Direct oxidative amidation of benzyl alcohols using EDTA@Cu(II) functionalized superparamagnetic nanoparticles

Article abstract of DOI:10.1016/j.apcata.2014.06.009

Superparamagnetic Fe₃O₄@EDTA-Cu(II) nanoparticles were readily prepared and identified as an effective catalyst for the tandem transformation of benzyl alcohols and amine hydrochloride salts into the corresponding amides with tert-bu

Full text of DOI:10.1016/j.apcata.2014.06.009

Accepted Manuscript
Title: Direct Oxidative Amidation of Benzyl Alcohols Using
EDTA@Cu (II) Functionalized Superparamagnetic
Nanoparticles
Author: Kobra Azizi Meghdad Karimi Fatemeh Nikbakht
Akbar Heydari
PII:
S0926-860X(14)00395-0
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.apcata.2014.06.009
APCATA 14869
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Applied Catalysis A: General
Received date:
Revised date:
Accepted date:
18-1-2014
7-6-2014
9-6-2014
Please cite this article as: K. Azizi, M. Karimi, F. Nikbakht, A. Heydari, Direct
Oxidative Amidation of Benzyl Alcohols Using EDTA@Cu (II) Functionalized
Superparamagnetic Nanoparticles, Applied Catalysis A, General (2014),
http://dx.doi.org/10.1016/j.apcata.2014.06.009
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Direct Oxidative Amidation of Benzyl Alcohols Using EDTA@Cu (II)
Functionalized Superparamagnetic Nanoparticles
Kobra Azizi, Meghdad Karimi, Fatemeh Nikbakht and Akbar Heydari*
Chemistry Department, Tarbiat Modares University, P. O. Box 14155-4838 Tehran, Iran
heydar_a@modares.ac.irFax: (+98)-21-82883455, Phone: (+98)-21-82883444, email:
Abstract
Superparamagnetic Fe3O4@EDTA- Cu (II) nanoparticles were readily prepared and identified as
an effective catalyst for the tandem transformation of benzyl alcohols and amine hydrochloride
salts into the corresponding amides with tert-butyl hydroperoxide (TBHP) as an oxidant. After
completion of the reaction, the catalyst can be removed from the reaction vessel by assistance of
an external magnet and reused at least six times without significant loss of its activity.
Keywords: benzyl alcohol, amine, oxidation, amidation, magnetic catalyst
1. Introduction
The amide functionality [1] is an important unit in organic molecules, synthetic intermediates,
polymers, natural products and pharmaceuticals [2] (Scheme 1). Consequently, amide bond
formation has been one of the most important transformations [1]. Coupling of activated
carboxylic acid derivatives and amines is one of the most conventional methods for the synthesis
of amides [3]. Nevertheless although these methodologies have been shown to be efficient for
the construction of amide bonds in small peptides; they pose meaningful challenges for the
synthesis of
many natural products [4]. These traditional approaches often require
stoichiometric amounts of coupling reagents and produce toxic chemical waste [5].
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Additionally, several alternative methods, such as the Schmidt, Ritter, Beckmann, Ugi, Wolff,
Staudinger reactions and hydration of nitriles have emerged to improve the preparation of amides
[6]. However, the above mentioned methods suffer from poor atom-efficiency and/ or the use of
highly hazardous reagents. Another alternative approach, which is quite attractive in terms of
green chemistry and economic considerations, is the oxidative amidation of aldehydes. Over the
past years, few reports adapting the above strategy have appeared in literature such as those
detailing ruthenium [7] rhodium [8] Au/TiO2 [9] Au/DNA nanohybrids [10] and Pd as catalyst
[11]. However, these methods require the use of expensive transition metals as catalyst, have
limited substrate scope and require harsh reaction conditions. Yoo and Li et al. improved the
oxidative amidation of aldehydes with amine hydrochlorides using CuI−AgIO3 as the catalyst
and TBHP as the oxidant [12].This work required a dual catalyst and had a narrower substrate
scope, applicable to the synthesis of secondary amides. Subsequently Ghosh et al. developed a
practical method for the amidation of aldehydes with amine hydrochloride salts using copper
sulfate as a catalyst and aqueous TBHP as an oxidant, too [13]. From the recent perspective of
green chemistry, the development of efficient and practical amide formation reactions remains a
great challenge. The direct amidation of alcohols with amines can be a potentially attractive
method since it uses cheap, abundant and stable starting materials and has potential industrial.
Recently, Beller and co-workers have reported oxidative amidation of benzyl alcohols in the
presence of ZnI2 [14]. A major drawback of these homogeneous catalysts is the intricacy of their
recovery from the medium reaction; also these catalysts cannot be re-utilized [15]. Chen and et
al. reported oxidative amidation of benzyl alcohols with amine salts using Fe(NO3)3 as the
catalyst. Air, TEMPO, and tert-butyl hydroperoxide act as oxidants [16]. The reaction was
carried out in a tandem fashion using an iron catalyst in conjunction with TEMPO as a co-
catalyst and molecular oxygen as an oxidant that oxidizes alcohol to benzaldehyde. After
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completion of oxidation, in the next step, the amine salt, calcium carbonate (as the base) and a
second oxidant (TBHP) were added. Also Fe(NO3)3 as catalyst wasn't recovered. Bantreil et al.
demonstrated that copper oxide could catalyze the oxidation of benzyl alcohols into amides in
the presence of hydrogen peroxide [17]. The separation of the desired product and the catalyst
from the reaction mixture can be challenging in heterogeneous catalytic reaction. Filtration and
centrifugation are available routes to recover heterogeneous catalysts but these methods can
result in lost catalyst. Also typical separations are difficult to apply for nanoparticles with less
than 100 nm diameter [15]. Therefore expensive ultra-centrifugation is often the only way to
separate product and catalyst.
With increasing environmental concerns, the development of magnetic nanoparticle-supported
catalysts has become an important research field. They can be easily separated with the aid of an
external magnet, which may optimize operational cost and enhance the product purity.
Moreover, magnetic nanoparticles can be functionalized easily with various groups.
Furthermore, magnetically functionalized reagents often show comparable and sometimes even
enhanced activity than their corresponding homogeneous analogues due to the highly accessible
surface area [18]. Very recently Hao et al. reported a solvothermal method to prepare of EDTA
(ethylenediamine- N, N, N', N'-tetraacetic acid) functionalized magnetic nano-particles (MNPs-
EDTA) as a magnetic nano-adsorbent for the removal of Cu(II) from aqueous solution [19].
The direct amidation of alcohols and amines using supported heterogeneous catalysts has been
rarely studied [20]. In the area of magnetic catalysts, no attempt has been focused on the direct
amidation from alcohols and amines in the presence of supported heterogeneous catalysts on the
magnetic nanoparticles. In continuation of our interest in using magnetic nanoparticles [21] as a
catalyst support in the oxidative amidation of aromatic aldehydes with amine hydrochloride salts
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[22], herein, we demonstrate the application of Fe3O4@EDTA- Cu (II) for the amide synthesis
via alcohol dehydrogenation in one-pot direct oxidative amidation.
The Fe3O4 nanoparticles were functionalized by EDTA and the Cu-EDTA complex was stable
under oxidation conditions with high efficiency in solvent. This atom-economical and cost
effective transformation can be used as the most favourable replacement for the synthesis of
amides.
Scheme 1: Pharmaceutical and biologically active amide compounds
2.
Experimental
All solvents and chemicals were purchased in analytical grade and used without further
purification. FT-IR spectra were obtained over the region 400-4000 cm-1 with a Nicolet IR100
FT-IR with spectroscopic grade KBr. The powder X-ray diffraction pattern was recorded at room
temperature using a Philips X-Pert 1710 diffractometer with Co Kα (α =1.78897Å) voltage: 40
Kv, current: 40 mA and in the range 10◦ to 90◦ (2θ) with a scan speed of 0.02°/s. The
morphology of catalyst was studied with scanning electron microscopy using SEM (Philips XL
30 and S-4160) on gold coated samples. The magnetic properties of Fe3O4@EDTA-Cu (II)
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nanoparticles were measured with a vibrating magnetometer/Alternating Gradient Force
Magnetometer (VSM/AGFM, MDK Co, Iran, www.mdk-magnetic.com). Thermal gravimetric
analysis / differential thermal analysis (TGA/DTA) were performed on a Thermal Analyzer with
a heating rate of 20 °C min-1 over a temperature range of 25–1100 °C under flowing compressed
N2.
The surface modification of Fe3O4
This magnetic catalyst (Fe3O4@EDTA- Cu (II)) was prepared by dissolving the mixture of 10
mmol FeCl3.6H2O and 5 mmol FeCl2.4H2O salts in 100 mL deionized water under vigorous
stirring (800 rpm). A NH3 (aq) solution (25%, w/w, 30 mL) was then dropped to the stirring
mixture to maintain the reaction pH about 11. Simultaneously, EDTA (disodium salt dihydrate)
solution (1.1 g, 2 mmol in 20 mL water) was added to this black suspension.
The resulting black dispersion was continuously stirred for 1 h at room temperature and then was
refluxed for 1 h. Fe3O4 nanoparticles was separated from the aqueous solution by magnetic
decantation, washed with water several times. Subsequently 2 mmol CuCl2.2H2O in 50 mL H2O
o
and 4 mmol of Na2CO3 was added to it and stirred at 40 C for 6 h (Scheme 2).The suspension
was refluxed for 2h. Finally, nanoparticles were separated from the aqueous solution by
magnetic decantation, washed with water, ethanol and diethyl ether several times before being
dried in an oven overnight.
Scheme 2: Preparation of Fe3O4@EDTA- Cu (II)
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Catalytic performance in the direct amidation of benzyl alcohols
Benzyl alcohol (0.75 mmol, 1.5 equiv), and 4 equiv TBHP (70 wt % in H2O) was added to the
mixture of hydrochloric salts of amines (0.5 mmol, 1 equiv), and CaCO3 (1.1 equiv) in MeCN (1
o
mL). The mixture was stirred at 80 C for 4 h. After completion of reaction, the catalyst was
removed by an external magnet. Then 1N HCl (5 mL) and EtOAc (5 mL) was added. The
mixture was extracted with EtOAc and the combined organic phase were washed with a
saturated aqueous solution of NaHCO3 (10 mL), brine (10 mL), dried over anhydrous Na2SO4.
After removal of the solvent under vacuum, the crude product was purified by column
chromatography to afford the desired product.
3.
Results and Discussions
XRD (X-ray diffraction pattern);
As can be seen in Fig. 1, six characteristic peaks of Fe3O4 (2ꢀ = 30.1°, 35.4°, 43.0°, 53.5°, 57.0°
and 62.5°) are observed. The six peaks correspond to the (220), (311), (400), (422), (511), and
(440) lattice planes respectively. As shown in Figure 1, the XRD peaks match well with Fe3O4,
which is in agreement with work done by Wei et al [23]. This fact indicates that the crystalline
structure of Fe3O4 MNPs is conserved after the surface modification with EDTA (XRD pattern
of Fe3O4@EDTA). The results indicate that the resultant particles are Fe3O4 with a spinel
structure. Also, the six peaks of the Fe3O4 could be seen for the synthesized Fe3O4@EDTA@-
Cu (II) (XRD pattern of Fe3O4@EDTA- Cu (II)). Additional diffraction peaks at around 16°,
17°, 31.6°, 40° and 46° are related to Cu2Cl (OH)3[24]. The diffraction patterns showed that
Cu2Cl (OH)3 crystallized into an orthorhombic cell. The peak positions of Fe3O4 are unchanged
during the production of Fe3O4@ EDTA- Cu (II), indicating that the crystalline structure of the
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magnetite is essentially maintained. The result suggests that Fe3O4@ EDTA- Cu (II) has been
successfully synthesized.
Figure 1: The X-ray diffraction patterns of Fe3O4@EDTA and Fe3O4@EDTA- Cu (II)
FT-IR spectra (Infrared Spectroscopy);
The FTIR spectra of Fe3O4, Fe3O4 coated with EDTA and assembly of magnetic nanoparticles
and complex of EDTA with Cu salt are depicted in Fig. 2. A characteristic band ascribed to the
Fe-O stretching vibration appeared at 561 cm-1 for the bare magnetic nanoparticles. The C-H
stretch of Fe3O4@EDTA (2800-2900) cm-1 was stronger than that of Fe3O4@EDTA- Cu (II) and
demonstrated that Cu interacts with the EDTA and weakens the C-H vibration. Broad band with
its shoulder at 566 cm-1 assigned to the formation of COO-Cu complex. Comparing C=O
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vibration in the FT-IR spectra of Fe3O4@EDTA at 1629 cm-1 with Fe3O4@EDTA- Cu (II) at
1606 cm-1 proved formation of the complex.
Figure 2:The FT-IR spectra of the Fe3O4(a), Fe3O4@EDTA(b), and Fe3O4@EDTA- Cu (II) (c)
TG/DTA (Thermo-Gravimetric/Differential Thermal Analyses);
The amount of the Cu(II)-EDTA complex supported on magnetic nanoparticles was estimated by
using Thermogravimetric/Differential Thermal Analyses (TG/DTA) (Fig. 3). The Cu complex
exhibits thermal stability up to 200 ºC, which confirms that this complex does not contain water
[25]. The second step within the temperature range 200-300 ºC was associated with an
exothermic DTA peak at this range. There were two peaks accompanied by mass loss of 4.5% at
the temperature range of 200–300°C in the DTA curve. The first peak was due to the partial
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decomposition of the ligand. The final decomposition step appeared above 280 ºC corresponding
to the complete thermal decomposition of the complexes and the loss of their organic portion.
From the change of weight percentage in the TGA curve, it can be estimated that the actual
EDTA content bounded on MNPs is about 0.15 mmol/g. The TGA curve of MNPs-EDTA
remains unchanged above 300 °C, implying that iron oxide is present in this temperature range
[19] and the weight loss pattern of Fe3O4@EDTA- Cu (II) up to about 600 oC corresponds to the
formation of copper oxide. Aggregated particles have been generated by thermal decomposition
of Fe3O4@EDTA- Cu (II). The final product upon calcination of Fe3O4@EDTA- Cu (II) is,
based on their XRD pattern, Fe2O3@CuO. No characteristic peaks of impurities are detected in
the XRD pattern. Through the inductively coupled plasma atomic emission spectroscopy (ICP-
AES), the Cu loading for Fe3O4@EDTA- Cu (II) was found to be 0.4 mmol per gram. The TGA
curve and ICP-AES analysis confirmed the high level coating of the Cu (II)-EDTA complex on
the magnetic nanoparticles.
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≈ 4.5 %
≈ 7 %
Figure 3: Thermogravimetric and Differential Thermogravimetric of Fe3O4@EDTA- Cu (II)
SEM (Scanning Electron Microscopy);
We investigated the morphology, size and structure of nano Fe3O4@EDTA (a) and
Fe3O4@EDTA- Cu (II) (b) using scanning electron microscopy (Fig. 4).
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Figure 4: SEM analysis of the Fe3O4@EDTA (up) and Fe3O4@EDTA- Cu (II) (down)
SEM indicated that the synthetic Fe3O4@EDTA and Fe3O4@EDTA- Cu (II) presented uniform
nanoparticles. A typical way to show the particle size and its distribution is in the form of a
number-frequency histogram. Histograms obtained from 100 nanoparticles illustrate the
frequency of occurrence versus the size range, the average particle size of
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Fe3O4@EDTA (44 nm±11) and Fe3O4@EDTA- Cu (II) (28 nm±6) were obtained (Fig. 5).
Figure 5: Histograms generated from the sizes of the Fe3O4@EDTA (red)
Fe3O4@EDTA- Cu (II) (grey) using the SEM images
VSM (Vibrational Sample Magnetometry);
The magnetic possession of the Fe3O4@EDTA- Cu (II) was studied by vibrating sample
magnetometry (VSM). Magnetizing (emu/g) as a function of applied field (Oe) depicted in
(Fig. 6) with the confined field from −10000 to 10000 Oe. Bare nanocrystals of Fe3O4 possessed
high saturation magnetization 73.7 emu/g at room temperature [26] and decreased to 57.0 emu/g
for Fe3O4@EDTA- Cu (II). The formation of the magnetite core and the EDTA coating takes
place simultaneously; therefore the interference of the EDTA in the crystallization step of iron
oxide nanoparticles, Fe3O4@EDTA had lower magnetization as compared with that of bare
Fe3O4.
Zero remanence and coercivity of the magnetization curve demonstrate that these nanoparticles
have superparamagnetic properties. Saturation magnetization decreases as the particle size is
reduced due to enhancement of the surface spin effects and as particle size decreases the
coercivity vanishes and becomes superparamagnetic state. The Fe3O4@EDTA- Cu (II) dispersed
in solvent and external magnetic field can immediately gather nanoparticles, then with slight
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shaking they can be promptly re-dispersed, the results showing that the particles display good
magnetic characteristics and can be applied as magnetic catalyst.
60
40
20
0
-20
-40
-60
-10000 -8000 -6000 -4000 -2000
0
2000 4000 6000 8000 10000
Applied Field(Oe)
Figure 6: Magnetization curve of the Fe3O4@EDTA- Cu (II)
The use of hydrochloric salts of amines and calcium carbonate as a base was necessary for the
efficient amidation of benzyl-alcohol derivatives. Bantreil had demonstrated fast oxidation of the
amine or coordination of amine to the metal interfered in the reaction [17]. Surprisingly in the
presence of K2CO3 as base, aldehyde was only product after 4h (80 %) and 20% of preliminary
benzyl alcohol was unreacted, amide was not observed at all. K2CO3 stopped the amidation
reaction (Table 1, entry 7). The reaction was completed in under 4h and only a small amount of
acid had been formed. The reaction of hydrochloric salts of benzylamine and benzyl alcohol was
nominated as our model reaction to optimize amidation conditions. The reaction showed strong
dependence upon oxidant. Among the oxidants used (Table 1, entries 6, 9, 10), TBHP was
demonstrated to be appropriate (Table 1, entry 6) and was superior to H2O2 and UHP.
Subsequently, the temperature role was investigated. Notably, the conversion of benzamide was
up to 76 %from 52% when the reaction temperature was increased to 80°C from 60°C. We found
that 80°C gave the best result (Table 1, entries 3, 4). Raising the reaction temperature doesn’t
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improve the yield so the temperatures higher than 80oC disfavoured for the reaction. The reaction
was carried out in the presence of 10 and 20 mg of catalyst at the same conditions, separately, in
which resulted a serious improvement of the capitulate (Table 1, entries 4 and 6). Acetonitrile
improved the yield compare of the DMF and DMSO. Also the reaction in the presence of Fe3O4
and Fe3O4@EDTA without Cu was investigated. This observation proved Cu to be essential for
the reaction. Accordingly, the optimum conditions were the following: benzyl alcohol (1.5
equiv), hydrochloric salts of amines (1 equiv), CaCO3 (1.1 equiv), 4 equiv TBHP (70 wt % in
H2O) in MeCN (1 mL) at 80oC by using of Fe3O4@EDTA- Cu (II) (20 mg, 1.6 mol% Cu2+) for 4
h.
Table 1. Optimization of the reaction conditions
Entry
Solvent
Oxidant
Base
Catalyst
(mg)
Temp. ( °C)
Conversion (%)
a
b
-
CH3CN
CH3CN
TBHP
TBHP
CaCO3
CaCO3
10
10
25
40
10
18
1
2
<5
CH3CN
CH3CN
TBHP
TBHP
CaCO3
CaCO3
10
10
60
80
52
76
15
20
3
4
CH3CN
TBHP
CaCO3
10
100
65
20
5
6
CH3CN
TBHP
CaCO3
20
80
93
<5
CH3CN
CH3CN
TBHP
-
K2CO3
CaCO3
20
20
80
80
-
-
35
-
7
8
CH3CN
CH3CN
H2O2
UHP
CaCO3
CaCO3
20
20
80
80
24
18
40
30
9
10
DMF
TBHP
TBHP
CaCO3
CaCO3
20
20
80
80
42
63
25
15
11
12
DMSO
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Reaction conditions: benzyl alcohol (1.5 eq), hydrochloric salt of benzylamine (1 eq) solvent (1 mL), base
(1.1 eq), oxidant (4 eq), in the presence of Fe3O4@EDTA- Cu (II) (mg), 4 h
TBHP: tert-Butyl hydroperoxide
H2O2: Hydrogen peroxide
UHP: Hydrogen peroxide - urea
Subsequently, the scope of the present Fe3O4@EDTA- Cu (II) catalyst with regard to a series of
secondary and tertiary amides was examined. Fe3O4@EDTA- Cu (II) showed high catalytic
activity for this transformation. As can be seen in Scheme 3, aliphatic amines were converted
into their corresponding amides in moderate to good yield. Notably, no oxidation was observed
on the alcohol functional group in 1l. The reaction is compatible with a series of primary and
secondary amines and both aromatic and aliphatic amines. The reaction is also compatible with
amino acids (1f, 2r). The desired pure products were characterized by comparison of their
physical data with those of known compounds. Nevertheless, imidazole hydrochloride salt failed
to produce the desired product and provided 98 % benzaldehyde in the short time as only
product. The colour of the reaction mixture changed to blue. Imidazole as an external component
could extract Cu from EDTA. This observation was confirmed when recovered magnetic catalyst
in this run couldn't convert benzyl alcohol to respective amide subsequently. Thus imidazole
could cause change in the structure of catalyst. Also, electron-donating or electron-withdrawing
substituents on benzylalcohol produced good to excellent yields of secondary amides, indicating
that the reaction is not sensitive to electronic effects.
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Scheme 3: Synthesis of amide derivatives (primary amine (1a-1l) and (secondary amine (2m-2t))
Yield of the isolated products are given
We observed that Fe3O4@EDTA- Cu (II) was reasonably active and selective for the direct
oxidative amidation of benzyl alcohol with benzyl amine (Fig. 7). Carbon balance (>95 mol %)
was within accepted limit.
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Figure 7: Catalytic results for the oxidative amidation of benzyl alcohol with benzyl amine
The proposed mechanism for this direct oxidative amidation was shown in Scheme 4. In the first
step in the presence of active catalyst and TBHP produced benzaldehyde and tert-butanol.
Aldehyde as an intermediate apparently was recognized in this reaction. The active copper was
regenerated in the reaction and went to second step. According to previous proposed mechanism
in the presence of Cu, hemiaminal was produced as an intermediate [17]. Benzaldehyde was
reacted with amine hydrochloride salt to yield amide much less than one hour in the presence of
CaCO3 and TBHP. If the catalyst was removed by external magnet in this step, the reaction
continued only 5 %. Thus, copper acts as an important factor also in this step. Oxidation of
benzyl alcohols to aldehydes was slower than the amidation of the aldehydes.
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Scheme 4: Proposed mechanism for the direct oxidative amidation in the presence of
Fe3O4@EDTA- Cu (II) as catalyst
Reusability of the catalyst was evaluated in the synthesis of N-benzylbenzamide (Fig. 8).After
completing the reaction; the catalyst was removed by an external magnet, washed with methanol
and dried for reuse. Fe3O4@EDTA- Cu (II) was recycled 6 times in the amidation reaction
without significant loss of its activity. To rule out any contribution of homogeneous catalysis, we
tested the reaction leakage. After 10 min from the beginning of the reaction and removal of
catalyst by magnet, no formation of aldehyde was observed, even after 24h. This clearly
confirmed that active species were not floated in the solvent.
Figure 8: Activity lost as a function of the number of reused times of the Fe3O4@EDTA- Cu (II)
MNPs for the synthesis of N-benzylbenzamide (reaction times: 4 h)
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4.
Conclusion
In summary, a heterogeneous Cu catalyst has been developed by supporting Cu (II) onto the
Fe3O4@EDTA. This catalyst exhibited impressive catalytic capacity to synthesis of benzamide
derivatives. This reaction was accomplished using benzyl alcohols and various primary and
secondary amines as their hydrochloride salts. Fe3O4@EDTA- Cu(II) can be used for at least six
consecutive runs without significant loss of its catalytic activity. It has the advantage of being
magnetically recoverable, therefore removing the requirement for catalyst filtration after the
reaction.
Acknowledgements
We acknowledge Tarbiat Modares University for partial support of this work.
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Direct Oxidative Amidation of Benzyl Alcohols Using EDTA@Cu (II)
Functionalized Superparamagnetic Nanoparticles
22
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Highlights
Direct oxidative amidation in the presence of a magnetic catalyst  
An effective protocol for a waste-minimized, environmentally  
benign approach for amidation
High catalytic activity of Fe3O4@EDTA- Cu (II) and convenient  
recovery without loss of its activity
Atom-economical
amidation
in
the
presence
of
 
Fe3O4@EDTA- Cu (II)
Fe3O4@EDTA- Cu (II) as an environmentally friendly  
heterogeneous catalyst
[27]
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