Green Oxidation Process in the Synthesis of LLM-105 with H2O2/Peroxotungstate System and its Theoretical Study

Article abstract of DOI:10.1002/jhet.2044

A new catalytic system was developed and applied to the oxidation reactions involved in the synthesis of LLM-105, in which protonated peroxotungstate combining chitosan was used as catalyst. With H₂O₂as oxidant, good to excellent yields could be achieved in the synthesis of pyrazine-1-oxide, 2,6-dimethoxypyrazine-1-oxide, 2,6-dichloropyrazine-1-oxide, and 2-chloro-6-methoxypyrazine-1-oxide without any addition of trifluoracetic acid, which provided a significant exploration toward novel and environmentally benign synthetic route for LLM-105. Theoretical studies were also carried out with Gaussian 03 to evaluate the oxidation process. All of the calculated data matched well with our experimental results.

Full text of DOI:10.1002/jhet.2044

Month 2016
Green Oxidation Process in the Synthesis of LLM-105 with H O /
1
2
2
Peroxotungstate System and its Theoretical Study
Jie Zhu, Xue-Jing Zhao, Peng-Cheng Wang, and Ming Lu*
Chemical Engineering College, Nanjing University of Science and Technology, Nanjing 210094, China
*
E-mail: luming302@126.com
Received January 29, 2013
DOI 10.1002/jhet.2044
Published online 00 Month 2016 in Wiley Online Library (wileyonlinelibrary.com).
A new catalytic system was developed and applied to the oxidation reactions involved in the synthesis of
LLM-105, in which protonated peroxotungstate combining chitosan was used as catalyst. With H
good to excellent yields could be achieved in the synthesis of pyrazine-1-oxide, 2,6-dimethoxypyrazine-1-oxide,
,6-dichloropyrazine-1-oxide, and 2-chloro-6-methoxypyrazine-1-oxide without any addition of trifluoracetic
2 2
O as oxidant,
2
acid, which provided a significant exploration toward novel and environmentally benign synthetic route for
LLM-105. Theoretical studies were also carried out with Gaussian 03 to evaluate the oxidation process. All of
the calculated data matched well with our experimental results.
J. Heterocyclic Chem., 00, 00 (2016).
INTRODUCTION
volatile liquid at room temperature, which is difficult to dry
and preserve [5].
There is a continuing need for developing energetic
materials because of their numerous military and industrial
applications. The general requirements for these potential
materials mainly include: high density and energy, thermal
stability/storability and low handling hazards (e.g., low
sensitivity to impact, friction, electrostatic discharge, and
low toxicity) [1]. Considering the comprehensive proper-
ties, 2,6-diamino-3,5-dinitropyrazine-1-oxide (LLM-105)
has emerged to show great application prospect because
of the existence of hydrogen bond in and between each
molecule leading to a crystal density at ambient as
However, Scheme 1 uses of plenty trifluoracetic acid to
proceed with the oxidation reaction, which was expensive,
corrosive, and difficult to recover, as well as leading to
bothersome post-treatment and serious environmental
pollution [6]. If LLM-105 could be produced without the
use of trifluoracetic acid, manufacturing cost would be
decreased significantly and easy scale-up would be
achieved. In many countries, much attention has been paid
on the development of new synthetic route of LLM-105, as
well as with the main purpose of avoiding the use of
trifluoroacetic acid [7]. For the same goal, we proposed
three experimental formulas as shown in Scheme 2 (route
1, 2, and 3), expecting to find a better design route. The
synthetic routes went through similar procedures including
nitration and ammoniation, and the oxidation process
became a pivotal step.
Herein, in this paper, a new catalytic system was devel-
oped and applied to the oxidation reactions involved in the
synthesis of LLM-105, in which protonated peroxotungstate
combining CS was used as catalyst. Good to excellent yields
could be achieved with pyrazine, 2,6-dimethoxypyrazine,
2,6-dichloropyrazine, and 2-chloro-6-methoxypyrazine as
substrates. Trifluoracetic acid was avoided completely in
the reactions that represent a significant step towards the
3
high as 1.91 g/cm . And its energy was 20% higher than
that of 2,4,6-triamino-1,3,5-trinitrobenzene (TATB) but
showed similar impact sensitivity with TATB [2].
The Lawrence Livermore National Laboratory had
got outstanding achievements for energetic materials
researches and synthesized LLM-105 completely for the first
time in 1995, which was published several years later [3].
After that, P. F. Pagoria improved the synthetic route of
LLM-105 as shown in Scheme 1 to achieve higher yields,
fewer steps, and shorter reaction period [4]. Then in 2001,
on the base of Scheme 1, Tran and Li further modified the
synthetic route by using 2,6-dimethoxypyrazine instead of
the intermediate 2-chloro-6-methoxypyrazine (1), a highly
©
2016 Wiley Periodicals, Inc.

2
J. Zhu, X-J. Zhao, P-C. Wang, and M. Lu
Vol 000
Scheme 1. Synthetic route of LLM-105 improved by P. F. Pagoria.
Scheme 2. Proposed synthetic route for LLM-105 to avoid trifluoroacetic acid.
new synthetic route for LLM-105. And theoretical studies
were carried out to explore the influence of functional groups
on pyrazine to the oxidation process. The energy and natural
bond orbital (NBO) was investigated to describe the nature
of the intermediates.
with different cations were prepared and tested because
TPAOH, the raw material of TPA [H{W O (O ) (m-O)} ],
3
2
2
2 4
2
is a little expensive for industrial production. Instead,
hexadecyl trimethyl ammonium bromide and tetrabutyl
ammonium bromide were tried respectively. Catalysts
were obtained through filtration after the protonation
process. The yields for catalyst preparation with CTA
and TBA cations, however, were very low as both
hexadecyl trimethyl ammonium bromide/HWO and
tetrabutyl ammonium bromide/HWO could dissolve a
little in water. Water addition would not facilitate the
separation of catalysts, and thus the catalyst isolation
remained to be a problem.
Chitosan (CS), a linear polymer of (1-4)-linked 2-amino-
2-deoxy-gucopyranose, is generally regarded to be
nontoxic, biocompatible, and biodegradable. The free
amines in CS provide various opportunities for chemical
modification to obtain different CS derivatives [10], which
makes CS an excellent candidate to serve as the cation of
prontonated peroxotungstate.
RESULTS AND DISCUSSION
Preparation and characterization of the catalyst. Recently,
peroxotungstate has emerged as an effective catalyst for
selective oxygen transfer to organic substrates with H O2
2
as a terminal oxidant [8]. Despite of the high activity, the
utilization of H O is relativity low because excessive
2
2
H O was needed. To circumvent the problem, Ishimoto
2
2
developed a protonated peroxotungstate TPA [H{W O
2 2
3
+
(
O ) (m-O)} ] (TPA = [(n-C H ) N] ), which showed
2 4 2 3 7 4
high catalytic activity and increased the utilization rate of
H O [9]. To introduce the system into the oxidation of
2
2
pyrazine derivatives, prontonated peroxotungstate catalyst
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Synthesis of LLM-105 with H O /Peroxotungstate and its Theoretical Study
3
2
2
The IR spectrum (Fig. 1) of CS/HWO (line d) showed
detectable peaks that are characteristic of CS (line b)
of weight loss reduced obviously, which was supposed to
be because of the existence of protonated peroxotungstate,
indicating the successful combination process. At around
À1
around 1150 and 3460cm . IR bands belong to the W-O
À1
ꢀ
vibrations at 803 and 895 cm were also exhibited in CS/
300 C, the TG curve of CS/HWO was not as sharp as that
HWO [11], which clearly differed from that of H WO4
of pure CS and CS/WO with a little advanced weight loss
as well. This was probably attributed to the protonation
process with the introduction of H to every peroxotungstate,
leading to an increased proportion of W along with a
decreased weight loss.
2
(
line a). Minor differences could be detected as well
at these bands when compared with that of CS/WO
line c), suggesting the successful protonation process
(
of CS/WO. These facts are consistent with the synthesis
design and confirm the successful combination of CS
and protonated peroxotungstate.
The affecting factors in oxidation process. To screen
the optimal oxidation conditions, key factors that
affecting the oxidation process were fully evaluated
with 2,6-dichloropyrazine as model substrate, including
the catalytic system, the amount of H O , the amount
Thermogravimetric (TG) studies showing the TG curves
for CS/HWO, CS/WO, and pure CS were also carried out
to help to characterize the catalyst as shown in Figure 2.
2
2
ꢀ
Within 200 C, the weight loss was probably attributed
of catalyst (Fig. 3), and the temperature.
completely to the absorbed water molecules. The catalyst
CS/HWO went through a similar process of weight loss
compared with that of pure CS, whereas the total amount
Catalytic system no doubt had a fundamental influence
on the oxidation process. Comparative experiments under
different catalytic systems mentioned previously were
carried out as listed in Table 1. It was found that almost
no product was obtained in acetonitrile only without any
catalyst (entry 2) or with CS only without peroxotungstate
(
entry 3). Oxidation yield remained almost constant when
altering the cation of protonated peroxotungstate (entries
–7). The yield of catalyst preparation, however, differs
4
much with CS/HWO exhibiting the highest preparation
yield because of its immiscibility with water. Taken that
into consideration, CH CN–CS/HWO system showing
3
the highest multiplied yields was chosen for the following
oxidation process. Comparable results could be obtained
under CF COOH–H O and CH CN–CS/HWO–H O
2 2
3
2
2
3
systems, suggesting that novel oxidation process for
4
000
3000
2000
1000
synthesis of LLM-105 intermediates without CF COOH
was possible to be achieved.
3
-
1
Wavenumbers (cm )
Under the CH CN–CS/HWO system, synthesis of 2,6-
3
Figure 1. IR spectrum of (a) H WO ; (b) chitosan (CS); (c) CS/WO;
2
4
dichloropyrazine-1-oxide with variant reaction conditions
were further conducted, and the results are summarized in
Table 2. CS/HWO of catalytic amount was enough to initiate
and (d) CS/HWO. [Color figure can be viewed in the online issue, which
is available at wileyonlinelibrary.com.]
100
1
00
8
6
4
2
0
0
0
0
0
8
6
4
2
0
0
0
0
0
2
00
400
Temperature ( C)
600
800
o
0
1
2
3
4
5
6
Amount of CS (g)
Figure 2. TG curves of (a) CS/HWO; (b) CS/WO, and (c) pure CS.
Color figure can be viewed in the online issue, which is available at
wileyonlinelibrary.com.]
[
Figure 3. Synthesis of 2,6-dichloropyrazine-1-oxide catalyzed by
CS/HWO with different amounts of CS.
Journal of Heterocyclic Chemistry
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J. Zhu, X-J. Zhao, P-C. Wang, and M. Lu
Vol 000
Table 1
Synthesis of 2,6-dichloropyrazine-1-oxide under different catalytic systems .
The effect of the reaction time on the oxidation was a
little complicated. The yield was not simply growing and
leveling off when prolonging the reaction time. Maximum
production of 1-oxo-2,6-dichloropyrazine was obtained at
a
4
h, whereas after that, the yield went down, probably
because of the generation of a salt between substrate 1-
oxo-2,6-dichloropyrazine and CS/HWO. Because the
catalyst was peroxotungstate itself, once the oxidation
process completed, the product may experience a
trans-salifying process. So for the oxidation of pyrazine
derivatives under this system, reaction termination
should be exactly controlled.
The oxidation efficiency with CS/HWO of different CS
amounts was also studied. As mentioned previously, there
are many free amines in CS so the amount of it could be
modified. As illustrated in Figure 4, CS alone hardly showed
any activity in the oxidation of 2,6-dichloropyrazine and a
maximum activity was observed with 3 g CS when 4 mmol
tungsten was used. With higher amount of CS, despite
of the high dispersion of catalyst, the active species
was not sufficient for the reaction. On the other hand,
with lower amount, the aggregation of peroxotungstate
lowered the dispersion, leading to a reduced conversion.
Therefore, 3 g CS was used for catalyst preparation used
in the following investigation.
Multiplied
yield/%
Entry
Oxidation system
t/h
Yield/%
1
2
3
4
5
6
7
CF
CH
CH CN–CS
3
CN–CS/HWO
3
COOH
2
12
12
4
7
5
89
trace
trace
73
70
71
89
trace
trace
62
29
33
3
CN
3
CH
CH
CH
3
CN–CTA/HWO
CN–TBA/HWO
3
CH
3
CN–TPA/HWO
4
75
57
a
Reaction conditions: 2,6-dichloropyrazine 10 mmol, solvent 30 mL, 30%
ꢀ
H
2
O
2
5 mL was added five times equably during the reaction time, 60 C.
Table 2
a
Synthesis of 2,6-dichloropyrazine-1-oxide with variant reaction conditions .
The CH CN- CS/HWO system undoubtedly played an
3
important role in exploring novel oxidation steps for syn-
thetic of LLM-105. Based on these results, oxidation of
2
6
,6-dichloropyrazine, 2,6-dimethoxypyrazine and 2-chloro-
-methoxypyrazine were tested respectively to explore novel
synthetic pathway for LLM-105 without CF COOH. Good
3
CS/HWO
(mmol)
30%
T
t
Conv Yield
ꢀ
to excellent results were achieved with CS/HWO as catalyst
and H O as oxidant under the optimized reaction condi-
Entry
H
2
O
2
(mL) ( C) (h)
(%)
(%)
2
2
1
2
3
4
5
6
7
8
9
0.05
0.1
0.2
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
5
5
5
1
3
60
60
60
60
60
60
60
25
40
80
60
60
60
6
5
5
8
8
4
4
12
8
4
98
100
100
82
66
69
69
43
48
70
73
36
49
72
54
65
58
tions. As can be seen from Table 3, the best reaction time
for 2,6-dichloropyrazine, 2,6-dimethoxypyrazine, 2-chloro-
6-methoxypyrazine and pyrazine was 4, 2, 3, and 3 h, respec-
tively. 2,6-dimethoxypyrazine was oxidized the fastest
among the pyrazine derivatives tested, probably because of
96
10
5
5
5
8
5
5
5
100
100
51
70
100
83
b
b
b
b
b
b
b
the electron donating effect of –OCH , leading to a high
3
cloud density on the N atom so as to be easily oxidized.
And for all of the four substrates, only mono-oxidation
products could be obtained.
1
1
1
1
0
1
2
3
2
8
12
100
100
On the basis of some previous studies [9,12], a possible
mechanism for the aerobic oxidation of alcohols in the
system was proposed. The catalyst is reduced by substrate
to generate a reduced form (in particular the valent change
of W). At the same time, substrate is oxidized to generate the
product N-oxide. Finally, the catalytic cycle is completed by
the reoxidation of HWOred to the peroxotungstate by using
H O . Simplified procedure for the catalytic degradation is
a
Reaction conditions: 2,6-dichloropyrazine 10 mmol, CH
H O 5 mL was added five times equably during the reaction time.
2 2
3
CN 30 mL.
b
the reaction and further increasing of the amount was not that
meaningful (entries 1–3). Excessive H O and high temper-
ature were obviously beneficial to the reaction (entries 4–6
and 8–10), but at the same time, high temperature would
accelerate the decomposition of H O and more H O would
2
2
2
2
generalized as shown in Scheme 3.
2
2
2
2
To further study the oxidation processes, theoretical
calculations of the intermediates involved in the synthetic
routes were performed.
be required to complete the reaction. So better results were
achieved when H O was added in batch (entry 7).
2
2
Journal of Heterocyclic Chemistry
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Month 2016
Synthesis of LLM-105 with H O /Peroxotungstate and its Theoretical Study
5
2
2
Figure 4. Second order perturbation (SOP) of 2,6-dichloropyrazine, 2,6-dimethoxypyrazine, and 2-chloro-6-methoxypyrazine. [Color figure can be
viewed in the online issue, which is available at wileyonlinelibrary.com.]
Table 3
a
Synthesis of oxides of pyrazine derivatives under the optimum reaction conditions
ꢀ
Entry
1
Substrate
Product
t(h)
4
Conv (%)
100
Yield (%)
73
mp ( C)
121–122
2
3
2
3
100
100
74
69
114–115
—
4
3
100
62
90–91
a
Reaction conditions: substrate 10 mmol, CH
3
CN 30 mL, CS/HWO 0.1 mmol (about 0.2 g), 30% H
2
O
2
5 mL was added five times equably during the
ꢀ
reaction time, 60 C.
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J. Zhu, X-J. Zhao, P-C. Wang, and M. Lu
Vol 000
Scheme 3. The proposed mechanism for oxidation process.
intermolecular hydrogen bond was not considered in this
single molecular model. The high stable energy meant that
the molecule was more sensitive than the precursors. This
sensitivity was the potential cause of dangerous accidents
although it showed a good explosive performance.
The electron cloud density was reflected by the possibil-
ity of a single electron in a position. So the higher the data
of the density, the greater the possibility of the occurrence
of electrons would be. The six peripheral electrons of O
atom, not full to be eight, led to an easy coordination to
the N atom, as the electron on the N atom was relatively
abundant compared with the whole pyrazine ring. That
is to say, high electron density may be beneficial to
the oxidation process. The charge distribution of 2,6-
dichloropyrazine, 2,6-dimethoxypyrazine, 2-chloro-6-
methoxypyrazine, and their oxidized products were listed
in Figure 6, respectively. It was found that the N atom in
2,6-dimethoxypyrazine exhibited the highest electron
density attributed to the electron donating property of
The stabilities of molecules measured by zero point
energy (ZPE) were calculated to evaluate the possibility of
the proposed synthetic routes as shown in Figure 5. The lower
the energy in value, the greater stability the molecule would
obtain. As can be seen, the –OCH group could obviously
3
reduce the energy owing to its electron-donating property
and the energy of 2,6-dimethoxypyrazine and 2-chloro-6-
methoxypyrazine decreased to À675.5 and À759.1 kJ/mol,
respectively. After oxidation, the energies decreased
again, probably because of the coordination of peripheral
electron of O to N atom, leading to the greater stability
of the whole molecule. The stability of the oxidized form
still followed the order of 2,6-dimethoxypyrazine > 2-
chloro-6-methoxypyrazine > 2,6-dichloropyrazine. In the
view of energy transformation, 2,6-dimethoxypyrazine
was the easiest to be oxidized with the smallest ΔE of
the –CH group, followed by 2-chloro-6-methoxypyrazine
3
and 2,6-dichloropyrazine, respectively. After the oxidation
process, the electron density on the N atom decreased
greatly because of the coordination of electrons between
the N and O atom. So in the view of charge distribution,
2,6-dimethoxypyrazine was still the easiest to be oxidized,
which matched well with the experimental results and
ZPE analysis mentioned previously.
All functional groups introduced into pyrazine could
affect the property of molecule from many aspects, such
as electron-withdrawing or donating and interaction to
other groups [13]. The former determined the reaction
difficulty in the next step including the oxidation step,
whereas the later was related to the stability of the whole
molecule [14]. NBO calculated with Gaussian 03 provides
3
78.9 kJ/mol, which was in accordance with the experimen-
tal results. The introduction of the energy group –NH would
2
also greatly increase the stable energy in the last step for the
systhesis of LLM-105, yet its positive effect especially
Figure 5. The stable energy of each molecule in route 1, 2, and 3. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Journal of Heterocyclic Chemistry
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Synthesis of LLM-105 with H O /Peroxotungstate and its Theoretical Study
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2
2
Two groups of lone pair electrons in each Cl atom were
shared with C–C and C–N antibonding orbital respectably.
This interaction focused mainly on the C2 or C3 atom of
2
,6-dichloropyrazine that could be seen obviously in
Figure 6 that the electron cloud showed partiality for C
atom. When –OCH3 was introduced into pyrazine,
pyrazine turned to accept the electron from –OCH and
3
another interaction center was formed at C3 of 2-chloro-6-
methoxypyrazine, resulting in the weakened effect of Cl as
demonstrated in Figure 3 that the electron cloud was not as
tendency to C atom as that in 2,6-dichloropyrazine. The
two –OCH3 groups in 2,6-dimethoxypyrazine played
the same role as in 2-chloro-6-methoxypyrazine, sharing
the “exploitation” of electron by pyrazine. Thus, a decrease
in E(CH O – pyrazine) was witnessed from 0.302 to 0.259.
3
Comparing the total interaction of these functional groups,
the value of E in 2,6-dimethoxypyrazine (0.259Â 2)
with two electron-donating groups was higher than both
2,6-dichloropyrazine and 2-chloro-6-methoxypyrazine
Figure 6. Charge distribution of C and N in the pyrazine ring. [Color
figure can be viewed in the online issue, which is available at
wileyonlinelibrary.com.]
(0.192 Â 2, 0.184 + 0.302), which enriched the electronic
density of pyrazine so as to be beneficial for oxidation.
Based on the calculation results to compare the proposed
routes, the two methoxy groups (in route 1) were beneficial
to the oxidation process, and route 1 should be the most
reliable one of the three. The energy transfer of oxidation
process, the electron density on the N atom and the interac-
tion between functional groups and pyrazine all indicated
the possibility for the oxidation process to follow the order
of 2,6-dimethoxypyrazine > 2-chloro-6-methoxypyrazine
pyrazine > 2,6-dichloropyrazine, showing the consistent
theoretical and experimental results.
a novel method for us to describe and explain the relative
phenomenon [15]. Some important calculation results of
the substrates were listed in Table 4. The interaction
between donor NBO (i) and acceptor NBO (j) was
described by stabilization energy Ei-j on the basis of the
second order perturbation theory [16]. The higher the value
of E was, the stronger their interaction would be, and thus
i-j
the electrons were more likely to be shared by two orbital.
Also Figure 3 gave visual statements of this interaction on
the basis of the values in the tables. E showed the intensity
of interaction and its change was similar with Ei-j.
For 2,6-dichloropyrazine, though Cl atom itself was an
electron-withdrawing group, pyrazine showed a stronger
electron-deficient property and thus became an acceptor.
CONCLUSION
In conclusion, we have developed a new catalytic system
for the oxidation reactions involved in the synthesis of LLM-
1
05, with protonated peroxotungstate combining CS as the
catalyst. Different from the traditional oxidation process in
the synthetic route for LLM-105, trifluoracetic acid was
avoided completely and thus provided a significant explora-
tion towards novel synthetic route for LLM-105. Also, all
intermediates involved in oxidation process and synthesis
of LLM-105 were evaluated by Gaussian 03 NBO, charge
distribution, and ZPE were discussed to describe the com-
plexity of the oxidation process for 2,6-dichloropyrazine,
Table 4
Natural bond orbital (NBO) of 2,6-dichloropyrazine,
,6-dimethoxypyrazine, 2-chloro-6-methoxypyrazine.
2
Donor
NBO (i)
Acceptor
NBO (j)
Ei-j
(kcal/mol)
Groups
2
,6-dichloropyrazine
Cl – pyrazine:
LP (3) Cl9
BD*(2) C3–C4
12.04
14.14
LP (3) Cl10 BD*(2) C2–N7
,6-dimethoxypyrazine
CH O – LP (2) O17
pyrazine:
2
-chloro-6-methoxypyrazine, 2,6-dimethoxypyrazine re-
2
spectively. All of the theoretical data matched well with
experimental results. And synthesis of other N-oxides
under CS/HWO system is still ongoing.
3
BD*(2) C3–C4
32.05
39.45
LP (1) O18 BD*(1) C2–N7
-chloro-6-methoxypyrazine
2
Cl – pyrazine:
LP (3) Cl9 BD*(2) C2–N8
LP (2) Cl9 BD*(1) C2–N8
13.50
5.25
EXPERIMENTAL SECTION
3
CH O –
LP (2) O10
BD*(2) C3–C4
35.19
pyrazine:
Materials and methods.
employed in the work were used as received from Sinopharm
All the solvents and reagents
LP (1) O10
BD*(1) C3–C4
7.10
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J. Zhu, X-J. Zhao, P-C. Wang, and M. Lu
Vol 000
Chemical Reagent Co., Ltd (China) unless otherwise stated. NMR
spectra were recorded on Bruker DRX500 spectrometer (Bruker,
Zürich, Switzerland). IR spectra were recorded on NICOLET
NEXUS870 (Nicolet Company, USA). TGA was performed on
TGA/SDTA851e (Mettler Toledo, Switzerland) under air
The residue was then extracted with CH Cl2 for three times
2
and the combined organic washings were dried over MgSO4,
filtered, and concentrated in vacuo. Further purification
was carried out by using column chromatography. For 1-oxo-
2,6-dichloropyrazine petroleum ether (PE): EtOAc = 8:2,
ꢀ
ꢀ
1
atmosphere from 50 to 800 C, with a heating rate of 20 C/min,
and an air flowing rate of 30 mL/min.
H-NMR (500 M, CDCl ) d ppm: 1.59 (s, 1H), 8.08 (s, 1H);
3
1
3
C-NMR (125 M, CDCl ) d ppm: 131.94, 149.49. For 1-oxo-
3
1
2
,6-dimethoxypyrazine, PE: EtOAc = 8:2; H-NMR (500 M,
Preparation of the catalyst. A suspension of H
2
WO
4
(1 g,
13
3
CDCl ) d ppm: 3.98 (s, 6H), 7.47 (s, 2H); C-NMR (125 M,
4
3
mmol) in 30% aqueous H
2 C for 90 min until a pale yellow solution was obtained.
2
O
2
(4 mL, 40 mmol) was stirred at
CDCl ) d ppm: 53.90, 115.32, 161.18. For 1-oxo 2-chloro-6-
ꢀ
3
1
methoxypyrazine, PE: EtOAc = 5:5; H-NMR (500 M, CDCl )
3
Chitosan (CS, deacetylated degree 85 ~ 95 wt.%, viscosity
0 ~ 800 mPa s, 3 g) dissolved in 40 mL H O was added into the
d ppm: 4.01 (s, 6H), 7.6997–7.7019 (m, 1H), 7.8095–7.8116
5
2
13
(
3
m, 1H); C-NMR (125M, CDCl ) d ppm: 54.72, 121.07,
solution. The resulting solution was stirred for another 30 min
before filtration to get yellow precipitate of CS immobilized
peroxotungstate CS/WO. For the protonation process, CS/WO
1
26.93, 147.26, 162.00. For 1-oxo-pyrazine, methanol:
1
EtOAc= 5:95; H-NMR (500 M, CDCl ) d ppm: 8.1162–8.1261
3
13
(
m, 2H), 8.4801–8.4895 (m, 2H); C-NMR (125 M, CDCl ) d
3
(
2
(
1.5 g, about 1.2 mmol for tungsten), and 70% HNO3 (0.18 g,
mmol) were dissolved in a solution of 30% aqueous H
1 mL) in DMSO (10 mL). After it was stirred for 30 min,
ppm: 133.71, 136.06, 147.23, 147.47.
2 2
O
Computational details. B3LYP/6-31G++(d,p) were carried
26
excessive water was added to the mixture with white crystals
generated. Then the white solid of protonated peroxotungstate
CS/HWO was obtained through filtration
out using Gaussian 03. Global minima of structures for use were
first computed and listed in the Supporting Information. ZPE with
enthalpy corrections and NBO based on these structures were
used to determine the energy surface and interaction between
the functional groups of each molecule.
Synthesis of 2,6-dimethoxypyrazine. 2,6-dichloropyrazine
(
1.49 g, 10 mmol) was added to into a fresh sodium methylate–
methanol solution (25% wt.%, 1.16 g Na, 12.2 mL methanol) at
ꢀ
0
C, and the reaction mixture was heated at reflux for 3 h. After
cooling down, the mixture was poured into 100 mL ice–water
mixture and filtrated. The filtrate was extracted with CH Cl
Acknowledgments. We thank the NSAF and NSFC of China
(no. 11076017) and the Scientific Innovation Program of Jiangsu
Province (no. CXZZ11_0264) for support of this research.
2
2
(
3Â 20 mL) and combined with the filter cake dissolved in
dichloromethane, followed by drying over anhydrous
magnesium sulfate. The colorless solid was obtained by vacuum
distillation with a yield of 1.36 g (97%), mp 29–30 C. H-NMR
ꢀ
1
REFERENCES AND NOTES
13
(
(
500M, CDCl
125 M, CDCl
3
) d ppm: 3.88 (s, 6H), 7.71 (s, 2H); C-NMR
) d ppm: 52.96, 123.98, 158.46.
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3
(b) Fried, L. E.; Manaa, M. R.; Pagoria, P. F.; Simpson, R. L. Annu Rev Mater
Synthesis of 2-chloro-6-methoxypyrazine.
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,6-Dichloropyrazine (1.49 g, 10 mmol) was added to
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2
a
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3
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ꢀ
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3
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saturated NaCl solution (20 mL) and CH
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2
Cl
2
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2
(
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4
2
[5] (a) Tran, T. D.; Pagoria, P. F.; Hoffman, M. D.; Cunningham,
1
H-NMR (500 M, CDCl ) d ppm: 3.99 (s, 3H), 8.13 (s, 1H),
3
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3
8
.15 (s, 1H);
C-NMR (125 M, CDCl ) d ppm: 53.87,
3
1
32.70, 134.68, 145.03, 159.20.
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(
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3
three-neck flask. 30% H O (5 mL) was added five times
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2
2
equably during the reaction time. The reaction was initiated by
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ꢀ
allowed to go on at 60 C temperature for a certain time. The
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drying, the catalyst could be reused without further treatment.
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Month 2016
Synthesis of LLM-105 with H O /Peroxotungstate and its Theoretical Study
9
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2
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet