aromatic aldehydes
were found more reactive irrespective of the substituent’s electronic nature present
on the aryl ring.
The present catalyst works very well for a wide range of both para-and meta-
substituted aryl aldehydes possessing both electron releasing substituents such as
methyl and methoxy groups (4b–4e, Table 2) and withdrawing substituents such as
chloro, bromo, fuoro, nitro, and nitrile groups (4f–4i, 4 k−4 m, Table 2) with good
to excellent isolated yield. Meanwhile, when the same substituents present on the
ortho-position (4j, 4n), a mild drop in the yield was observed owing to the steric
factor. Similarly, compared to other electron-withdrawing groups, nitrile substituted
aldehyde (4o), and heteroaryl aldehyde, 4-pyridinecarboxaldehyde (4v) gave moder-
ate yields. Next, while studying the role of substituents on aniline motifs (3q–3v),
no notable change was observed. Irrespective of the electronic nature of the sub-
stituents on aniline, good to excellent yield was found. However, the hetero amine,
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Synthesis of β-Amino Ketones using graphene oxide: a benign…
Table 2 Graphene oxide catalyzed synthesis of β-amino ketones a
1203
R3
HN
O
O
H
NH2
GO
4.7 wt
%)
mg,
(5
O
+
+
Ethanol, RT
R1
R2
R1
R2
2
R3
3
4
1
68-96%)
(Yield
Entry
R1
R2
H
4−CH3
3−CH3
4−OCH3
3−OCH3
4−Cl
3−Cl
4−Br
3−Br
2−Br
4−F
4−NO2
3−NO2
2−NO2
4−CN
4−Pyridine
H
H
H
H
H
H
H
H
H
H
H
H
R3
Product
Yieldb (%)
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
4a
4b
4c
4d
4e
4f
96
90
81
93
91
88
88
93
4 g
4 h
4i
9
83
74
86
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
4j
4 k
4 l
4 m
4n
4o
4p
4q
4r
84, 82c
82
71
76
68
93
96
92
92
86
77
87
91
90
H
H
H
H
H
H
4−CH3
4−OCH3
4−Cl
4−Br
4−NO2
4s
4t
4u
4v
4w
4x
4y
4z
4−Pyridine
4−OCH3
4−Cl
4−Br
4−I
4−NO2
2−NO2
H
H
H
H
H
H
91, 90c
94
90
4aa
4ab
a
Reaction conditions: Aldehyde (1 mmol), acetophenone (1 mmol) and aniline (1 mmol), GO (5 mg),
5 h in ethanol (5 mL) at room temperature.b All are isolated yield.c Isolated yield in grams
such as pyridine-4-amine (3v), showed moderate yield only. It is noticed that when
nitrogen is present on either in aldehyde or aniline ring system, the reaction was
suppressed, resulted in average yield (4p, and 4v, Table 2). It is because of the
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N. Saravana Ganesan, P. Suresh
catalytic poisoning of the pyridine moiety, which hampers the catalytic acidic sites
of the GO. Furthermore, the role of substitutes on the acetophenone (1w–1ab) motif
was also screened. The results revealed that acetophenone with electron-withdraw-
ing substituents proceeded smoothly and gave excellent yield compared to electron
releasing (4w) substitutes. To demonstrate the potential of the present catalyst, for
the preparative purpose, the reaction was also performed on a gram scale, gave the
isolated yield (4 l, 4z, Table 2), which is comparable to those obtained for a small-
scale reaction.
After explored the scope of the GO catalyst in Mannich reaction with minimum
catalyst loading under ambient condition, to demonstrate the inherent catalytic
activity of GO and to understand the catalytic active sites which are responsible for
this transformation, control experiments were performed with other similar types of
materials such as RGO (reduced graphene oxide), graphite and activated carbon. All
were entirely unreactive under optimized conditions (entry 1–3, Table 3). It shows
that the presence of oxygen functionalities such as hydroxyl and epoxide groups on
GO surface is acting as catalytic sites. Notably, the edge carboxylic acid groups are
expected as a responsible catalytic active site for the formation of β-amino ketones.
To ascertain the role of carboxylic acid groups, they were protected through func-
tionalization and tested as a catalyst. For this purpose, carboxylic acid protected 2
GOs, BGO [31, 32] (all carboxylic acid groups converted to corresponding carboxy-
late group by treating GO with aqueous sodium hydroxide) and ester-GO [33, 34]
(carboxylic acid groups are converted as methyl ester through esterifcation) were
prepared and characterized using FT-IR (SI in Fig S3).
When reactions were carried out using the as-prepared BGO (entry 4, Table 3)
and ester-GO (entry 5, Table 3), the frst one was highly inert, and the later one gave
Table 3 Catalytic control experiments a
H
O
NH2
3a
NH
O
Catalysts
rt.,
O
+
+
EtOH,
5-24 h
4a
Yield c
1a
2a
Entry
Catalysts b
1
2
3
4
5
6
7
8
9
RGO
Graphite
Activated Carbon
BGO
Ester-GO
Amberlyst A21
Citric acid d
Oxalic acid d
GO e
–
–
–
–
5
12
62
67
96
a
Reaction conditions: Reactants benzaldehyde (1 mmol), acetophenone (1 mmol) and aniline (1 mmol),
b Catalyst 5 mg, c isolated yield, d 20 mmol in 5 mL of ethanol at RT stirring 24 h, e 5 mg, 5 h
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Synthesis of β-Amino Ketones using graphene oxide: a benign…
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poor or negligible conversion in the Mannich reaction. These results are strongly
proved the pivotal role of the Brønsted acidic carboxyl group on the GO surface,
which is responsible for the formation of β-amino ketones. Furthermore, the unique-
ness of the present catalyst was compared with commercial acid reagents such as
Amberlyst A21, citric acid, and oxalic acid (entries 6–8, Table 3), which clearly
demonstrate that the GO has better activity than other acids catalysts. All the control
and comparative studies strongly enlighten the uniqueness of the present GO cata-
lyst in the synthesis of β-amino ketones.
Further, to understand the stability and sustainable nature of the GO, reusability
studies were carried out. After fnished the reaction, the catalyst was recovered by
simple fltration, followed by washed with methanol and water dried under vacuum
in a glass oven. To synthesis 4a another fresh batch of the reaction was performed
with the recovered catalyst under identical screened condition. Results indicate that
the recovered GO remains equally active and exhibited high stability for six con-
secutive reuses without any noticeable decay in activity (Fig. 1). The outcome of
the recycling studies clearly demonstrates the robustness and sustainable nature of
the present GO catalyst. Remarkably, the reused catalyst remains highly stable with-
out any notable change in its physical and chemical properties, which was recog-
nized using analytical techniques such as FT-IR, powder X-ray difraction (PXRD),
scanning electron microscope (SEM), and transmission electron microscopy (TEM).
The FT-IR spectra of the fresh and reused GO showed identical stretching frequen-
cies (Fig. 2a). Peaks at 3350 cm−1, 1730 cm−1, and 1600 cm−1 corresponding to
O–H stretching, C=O stretching of carboxylic acid, and stretching vibration of
C=C/C–C are present both in fresh and sixth time reused GO.
Similarly, peaks at 1395 cm−1, 1222 cm−1, 1049 cm−1 corresponding to C–OH,
C–O–C, and C-O retained even after the sixth time reused GO, which strongly
Fig. 1 Reusability profle of GO catalyst in β-amino ketones synthesis (a isolated yield)
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1206
N. Saravana Ganesan, P. Suresh
Fig. 2 FTIR spectra and PXRD pattern of GO a fresh, b frst time reused, c forth time reused d sixth
time reused
ascertained the chemical stability of the reused GO. Similarly, the PXRD pattern
of fresh and reused GO exhibits an identical peak pattern at 12.5˚ without any addi-
tional peaks. Furthermore, these results confrmed by the single sheet with a couple
of layers and the nature of crumpled sheet-like morphology in SEM and TEM analy-
sis of the sixth time reused catalyst (Fig. 3). All the above analytical studies on the
reused catalyst strongly confrmed the stability of the GO in the Mannich reaction
and proved its sustainable nature in organic catalysis.
Following the previous report [33] and based on the experimental observations,
a plausible mechanism for the GO-catalyzed synthesis of β-amino ketones has been
proposed (Scheme 1). The presence of the high surface area with aromatic graphitic
domain and the oxygen functionalities such as hydroxyl, epoxide, and carboxyl
groups of GO catalyzes the Mannich reaction. The aryl substrates benzaldehyde (1a)
and aniline (2a) are strongly binding on the surface of the GO through π-π interac-
tion (II). Notably, the intermolecular hydrogen bonding between the aldehyde and
aniline with carboxylic acid groups present on the edges of GO also facilitates the
strong binding of the substrates on the GO surface (II). The hydrogen bonding with
oxygen functionalities promotes the condensation resulting in an imine intermediate
(IV). Meanwhile, the Brønsted acidic carboxylic group accelerates the acetophenone
(3a) through enol formation, and the resulting enol undergoes a nucleophilic attack
on imine the desired β-amino ketone (4a). Notably, the hydrogen bonding between
the azomethine nitrogen atom and the oxygen atom of the GO’s carboxylic acid also
favors the nucleophilic attack, which resulted in the formation β-amino ketone (4a).
The comparisons of GO catalyzed Mannich reaction with the existing catalytic
systems listed in Table 4, strongly validate the advantages of carbon-based GO as a
solid Brønsted acid catalyst for the present Mannich reaction. The comparison table
understands that the present GO is a metal-free carbonaceous catalyst without any
unique functionalization with good reactivity even with minimum catalyst load.
Conclusion
A simple, economical, and efcient methodology has been developed to synthesize
synthetically important β-amino ketones using graphene oxide as a carbonaceous
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Synthesis of β-Amino Ketones using graphene oxide: a benign…
1207
Fig. 3 SEM image of a. fresh b. sixth time reused GO and TEM images of c. fresh d. sixth time reused
GO
solid-acid catalyst via a one-pot three-component reaction. In this metal-free, Man-
nich reaction, graphene oxide acts as a sustainable organo-Brønsted acid catalyst
without any external hazardous acid and additives. The catalyst showed good func-
tional group tolerance and afording a spectrum of the desired β-amino ketones
without any chromatographic purifcation, using renewable ethanol as a greener
solvent under ambient condition. The control experiments with basifed GO and
esterifed GO evidenced GO’s carboxylic acid sites’ catalytic responsibility. The six-
time consecutive reused profle also proved the catalytic stability of the GO in the
Mannich reaction without any loss in activity. To our delight, this carbocatalyst may
fnd broad applications as an alternative solid-acidic catalyst in synthetic as well as
medicinal chemistry.
Acknowledgements We gratefully acknowledge the fnancial support from the Council for Scientifc
and Industrial Research, New Delhi, India (CSIR grant No.: 02(0191)14/EMR-II). We thank University
Grants Commission under University with Potential for Excellence program (UGC-UPE), DST-FIST (for
LC-MS), and DST-PURSE (for FT-IR, SEM, and EDX) for the instrumental facility.
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N. Saravana Ganesan, P. Suresh
O
OH
O
OH
O
OH
O
O
HO
N
H
O
HO
O
O
HO
4a
GO
I
O
OH
CH2
OH
H
H
O
O
O
H
H
OH
O
OH
O
N
O
OH
O
O
OH
HO
O
N
O
HO
HO
O
O
O
O
HO
H
O
CH2
OV
O
II
HO
H
O
OH
O
OH
O
O
OH
OH
O
OH
OH
O
OH
O
N
HO
H
O
O
N
HO
HIOIIO
O
O
HO
HO
O IV
O
HO
H
2O
Scheme 1 Proposed mechanism for GO catalyzed Mannich reaction
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Afliations
Nagappan Saravana Ganesan1 · Palaniswamy Suresh1
1
Supramolecular and Catalysis Lab, Dept. of Natural Products Chemistry, School of Chemistry,
Madurai Kamaraj University, Madurai 625 021, India
1 3