Synthesis of coenzyme Q0 through divanadium-catalyzed oxidation of 3,4,5-trimethoxytoluene with hydrogen peroxide

Article abstract of DOI:10.1039/c7dt00552k

The selective oxidation of methoxy/methyl-substituted arenes to the corresponding benzoquinones has been first realized using aqueous hydrogen peroxide as a green oxidant, acid tetrabutylammonium salts of the γ-Keggin divanadium-substituted phosphotungstate [γ-PW₁₀O₃₈V₂(μ-O)₂]^5- (I) as a catalyst, and MeCN as a solvent. The presence of the dioxovanadium core in the catalyst is crucial for the catalytic performance. The reaction requires an acid co-catalyst or, alternatively, a highly protonated form of I can be prepared and employed. The industrially relevant oxidation of 3,4,5-trimethoxytoluene gives 2,3-dimethoxy-5-methyl-1,4-benzoquinone (ubiquinone 0 or coenzyme Q₀, the key intermediate for coenzyme Q₁₀ and other essential biologically active compounds) with 73% selectivity at 76% arene conversion. The catalyst retains its structure under turnover conditions and can be easily recycled and reused without significant loss of activity and selectivity.

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ARTICLE
Synthesis of coenzyme Q through divanadium-catalyzed
0
oxidation of 3,4,5-trimethoxytoluene with hydrogen peroxide
†
Received 00th January 20xx,
Accepted 00th January 20xx
a
ab
a
a
Olga V. Zalomaeva, Vasilii Yu. Evtushok, Gennadii M. Maksimov, Raisa I. Maksimovskaya and
ab
Oxana A. Kholdeeva*
DOI: 10.1039/x0xx00000x
The selective oxidation of methoxy/methyl-substituted arenes to corresponding benzoquinones has been first realized
using aqueous hydrogen peroxide as green oxidant, acid tetrabutylammonium salts of the γ-Keggin divanadium-
www.rsc.org/
5
]
-
substituted phosphotungstate [γ-PW10
O
38
V
2
(µ-O)
2
(I) as catalyst, and MeCN as solvent. The presence of the
dioxovanadium core in the catalyst is crucial for the catalytic performance. The reaction requires acid co-catalyst or,
alternatively, a highly protonated form of I can be prepared and employed. The industrially relevant oxidation of 3,4,5-
0
trimethoxytoluene gives 2,3-dimethoxy-5-methyl-1,4-benzoquinone (ubiquinone 0 or coenzyme Q , the key intermediate
for coenzyme Q10 and other essential biologically active compounds) with 73% selectivity at 76% arene conversion. The
catalyst retains its structure under turnover conditions and can be easily recycled and reused without significant loss of
activity and selectivity.
The selective oxidation of methoxytoluenes to
corresponding p-benzoquinones can be accomplished using
dimethyldioxirane as oxidant, mineral acid as catalyst and
Introduction
The selective aromatic oxidation of arenes bearing methoxy
and methyl substituents offers an efficient access to a range of
benzoquinones, which play an important role in biological
systems and are useful intermediates in the synthesis of fine
7
acetone as solvent. Several synthetic methods were reported
for the production of CoQ through oxidation of commercially
available 3,4,5-trimethoxytoluene (TMT) with the green
0
8
-16
1
oxidant – hydrogen peroxide. Among catalysts applied were
8
potassium hexacyanoferrate(III), methyltrioxorhenium(VII)
chemicals, nutraceuticals and pharmaceuticals. Ubiquinones
(also called coenzymes Q , among which Q is the most
n 10
11,12
MTORe), or HNO
10,16
15
3
), and
(
mineral acids (H
2
SO
4
known one) act as biochemical oxidizing agents that mediate
2
,3 heteropolyacids of the general formula H XM12O40 (where X =
n
electron-transfer processes involved in energy production.
1
3,14
P or Si, n = 3 (P) or 4 (Si), and M = Mo or W).
best yields of CoQ were claimed for systems that employed
formic acid as solvent and phosphomolybdic heteropolyacid as
So far, the
Their synthetic analogue, idebenone, has been developed as a
drug for the treatment of Alzheimer’s disease and other
4
cognitive defects. 2,3-Dimethoxy-5-methyl-1,4-benzoquinone,
0
1
4
catalyst or a mixture of acetic and formic acids without any
16
catalyst. However, use of hydrogen peroxide in combination
known as ubiquinone 0 or coenzyme Q (CoQ ), can serve as a
0
0
key intermediate in the synthesis of coenzyme Q and other
1
0
5
,6
with carboxylic acids imposes practical problems related to
reactor corrosion and safety risks associated with the in situ
formation of explosive peroxy acids. Growing environmental
concerns stimulated the development of more safe and
sustainable catalytic methods for the production of methoxy-
ubiquinones (Scheme 1).
1
d,17,18
substituted p-benzoquinones.
In 2012, Mizuno and co-workers discovered an efficient
system for hydroxylation of arenes that involved the
divanadium-substituted γ-Keggin phosphotungstate (Bu
(µ-O)(µ-OH)] (hereinafter, TBA H- ) as catalyst,
mineral acid as co-catalyst, H as oxidant, and MeCN/t-BuOH
4 4
N) [γ-
PW10
O
38
V
2
4
I
2 2
O
1
9
Scheme 1 Bioactive compounds derived from CoQ
0
.
(1:1) as solvent. At a substrate to oxidant ratio of 50, mono-
and dialkyl(alkoxy)arenes afforded corresponding phenols with
excellent chemoselectivity and unusual regioselectivity. More
a.
Boreskov Institute of Catalysis, Pr. Ac. Lavrentieva 5, Novosibirsk 630090, Russia.
E-mail: khold@catalysis.ru; Fax: +7-383-330-9573; Tel: +7-383-326-9433
Novosibirsk State University, Pirogova str. 2, Novosibirsk 630090, Russia.
recently, we investigated the catalytic performance of TBA
4
H-I
b.
c.
in some industrially important reactions, such as oxidation of
† Electronic supplementary informaꢀon (ESI) available: FTIR, NMR and
potentiometric titration data. See DOI:
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a
2 2 4
Table 1. TMT oxidation with H O in the presence of HClO and I
Entry
TBA3.5
H1.5-I
HClO
4
Time
(min)
60
TMT
CoQ
0
b
(mM)
(mM)
-
conv. (%)
select. (%)
1
2
3
4
5
6
-
3
-
-
2.5
-
40
22
36
65
70
69
17
83
66
73
53
2.5
2.5
2.5
2.5
30
0.6
1.25
2.5
30
30
n
Scheme 2 Oxidation of TMT in the presence of TBA5-nH -I.
30
a
b
Reaction conditions: TMT (0.1 M), H
on converted TMT.
2
O
2
(0.2 M), MeCN 1 mL, 60 °C. Yield based
2
,3,6-trimethylphenol (TMP) and pseudocumene to 2,3,5-
0
21
2
trimethyl-p-benzoquinone (TMBQ, Vitamin E precursor) using
H O , and found that TMP can be converted to TMBQ with a
2
2
nearly quantitative yield and 80–90% oxidant utilization
2
0
efficiency. In contrast to the oxidation of alkylarenes, this
reaction did not require acid co-catalyst.
-13.73
31P
TBA H -I
3
2
In the present work, we explored further the catalytic
properties of TBA5-nHn-I (n = 1–2) in H O -based aromatic
2 2
-
14.1
oxidation and first employed this catalyst system to
accomplish the challenging oxidative transformation of TMT to
TBA H-I
4
coenzyme Q (Scheme 2). The extension of this method toward
0
other methoxyarenes is also reported. We carefully
investigated the role of acid co-catalyst and a possibility to
replace it by using a highly protonated form of
I. The catalyst
-13
-14
-15
stability and recyclability issues have been also addressed.
chemical shift (ppm)
31
3
Fig. 1 P NMR spectrum of TBA3.3H1.7-I (0.0015 M) in dry CH CN.
Results
In most procedures reported in the literature for TMT
TBABr (see Experimental for details), allowed us to obtain
+
POM with an increased amount of protons (1.5−1.7 H per
oxidation with H
2
O
2
, the reaction proceeds in acidic medium,
9
-11,13,15,16
such as acetic or formic acid.
Some of them require
POM molecule). IR spectroscopy corroborated retention of the
polyanion structure (Fig. S1†). In dry dilute MeCN soluꢀon,
addition of mineral acid in catalytic amounts to accelerate the
formation of peroxy acid, which is the real oxidizing species in
31
such POM revealed two separate P NMR signals at −13.7 and
1
0,15,16
these systems.
development of a more safe and environmentally friendly
approach to the synthesis of CoQ , we have checked whether
In view of our interest in the
22
14.1 ppm, which according to the literature, can be
−
assigned to di- and monoprotonated forms, TBA
3
H
2
-
I
and
, respectively. Fig. 1 shows a typical P NMR spectrum
where the ratio of the two signals is ca. 2:1, which implies the
31
0
4
TBA H-I
mineral acid can play a role of the sole catalyst in a less
corrosive and harmful solvent, for example, MeCN. While TMT
conversion was negligible without any catalyst (Table 1, entry
51
formulation of TBA3.3
spectrum revealed two poorly resolved signals at −579
TBA H-I) ppm (Fig. S2 in ESI†). In more
I) and −581 (TBA
concentrated or wet solutions only one averaged NMR signal is
1.7
H -I The corresponding V NMR
1
), in the presence of HClO
C. However, selectivity toward the target product was low
Table 1, entry 2) and the yield of CoQ did not exceed 4%.
Previously, the group of Mizuno demonstrated that
4
, it attained 22% after 40 min at 60
(
3
H
2
-
4
°
(
0
31
51
observed at −13.9 ( P) and −579 ( V) due to fast exchange on
the NMR time scale. Potentiometric titration with aqueous
TBAOH confirmed the presence of two types of acid protons in
the POM and made possible accurate determination of the
efficient hydroxylation of arenes can be realized in the
presence of the divanadium-substituted polyoxometalate
1
9,21
(
POM) TBA
rationalized the effect of co-catalyst in terms of the in situ
generation of a catalytically active diprotonated form of
4
H-I
and 1 equiv. of HClO
4
as co-catalyst.
They
ratio between the two forms of
representative potentiometric titration curve for the sample of
. The results of the potentiometric titration are in
good agreement with CNH analysis (see Experimental).
It is noteworthy that TBA3.5 itself is able to convert
TMT to CoQ with selectivity as high as 83% (Table 1, entry 3).
However, arene conversion was only 36% and could not be
I. Figure S3† depicts a
I,
1.5
TBA3.5H -I
1
9
3 38 2 2 3 2
TBA [γ-PW10O V (µ-OH) ] (TBA H -I). To minimize the use of
acid co-catalyst, we attempted to develop a simple and
affordable procedure for the preparation of a TBA salt of
1.5
H -I
0
polyanion
I that would contain an increased amount of
protons as counter cations. Some modification of the
enlarged by increasing the reaction time. The addition of HClO
led to improvement of both substrate conversion and CoQ
4
2
previously reported synthetic procedure, viz. additional
2
0
acidification of the reaction mixture (pH 0.8 versus pH 2.0 used
yield. The optimal amount of acid turned out close to 0.5
equiv. (Table 1, compare entries 4, 5 and 6), corroborating the
4
for the preparation of TBA H-I) before final precipitation with
2
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Keggin heteropoly acids, such as vanadium-free H
3 40
PW12O
TMT conversion
CoQ0 yield
5 2
and divanadium-substituted H PMo10V O40 (the latter has two
Selectivity to CoQ0
vanadium atoms statistically distributed over 12 positions of
the α-Keggin structure). A comparison of their catalytic
properties is shown in Fig. 3. One can see that both the Si-
1
00
8
6
4
2
0
0
0
0
0
analogue of
I
and the heteropoly acids are poor catalysts for
. Although 35−60% conversion of TMT
the production of CoQ
0
was attained after 1 h, selectivity towards ubiquinone 0 did
not exceed 27%. On the other hand, 73% selectivity at 70%
TMT conversion was reached after 0.5 h in the presence of 2.5
1.5
mol.% of TBA3.5H -I combined with 0.5 equiv. of mineral acid.
These results indicate that the presence of both the dimeric
vanadium core and P central atom in the specific γ-Keggin
structure are imperative for efficient catalysis of the title
2
reaction. A simple vanadium complex, VO(acac) , revealed 42%
TMT conversion in 5 min, but the yield of CoQ was below 2%.
0
To figure out optimal reaction conditions, we studied the
influence of all reaction parameters on TMT conversion and
Fig. 2 TMT oxidation in the presence of TBA5-n
H
n
-I. Reaction conditions: TMT (0.1 M),
2 2
H O (0.2 M), I (2.5 mM), MeCN 1 mL, 60 °C, 30 min.
CoQ
Previously, it was shown that
gave better yields of oxygenated products in a solvent mixture
0
selectivity. The results are presented in Table 2.
I-based oxidation of alkylarenes
TMT conversion
Selectivity to CoQ0
Reaction time
1
00
100
80
60
40
20
0
1
9,21
of MeCN and t-BuOH (1:1, v/v).
However, in the case of
8
6
4
2
0
0
0
0
0
TMT, the addition of t-BuOH resulted in worsening of both
arene conversion and quinone selectivity relative to the
reaction in MeCN (Table 2, compare entries 1 and 2).
The oxidation rate was reduced significantly with
decreasing the reaction temperature: after 4 h at 30 °C, TMT
conversion reached only 39%. However, some enhancement of
the CoQ
and 3). At 80 °C, the attainable level of conversion was the
same as at 60 °C, but selectivity to CoQ decreased to 66%
Table 2, entry 4). A 2-fold reduction of the catalyst
0
selectivity was observed (Table 2, compare entries 1
0
(
concentration with simultaneous alteration of the co-catalyst
amount did not strongly affect the catalytic performance
(
Table 2, compare entries 1 and 5). On the other hand, a 2-fold
augmentation of the catalyst concentration led to some
decrease of TMT conversion and CoQ selectivity (Table 2,
Fig. 3 TMT oxidation in the presence of different POMs. Reaction conditions: TMT (0.1
M), H (0.2 M), POM (2.5 mM), MeCN 1 mL, 60 °C.
0
2 2
O
entry 6). A proportional diminution of concentrations of all the
reactants relative to the standard conditions resulted in some
above mentioned hypothesis that the role of acid co-catalyst is
to generate the diprotonated form TBA
Fig. 2 demonstrates how the protonation state of
its catalytic performance. Both TMT conversion and CoQ
increase with increasing amount of protons in the catalyst. In
the presence of TBA , 73% selectivity could be attained at
8% TMT conversion. Importantly, a similar result was
acquired using either TBA3.5 and 0.5 equiv. of HClO or
and 0.3 equiv. of HClO , indicating that it does not
matter what is the source of protons, POM or mineral acid.
Given that the synthesis of TBA3.5 is more simple and
reproducible than the synthesis of TBA (see Experimental
for details), we performed further studies and optimization of
the catalyst system using TBA3.5
To verify the uniqueness of polyanion
TMT, we compared the catalytic performance of TBA3.5
with some other representative POMs, including a Si-
containing analog, TBA [γ-SiW10 40], and conventional α-
growth of TMT conversion but led to reduction in CoQ
0
3 2
H -I.
selectivity (Table 2, entry 7). Oppositely, only 51% substrate
conversion was reached in a more concentrated reaction
mixture, showing a similar level of selectivity (Table 2,
compare entries 1 and 8).
I
affects
yield
0
3 2
H -I
According to the reaction stoichiometry (see Scheme 2),
6
two equivalents of H
However, under the standard reaction conditions of entry 1
Table 2), the reaction stopped after 30 min, reaching a
2 2 0
O are required to convert TMT to CoQ .
H
1.5
-
I
4
TBA3.3
H
1.7
-I
4
(
substrate conversion of 70%. Semiquantitative evaluation with
Quantofix peroxide test sticks revealed that practically no
oxidant was present in the final reaction mixture. Therefore,
1.5
H -I
3 2
H -I
incomplete TMT conversion with 2 equiv. of H
indication of some unproductive decomposition of the oxidant.
When the concentration of H was reduced twice relative to
2 2
O may be an
1.5
H -I.
I
in the oxidation of
2 2
O
1.5
H -I
the required stoichiometric amount, the oxidant utilization
efficiency was improved considerably (70% versus 52%) along
with selectivity to the target quinone (82% versus 73%). Fig. 4
4
H
2
2
V O
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a
Table 2. TMT oxidation in the presence of TBA3.5H1.5-I
2
5
Entry
Cat:TMT:H
2
O
2
TMT
M)
Time
TMT
conv. (%)
70
CoQ
0
.
b
(
(min)
30
15
240
5
select (%)
20
c
1
0.025:1:2
0.025:1:2
0.025:1:2
0.025:1:2
0.013:1:2
0.05:1:2
0.1
0.1
0.1
0.1
0.1
0.1
0.05
0.2
0.1
0.1
0.1
0.1
73 (67)
1
5
d
2
43
56
77
66
70
64
67
75
63
64
73
65
e
3
39
10
5
f
4
71
TMT conversion
CoQ0 yield
5
6
7
8
30
5
69
66
TMMP yield
0
0.025:1:2
0.025:1:2
0.025:1:3
0.025:1:3
0.025:1:2
0.025:1:2
45
15
15
45
30
30
75
0
10
20
30
40
50
Time (min)
51
9
65
g
Fig. 5 TMT consumption and product formation versus time. Reaction
conditions: TMT (0.1 M), H (0.05 M), TBA3.5 1.5-I (2.5 mM), HClO (1.25
mM), MeCN 1 mL, 40 °C.
1
1
1
0
1
2
85
h
i
2
O
2
H
4
76
64
a
b
4
Reaction conditions: HClO (1.25 mM), MeCN 1 mL, 60 °C. GC yield based on
c
d
e
converted TMT. Isolated yield. MeCN/t-BuOH (1:1, v/v) instead of MeCN. 30
f
g
h
i
°
C. 80 °C.
2 2 2 2
H O added in three portions. H O added in two portions. 0.1 M of
MeOH was added.
shows that H
2 2
O efficiency tends to decrease with increasing
2 2
H O
concentration. The reaction selectivity follows a similar
trend. A stepwise addition of the oxidant to the reaction Scheme 3 Plausible route of TMT oxidative transformation to CoQ
0
.
mixture allowed higher TMT conversions to be achieved,
keeping quinone selectivity at the same level (Table 2,
compare entries 9 and 10, 1 and 11).
At high conversions, CoQ
0
was the only product detected
1
by GC, GC-MS, and H NMR. However, CoQ yields determined
0
1
During the reaction course, we revealed the formation of a by means of GC or H NMR using internal standard suggested
product that reached a maximum yield of ca. 15% at the initial the presence of some by-products, most likely, tars.
stage and then disappeared (Fig. 5). In the final reaction
1.5
To examine reusability of TBA3.5H -I in the oxidation of
mixture, only 1−2% of this compound was detected. GC−MS TMT, we performed 3-fold scaled experiments, in which the
analysis identified it as 2,3,4-trimethoxy-6-methylphenol catalyst was separated from the reaction mixture by
(
TMMP). The bell-shaped accumulation curve depicted in Fig. 5 precipitation with diethyl ether and used repeatedly under the
suggests that TMMP is, most likely, an intermediate product conditions of entry 1, Table 2. The recycling performance is
on the way from TMT to CoQ
. GC−MS also detected trace shown in Fig. 6. Only minor reduction of arene conversion and
0
amounts of a compound that could be assigned to 3,4- product selectivity was observed during at least four recycles.
dimethoxy-6-methylpyrocatechol or 2,3-dimethoxy-6-methyl- Importantly, the reaction time did not increase, indicating
hydroquinone. These facts strongly support a mechanism that stable catalytic activity. The FTIR spectrum of the recovered
involves electrophilic hydroxylation of TMT to form TMMP at catalyst confirmed retention of the POM structure (see Fig.
the first step of the oxidation process (Scheme 3).
S1†).
Some decrease of TMT conversion and product yield might
be caused by a partial transformation of the POM catalyst to a
methoxy derivative, (Bu N) [γ-PW10 (µ-OH)(µ-OMe)], that
could be formed during the reaction course upon interaction
of polyanion with methanol, which is one of the reaction
TMT conversion
Selectivity to CoQ0
4
3
38 2
O V
H O2 efficiency
2
1
00
100
I
8
6
4
2
0
0
0
0
0
80
60
40
20
0
products (see Scheme 2). Earlier, Nakagawa et al. studied
interaction of methanol and other alcohols with the Si-
containing analogue of
23
I and proved the formation of such
51
methoxy derivatives. Indeed, V NMR detected appearance
of a signal at −562 ppm during the reacꢀon progress, which
could be assigned to methoxy derivative of
this hypothesis, we performed an experiment where 1 equiv.
of MeOH was added to a solution of TBA3.5 in MeCN.
Indeed, the appearance of the V NMR signal at −562 ppm
I (Fig. 7b). To verify
0
.05
0.1
0.2
0.3
1.5
H -I
[
H O ] (M)
51
2
2
Fig.
4
The effect of
H O
2 2
concentration on TMT oxidation in the presence of was detected (Fig. 7c). The addition of methanol to the initial
TBA3.5H1.5-I. Reaction conditions: TMT (0.1 M), I (2.5 mM), HClO
4
(1.25 mM), MeCN 1
reaction mixture produced a rate-retarding effect (Fig. 8) and
decreased TMT conversion and selectivity to CoQ (Table 2,
mL, 60 °C.
0
entry 12). It should be noted, however, that most of the
4
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TMT conversion
CoQ0 selectivity
methoxy derivative was hydrolyzed back to
I upon the
1
00
recycling workup since the recovered POM was present in its
3
1
51
initial state (δ −579 ppm). Therefore, P and V NMR along
with FTIR spectroscopic technique confirmed the retention of
8
6
4
2
0
0
0
0
0
the γ-Keggin structure of
I after the catalysis.
To estimate the scope of the TBA3.5
1.5 2 2
H -I/H O catalytic
system, we studied oxidation of some other representative
methoxyarenes (Scheme 4). The results are summarized in
Table 3. For all substrates, the formation of the corresponding
quinones occurred with moderate to good yields (22−70%) at
conversions ≥ 74%. It is noteworthy that the oxidation of 1,2,3-
1
2
3
4
TBA3.5H1.5- I reuse
trimethoxybenzene (Scheme 4, d) gave only 2,3-dimethoxy-
8
]-catalyzed and non-
Fig. 6 Reuse of TBA3.5
H
1.5-I in TMT oxidation. Reaction conditions: TMT (0.1 M), H
(1.25 mM), MeCN (3 mL), 60 °C, 15 min.
O
2 2
1
,4-benzoquinone while, for K
9
3
[Fe(CN)
6
(
0.2 M), TBA3.5
H
1.5-I (2.5 mM), HClO
4
catalytic oxidations, the formation of two isomeric quinones,
,3- and 2,6-dimethoxy-1,4-benzoquinone, was observed. This
2
fact implies that steric factors, most likely, control the
oxidation process in the case of the bulky divanadium-POM
catalyst.
-
579
For the sake of comparison, we also performed TMT
1
4,16
oxidation following two protocols reported in the literature
but in a lower scale (1 mL). The comparison is shown in Fig. 9.
In a mixture of formic and acetic acids, CoQ yield achieved
58%, which is a bit higher than the yield obtained in the
presence of TBA3.5 (52%). On the contrary, the quinone
(a)
0
-562
1.5
H -I
yield was significantly lower (ca. 30%) in the presence of
phosphomolibdic acid in AcOH. An evident advantage of the
-579
1.5
TBA3.5H -I-based catalyst system is greater oxidant utilization
(b)
efficiency (see Fig. 9), which allows one to attain a good
product yield using just stoichiometric amount of the oxidant.
In addition, we avoid the use of carboxylic acids as solvents
and, therefore, preclude corrosion and formation of explosive
-562
2 2
peroxy acids upon interaction with H O .
(
c)
-
560
-580
chemical shift (ppm)
5
1
Fig. 7 V NMR spectra in CH
3
CN: (a) initial TBA3.5H1.5-I (0.0025 M), (b) reaction mixture
after 10 min, and (c) TBA3.5H1.5-I (0.0025 M) + 1 equiv. of MeOH.
8
6
4
2
0
0
0
0
0
1.5
Scheme 4 Oxidation of methoxyarenes in the presence of TBA3.5H -I.
a
Table 3. Oxidation of methoxyarenes catalyzed by TBA3.5H1.5-I.
Entry
Substrate
Conversion [%]
Selectivity to
[
b]
quinone [%]
without MeOH
with MeOH
1
2
3
4
5
a
b
c
92
81
74
82
77
76
59
39
27
56
0
5
10
15
20
25
30
Time (min)
d
e
Fig. 8 The effect of MeOH on TMT conversion. Reaction conditions: TMT (0.1 M), H
0.2 M), TBA3.5 1.5-I (2.5 mM), HClO (1.25 mM), [MeOH] 0.1 M, MeCN 1 mL, 60 °C.
2 2
O
[
a]
Reaction conditions: arene (0.1 M), H
2
O
2
(0.2 M), TBA3.5
H
1.5-I (2.5 mM), HClO
4
(
H
4
[b]
(
1.25 mM), MeCN 1 mL, 60 °C, 5-30 min. Based on converted substrate.
This journal is © The Royal Society of Chemistry 20xx
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ARTICLE
Journal Name
ionization detector and a quartz capillary column BPX5 (30 m ×
.25 mm). GC–MS analyses were carried out using an Agilent
TMT conversion
CoQ0 yield
0
H O2 efficiency
2
1
00
100
80
60
40
20
0
7000B system with the triple-quadrupole mass-selective
detector Agilent 7000 (HP-5ms quartz capillary column 30 m ×
80
60
40
20
0
1
31
51
0
.25 mm). H, P and V NMR spectra were recorded on a
Brüker AVANCE-400 spectrometer at 400.130, 161.67 and
05.24 MHz, respectively. Chemical shifts for P and V, δ, were
determined relative to 85% H PO and VOCl , respectively.
1
3
4
3
Infrared spectra were recorded in KBr pellets on an Agilent 660
FTIR spectrometer.
General catalyst preparation
7 2
γ-Cs PW10O36·5H O. The synthesis of the cesium salt of the
dilacunary phosphotungstate was carried out either following
the protocol reported in the literature that employs expensive
2
4
and caustic CsOH, or using a modified procedure described
were mixed with 20 g of anhydrous
2 2 3
O (7 M), H PMo12O40 (0.7 M), Cs CO in a nickel melting pot. A small amount of Cs CO was
Fig. 9 Comparison of I-catalyzed TMT oxidation with reported systems. Reaction
conditions: (a) TMT (1.4 M), H
(5.5 M) added dropwise during 10 min, HCOOH 0.35 below. 14.6 g of WO
3
O
2 2
mL, AcOH 0.18 mL, 35 °C; (b) TMT (2.2 M), 50% H
HCOOH 0.5 mL, 25 °C; and (c) as in Table 2, entry 1.
2
3
2
3
3
added to cover WO . The mixture was calcined at 620 °C for 6
h. Then the residue was stored in air overnight. Upon storing,
the mixture adsorbs water from air that leads to its swelling
and makes it easier to be removed from the melting pot. The
solid was mixed with 50 ml of water. The white precipitate was
Conclusions
In summary, we have developed a new method for the
synthesis of the important fine chemical coenzyme Q0 via
oxidation of commercially available 3,4,5-trimethoxytoluene
with 30% H O in MeCN employing acid tetrabutylammonium
removed by filtration. Firstly, 2 ml of 3.25 M H
3 4
PO (W:P = 5
mol/mol), then 3 M HNO were added to the mother liquor
3
until pH reached 7. During the pH adjusting a white precipitate
was formed. The mixture was heated to boiling and then
filtered. The white solid was separated, washed with hot water
2
2
salts of the divanadium-substituted polyoxometalate [γ-
5
PW V O ] as catalyst. Coenzyme Q0 was obtained with
-
1
0 2 40
3
and dried. Then another portion of 3 M HNO was added to
selectivity as high as 73% at 76% arene conversion. The
procedure is affordable, safe and sustainable. The catalyst
system is applicable to oxidation of a variety of di- and
trimethoxyarenes, producing corresponding benzoquinones in
moderate to good yields. Since the presence of acid is crucial
for the catalytic performance, a simple procedure for the
the filtrate until pH reached 7, and a new portion of the white
solid was treated as described above. Total yield of γ-
Cs
7 2
PW10O36·5H O was ca. 80% (17.5 g). The IR spectrum of the
obtained solid corresponded to that of γ-Cs
7
2
PW10O36·5H O
2
4
prepared by the conventional procedure. IR (KBr, cm ):
-1
1
080, 1050, 1025, 937, 892, 829, 755.
TBA H-I. The monoprotonated derivative TBA
40] was prepared according to the procedure reported
preparation of a highly protonated derivative TBA3.5H1.5-I has
4
4
H[γ-
been developed. The use of this derivative enables significant
reduction of the amount of acid co-catalyst without
deterioration of the catalytic performance. The catalyst could
be easily separated from the reaction mixture and recycled
without appreciable loss of activity and selectivity.
2 10
PV W O
2
2
by Kamata et al.
51
with some modifications reported
31
V NMR (MeCN): −581 ppm, P NMR (MeCN):
2
0
elsewhere.
14.1 ppm.
−
+
1.5-I. POM with the increased amount of H , that is
TBA3.5
H
the mixture of mono- and diprotonated forms, TBA
TBA , having an averaged composition of TBA3.5
prepared according to the following procedure. NaVO
145 mg) was dissolved in 12 mL of H O and the pH of the
solution was adjusted to 0.8 with 3 M HCl. Then Cs [γ-
O (1.3 g) was added to the solution, and a yellow
precipitate was formed. The mixture was diluted with 20 mL of
4
H-
I
and
, was
·2H
Experimental
3
H
2
-
I
1.5
H -I
3
2
O
Materials and instrumentation
(
2
3
,4,5-Trimethoxytoluene (97%) and 2,3-dimethoxy-5-methyl-
,4-benzoquinone (99%) were obtained from Aldrich, 2,3-
7
PW10O36]·5H
2
1
dimethoxytoluene (98%) and 2,4,6-trimethoxytoluene (97%)
were purchased from Alfa, 3,5-dimethoxytoluene (99%), 1,2,3-
trimethoxybenzene (98%) and 1,3,5-trimethoxybenzene (99%)
were obtained from Acros. 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
H
3
2
O and the pH of the solution was again adjusted to 0.8 with
M HCl. After separation of an insoluble residue by filtration,
TBABr (474 mg) was added to the liquor. A yellow precipitate
was separated, washed with water and dried in air.
Potentiometric titration with TBAOH (0.39 M in H
the presence of ca. 1.5 acid protons per anion . CHN analysis
calcd (%) for TBA3.5 40]: C 19.4, H 3.7, N 1.4; found:
C 19.1, H 3.45, N 1.4. V NMR (MeCN, 0.005 M): −579 ppm;
2
O) revealed
I
H
2 10
1.5[PV W O
H
2
O
2
(ca. 35 wt.% aqueous solution) was determined
5
1
31
P
iodometrically prior to use. GC analyses were performed using
a gas chromatograph Chromos GC-1000 equipped with a flame
6
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ARTICLE
-1
NMR (MeCN): −13.9 ppm. IR (KBr, cm ): 1623, 1481, 1380, vessels at 60 °C under vigorous stirring (500 rpm).
1
097, 1061, 1039, 964, 911, 876, 805, 700, 535.
TBA -I. The diprotonated derivative
PV 40] was prepared according to the reported M. The reactions were initiated by the addition of H
Concentrations of the reactants were as follows: [substrate] =
[γ- 0.1, [TBA3.5 ] = 0.0025, [HClO ] = 0.00125, and [H ] = 0.2
to a
catalyst and
in 1 mL of MeCN. The oxidation products were identified
3
H
2
TBA
3
H
1.5
-I
4
2 2
O
H
2
2
W
10
O
2
O
2
2
2
procedure: TBA
ml of MeCN and 1 equiv. of HClO
The mixture was diluted with 20 ml of diethyl ether. After by GC–MS and H NMR (Figs. S5-S9). All GC-MS and H NMR
4
[γ-HPV
2
W
10
O40] (150 mg) was dissolved in 2 mixture containing aromatic substrate, TBA3.5
1.5
H -I
4
was added to the solution. HClO
4
1
1
7
,8
precipitation of yellow oil, the mother liquor was separated. spectra are in accordance with the reported data. The
The oil was dried under vacuum to obtain yellow crystals of substrate conversions and product yields were quantified by
5
1
31
1
TBA
ppm. IR (KBr, cm ): 1630, 1480, 1380, 1090, 1062, 1042, 1015, standard. Each experiment was reproduced at least two times.
67, 876, 805, 700, 536. It should be noted, however, that
scaling up of this synthesis protocol to obtain a sufficient
quantity of crystalline TBA -I was not successful.
Other POMs. TBA [γ-SiW10 (μ-OH) ] was synthesized 2,3-Dimethoxy-5-methyl-1,4-benzoquinone: H NMR (400 MHz;
3
following the protocol described by Nakagawa et al. CDCl , 25 °C): δ 6.41 (q, J = 1.9 Hz, 1H); 3.91 (s, 3H); 3.89 (s,
3
H
2
-I.
V NMR (MeCN): −579 ppm, P NMR (MeCN): −13.7
H NMR and/or GC using chlorobenzene as the internal
-
1
9
Product characterization
3 2
H
1
4
O
38
V
2
2
2
5
+
Heteropolyacid H
2
literature.
5
PMo10
V
2
O
40 was prepared according to the 3H); 2.07 (s, 3H). GC–MS (EI): m/z 182 (M , 25%), 167 (13), 154
6
(7), 137 (66), 126 (23), 111 (28), 96 (17), 83 (100), 69 (70), 68
(
60).
2,3,4-Trimethoxy-6-methylphenol: GC–MS (EI): m/z 198 (M ,
00%), 183 (95), 168 (10), 155 (16), 140 (61), 137 (23), 122
15), 69 (75).
,4-Dimethoxy-6-methylpyrocatechol (or 2,3-dimethoxy-6-
+
General methods for catalytic oxidation and product analysis
TMT oxidation. Catalytic oxidations of TMT with H in the
presence of TBA H- were carried out in
1
2
O
2
(
4
1.5
I or TBA3.5H -I
3
temperature-controlled glass vessels at 30–80 °C under
vigorous stirring (500 rpm). Concentrations of the reactants
+
methyl-hydroquinone): GC–MS (EI): m/z 184 (M , 96%), 169
100), 154 (15), 141 (19), 137 (13), 126 (60), 123 (27), 69 (85).
(
were in the range of [TMT] = 0.05–0.2, [
HClO ] = 0–0.025, and [H ] = 0.1–0.45 M. Typically, the
reactions were initiated by addition of H either in one
portion or stepwise to a mixture containing aromatic
substrate, , HClO , and internal standard in 1 mL of a solvent
MeCN or its mixture with t-BuOH). Samples were taken during
I] = 0.0013–0.05,
1
2
-Methoxy-5-methyl-1,4-benzoquinone: H NMR (400 MHz;
CD CN, 25 °C): δ 6.52 (q, J = 1.6 Hz, 1H); 5.94 (s, 1H); 3.75 (s,
H); 2.07 (s, 3H). GC–MS (EI): m/z 152 (M , 14%), 137 (4), 122
10), 109 (6), 69 (100).
[
4
2 2
O
3
2 2
O
+
3
(
I
4
1
2
-Methoxy-6-methyl-1,4-benzoquinone: H NMR (400 MHz;
(
3
CD CN, 25 °C): δ 6.49 (m, 1H); 5.89 (d, J = 2.3 Hz , 1H); 3.75 (s,
the reaction course by a syringe and analyzed. The oxidation
1
products were identified by GC, GC–MS and H NMR using
+
3H); 2.07 (s, 3H). GC–MS (EI): m/z 152 (M , 15%), 137 (4), 124
17), 122 (13), 109 (11), 69 (100).
(
authentic samples. The substrate conversions and product
yields were quantified by GC using chlorobenzene as the
internal standard. Each experiment was reproduced at least
two times. The experimental error in the determination of
substrate conversions and product yields by GC normally did
not exceed 2%. Semiquantitative Quantofix peroxide test sticks
1
,6-Dimethoxy-3-methyl-1,4-benzoquinone: H NMR (400 MHz;
2
3
CDCl , 25 °C): δ 5.85 (s, 1H); 3.97 (s, 3H); 3.80 (s, 3H); 1.97 (s,
+
H). GC–MS (EI): m/z 182 (M , 47%), 167 (6), 149 (6), 139 (40),
3
1
2
2
1
2
2
2
11 (21), 83 (83), 69 (100).
1
,3-Dimethoxy-1,4-benzoquinone: H NMR (400 MHz; CH
3
CN,
+
5 °C): δ 6.53 (s, 2H); 3.86 (s, 6H). GC–MS (EI): m/z 168 (M ,
2 2
were used for estimation of the amount of H O at the end of
2%), 153 (11), 123 (28), 82 (20), 69 (100).
1
,6-Dimethoxy-1,4-benzoquinone: H NMR (400 MHz; CDCl
catalytic reactions. Catalyst reusability was examined in 3-fold
scaled experiments (the total reaction mixture volume 3 mL).
The catalyst was separated from the reaction mixture by
precipitation with diethyl ether, dried in air and used
repeatedly with the next portion of the reagents. To isolate
the ubiquinone product, the reaction mixture was diluted with
3
,
+
5 °C): δ 5.84 (s, 2H); 3.81 (s, 6H). GC–MS (EI): m/z 168 (M ,
4%), 138 (22), 125 (55), 97 (14), 80 (16), 69 (100).
Acknowledgements
water followed by extraction with CH
2
Cl
2
. After concentration
was isolated The authors thank Dr. I. E. Soshnikov and Dr. M. V. Shashkov
under vacuum at room temperature, pure CoQ
0
1
by preparative column chromatography on silica gel using for their help with products identification by H NMR and GC–
1
gradient elution with hexane and hexane/ethyl acetate. The H MS, respectively. This work was carried out in the framework
NMR spectrum of the isolated product (Fig. S4 in ESI) was of budget project No. 0303-2016-0005 for Boreskov Institute
identical to that of the authentic sample. The vanadium of Catalysis and partially supported by the Russian Foundation
content in the isolated product was below detection limit of for Basic Research (RFBR grant 13-03-12042).
ICP-AES analysis.
Oxidation of methoxyarenes. Catalytic oxidations of
References
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2
O
2
in the presence of
TBA3.5
H
1.5
-I
were carried out in temperature-controlled glass
1
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TBA5ꢀnH [γꢀPW V O40]
n
10 2
(n = 1ꢀ2)
H O
2 2
/ H+
°
MeCN, 60 C
3,4,5ꢀTrimethoxytoluene
Coenzyme Q0
Conversion 76%
Selectivity 73%
The divanadium-substituted polyoxometalate (Bu
4
N)5-nH
n
[γ-PW10
V
2
O40] (n = 1-2) is an efficient
0
and recyclable catalyst for the synthesis of coenzyme Q using hydrogen peroxide as green
oxidant.