Selective oxidation of pseudocumene and 2-methylnaphthalene with aqueous hydrogen peroxide catalyzed by γ-Keggin divanadium-substituted polyoxotungstate

Article abstract of DOI:10.1016/j.jorganchem.2015.04.020

The catalytic performance of a γ-Keggin divanadium-substituted phosphotungstate, (Bu₄N)₄[γ-PW₁₀O₃₈V₂(μ-O)(μ-OH)], has been evaluated in the selective oxidation of 1,2,4-trimethylbenzene (pseudocumene, PC) and 2-methylnaphthalene with the green oxidant, 35% aqueous hydrogen peroxide. Under conditions of H₂O₂ deficiency ([PC]/[H₂O₂] = 17-22), PC oxidation proceeded with unusually high chemo- and regioselectivity, producing exclusively 2,4,5-trimethylphenol (2,4,5-TMP) and 2,3,5-TMP in a molar ratio of 7.3/1 and a yield of 73% based on the oxidant. Isomeric 2,3,6-trimethylphenol was found in trace amounts. Under conditions of H₂O₂ excess ([H₂O₂]/[PC] = 8), 2,3,5-trimethyl-1,4-benzoquinone (TMBQ, vitamin E key intermediate) formed with 41% selectivity at 41% substrate conversion. Atypical regioselectivity was also found in the oxidation of 2-methylnaphthalene which gave predominantly 6-methyl-1,4-naphthoquinone (6-MNQ) rather than isomeric 2-MNQ. The ratio between the isomers could be altered by varying the catalyst and oxidant amounts.

Full text of DOI:10.1016/j.jorganchem.2015.04.020

Accepted Manuscript
Selective oxidation of pseudocumene and 2-methylnaphthalene with aqueous
hydrogen peroxide catalyzed by γ-Keggin di-vanadium-substituted polyoxotungstate
Olga V. Zalomaeva, Vasiliy Yu. Evtushok, Gennadii M. Maksimov, Oxana A.
Kholdeeva
PII:
S0022-328X(15)00221-1
10.1016/j.jorganchem.2015.04.020
JOM 19006
DOI:
Reference:
To appear in: Journal of Organometallic Chemistry
Received Date: 30 December 2014
Revised Date: 6 April 2015
Accepted Date: 7 April 2015
Please cite this article as: O.V. Zalomaeva, V.Y. Evtushok, G.M. Maksimov, O.A. Kholdeeva, Selective
oxidation of pseudocumene and 2-methylnaphthalene with aqueous hydrogen peroxide catalyzed by
γ-Keggin di-vanadium-substituted polyoxotungstate, Journal of Organometallic Chemistry (2015), doi:
10.1016/j.jorganchem.2015.04.020.
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ACCEPTED MANUSCRIPT
The divanadium-substituted phosphotungstate (Bu4N)4[γ-PW10O38V2(ꢀ-O)(ꢀ-OH)] catalyzes
aromatic oxidation of pseudocumene and 2-methylnaphthalene with H2O2 demonstrating unusual
regioselectivity.

ACCEPTED MANUSCRIPT

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Selective oxidation of pseudocumene and 2-methylnaphthalene
with aqueous hydrogen peroxide catalyzed by γ-Keggin di-
vanadium-substituted polyoxotungstate
Olga V. Zalomaevaa, Vasiliy Yu. Evtushoka,b, Gennadii M. Maksimova, Oxana A.
Kholdeevaa,b
a Boreskov Institute of Catalysis, Pr. Ac. Lavrentieva 5, Novosibirsk 630090, Russia.
E-mail: khold@catalysis.ru
b Novosibirsk State University, Pirogova str. 2, Novosibirsk 630090, Russia
This paper is dedicated to the memory of Aleksandr Evgenievich Shilov (1930-2014).
Abstract
The catalytic performance of a γ-Keggin divanadium-substituted phosphotungstate,
(Bu4N)4[γ-PW10O38V2(ꢀ-O)(ꢀ-OH)], has been evaluated in the selective oxidation of 1,2,4-
trimethylbenzene (pseudocumene, PC) and 2-methylnaphthalene with the green oxidant, 35%
aqueous hydrogen peroxide. Under conditions of H2O2 deficiency ([PC]/[H2O2] = 17–22), PC
oxidation proceeded with unusually high chemo- and regioselectivity, producing exclusively
2,4,5-trimethylphenol (2,4,5-TMP) and 2,3,5-TMP in a molar ratio of 7.3/1 and a yield of 73%
based on the oxidant. Isomeric 2,3,6-trimethylphenol was found in trace amounts. Under
conditions of H2O2 excess ([H2O2]/[PC] = 8), 2,3,5-trimethyl-1,4-benzoquinone (TMBQ,
vitamin E key intermediate) formed with 41% selectivity at 41% substrate conversion.
Atypical regioselectivity was also found in the oxidation of 2-methylnaphthalene which gave

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predominantly 6-methyl-1,4-naphthoquinone (6-MNQ) rather than isomeric 2-MNQ. The
ratio between the isomers could be altered by varying the catalyst and oxidant amounts.
Key words: selective aromatic oxidation, pseudocumene, 2-methylnaphthalene, hydrogen
peroxide, vanadium, homogeneous catalysis
1. Introduction
The selective aromatic oxidation plays a central role in organic synthesis and biological
systems [1, 2]. Phenols are important antioxidants and intermediates in the production of
resins, plastics, fine chemical, and pharmaceuticals [1, 3, 4], while quinones serve as versatile
building blocks of many biologically active compounds [2, 5-7]. The insertion of oxygen atom
into aromatic rings, which are not activated by oxygen-containing electron-donating groups, is
one of the most difficult transformations in the organic synthesis [8-11]. Alkyl substituents,
from one hand, activate the aromatic nuclei toward oxygenation but, from another hand, they
also undergo oxidation, resulting in poor aromatic oxidation selectivity.
Until recently, oxyfunctionalization of arenes was accomplished through multistage
technologies, employing environmentally unfriendly reagents, such as CrO3, MnO2, OsO4,
Pb(OAc)4, Tl(NO3)3, nitric acid, ceric ammonium nitrate (CAN), and others [1, 2, 5, 12].
However, the ever-increasing attention towards the economical and environmental
sustainability is prompting the scientific community to develop chemical processes, which
eliminate the use of hazardous reactants and reduce generation of waste [13-15]. Therefore,
the selective catalytic oxidation of alkylsubstituted arenes to corresponding phenols and
quinones with atom efficient and environmentally benign oxidants (O2, H2O2) is a demanding
task of the modern organic synthesis.

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A
challenging goal is the aromatic oxidation of 1,2,4-trimethylbenzene
(pseudocumene), which is considered as an economically sound way to 2,3,5-trimethyl-1,4-
benzoquinone (vitamin E key intermediate) [16]. TMBQ is currently produced in industry
through oxidation of 2,3,6- and 2,3,5-trimethylphenol (hereinafter, TMP), by-products in the
process of methylation of phenol to 2,6-dimethylphenol [17-19]. The direct aromatic oxidation
of PC has been scarcely described in the literature. Non-catalytic procedures based on the use
of m-chloroperbenzoic acid in CHCl3 [20] and H2O2 in formic acid [21] have been reported.
The yield of TMBQ attained 16.5 and 19%, respectively. Beller and co-workers suggested
oxidation of PC with a 4-fold excess of 50% H2O2 in t-amyl alcohol in the presence of easily
available iron complexes formed upon interaction of FeCl3·6H2O, pyridine-2,6-dicarboxylic
acid, and benzylamine derivatives [17]. However, the yield of TMBQ did not exceed 26% at a
substrate conversion of 69%. For now, the most efficient procedure for the direct oxidation of
PC to TMBQ was reported for the catalytic system that employed methylrhenium trioxide
(MTO, CH3ReO3) as the catalyst and H2O2 as the oxidant [16, 22, 23]. In acetic acid with a
20-fold excess of the oxidant, TMBQ could be obtained with the yield of 50% at 75% PC
conversion [22]. A mild procedure (4-fold excess of H2O2, nitromethane) for the oxidation of
PC based on the use of MTO and neutral amphiphile Brij 30 led to the TMBQ yield 22% at
28% conversion [23].
Several vanadium-based catalytic systems have been reported for the nuclear
hydroxylation of alkylaromatics [24-29]. Recently, Mizuno and co-workers have discovered a
very efficient homogeneous polyoxometalate (POM) catalyst, γ-Keggin divanadium-
substituted phosphotungstate (see Figure 1 for the polyanion structure) (Bu4N)4[γ-
PW10O38V2(ꢀ-O)(ꢀ-OH)] (shortly, γ-PW10V2) for the selective aromatic hydroxylation of a
range of alkylarenes with H2O2 as oxidant [29]. Additives of a mineral acid (HClO4) were
required to activate the catalyst system.

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Figure 1. γ-Keggin divanadium-phosphotungstate (Bu4N)4[γ-PW10O38V2(ꢀ-O)(ꢀ-OH)].
This finding has prompted us to explore the possibility of application of this POM as
catalyst for the H2O2-based selective oxidation of pseudocumene to obtain either TMP or
TMBQ. We also evaluated the catalytic performance of γ-PW10V2 in the selective oxidation of
2-methylnaphthalene (2-MN), another industrially relevant arene substrate that could
potentially lead to 2-methyl-1,4-naphthoquinone (2-MNQ, the so-called menadione or vitamin
K3) [17, 18].
2. Experimental
2.1. Materials
Pseudocumene (97+%) was obtained from Aldrich. 2,3,5-Trimethylphenol (2,3,5-TMP, 98%),
2,3,6-trimethylphenol (2,3,6-TMP, 98%), 2-methylnaphthalene (2-MN, 99%), and 2-methyl-
1,4-naphthoquinone (2-MNQ, 98%) were purchased from Acros. 2,4,5-Trimethylphenol
(2,4,5-TMP, 99%) was purchased from Alfa Aesar. Acetonitrile (Panreac, HPLC grade) was
dried and stored over activated 4 Å molecular sieves. All the other compounds were the best
available reagent grade and used without further purification. The concentration of H2O2 (ca.
35 wt.% in water) was determined iodometrically prior to use.

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2.2. Catalyst preparation and characterization
The cesium salt of the dilacunary phosphotungstate Cs7[γ-PW10O36]·xH2O was synthesized as
described in the literature [30]. Polyoxometalate (Bu4N)4[γ-PW10O38V2(ꢀ-O)(ꢀ-OH)] was
prepared according to the procedure reported by Kamata et al. [31] with some modifications.
NaVO3·2H2O (0.83 g) was dissolved in 50 mL of H2O and the pH of the solution was adjusted
to 0.8 with 3 M HCl. Then Cs7[γ-PW10O36]—xH2O (8 g) was added to the solution and a yellow
precipitate was formed. The mixture was diluted with 150 mL of H2O and slightly heated to
give a yellow solution to which 3 g of TBABr dissolved in water was added. A yellow
precipitate of the TBA-salt was separated, washed with water, and dried at 100 °C. The crude
γ-PW10V2 was purified by precipitation with H2O from a MeCN solution and dried again. Its
spectroscopic characteristics were in accordance with the literature [29, 31]. 51V NMR
(MeCN): -579 ppm. 31P NMR (MeCN): -14.0 ppm. IR (KBr): 1094, 1062, 1039, 953, 875,
806, 704, 533 cm-1.
Polyoxometalate (Bu4N)4[γ-SiW10O38V2(ꢀ-OH)2] (γ-SiW10V2) was synthesized as
described in the literature [32]. 51V NMR (MeCN): -564 ppm. IR (KBr): 1006, 995, 967, 914,
877, 840, 787, 692, 547 cm-1. The number of TBA cations was determined by ignition at
600 oC. Potentiometric titration with TBAOH was used to determine the number of acidic
protons. Heteropolyacid H5PMo10V2O40 was prepared according to the literature [33].
2.3. General procedure for PC oxidation
Catalytic oxidations of PC with H2O2 in the presence of γ-PW10V2 were carried out in
temperature-controlled glass vessels at 30–80 ºC under vigorous stirring (500 rpm). In case of
H2O2 deficiency, concentrations of the reactants were in the range of [PC] = 0.8–2.4, [γ-
PW10V2] = 0.0009–0.0045, [HClO4] = 0.0009–0.0045, and [H2O2] = 0.036–0.180 M. In case
of H2O2 excess, the concentrations were as follows: [PC] = 0.1–0.5, [γ-PW10V2] = 0.0025–

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0.0125, [HClO4] = 0.0025–0.0125, and [H2O2] = 0.8–2 M. Typically, the reactions were
initiated by the addition of H2O2 either in one portion or stepwise to a mixture containing
aromatic substrate, γ-PW10V2 catalyst and HClO4 in 1 mL of a solvent mixture MeCN/t-BuOH
(1:1 v/v). Samples were taken during the reaction course by a syringe and analyzed by GC,
1
1
GC–MS, HPLC and H NMR. Before HPLC and H NMR measurement, the catalyst was
separated by precipitation with diethyl ether; the reaction mixture was concentrated on a
rotary evaporator and then diluted with iPrOH/H2O and CDCl3, respectively.
2.4. General procedure for 2-MN oxidation
Catalytic oxidations of 2-methylnaphthalene with H2O2 in the presence of γ-PW10V2 were
carried out in temperature-controlled glass vessels at 60 ºC under vigorous stirring. The
reaction was initiated by addition of 0.3 mmol of H2O2 to the mixture containing 0.1 mmol of
2-MN, 0.0039 mmol of γ-PW10V2 and HClO4 in 1 mL of MeCN/t-BuOH (1:1 v/v). Samples
were taken during the reaction course by a syringe and analyzed by GC and GC–MS.
2.5. Product analysis
The oxidation products were identified by GC, GC–MS and 1H NMR using authentic samples.
The substrate conversions and product yields were quantified by GC using biphenyl as the
internal standard. Each experiment was reproduced at least two times. The experimental error
in the determination of the substrate conversions and product yields by GC normally did not
exceed 2%. The ratio of 2,3,5- and 2,4,5-TMP isomers, which could not be distinguished by
1
GC, was determined by H NMR and HPLC (270 nm, eluent iPrOH/H2O = 67/33, isocratic
flow, 1 mL/min) using authentic samples for comparison. The amount of H2O2 at the end of
the reaction was estimated using semiquantitative test sticks “Peroxide 100”.

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2,4,5-Trimethylphenol (2,4,5-TMP)
1H NMR (CDCl3, 25 °C, 400 MHz): 6.87 (s, 1H, Ar-H); 6.58 (s, 1H, Ar-H); 4.39 (s, 1H, OH);
2.184 (s, 3H, Ar-CH3); 2.180 (s, 3H, Ar-CH3); 2.16 (s, 3H, Ar-CH3).
GC–MS (EI): m/z (relative int.): 136 (77) [M]+, 121 (100) [M – CH3]+, 91 (21) [M – 3CH3]+.
2,3,5-Trimethylphenol (2,3,5-TMP)
1H NMR (CDCl3, 25 °C, 400 MHz): 6.59 (s, 1H, Ar-H); 6.47 (s, 1H, Ar-H); 4.51 (s, 1H, OH);
2.23 (s, 6H, Ar-CH3); 2.12 (s, 3H, Ar-CH3).
2,3,5-Trimethyl-1,4-benzoquinone (TMBQ)
GC–MS (EI): m/z (relative int.): 150 (100) [M]+, 122 (47) [M – CO]+, 107 (64) [M – CO, –
CH3]+, 79 (48) [M – 2CO, – CH3]+.
2-Hydroxy-3,5,6-trimethyl-1,4-benzoquinone (OH-TMBQ)
GC–MS (EI): m/z (relative int.): 166 (100) [M]+, 137 (13) [M – COH]+, 136 (13) [M – CO]+,
123 (13) [M – CH3, – CO]+, 109 (15) [M – CCH3, – 2CH3]+, 95 (22) [M – CCH3, – CH3, –
COH]+.
4-Hydroxy-2,4,5-trimethyl-2,5-cyclohexadien-1-one (TMQL)
GC–MS (EI): m/z (relative int.): 152 (44) [M]+, 137 (100) [M – CH3]+, 124 (32) [M – CO]+,
109 (60) [M – CH3, – CO]+.
2-Methyl-1,4-naphthoquinone
GC–MS (EI): m/z (relative int.): 172 (100) [M]+, 144 (19) [M – CO]+, 116 (42) [M – 2CO]+.
6-Methyl-1,4-naphthoquinone
GC–MS (EI): m/z (relative int.): 172 (100) [M]+, 157 (11) [M-CH3]+, 144 (31) [M – CO]+, 118
(39) [M – CO; -CH=CH]+, 116 (38) [M – 2CO]+.

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2.4. Instrumentation
GC analyses were performed using a gas chromatograph Chromos GC-1000 equipped with a
flame ionization detector and a quartz capillary column BPX5 (30 m × 0.25 mm). GC–MS
analyses were carried out using an Agilent 7000B system with the triple-quadrupole mass-
selective detector Agilent 7000 (HP-5ms quartz capillary column 30 m × 0.25 mm). HPLC
measurements were carried out using an Agilent Technologies 1220 Infinity LC (ZORBAX
1
Eclipse plus C18). H, 31P and 51V NMR spectra were recorded on a Brüker AVANCE-400
spectrometer at 400.130, 161.67 and 105.24 MHz, respectively. Chemical shifts, δ, were
determined relative to tetramethylsilane, 85% H3PO4 and VOCl3, respectively. Infrared
spectra were recorded for 0.5-1.0 wt.% samples in KBr pellets on an Agilent 660 FTIR
spectrometer.
3. Results and discussion
3.1. Oxidation of pseudocumene
One of the difficulties in the selective oxidation of hydrocarbons is high reactivity of the
oxygenated products, which rapidly undergo further oxidation. To prevent overoxidation
processes, oxidant is often taken in a deficiency. Following the work of Mizuno [29], we first
evaluated the catalytic performance of γ-PW10V2 in pseudocumene oxidation under the
conditions of a high substrate excess: [PC] = 1.9 M, [H2O2] = 0.036 M, [γ-PW10V2] = 0.9 mM,
1
[HClO4] = 0.9 mM, MeCN/t-BuOH = 1:1, 60 °C. H NMR and HPLC studies with authentic
samples identified 2,4,5-TMP as the principal oxidation product that formed along with minor
amounts of 2,3,5-TMP (Scheme 1).

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Scheme 1. PC oxidation with H2O2 catalyzed by (Bu4N)4[γ-PW10O38V2(ꢀ-O)(ꢀ-OH)].
The main results acquired on the PC oxidation in the presence of γ-PW10V2 are
presented in Table 1. Under standard Mizuno’s conditions, TMP yield (sum of 2,4,5- and
2,3,5-isomers in the ratio of ca. 7.3/1) attained 64% based on H2O2 added (Table 1, entry 1).
The reaction was fast and completed within 10 min. The isomeric 2,3,6-TMP was formed in
negligible amounts (< 2%). Importantly, only traces of products of the oxidation of methyl
groups (corresponding isomeric benzylic alcohols and benzaldehydes) were found, thus
indicating electrophilic hydroxylation mechanism. The lack of 2,3,6-TMP is consistent with
the observation of Mizuno and co-workers, who found high regioselectivity in the
hydroxylation of methoxy(methyl)- and dimethoxy(methyl)benzenes producing less sterically
hindered phenols [29]. Note that variation of the reaction conditions within the diapason
indicated in Table 1 had very minor influence on the ratio of TMP isomers that remained ca.
7.3/1/<0.15.
With high excess of PC, further oxidation of the phenolic products was insignificant
and the yield of TMBQ and TMQL, the quinone and quinol formed presumably from 2,3,5-
and 2,4,5-TMP, respectively, did not exceed 2%. Hence, the phenol selectivity, i.e. TMP yield
based on the aromatic substrate consumed, was high (>95%). On the other hand, we may
conclude that some unproductive decomposition of the oxidant occurred parallel to the

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hydroxylation process since no H2O2 was found in the reaction mixture after the TMP yield
reached the maximal value of 64%.
The hydroxylation reaction did not proceed in the absence of any catalyst (Table 1,
entry 2) or with the addition of only HClO4 (Table 1, entry 3). Therefore, in agreement with
the results of Mizuno and co-workers [29], the catalytic performance of the combination of γ-
PW10V2 and HClO4 was found to be unique. Conventional heteropoly acids H3PW12O40 (Table
1, entry 4) and divanadium-substituted H5PMo10V2O40 (Table 1, entry 5) with two vanadium
atoms statistically distributed over 12 positions of the α-Keggin structure produced TMP in 0
and 5% yield, respectively, indicating that namely the presence of the dimeric vanadium core
in the γ-Keggin POM is crucial for the selective aromatic hydroxylation. The nature of the
POM central atom (Si or P) had a strong impact on the catalytic activity: silicotungstate γ-
SiW10V2 was significantly less active than phosphotungstate γ-PW10V2 (Table 1, compare
entry 6 with entry 1).
The solvent nature played important role in the title reaction. In MeCN, the yield of
TMP was only 4% (Table 1, entry 7), but the addition of tert-butanol (t-BuOH/MeCN 1:2 v/v)
increased the yield up to 44% (Table 1, entry 8). At t-BuOH/MeCN ratio of 1:1, the phenol
yield reached 64% and remained constant upon further increase of the t-BuOH/MeCN ratio
(2:1) (Table 1, entry 9). In neat t-BuOH, the POM catalyst was not soluble.
Based on the results of the Mizuno group [29], we started investigation of PC
hydroxylation using 1 equiv. of H+ (in form of HClO4) relative to γ-PW10V2. Then we varied
the amount of HClO4 relative to γ-PW10V2 and confirmed that the maximum TMP yield
corresponds to 1 equiv. of H+, irregardless the other reaction conditions (Figure 2). In the
absence HClO4, only 24% yield of TMP was attained (Table 1, entry 10). This contrasts with
the selective H2O2-based oxidation of 2,3,6-TMP to TMBQ catalyzed by γ-PW10V2, for which
the impact of protons on the product yield was found to be insignificant [34].

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70
60
50
40
30
20
10
0
0.5
1.0
1.5
2.0
HClO4 (equiv. to γ-PW10V2)
Figure 2. TMP yield versus amount of HClO4. Reaction conditions: PC 2.4 mmol, γ-PW10V2
0.9 µmol, H2O2 0.036 mmol, 1 mL MeCN/t-BuOH (1/1), 60 °C (■) and PC 0.8 mmol, γ-
PW10V2 1.8 µmol, H2O2 0.036 mmol, 1 mL (MeCN/t-BuOH (1/1), 40 °C (●).
We also assessed effects of the reaction temperature and amounts of catalyst, substrate,
oxidant and water on the yield of TMP. The decrease in the temperature to 30 °C (Table 1,
entry 11) or, oppositely, its increase to 80 °C (Table 1, entry 12) led to the change of the
reaction rate but did not strongly affect the yield of TMP, which attained 56 and 61% at 30
and 80 °C, respectively. The phenol yield grew up and reached 74% when the concentration
of γ-PW10V2 was increased four times (Table 1, entry 14). Further increase in POM
concentration resulted in reduction of TMP yield (Table 1, entry 15). At a lower concentration
of PC (0.8 M), TMP was obtained in a similar yield as at [PC] = 1.9 M (Table 1, entry 16).
However, when substrate concentration was enlarged to 2.4 M, the yield of phenol dropped to
50% (Table 1, entry 17).

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We tried to get a higher PC conversion and TMP volume yield (which is the amount of
product formed per L of reaction mixture) by increasing the amount of H2O2 introduced into
the reaction mixture. However, this resulted in a significant decrease of the TMP yield based
on the oxidant (Table 1, compare entries 18 and 19 with entry 1). Apparently, phenol
overoxidation could compete with its formation from PC when higher oxidant concentrations
are employed. However, the amount of TMP overoxidation products, such as TMBQ and
TMQL, remained at the same level as in entry 1 (below 2%). Another reason for the lower
TMP yield could be a higher rate of unproductive decomposition of H2O2 relative to the target
oxygenation reaction. In fact, the amount of products related to the oxidation of the methyl
groups of PC increased in entries 18 and 19 as compared with entry 1.
A standard method that often helps to enhance the oxidant utilization efficiency is a
stepwise addition of H2O2 into reaction mixture. Indeed, we found that addition of H2O2 by
small portions (5.5 µmol every 5 min) enabled improvement of the product yield from 64 to
73% (Table 1, compare entry 20 and entry 1). Moreover, the stepwise mode of the oxidant
introduction made possible a 3-fold enlargement of the amount of H2O2 used without an
evident deterioration of TMP yield, which maintained at the level of 70–73% based on the
oxidant (Table 1, entry 20). As a result, the volume yield of the phenolic product could be
increased from 3.6 to 10.5 g/L.
Figure 3 shows how TMP yield depends on the amount of H2O2 added. One can see
that in the range of 0.03–0.09 mmol H2O2 the yield is kept quasi constant (71–73 %), but
further addition of the oxidant eventually leads to decreasing yield, most probably, because
overoxidation processes become significant.

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75
60
45
30
15
0
0.00
0.05
0.10
0.15
0.20
H2O2 (mmol)
Figure 3. Dependence of TMP yield on H2O2 amount. Reaction conditions: PC 1.9 mmol, γ-
PW10V2 0.9 µmol, HClO4 0.9 µmol, 1 mL MeCN/t-BuOH (1/1), 60 °C. H2O2 was added by
portions of 5.5 µmol every 5 min. TMP yield is based on H2O2 added.
Since H2O2 was introduced into the reaction mixture as an aqueous solution (35 wt.%),
the increasing amount of water during the reaction course could affect the catalytic activity.
This prompted us to evaluate the effect of water concentration in the system on the catalytic
performance. We found that in the range of [H2O] = 0.002–0.03 M, where the reaction
mixture remained homogeneous, TMP yield was quasi constant.
The stability of POMs under turnover conditions is a key issue that have to be
addressed when hydrogen peroxide is employed as the oxidant [35, 36]. Under the conditions
of the oxidant deficiency relative to the substrate (Table 1), γ-PW10V2 was rather stable as
confirmed by IR and 31P and 51V NMR spectra of the catalyst recovered from the reaction
mixture. Furthermore, the POM catalyst could be reused under the conditions of Entry 1,
Table 1, showing a similar reaction rate and TMP yield.
The oxidation of PC was also studied under conditions of the oxidant excess with
respect to the arene substrate, when formation of TMBQ could be expected (Scheme 2).

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Scheme 2. Pseudocumene oxidation with excess of H2O2
The main results are presented in Table 2. In contrast to the conditions of H2O2
deficiency (Table 1, entry 1), practically no conversion of PC was observed when an 8-fold
excess of H2O2 was added in one portion (Table 2, entry 1). A possible reason for that could
be completely different ratios of the reactants in the two cases: cat/Ox/PC = 1/40/2100 (Table
1) and 1/320/40 (Table 2). 31P and 51V NMR spectroscopic studies revealed that under the
high oxidant excess conditions, POM destruction occurred and the mode of the oxidant
addition affected this process. We may tentatively suppose that the addition of H2O2 in one
portion led to the fast formation of forms, which are not active in PC oxidation. A stepwise
addition of H2O2 changed the situation drastically and PC was easily converted to afford TMP
(sum of 2,4,5- and 2,3,5-isomers) and TMBQ as the main oxidation products. The yield of
TMBQ increased with increasing amount of the oxidant and PC conversion (Table 2, entry 2).
4-Hydroxy-2,4,5-trimethyl-2,5-cyclohexadien-1-one and 2-hydroxy-3,5,6-trimethyl-
1,4-benzoquinone were the main by-products. The former, most likely, derived from 2,4,5-
TMP while the latter could be a product of TMBQ overoxidation. Figure 4 shows kinetic
curves for PC conversion and product accumulation, which confirm that TMP is the primary
oxidation product on the way from PC to TMBQ. While the carbon mass balance is >99% at
the initial stages of the reaction, then it becomes poor because of overoxidation processes. At
the end of the reaction, the selectivity to quinone attained 39% at PC conversion of 46%
(Table 1, entry 2).

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60
PC
TMP
50
40
30
20
10
0
TMBQ
TMQL
OH-TMBQ
0
1
2
3
4
5
6
7
Time (h)
Figure 4. PC conversion and product yields versus time. Reaction conditions: PC 0.1 M, H2O2
0.8 M, γ-PW10V2 2.5 mM, HClO4 2.5 mM, MeCN/t-BuOH (1/1), 60 °C.
The amount of H2O2 added in one step could be redoubled without significant
deterioration of the results (Table 2, entry 3). An attempt to increase loading of all the
reactants (Table 2, entry 4) led to some decrease in TMBQ selectivity (32% versus 38% in
entry 2, 4-fold excess of H2O2) but the yield of TMBQ based on PC remained similar. As a
result, the volume yield of TMBQ could attain 9 g/L. Further increase in the initial PC
concentration was not possible because of the restricted solubility of the POM catalyst.
3.1. Oxidation of 2-methylnaphthalene
To estimate further the reaction scope, we assessed catalytic properties of γ-PW10V2 in the
oxidation of 2-methylnaphthalene. With three equivalents of H2O2 ([2-MN] = 0.1 M, [γ-
PW10V2] = [HClO4] = 8 mM) conversion of 2-MN reached 72% after 10 min at 60 °C in

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MeCN/t-BuOH (1/1). The reaction products were two isomeric quinones, 2- and 6-MNQ
formed with the yields of 7 and 27%, respectively (Scheme 3).
Scheme 3. 2-MN oxidation with H2O2 catalyzed by (Bu4N)4[γ-PW10O38V2(ꢀ-O)(ꢀ-OH)].
Note that such isomer distribution is not typical for catalytic oxidation of 2-MN where 2-
MNQ generally prevails over 6-MNQ because the methyl group activates the aromatic ring
towards oxidation [17, 37-42]. Typical ratios of 2-MNQ/6-MNQ are, for example, 7:1
(CH3ReO3/H2O2) [37], 4:1 (FeCl3·6H2O/H2O2) [17] and (FePcS-SiO2/t-BuOOH) [38], 2:1
(Fe(ClO4)3 or (CH3COO)3Fe/H2O2) [39], 8:1 (H2SO4/H2O2) [40], 5:1 or 10:1
(Ru(II)(terpyridine)(2,6-pyridinedicarboxylate)/H2O2) depending on reaction conditions [41,
42]. The only exception found in the literature, where 6-MNQ dominated over 2-MNQ with
the ratio of 2.5:1, was 2-MN oxidation with FeTDCPPS/KHSO5 catalyst system (FeTDCPPS
= tetrasodium meso-tetrakis(2,6-dichloro-3-sulfonatophenyl)porphyrin) [43]. On the other
hand, the unusually high regioselectivity toward 6-MNQ in the oxidation of 2-MN in the
presence of γ-PW10V2 is consistent with the results reported by Mizuno and co-workers for
dimethoxy- and dimethyl-substituted benzenes [29] and the results acquired by us in this work
for the oxidation of PC. Although the oxidation of 2-MN with H2O2 catalyzed by γ-PW10V2
gives the quinone isomer (6-MNQ) which is not industrially relevant, this reaction provides
one more confirmation that steric effects rather than electronic ones govern the arene
oxidation regioselectivity over γ-PW10V2.

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In addition, we studied the influence of different reaction parameters on the
distribution of MNQ isomers. Variation of temperature in the range of 30–80 °C and H2O
concentration in the range of 0.06–5 M, as well as substitution of MeCN/t-BuOH solvent for
MeCN did not affect the ratio of 6- and 2-MNQ. However, interesting dependences were
found upon varying the amounts of HClO4, POM and H2O2 (Figure 5). The increase in the
number of HClO4 equivalents relative to γ-PW10V2 (Figure 5A) as well as the increase in γ-
PW10V2 concentration (Figure 5B) led to enlargement of 6-MNQ selectivity at the expense of
2-MNQ. An opposite effect was found when the amount of the oxidant was increased: the 6-
/2-MNQ ratio was reduced in this case (Figure 5C).
A
100
Selectivity 2-MNQ
2-MN conversion
Selectivity 6-MNQ
80
60
40
20
0
0.0
0.5
1.0
1.5
2.0
2.5
3.0
HClO4 (equiv.)
B
100
80
60
40
20
0
Selectivity 2-MNQ
Selectivity 6-MNQ
2-MN conversion
1
2.5
5
8
10
15
[PW10V2] (M)

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C
100
80
60
40
20
0
Selectivity 2-MNQ
Selectivity 6-MNQ
2-MN conversion
0.1
0.3
0.5
0.8
[H2O2] (M)
Figure 5. Effect of reaction conditions on 2-MN conversion and selectivities toward 2- and 6-
MNQ: (A) γ-PW10V2 8 mM, H2O2 0.3 M, H2O 1.15 M; (B) HClO4 1 equiv. to γ-PW10V2,
H2O2 0.3 M, H2O 1.15 M; (C) γ-PW10V2 8 mM, HClO4 8 mM, H2O 0.15 M (90% H2O2 was
used). In all experiments: 2-MN 0.1 M, MeCN/t-BuOH (1/1), 60 °C, 10 min.
4. Conclusions
The divanadium-substituted phosphotungstate (Bu4N)4[γ-PW10O38V2(ꢀ-O)(ꢀ-OH)] catalyzes
the selective oxidation of pseudocumene with aqueous H2O2 to produce either 2,4,5-/2,3,5-
trimethylphenols (ca. 7:1) or 2,3,5-trimethyl-1,4-benzoquinone along with some other phenol
overoxidation products, depending on the substrate to oxidant ratio. The lack of products of
the oxidation of methyl groups certainly indicates electrophilic hydroxylation mechanism and
argues against electron transfer or hydrogen atom transfer mechanisms. The presence of
mineral acid (HClO4) is crucial for the catalytic activity. Under the conditions of H2O2
deficiency, the reaction revealed unusually high chemo- and regioselectivity towards 2,4,5-
trimethylphenol, indicating that steric factors most likely control the oxidation process. This
was also corroborated by the atypical regioselectivity observed in the oxidation of 2-
methylnaphthalene where 6-methylnaphthoquinone prevailed over 2-methylnaphthoquinone

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(ca. 4:1). Kinetic and DFT studies are in progress in our group to get further insight into the
mechanism of this unusual oxygenation reaction.
Acknowledgments
The authors thank Dr. R. I. Maksimovskaya and Dr. N. V. Maksimchuk for the POM
characterization by 31P and 51V NMR, Dr. I. E. Soshnikov and Dr. M. V. Shashkov for the
1
product identification by H NMR and GC–MS, respectively. The research was partially
supported by the Russian Foundation for Basic Research (RFBR grants 13-03-12042 and 14-
03-31431).
References
[1] Z. Rappoport (Ed.), The Chemistry of Phenols, Wiley, Chichester, 2003.
[2] S. Patai, Z. Rappoport (Eds.), The Chemistry of the Quinonoid Compounds, Wiley, New
York, 1988.
[3] J.F. Lorenc, G. Lambeth, W. Scheffer, in: Kirk-Othmer Encyclopedia of Chemical
Technology, vol. 2, Wiley-VCH, Weinheim, 2003, pp. 203–233.
[4] H. Fiege, H.-W. Voges, T. Hamamoto, S. Umemura, T. Iwata, H. Miki, Y. Fujita, H.-J.
Buysch, D. Garbe, W. Paulus, in: Ullmann's Encyclopedia of Industrial Chemistry, Wiley-
VCH, Weinheim, 2002.
[5] P. Schudel, H. Mayer, O. Isler, in: W.H. Sebrell, R. S. Harris (Eds.), The Vitamins, vol. 5,
Academic Press, New York, 1972, pp. 168–218.
[6] R.B. Rucker, J.W. Suttie, D.B. McCormick, L.J. Machlin (Eds.), Handbook of Vitamins,
Marcel Dekker, New York, 2001.

ACCEPTED MANUSCRIPT
[7] K.C. Nicolaou, J.S. Chen, D.J. Edmonds, A. A. Estrada, Angew. Chem. Int. Ed. 48 (2009)
660–719.
[8] A.E. Shilov, G.B. Shul'pin, Chem. Rev. 97 (1997) 2879−2932
[9] B. Lücke, K.V. Narayana, A. Martin, K. Jähnisch, Adv. Synth. Catal. 346 (2004)
1407−1424.
[10] D.A. Alonso, C. Nájera, I.M. Pastor, M. Yus, Chem. Eur. J. 16 (2010) 5274−5284.
[11] S. Enthaler, A. Company, Chem. Soc. Rev. 40 (2011) 4912–4924.
[12] A.H. Haines, Methods for the Oxidation of Organic Compounds: Alkanes, Alkenes,
AIkynes and Arenes, Academic Press, London, 1985.
[13] R. Sheldon, I.W.C.E. Arends, U. Hanefeld, Green Chemistry and Catalysis, Wiley-VCH,
Weinheim, 2007.
[14] F. Cavani, G. Centi, S. Perathoner, F. Trifiro (Eds.), Sustainable Industrial Processes,
Wiley-VCH, Weinheim, 2009.
[15] M.G. Clerici, O.A. Kholdeeva (Eds.), Liquid Phase Oxidation via Heterogeneous
Catalysis: Organic Synthesis and Industrial Applications, Wiley, Hoboken, New Jersey, 2013.
[16] M. Carril, P. Altmann, M. Drees, W. Bonrath, T. Netscher, J. Schutz, F.E. Kuhn, J. Catal.
283 (2011) 55–67.
[17] K. Möller, G. Wienhöfer, F. Westerhaus, K. Junge, M. Beller, Catal. Today 173 (2011)
68–75.
[18] W. Bonrath, T. Netscher, Appl. Catal. A 280 (2005) 55−73.
[19] R. Casani, in: Kirk-Othmer Encyclopedia of Chemical Technology, vol. 25, Wiley-VCH,
Weinheim, 2003, pp. 144–150.
[20] Y. Asakawa, R. Matsuda, M. Tori, M. Sono, J. Org. Chem. 53 (1988) 5453–5457.

ACCEPTED MANUSCRIPT
[21] H. Orita, M. Shimizu, T. Hayakawa, K. Takehira, Bull. Chem. Soc. Jpn. 62 (1989) 1652–
1657.
[22] J. Jacob, J.H. Espenson, Inorg. Chim. Acta 270 (1998) 55–59.
[23] M. Carril, P. Altmann, W. Bonrath, T. Netscher, J. Schutz, F. Euhn, Catal. Sci. Technol.
2 (2012) 722–724.
[24] A.M. Kirillov, G.B. Shul'pin, Coord. Chem. Rev. 257 (2013) 732–754.
[25] N. Mizuno, K. Kamata, Coord. Chem. Rev. 255 (2011) 2358–2370.
[26] M. Bianchi, M. Bonchio, V. Conte, F. Coppa, F. Difuria, G. Modena, S. Moro, S.
Standen, J. Mol. Catal. 83 (1993) 107–116.
[27] J. Arichi, M. Eternot, B. Louis, Catal. Today 138 (2008) 117–122.
[28] J.K. Joseph, S. Singhal, S.L. Jain, R. Sivakumaran, B. Kumar, B. Sain, Catal. Today 141
(2009) 211–214.
[29] K. Kamata, T. Yamaura, N. Mizuno, Angew. Chem. Int. Ed. 51 (2012) 7275–7278.
[30] P.J. Domaille, G. Hervéa, A. Téazéa, in: Alvin P. Ginsberg (Ed.) Inorganic Syntheses,
vol. 27, John Wiley & Sons, Inc., 1990, pp. 96–104.
[31] K. Kamata, K. Yonehara, Y. Nakagawa, K. Uehara, N. Mizuno, Nature Chem. 2 (2010)
478–483.
[32] Y. Nakagawa, K. Kamata, M. Kotani, K. Yamaguchi, N. Mizuno, Angew. Chem. Int. Ed.
44 (2005) 5136–5141.
[33] G.A. Tsigdinos, C.J. Hallada, Inorg. Chem. 7 (1968) 437–441.
[34] I.D. Ivanchikova, N.V. Maksimchuk, R.I. Maksimovskaya, G.M. Maksimov, O.A.
Kholdeeva, ACS Catal. 4 (2014) 2706–2713.
[35] C. L. Hill, In Comprehensive Coordination Chemistry II; Wedd, A. G., Ed.; Elsevier
Science: New York, 2004; Vol. 4, pp. 679-759.

ACCEPTED MANUSCRIPT
[36] R. Neumann, In Transition Metals for Organic Synthesis; 2nd edn; Beller, M., Bolm, C.,
Eds.; Wiley-VCH: Weinheim, 2004; Vol. 2, pp. 415-426.
[37] W. Adam, W.A. Herrmann, J. Lin, C.R. Saha-Möller, R.W. Fischer, J.D.G. Correia,
Angew. Chem. Int. Ed. 33 (1994) 2475–2477.
[38] A. Sorokin, A. Tuel, New. J. Chem. 23 (1999) 473–476.
[39] J. Kowalski, J. Płoszyńska, A. Sobkowiak, Catal. Commun. 4 (2003) 603–608.
[40] A. Bohle, A. Schubert, Y. Sun, W.R. Thiel, Adv. Synth. Catal. 348 (2006) 1011–1015.
[41] F. Shi, M.K. Tse, M. Beller, Adv. Synth. Catal. 349 (2007) 303–308.
[42] G. Wienhöfer, K. Schröder, K. Möller, K. Junge, M. Beller, Adv. Synth. Cat. 352 (2010)
1615–1620.
[43] R. Song, A. Sorokin, J. Bernadou, B. Meunier, J. Org. Chem. 62 (1997) 673–678.

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Table 1. PC oxidation in the presence of γ-PW10V2 in conditions of H2O2 deficiency a
Entry
1
[POM] (mM) [HClO4] (mM) [H2O2] (mM) Time (min) TMP yield b (%)
0.9
-
0.9
-
36
10
60
60
60
60
60
180
10
10
60
240
10
10
10
10
10
10
10
10
35
80
100
64
0
2
36
3
-
0.9
0.9
0.9
0.9
0.9
0.9
0.9
-
36
0
4
0.9 c
0.9 d
0.9 e
0.9
0.9
0.9
0.9
0.9
0.9
1.8
3.6
4.5
0.9
0.9
0.9
0.9
0.9
36
0
5
36
5
6
36
15
4
7 f
8 g
9 h
10
11 i
12 j
13
14
15
16 k
17 l
18
19
20
36
36
44
63
24
56
61
70
74
63
61
50
35
17
73
73
70
36
36
0.9
0.9
1.8
3.6
4.5
0.9
0.9
0.9
0.9
0.9
36
36
36
36
36
36
36
110
180
36 m
88
110
a
b
Reaction conditions: PC 1.9 M, POM = γ-PW10V2, MeCN/t-BuOH (v/v=1/1), 60 °C. GC
c
d
yield of 2,4,5- and 2,3,5-TMP (7:1) based on H2O2 added. POM = H3PW12O40. POM =
e
f
g
h
H5PMo10V2O40. POM = γ-SiW10V2. Without t-BuOH. MeCN/t-BuOH (v/v=2/1).
i
j
k
l
m
MeCN/t-BuOH (v/v=1/2). 30 °C. 80 °C. PC 0.8 M. PC 2.4 M. Stepwise addition of
H2O2: 5.5 µmol every 5 min.

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Table 2. Pseudocumene oxidation in the presence of γ-PW10V2 in conditions of H2O2 excess a
entry [PC]
(M)
[POM] [H2O2] Time PC conversion TMP yield TMBQ yield
(h)
(%)
(%) b
(%) b
(mM)
2.5
(M)
0.8
0.13
0.4
0.8
0.13
0.8
0.7
2
1
2 c
0.1
0.1
0.5
1
<1
17
32
46
17
41
23
37
-
-
2.5
12 (71)
7.5 (23)
4 (9)
3.5 (21)
12 (38)
18 (39)
3 (18)
17 (41)
6 (26)
12 (32)
3
6
3 d
4 e
0.1
0.5
2.5
0.5
3
12 (71)
1 (2)
12.5
1
12 (52)
2 (5)
3
a Reaction conditions: HClO4 1 equiv. to POM, MeCN/t-BuOH (1/1), 60 °C. b Yield based on
initial PC; selectivity is given in parentheses. c-e H2O2 was added stepwise: c 11 µmol every 5
min; d 22 µmol every 5 min; e 55 µmol every 5 min.

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Highlights
- Polyoxometalate (Bu4N)4[γ-PW10O38V2(ꢀ-O)(ꢀ-OH)] catalyzes oxidation of pseudocumene and
2-methylnaphthalene with H2O2.
- Pseudocumene is converted to 2,4,5-trimethylphenol with unusually high regioselectivity.
- 2,3,5-Trimethyl-1,4-benzoquinone becomes the main product under excess of H2O2.
- 2-Methylnaphthalene gives predominantly 6-methyl-1,4-naphthoquinone.