Direct oxidative esterification of toluene with 1,3-dicarbonyl compounds catalysed by copper complex supported on magnetic nanoparticles

Article abstract of DOI:10.1002/aoc.3658

Toluene oxidation is one of the substantial industrial technologies since oxidized products are industrially very important intermediates. A Fe₃O₄@cysteine@Cu-catalysed reaction that uses tert-butyl hydroperoxide as oxidant to produce esters from toluene and β-diketones or β-keto esters, enolate precursors, has been developed. Oxidative esterification of toluene with 1,3-dicarbonyl derivatives led to C─O bond formation and direct C─H functionalization.

Full text of DOI:10.1002/aoc.3658

Received: 19 August 2016
DOI 10.1002/aoc.3658
Revised: 9 September 2016
Accepted: 19 September 2016
F U L L PA P E R
Direct oxidative esterification of toluene with 1,3‐dicarbonyl
compounds catalysed by copper complex supported on magnetic
nanoparticles
Kobra Azizi | Naghmeh Esfandiary | Meghdad Karimi | Maryam Kazemi | Akbar Heydari
Chemistry Department, Tarbiat Modares
Toluene oxidation is one of the substantial industrial technologies since oxidized
products are industrially very important intermediates. A Fe3O4@cysteine@Cu‐
catalysed reaction that uses tert‐butyl hydroperoxide as oxidant to produce esters
from toluene and β‐diketones or β‐keto esters, enolate precursors, has been
developed. Oxidative esterification of toluene with 1,3‐dicarbonyl derivatives led
to C─O bond formation and direct C─H functionalization.
University, PO Box 14155‐4838, Tehran, Iran
Correspondence
Akbar Heydari, Chemistry Department, Tarbiat
Modares University, PO Box 14155‐4838, Tehran,
Iran.
Email: heydar_a@modares.ac.ir
Funding information
Tarbiat Modares University
KEYWORDS
esterification, magnetic, nanoparticles, oxidation, toluene
1
|
INTRODUCTION
Volatile organic compounds can lead to serious environ-
mental problems. Catalytic oxidation is an effective way for
reducing the distribution of these compounds.[10]
The ester moiety is among the most abundant functional
groups in natural products, polymers, fine chemicals, bulk
chemicals and pharmaceuticals.[1] Traditionally, esters are
often prepared by the nucleophilic addition of an alcohol to
activated carboxylic acid derivatives such as acid anhydrides
or chlorides.[2] Further efforts have been devoted to the direct
synthesis of esters using Steglich esterification,[3] Mitsunobu
reaction[4] and Baeyer–Villiger oxidation.[5] However,
because of several reaction steps, production of unwanted
by‐products, poor atom economy and difficulty of product
isolation in all of the above three methods, it is one of the
challenges of green and sustainable chemistry to update these
old processes.
Toluene as the simplest member of the alkyl aromatics is
one of the inactive row materials that can be oxidized to
benzyl alcohol, benzaldehyde, benzoic acid and benzyl
benzoate. Khan et al. reported the benzylation of aromatic
carboxylic acids with toluene in the presence of NaBrO3/
NaHSO3.[11] After the pioneering work reported by Fu and
co‐workers where Bu4NI was used for oxidative esterification
of alcohols with toluene,[12] subsequently, Zhang and co‐
workers described Pd(II)‐catalysed benzylation of carboxylic
acids with toluene.[13] In 2012, ZhiPing and co‐workers
reported oxidative C─C bond formation from benzylation
of 1,3‐dicarbonyl compounds with simple toluene deriva-
tives. Fe‐activated 1,3‐dicarbonyl compound and reduced
peroxide thus improved hydrogen abstraction from the ben-
zylic C─H bond.[14]
This motivated us to repeat the reaction in the pres-
ence of a magnetic catalyst and we found that this catalyst
could construct C─O bonds through oxidative coupling of
toluene with 1,3‐dicarbonyl compounds. Heating a mixture
of methylacetoacetate, 4 eq. of oxidant tert‐butyl hydroper-
oxide (TBHP; 70% aqueous solution) and 10 mg of cata-
lyst in toluene gave 25% yield of enol ester and no
benzylation of 1,3‐dicarbonyl compound product
(Scheme 1).
The selective oxidation of C─H bonds is of fundamental
and technological importance, from biological and industrial
chemistry viewpoints.[6] C─H bonds are omnipresent in
nature and thus the capability for selective C─H bond
functionalization is of considerable interest to chemists.[7]
A
rapidly increasing number of new organic reactions based
on C─H cleavage have been developed.[1] Many of new bond
have been formed through this efficient way, including car-
bon–carbon[2] and carbon–heteroatom[3] bond formation.[8]
One of the crucial methods of activation for passive row
material is selective oxidation of primary carbon–hydrogen
bonds to form intermediates and final products.[9]
Appl Organometal Chem 2016; 1-7
wileyonlinelibrary.com/journal/aoc
Copyright © 2016 John Wiley & Sons, Ltd.
1

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AZIZI ET AL.
linkage of the amino acid to a magnetite support and the
amino and thiol side chains render it suitable to serve as a
complexing agent for most of transition metal ions. Among
transition metals, copper is of considerable interest. It is found
normally with oxidation states of +1 or +2 which can be sta-
bilized depending on the nature of ligands, counter ion and
solvent. So interconversion of these oxidation states makes
copper suitable to serve as a catalyst for oxidation reactions.
Furthermore, copper shows advantages of being cost effective
and comparatively safe for biological organisms.
SCHEME 1 Oxidative coupling of toluene with 1,3‐dicarbonyl compounds
In extension to our recent work,[21] we have now prepared
a new catalyst consisting of a Cys–copper acetate complex
supported on magnetic nanoparticles (NPs). This catalyst is
very effective and has several advantages such as being cost
effective, high yielding, involving shorter reaction times, no
by‐product formation and most importantly its easy usage
with negligible reduction in catalytic activity.
A major advantage of the direct oxidative esterification of
toluene approach is that it provides efficient fast access to
enol esters under mild conditions, while isolation of the cata-
lyst is also easy.
Modification of a magnetic surface with Cys is an
effective method to increase the catalytic activity of Cu in
the oxidation of toluene. The conversion was improved when
Cu was complexed with Cys. This organic modification
strategy of magnetic NPs could also be useful for easy sepa-
ration of catalyst from reaction mixture.
Yoo and Li reported CuBr‐catalysed oxidative esterifica-
tion of aldehydes with β‐dicarbonyl compounds.[15] Although
direct transformations of aldehydes into esters have been
reported, a one‐pot procedure that integrates oxidation of tol-
uene and CO bond formation into a single operation has not
been published. Examples of oxidative coupling are shown
in Scheme 2.
Recently,wehavedescribedahypervalentiodine‐catalysed
oxidative amidation in which the sp3‐hybridized C─H
bond was oxidized adjacent to an amine in the presence of
oxidant which then can be functionalized with a variety of
heteroatoms.[16] We found that toluene undergoes
stereoselective transformation to enol esters in the presence of
a1,3‐dicarbonylcompound,20mol%ofFe3O4@cysteine@Cu
and 4 eq. of TBHP.
Heterogeneous catalysts are usually preferred over homo-
geneous catalysts; in addition to easily separation from a
reaction mixture, heterogeneous catalysts can be used in flow
reactors.[17] To oxidize toluene, copper‐based binary metal
oxides,[18] phenyl modification of Mn‐containing mesopo-
rous silica,[19] CoSBA‐15[20] and Au–Pd alloy nanoparti-
cles[9] have been used to find a most suitable oxidation
catalyst but all of these showed low turnover numbers.
L‐Cysteine (Cys) is a semi‐essential α‐amino acid with a
thiol side chain. Its carboxylic acid group facilitates the easy
2
| RESULTS AND DISCUSSION
The prepared heterogeneous catalyst was characterized using
Fourier transform infrared (FT‐IR) spectroscopy, scanning
electron microscopy (SEM), powder X‐ray diffraction
(XRD), thermogravimetric/differential thermal analysis (TG/
DTA), vibrating sample magnetometry (VSM), inductively
coupled plasma atomic emission spectroscopy and energy‐
dispersive X‐ray (EDX) analysis.
The crystalline structure of Fe3O4@Cys@Cu NPs and
phase purity were determined using powder XRD as shown
in Figure 1. The XRD pattern of magnetic NPs is indexed
to the spinel phases of iron oxide and six peaks
(2θ = 30.1°, 35.5°, 43.2°, 53.5°, 57.0° and 62.8°) are related
to their corresponding indices (220), (311), (400), (422),
(511) and (440), respectively.
For investigating the surface, morphology and size of
NPs, we used SEM. The resulting image (Figure 2) shows
uniform and minuscule NPs. The approximate size of the
particles is determined to be about 30–50 nm.
The TG technique is very helpful to understand the
degradation temperatures, moisture content and percentage
of inorganic and organic components in a material. Figure 3
shows the TG analysis of Fe3O4@Cys@Cu NPs, indicating
that around 7.5% of the Cys gets disintegrated between 200
and 500 °C. The weight loss of the NPs below 200 °C can
SCHEME 2 Representative oxidative coupling of arylmethane with ketones

AZIZI ET AL.
3
FIGURE 4 EDX pattern of Fe3O4@Cys@Cu NPs
depicts no other peaks except those for Fe3O4@Cys@Cu
NPs (Fe, Cu, S, C, N, O) indicating the high purity of
thecomposite. The results of this analysis for the
Fe3O4@Cys@Cu NPs are summarized in Table 1. The ele-
mental compositions of magnetic Fe3O4@Cys@Cu NPs are
(%): 0.43 (C), 0.20 (N), 4.24 (O), 0.53 (S), 1.22 (Cu) and
93.38 (Fe) (Table 1). This implies that Cys@Cu complex is
on the surface of Fe3O4 NPs.
FIGURE 1 XRD pattern of Fe3O4@Cys@Cu NPs
Bare nanocrystals of Fe3O4 have high saturation magneti-
zation of 73.7 emu g−1 at room temperature.[24] The result of
VSM (Figure 5) shows that the saturation magnetization
value of Fe3O4@Cys@Cu (55 emu g−1) is lower than that
of Fe3O4 NPs due to the coating of the Cys@Cu complex.
The FT‐IR spectra of magnetic NPs (Fe3O4), Cys and
magnetic NPs coated by Cys (Fe3O4@Cys) are shown in
TABLE 1 Weight percent of various elements on the surface of
Fe3O4@Cys@Cu NPs from EDX analysis
FIGURE 2 SEM image Fe3O4@Cys@Cu NPs
Element
Line
Intensity
Wt%
C
Ka
Ka
Ka
Ka
Ka
La
28.2
14.6
0.43
N
0.20
O
820.2
131.2
2167.3
72.1
4.24
0.53
S
Fe
Cu
93.38
1.22 (0.31 mmol g−1
)
100.00
FIGURE 3 TG/DTA of Fe3O4@Cys@Cu NPs
be assigned to the release of physically adsorbed solvent and
organic groups.
In order to deduce the composition of the NPs, EDX
analysis was carried out (Figure 4). The EDX spectrum
FIGURE 5 Magnetization curve of Fe3O4@Cys@Cu NPs

4
AZIZI ET AL.
Figure6.TheFT‐IRspectrumofCysischaracterizedbythefol-
lowing absorption bands: NH2 and OH arising at 3431 cm−1 as
a broad band and carbonyl group at 1739 cm−1. Compared
with the FT‐IR spectrum of Fe3O4, the presence of Cys covers
the vibration of Fe3O4. The band shift of the C═O bending
vibration from 1739 to 1705 cm−1 is significant. This phe-
nomenon indicates that the O from CO coordinates with Fe
on the surface of the magnetite nanocrystals. The spectrum
of the Fe3O4@Cys@Cu catalyst shows a characteristic band
at 1630 cm−1 (C═O) and a broad band with a shoulder at
569 cm−1 is assigned to the formation of Cu complex.
2.1 | Catalytic performance
We began our study with selective toluene oxidation in the
presence of Cu(OAc)2. Although Cu(OAc)2 led to aldehyde
(35%) using TBHP as oxidant, interestingly, the conversion
was improved when Fe3O4@Cys‐Cu(OAc)2 was used in the
reaction (52%). While this procedure has been demonstrated
to be useful for toluene oxidation to aldehyde, it could be
used for coupling reactions.
In an initial attempt, the reaction of toluene (3 ml) and
methylacetoacetate (1 mmol) in the presence of heteroge-
neous catalyst (10 mg) with TBHP as oxidant (30% in water,
4 eq.) was performed at 80 °C. Enol ester was produced in
low yield (25%). Key results of optimization of conditions
are summarized in Table 2. Evaluation was initially examined
with toluene and 1,3‐dicarbonyl as starting materials, with a
series of oxidants such as TBHP, H2O2 and m‐
chloroperoxybenzoic acid (mCPBA) and solvents like
dimethylsulfoxide (DMSO), acetonitrile, tetrahydrofuran
(THF) and dioxane. The results show that mixed solvent ace-
tonitrile–toluene (4:1 v/v) is effective in increasing the yield.
No reaction occurs in the absence of oxidant and only 10%
yield of enol ester is observed using TBHP without catalyst
(Table 2, entries 17 and 18). Subsequently, the role of temper-
ature was investigated. We find that 100 °C gives the best
result for this reaction. Control experiments indicate that ace-
tonitrile–toluene solvent and TBHP as oxidant are essential
for achieving a high level of transformation (Table 2, entry
14). In the next step, the amount of catalyst was also opti-
mized. Indeed, desired product is formed in the presence of
FIGURE 6 FT‐IR spectra
TABLE 2 Optimization of reaction conditions
Entry
Catalyst amount (mg)
Oxidant
Solvent
Temp. (°C)
Yield (%)
1
2
10
10
10
10
10
10
10
10
10
10
10
10
5
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
mCPBA
H2O2
Toluene
80
80
25
25
5
THF–toluene (4/1)
3
DMSO–toluene (4/1)
80
4
Dioxane–toluene (4/1)
80
20
40
5
5
Acetonitrile–toluene (4/1)
Acetonitrile–toluene (4/1)
Acetonitrile–toluene (4/1)
Acetonitrile–toluene (4/1)
Acetonitrile–toluene (4/1)
Acetonitrile–toluene (4/1)
Acetonitrile–toluene (4/1)
Acetonitrile–toluene (4/1)
Acetonitrile–toluene (4/1)
Acetonitrile–toluene (4/1)
Acetonitrile–toluene (4/1)
Acetonitrile–toluene (4/1)
Acetonitrile–toluene (4/1)
Acetonitrile–toluene (4/1)
80
6
25
7
40
20
35
60
10
25
35
15
65
75
75
<10
ND
8
60
9
100
100
100
100
100
100
100
100
100
100
10
11
12
13
14
15
16
17
18
UHP
TBHP
TBHP
TBHP
TBHP
TBHP
—
15
20
25
—
10

AZIZI ET AL.
5
With optimal conditions in hand, we investigated the
scope of 1,3‐dicarbonyls (Scheme 3). Oxidative esterification
using dimedone was not successful, while enol ester was pro-
duced when 2,4‐pentanedione as another cyclic β‐diketone
was used, showing moderate yield.
To probe the details of the mechanism, a series of control
experiments were designed and performed. When using
hydroquinone as a radical scavenger, the reaction is
completely inhibited. As outlined in Scheme 4, the suggested
esterification reaction occurs through a sequential oxidation:
(1) oxidation of toluene to alcohol; (2) oxidation of alcohol
to aldehyde; (3) oxidative coupling of aldehyde with 1,3‐
dicarbonyl compound (Scheme 4).
The reusability of the catalyst was also evaluated. After
accomplishing the reaction, the superparamagnetic
nanocatalyst was separated from the medium with application
of an external magnet, then washed and dried under vacuum
at room temperature for 12 h, and used for the next reaction.
The catalyst could be reused at least six times without any
significant loss of the catalytic activity (Figure 7). Also, there
is no change in the structure of the catalyst after the reaction:
all of the observed XRD peaks are the same as the recorded
pattern of primary catalyst (Figure 8).
SCHEME 3 Scope of reaction with respect to dicarbonyl compound
substrates
20 mg of catalyst (Table 2, entry 15). Thus the optimal reac-
tion conditions are considered to include toluene (3 ml), ace-
tonitrile (1 ml), 1,3‐dicarbonyl (1 mmol) and TBHP (4 mmol)
at 100 °C for 24 h.
3
| EXPERIMENTAL
All purchased solvents and chemicals were of analytical
grade and used without further purification. FT‐IR spectra
SCHEME 4 Proposed mechanism

6
AZIZI ET AL.
gradient force magnetometer (MDK Co., Iran, www.mdk‐
magnetic.com). TG/DTA was performed using a thermal
analyser with a heating rate of 20 °C min−1 over a tempera-
ture range of 25–1100 °C under flowing compressed
nitrogen.
3.1 | Synthesis of magnetic catalyst
3.1.1
| Preparation of Fe3O4 coated with Cys
Amounts of 5 mmol of FeCl3⋅6H2O and 2.5 mmol of
FeCl2⋅4H2O salts were dissolved in 100 ml of deionized
water under vigorous stirring. Then 30 ml of NH4OH
solution (25%, w/w) and Cys (1 mmol) were added to the
mixture until the pH was raised to 11 at which a black
suspension was formed, followed by refluxing for 24 h. The
residue was collected using a magnet, and washed several
times with water and then ethanol to obtain Fe3O4@Cys.
FIGURE 7 Activity lost as a function of number of reuse cycles of the
catalyst
3.1.2
| Immobilization of Fe3O4@Cys@Cu
An amount of 2 mmol of Cu(OAc)2⋅2H2O in 50 ml of water
was added to Fe3O4@Cys NPs and stirred at room tempera-
ture for 24 h (Scheme 5). Finally, NPs were separated from
the aqueous solution by magnetic decantation, washed with
water and ethanol several times before being dried in an oven
overnight.
3.2 | General procedure for oxidative esterification
catalysed by Fe3O4@Cy@Cu(II)
FIGURE 8 XRD pattern of reused catalyst after sixth run
were obtained over the range 400–4000 cm−1 with Nicolet
IR100 FT‐IR with spectroscopic grade KBr. Powder XRD
patterns were recorded at room temperature with a Philips
X‐Pert 1710 diffractometer using Co Kα (λ = 1.78897 Å)
at 40 kV and 40 mA. The data were collected from 10° to
90° (2θ) with a scan speed of 0.02° s−1. The morphology of
the catalyst was studied using SEM (Philips XL 30 and
S‐4160) with gold coating equipped with EDX facility. The
magnetic properties of the Fe3O4@Cys@Cu NPs were
measured with a vibrating sample magnetometer/alternating
To a mixture of catalyst (20 mol%) and 3 ml of toluene was
added TBHP (2 mmol) as the oxidant. The mixture was
magnetically stirred for 4 h at 100 °C. Then 1,3‐dicarbonyl
(1 mmol) and TBHP (70 wt% in water, 2 mmol) were added.
The progress of the reaction was monitored by TLC. After
the completion of the reaction, the catalyst was separated
using an external magnet. Then, HCl (1 N, 5 ml) and EtOAc
(5 ml) were added to the residual mixture and washed with
NaHCO3 (10 ml) and brine and dried over anhydrous
Na2SO4. The organic layer was concentrated under reduced
SCHEME 5 Preparation of Fe3O4@Cys@Cu(II) catalyst

AZIZI ET AL.
7
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4
| CONCLUSIONS
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Rahman, Tetrahedron 2003, 59, 5549.
A robust and effective Fe3O4@Cys@Cu(II) catalyst for
oxidative esterification of a variety of 1,3‐dicarbonyls was
discovered and studied. When TBHP was used as an oxidant,
oxidative esterification can be carried out to afford desired
products in good yields. So, we have reported this new
catalyst system which proves to be very effective.
It involves a simple procedure and is environmentally
friendly and also incorporates special features like reagent
economy, easy work‐up and easy handling. Recovery of the
catalyst was simple using an external magnet, allowing its
reuse without significant loss of its catalytic activity (over
six cycles).
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ACKNOWLEDGMENTS
We are grateful to Tarbiat Modares University and National
Elite Foundation of IR Iran for partial support of this work.
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Direct oxidative esterification of toluene with 1,3‐
dicarbonyl compounds catalysed by copper complex
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