Selective Aerobic Oxidation of 4-Ethylnitrobenzene to 4-Nitroacetophenone Promoted by Metalloporphyrins

Article abstract of DOI:10.1021/acs.oprd.9b00030

A solvent-free and environment-friendly process for the oxidation of 4-ethylnitrobenzene to 4-nitroacetophenone promoted by metalloporphyrins was developed in a pressure reactor using O₂ as a clean oxidant. The activities and reaction selectivities of the metalloporphyrins could be significantly affected by their central metal ions as well as the nature and position of the substituted groups, which were systematically investigated by employing more than 60 metalloporphyrins. Generally, the Fe(III)- and Mn(II)-porphyrins exhibited high activities. Moreover, metalloporphyrins with electron-withdrawing substituents on the para-positions of the phenyl rings showed activities in the order T(p-Br)PPM < T(p-Cl)PPM < T(p-F)PPM. The substituent position effect on the activities of T(o-Cl)PPM > T(m-Cl)PPM > T(p-Cl)PPM and T(o-OMe)PPM < T(m-OMe)PPM < T(p-OMe)PPM were observed. Furthermore, selectivities over 90.0% and a TON of 5370 could be achieved for the desired ketone. Especially, the T(p-Cl)PPMn demonstrated a selectivity of up to 93.6% and a conversion of 51.9% with only 3.3% acid and no alcohol observed, and the selectivity was nearly the same for a large-scale experiment (100 g).

Full text of DOI:10.1021/acs.oprd.9b00030

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Communication
Selective Aerobic Oxidation of 4-Ethylnitrobenzene to
-Nitroacetophenone Promoted by Metalloporphyrins
4
Yuning Yang, Guijie Li, Xinbiao Mao, and Yuanbin She
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.9b00030 • Publication Date (Web): 08 Mar 2019
Downloaded from http://pubs.acs.org on March 10, 2019
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Selective Aerobic Oxidation of 4-Ethylnitrobenzene
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to
4-Nitroacetophenone
Promoted
by
Metalloporphyrins
Yuning Yang, Guijie Li*, Xinbiao Mao, Yuanbin She*
State Key Laboratory Breeding Base of Green Chemistry-Synthesis Technology, College of
Chemical Engineering, Zhejiang University of Technology, Hangzhou, Zhejiang 310014, China
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ABSTRACT: A solvent-free and environment-friendly process for the oxidation of 4-
ethylnitrobenzene to 4-nitroacetophenone promoted by metalloporphyrins was developed in
pressure reactor using O as clean oxidant. The activities and reaction selectivities of the
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metalloporphyrins could be significantly affected by their central metal ions, the nature and
position of the substituted groups, which were systematically investigated by employing more
than 60 metalloporphyrins. Generally, the Fe(III)- and Mn(II)-porphyrins exhibited high
activities. Moreover, metalloporphyrins with electron-withdrawing substituents on the para-
positions of the phenyl rings showed activities with an order of T(p-Br)PPM < T(p-Cl)PPM <
T(p-F)PPM. The substituent positions effect on the activities of T(o-Cl)PPM > T(m-Cl)PPM >
T(p-Cl)PPM, and T(o-OMe)PPM < T(m-OMe)PPM < T(p-OMe)PPM were observed.
Furthermore, selectivites over 90.0% and TON of 5370 could be achieved for the desired ketone.
Especially, the T(p-Cl)PPMn demonstrated a selectivity of up to 93.6% and a conversion of
5
1.9% with only 3.3% acid and no alcohol observed, and the selectivity was nearly keeping the
same for a large-scale experiment (100 g).
KEYWORDS: solvent-free, aerobic oxidation, 4-ethylnitrobenzene, 4-nitroacetophenone,
metalloporphyrin, ARC
INTRODUCTION: Selective side-chain oxidation of alkyl aromatic compounds to valuable
ketones, alcohols, aldehydes or carboxylic acids catalyzed by designed catalysts has been
attracting a great deal of attentions in recent years.1-3 4-Nitroacetophenone is an essential
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intermediate for pharmaceutical industry, agricultural and widely used in synthesizing chirality
compounds.4-6 The 4-nitroacetophenone cannot be synthesized through Friedel–Crafts acylation
of cheap nitrobenzene, thus, direct constructing carbonyl from 4-ethylnitrobenzene through
highly selective oxidation of C-H bond is one of the most efficient method to prepare 4-
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nitroacetophenone. Traditionally, stoichiometric amount of hazardous oxidants, such as
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KMnO , H O TBHP or Ozone were employed in direct oxidation inert α-H of alkylarenes
4
2
2,
catalyzed by metal catalysts,12 nanometer materials,13 MOFs,14 mesoporous materials15 or
organic metal compounds16 and great progress has been made. The oxidation of 4-
ethylnitrobenzene to 4-nitroacetophenone were also developed by using various of catalysts, like
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sodium o-iodobenzenesulfonate, co-doped material, cis-[Ru(dtbpy) Cl ] and nanocatalyst.
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However, some problems are still needed to be resolved, for example, the development of
environmentally friendly oxidants and mild reaction conditions, the design of economical
catalysts and enhancement of the reaction selectivity.
In contrast, molecular oxygen as a clean, and atom-economical oxidant for large-scale
21
production has attracted considerable attentions in chemical industry. However, the triplet-state
nature of molecular oxygen hampers its reaction with hydrocarbon molecule in singlet state,
hence, the aerobic oxidation processes are largely dependent on the development of catalysts to
22
realize the preparation of corresponding products. Moreover, because of the unique chemical
and physical properties, metalloporphyrins have played an important role in molecule bonding,23
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photochemical catalysis, biomimetic catalyst, and especially the selective aerobic oxidation
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reactions. Inspired by the distinctive molecular structure and capability of heme and related
enzymes,27-34 several mono-substituted or multi-substituted tetraphenyl porphyrins bionic
catalytic systems have been reported.35 Many specific advantages of metalloporphyrins in
oxidation systems have been demonstrated, like easily modified molecular structures,36 low
catalyst loading,37 high reaction selectivity.38 Metalloporphyrins promoted highly selective
functionalization of the side-chain C-H bond of alkyl aromatic compounds provides an
environmentally friendly and convenient approach for the biomimetic catalytic oxidation
reactions. However, systematic investigation of the effect of ring-substituent groups and their
positions on the catalytic activities and selectivities of the metalloporphyrins is quite rare.
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The aerobic oxidation of 4-ethylnotrobenzene (1) is a very complicated reaction process
(Scheme 1) involving radical mechanism. Besides the desired product 4-nitroacetophenone (2),
there may be also other byproducts, like 1-(4-nitrophenyl)ethanol (3), 4-nitrobenzaldehyde (4),
and 4-nitrobenzoic acid (5) (Scheme 1). To increasing the selectivity of the aerobic oxidation, we
tried to regulate the central metal irons, the substituent groups and their positions of
metalloporphyrins to realize a considerable catalytic activity and selectivity.
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Scheme 1. Aerobic Oxidation of 4-Ethylnitrobenzene Promoted by Metalloporphyrins.
O
OH
CHO
COOH
cat. metalloporphyrin
O (1.8 MPa)
2
+
+
+
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40 C, 6 h
solvent-free
NO2
NO2
NO2
NO2
NO2
1
2
3
4
5
R
R
R
N
N
N
N
M
M = Mn, Fe(Cl), Co, Ni, Cu, Zn
R = NO , CN, F, Cl, Br, Me, Et, OMe, OH
R
2
EXPERIMENTAL SECTION
The oxidation of 4-ethylnitrobenzene with pure O gas (1.8 MPa) was performed in a pressure
2
reactor with solvent-free. Compared with the reported procedure in an open reactor with O gas
2
bubbling, this solvent-free procedure can save a plenty of O gas, and avoid the loss of 4-
2
ethylnitrobenzene. Importantly, this can significantly reduce emission of organic pollutants and
solid waste to the surrounding environment, and avoid the explosion risk caused by high
concentration of organic emissions.
Chemicals and reagents. All commercial reagents were purchased and used without further
purification. Oxygen (99.99% of purity) provided by Jingong Gas Company in Hangzhou of
China.
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General procedure of 4-ethylnitrobenzene oxidation. The aerobic oxidation of 4-
ethylnitrobenzene was carried out in a 100 mL pressure reactor. In a typical experiment, 4-
ethylnitrobenzene (4.53 g, 30 mmol) and metalloporphyrin (0.01 mol%) were charged to the
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pressure reactor. After being sealed tightly, the pressure reactor was flushed with O gas to 0.4
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MPa, and then the gas was released very slowly to avoid the loss of the 4-ethylnitrobenzene. This
procedure was repeated once again and then the reactor was pressurized with O gas to 1.8 MPa.
2
o
Then the pressure reactor content was heated to 140 C in an oil bath and stirred at 140 rpm for
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.0 h. After that, the pressure reactor was taken out of the oil bath and cooled down to room
temperature. Then the excess O gas was released slowly to give the reaction mixture containing
2
oxidation products and the 4-ethylnitrobenzene.
Safety concerns. Aerobic oxidation of hydrocarbons is usually exothermic reaction. For safety
reasons, the thermal stabilities of the reactant, products and reaction mixture were typically
screened by thermogravimetric analysis (TGA), differential screening calorimetry (DSC) and
accelerating rate calorimetry (ARC) (Figure 1 and S2). The TGA of ketone 2 showed an
o
obviously weight lost at about 145 C due to thermal volatilization. However, acid 5 exhibited a
o
significantly decomposition at 245-250 C (Figure 1a, b). The ARC test curves showed an
o
exotherm event and pressure raising at about 250 C, which could be attributing to the gas
generation, like nitrogen oxides and carbon oxides, from the decomposition of the acid 5. This
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was also consistent with the TGA result. Fortunately, the reaction temperature in this work is less
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than 145 C, without the risk of explosion.
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(
c)450
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(
a)1.0
Temperature
Pressure
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00
50
Test termination
Self-heating up
3
0.8
0.6
0.4
4
4
-ethylnitrobenzene (1)
-nitroacetophenone (2)
300
4-nitrobenzoic acid (5)
250
200
150
Exotherm event
Self-heating up
(
b) Compound
m.p.
b.p.
Gas generation
-32 o
245 o
C
100
50
0
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2
5
C
0.2
0.125
78 o
C
C
202 o
---
C
238 o
0.0
0.100
50
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150
200o
250
300
0
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30
40
50
Temperature ( C)
Time (h)
Figure 1. (a) TGA curves for 1, 2 and 5. (b) The melting point (m.p.) and boiling point (b. p.) of
the 1, 2 and 5 at 760 mmHg. (c) ARC test temperature and pressure history for a mixture of 1
(0.24 g), 2 (0.24 g) and 5 (0.01 g).
Sampling and analytical methods. The reaction mixture obtained above was transferred out
and then diluted to 100 ml in a volumetric flask with methanol. Then sampling 2 ml by pipette
transferred to another 50 ml volumetric flask, and 4-nitrotoluene (6) (69.3 mg, 0.5 mmol, 99%
purity) was added as internal reference. The mixture was then diluted to 50 ml, in order to that
the sample concentration was applicable for the detector of HPLC to display regular
chromatographic peaks. Then quantitative measurements of the 4-ethylnitrobenzene (1), ketone 2,
alcohol 3, aldehyde 4 and acid 5 were performed by HPLC analysis using the corresponding
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calibration curves in Figure 2 (see supporting information for details). The conversion of 4-
ethylnitrobenzene (1) was determined by the total amount of the yield of all oxidized products in
order to eliminate the experiments errors, because of the volatility of 4-ethylnitrobenzene.
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1.4
4-ethylnitrobenzene (1)
y = 1.0492x + 0.0026
2
R = 0.9995
4
-nitroacetobenzene (2)
1.2
1.0
0.8
0.6
0.4
0.2
0.0
y = 2.6154x + 0.0115
2
R = 0.9998
1-(4-nitrophenyl)ethanol (3)
y = 1.2300x - 0.0063
2
R = 0.9986
4-nitrobenzaldehyde (4)
y = 2.6527x - 0.0270
2
R = 0.9966
4-nitrobenzoic acid (5)
y = 2.4095x + 0.0033
2
R = 0.9995
0.001
0.002
0.003
0.004
0.005
0.006
0.007
Concentration (mmol/mL)
Figure 2. Calibration curves for compounds 1, 2, 3, 4 and 5.
RESULTS AND DISCUSSIONS:
It is a challenge to achieve both high selectivity and high yield for the 4-nitroacetophenone (2) of
the aerobic oxidation. However, the selectivity and yield can be improved by adding various
metalloporphyrins though adjusting their central metal ions and porphyrin ligands. In this study,
the 1-(4-nitrophenyl)ethanol (3) and over-oxidation product 4-nitrobenzoic acid (5) involving C-
C bond cleavage also generate, which were observed in our recent report of metal-free aerobic
oxidation of nitro-substituted alkylarenes.39 However, the 4-nitrobenzaldehyde (4) was not
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observed in the HPLC analysis in this study attributing to its instability in the reaction system,
and was quickly further oxidized to acid 5.
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Effect of central metal ions: In the absence of metalloporphyrin, the aerobic oxidation of the 4-
o
ethylnitrobenzene could proceed under 1.8 MPa O at 140 C, to give 14.5% conversion with
2
11.5%, 2.7% and 0.3% yields for the ketone 2, alcohol 3 and acid 5 respectively, and a
selectivity of 79.3% for the desired product ketone 2 was obtained (Table 1, entry 1). Then,
2
+
3+
2+
2+
metalloporphyrins T(p-F)PPM with various transition metal ions, like Mn , Fe , Co , Ni ,
2
+
2+
Cu , Zn , were used to investigate their activities and selectivities in the aerobic oxidation. All
the conversions were significantly enhanced after adding only 0.01 mol% metalloporphyrins.
The T(p-F)PPMn, T(p-F)PPFeCl and T(p-F)PPCo showed high activities with conversions of
4
3.6%, 54.5% and 48.7% respectively, and considerable yields of 37.2%, 47.3% and 41.5%
respectively for ketone 2 (Table 1, entries 2, 3 and 4). The T(p-F)PPFeCl and T(p-F)PPCo gave
the highest selectivity of 86.8% (Table 1, entries 3, 4). These phenomena can be explained by the
fact that the different valences of the central metal ions caused corresponding redox potential
2+
3+
40
make the activation of Fe /Fe be more positive than other ions. By contrast, the valance of
2
+
41
Zn is difficult to change, making T(p-F)PPZn show low activity in the aerobic oxidation.
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Table 1. Effect of the Central Metal Ions of Metalloporphyrins in the Aerobic Oxidation of
4
-Ethylnitrobenzenea
entry T(p-F)PPM conversionb
%)
b
b
yield (%)
selectivity (%)
(
ketone alcohol acid
ketone alcohol acid
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
14.5
43.6
11.5
37.2
47.3
2.7
3.8
3.8
0.3
2.6
3.4
79.3
85.3
86.8
18.6
8.7
2.1
6.0
6.2
T(p-F)PPMn
T(p-F)PPFeCl 54.5
7.0
4
5
6
T(p-F)PPCo
T(p-F)PPNi
T(p-F)PPCu
T(p-F)PPZn
48.7
25.9
38.8
36.9
41.5
21.3
31.3
30.5
3.0
3.7
5.3
2.4
4.2
0.9
2.2
4.0
86.8
82.2
80.6
82.6
6.3
14.3
13.7
8.8
3.5
5.7
7
6.5 10.8
a
30 mmol scale, 0.01 mol% T(p-F)PPM, O2 (1.8 MPa), 140 C, 6.0 h. b By HPLC analysis.
o
Effect of ligands. Besides the central metal ions discussed above, the ligands of the
metalloporphyrins, like the electronic properties and positions of the substituents on the
porphyrins, can also significantly affect the electron density of the metal ions, and further adjust
the activities of the metalloporphyrins and the selectivities of the aerobic oxidations. Hence, the
effect of the ligands should be also studied systematically.
The environmentally friendly Fe(III)-porphyrins with various electron withdrawing and
donating groups of the para-positions on the phenyl rings were investigated firstly (Table 2).
Basically, with the increase of the electron withdrawing capacity of the substituents, the
activities of the Fe(III)-porphyrins were also enhanced except the T(p-NO )PPFeCl (Table 2,
2
entries 2-6). The T(p-CN)PPFeCl exhibited the highest reaction activity with conversion of
6
3.1%, and a yield of 53.7% for the desired ketone 2 (Table 2, entry 3), this was corresponding
to a turnover number (TON) of up to 5370, and over 20 times higher than the reported
catalysts,11,14,42-46 ZJU-18,14 CoSBA-15,42 complex,43
like cobalt(II) Salen
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
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5
5
5
5
5
5
5
6
III
44
Ru (TDCPP)(Ph)(OEt ) (see supporting information Table S2). All the Fe(III)-porphyrins with
2
electron donating groups showed similar activities (Table 2, entries 7-9) except the T(p-
OH)PPFeCl (Table 2, entry 10). Compared with the blank experiment, the T(p-OH)PPFeCl acted
as an inhibitor for the aerobic oxidation, this could be attributed to the high activity of the
phenolic hydroxyl groups to quench the free radicals in the reaction system. To our delighted,
most of the Fe(III)-porphyrins demonstrated high reaction selectivity of over 85.0% for desired
ketone 2. Notably, the T(p-Br)PPFeCl and T(p-Et)PPFeCl exhibited high reaction selectivity of
up to 90.7%, 91.0% (Table 2, entries 6, 8), and the activity of the T(p-Et)PPFeCl was also over
50% (Table 2, entry 8). Thus, the reaction condition needs to be further optimized to get higher
activity and selectivity.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Table 2. Aerobic Oxidation of 4-Ethylnitrobenzene Promoted by T(p-R)PPFeCla
b
b
entry T(p-R)PPFeCl conversionb
yield (%)
selectivity (%)
(%)
ketone alcohol acid ketone alcohol acid
1
2
3
4
5
6
7
8
9
0
14.5
11.5
38.9
53.7
47.3
42.2
32.2
2.7
3.7
4.3
3.8
2.8
3.2
0.3
3.7
5.1
3.4
4.1
0.0
79.3
84.0
85.1
86.8
85.9
90.7
2.1
8.0
8.2
6.2
8.4
0.0
1
8.0
8.6
T(p-NO )PPFeCl 46.3
2
T(p-CN)PPFeCl 63.1
T(p-F)PPFeCl 54.5
T(p-Cl)PPFeCl 49.1
T(p-Br)PPFeCl 35.4
T(p-Me)PPFeCl 55.2
T(p-Et)PPFeCl 51.3
T(p-OMe)PPFeCl 55.1
6.8
7.0
5.7
9.0
7.2
2.0
7.3
47.7
46.7
47.7
2.1
4.0
1.0
4.0
0.5
3.4
3.6
3.4
0.0
86.4
91.0
86.6
80.7
6.2
7.0
6.2
0.0
1
T(p-OH)PPFeCl
0 mmol scale, 0.01 mol% T(p-R)PPFeCl, O2 (1.8 MPa), 140 oC, 6.0 h.
2.6
19.2
a
3
b
By HPLC analysis.
Then, the activities and selectivities of the Co(II)-, Ni(II)- and Mn(II)-porphyrins, which
showed reasonable activities for their fluorinated derivatives observed above, were also
investigated (Tables 3-5). The reaction activities of the Co(II)-porphyrins were improved with
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the increase of the electron withdrawing capacity of the substituents, especially for the p-F, p-Cl,
and p-Br substituted Co(II)-porphyrins, and similar effect was also observed for the discussed
Fe(III)-porphyrins. Compared with the Fe(III)-porphyrins, most Co(II)- and Ni(II)-porphyrins
showed lower activities. However, the T(p-Br)PPCo demonstrated higher activity than that of the
T(p-Br)PPFeCl (44.7% vs 35.4%), and had a high reaction selectivity of 87.5% for ketone 2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(Table 3, entry 6), which was also the highest among all the Co(II)-porphyrins. As expected, the
T(p-OH)PPCo and T(p-OH)PPNi also showed very poor activities (Table 3, entry 10; Table 4,
entry 10). Moreover, the Mn(II)-porphyrins with electron withdrawing substituents, like -F, -Cl,
and -Br, demonstrated even higher activities compared with the discussed Co(II) and Ni(II)-
porphyrins. Unexpectedly, the T(p-OH)PPMn could significantly promote the aerobic oxidation,
which was much different with the Fe(III)-, Co(II) and Ni(II)-based T(p-OH)PPM, this can be
2
+
attributed to the high reaction activity of the central metal ion Mn . Furthermore, these three
type metalloporphyrins with electron-withdrawing substituents usually exhibited higher reaction
activities than their metalloporphyrins with electron-donating substituents.
Generally, all the Co(II)-, Ni(II)- and Mn(II)-porphyrins exhibited reaction selectivities over
80% for the desired product ketone 2. The selectivities were enhanced if decreasing the electron-
withdrawing ability of the Co(II)-porphyrins (Table 3, entries 2-6), and similar results were also
observed for the Co(II)-porphyrins with electron-donating groups (Table 3, entries 7-9).
Moreover, the Ni(II)- and Mn(II)-porphyrins bearing electron-withdrawing groups usually
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
exhibited higher selectivities than these with electron-donating groups (Tables 4, 5). The T(p-
Cl)PPNi demonstrated the highest activity (46.2%) and selectivity (87.7%) compared to other
Ni(II)-porphyrins (Table 4, entry 5). Similar result was also observed for the T(p-Cl)PPMn.
Especially, the T(p-Cl)PPMn gave the selectivity of up to 93.6% for ketone 2 with only a little
acid 5, which was easily removed from the reaction mixture, and no alcohol 3 was observed,
importantly, the conversion was also over 50% (Table 5, entry 5).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Table 3. Aerobic Oxidation of 4-Ethylnitrobenzene Promoted by T(p-R)PPCoa
b
b
entry T(p-R)PPCo conversionb
yield (%)
selectivity (%)
(%)
ketone alcohol acid
ketone alcohol acid
1
2
3
4
5
6
7
14.5
36.1
45.9
48.7
48.4
44.7
40.7
11.5
28.6
37.5
41.5
41.8
39.1
33.0
2.7
5.9
5.7
3.0
3.2
3.2
5.9
0.3
1.6
2.7
4.2
3.4
2.4
1.8
79.3
79.2
82.0
85.2
86.4
87.5
81.1
18.6
16.3
12.4
6.1
7.0
7.2
2.1
4.4
5.9
8.6
7.6
5.4
4.4
T(p-NO )PPCo
2
T(p-CN)PPCo
T(p-F)PPCo
T(p-Cl)PPCo
T(p-Br)PPCo
T(p-Me)PPCo
14.5
8
9
0
T(p-Et)PPCo
T(p-OMe)PPCo
T(p-OH)PPCo
44.4
44.5
1.3
36.5
38.8
0.6
4.9
2.9
0.0
3.0
2.8
0.7
82.2
87.2
46.2
11.0
6.5
6.8
6.3
1
0.0 53.8
a
o
3
0 mmol scale, 0.01 mol% T(p-R)PPCo, O2 (1.8 MPa), 140 C, 6.0 h.
b
By HPLC analysis.
Table 4. Aerobic Oxidation of 4-Ethylnitrobenzene Promoted by T(p-R)PPNia
b
b
entry T(p-R)PPNi conversionb
yield (%)
selectivity (%)
(%)
ketone alcohol acid
ketone alcohol acid
1
2
3
4
5
6
7
14.5
25.1
33.3
25.9
46.2
35.4
40.7
11.5
21.4
26.8
21.3
40.5
30.1
33.0
2.7
3.6
4.1
3.7
3.0
3.4
5.9
0.3
0.1
2.4
0.9
2.7
1.9
1.8
79.3
85.3
80.5
82.2
87.7
85.0
81.1
18.6
14.3
12.3
14.3
6.5
2.1
0.4
7.2
3.5
5.8
5.4
4.4
T(p-NO )PPNi
2
T(p-CN)PPNi
T(p-F)PPNi
T(p-Cl)PPNi
T(p-Br)PPNi
T(p-Me)PPNi
9.6
14.5
8
9
0
T(p-Et)PPNi
T(p-OMe)PPNi
T(p-OH)PPNi
34.0
37.2
8.0
27.2
29.4
6.1
5.0
6.2
1.6
1.8
1.6
80.0
79.0
76.3
14.7
16.7
20.0
5.3
4.3
3.8
1
0.3
a
o
3
0 mmol scale, 0.01 mol% T(p-R)Ni, O2 (1.8 MPa), 140 C, 6.0 h.
b
By HPLC analysis.
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Table 5. Aerobic Oxidation of 4-Ethylnitrobenzene Promoted by T(p-R)PPMna
b
selectivityb (%)
entry T(p-R)PPMn conversionb
yield (%)
(%)
ketone alcohol acid
ketone alcohol acid
1
2
3
4
5
6
7
8
9
14.5
34.2
47.6
43.6
51.9
51.0
44.5
50.9
51.3
11.5
29.2
40.5
37.2
48.6
44.5
38.8
38.2
42.6
2.7
2.4
3.4
3.8
0.0
3.1
2.9
4.0
3.4
0.3
2.6
3.7
2.6
3.3
3.4
2.8
8.7
5.3
79.3
85.4
85.1
85.3
93.6
87.3
87.2
75.0
83.0
18.6
7.0
7.1
8.7
0.0
6.1
6.5
7.9 17.1
6.6 10.3
10.8 28.7
2.1
7.6
7.8
6.0
6.4
6.7
6.3
T(p-NO )PPMn
T(p-CN)PPMn
T(p-F)PPMn
T(p-Cl)PPMn
T(p-Br)PPMn
T(p-Me)PPMn
T(p-Et)PPMn
T(p-OMe)PPMn
2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
10 T(p-OH)PPMn
32.4
19.6
3.5
9.3
60.5
a
o
3
0 mmol scale, 0.01 mol% T(p-R)PPMn, O2 (1.8 MPa), 140 C, 6.0 h.
b
By HPLC analysis.
Encouraged by these results, we next also examined the aerobic oxidation promoted by the
T(p-R)PPZn, whose valance were difficult to change (Table 6). Most of the T(p-R)PPZn
exhibited relatively low activities with conversions less than 50%, however, they showed high
selectivities over 80% except the T(p-OH)PPZn. Surprisingly, the T(p-NO )PPZn demonstrated
2
a very high activity with conversion up to 58.7%, by contrast, other nitro-based
metalloporphyrins, like T(p-NO )PPFeCl, T(p-NO )PPCo, T(p-NO )PPNi and T(p-NO )PPMn,
2
2
2
2
all showed very low activities. Besides, the T(p-NO )PPZn also exhibited the highest selectivity
2
of 86.7% for ketone 2 with only 4.1% alcohol among all the T(p-R)PPZn. Additionally, the T(p-
OH)PPZn also showed remarkably reaction activity with nearly double conversion yield
compared to the blank experiment, although the reason was still unclear.
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Table 6. Aerobic Oxidation of 4-Ethylnitrobenzene Promoted by T(p-R)PPZna
entry T(p-R)PPZn conversionb
b
b
yield (%)
selectivity (%)
(%)
ketone alcohol acid
ketone alcohol acid
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
14.5
58.7
26.9
36.9
26.6
44.6
40.7
32.4
40.4
28.6
11.5
50.9
22.6
30.5
22.8
37.2
35.3
26.0
34.1
21.7
2.7
2.4
3.3
2.4
3.1
5.3
4.0
5.0
3.9
5.8
0.3
5.4
1.0
4.0
0.7
2.1
1.4
1.4
2.4
1.1
79.3
86.7
84.0
82.7
85.7
83.4
86.7
80.2
84.4
75.9
2.1
9.2
3.7
1
4.1
8.6
T(p-NO )PPZn
2
T(p-CN)PPZn
T(p-F)PPZn
12.3
7.9 10.8
T(p-Cl)PPZn
T(p-Br)PPZn
T(p-Me)PPZn
T(p-Et)PPZn
T(p-OMe)PPZn
T(p-OH)PPZn
11.7
2.6
4.7
3.4
4.3
5.9
3.8
11.9
9.8
15.4
9.7
20.3
1
a
o
3
0 mmol scale, 0.01 mol% T(p-R)PPZn, O2 (1.8 MPa), 140 C, 6.0 h.
b
By HPLC analysis.
Effect of substituent position. The above studies focused on the various metalloporphyrins
bearing substituents on the para-positions of the phenyl rings. Next, metalloporphyrins with
substituents on the meta- and ortho-positions of the phenyl rings, which had greater effect on the
spatial configuration of the metalloporphyrins, were also investigated.
Table 7. Aerobic Oxidation of 4-Ethylnitrobenzene Promoted by T(o/m/p-Cl)PPMa
entryT(o/m/p-Cl)PPM conversionb
yield (%)
b
selectivityb (%)
(%)
ketone alcohol acid ketone alcohol acid
1
2
3
T(o-Cl)PPFeCl
T(m-Cl)PPFeCl
T(p-Cl)PPFeCl
55.3
54.2
49.1
48.7
46.9
42.2
3.2
3.6
2.8
3.4
3.6
4.1
88.1
86.5
85.9
5.8
6.6
5.7
6.1
6.6
8.4
4
5
6
T(o-Cl)PPCo
T(m-Cl)PPCo
T(p-Cl)PPCo
61.8
53.7
49.0
52.7
46.0
41.8
5.1
4.2
3.8
4.0
3.5
3.4
85.3
85.7
85.3
8.3
7.8
7.8
6.5
6.5
6.9
7
8
9
T(o-Cl)PPMn
T(m-Cl)PPMn
T(p-Cl)PPMn
55.0
53.6
51.9
47.8
47.7
48.6
3.2
2.0
0.0
4.0
3.9
3.3
86.9
89.0
93.6
5.8
3.7
0.0
7.3
7.3
6.4
10
11
12
T(o-Cl)PPZn
T(m-Cl)PPZn
T(p-Cl)PPZn
42.2
29.7
26.6
38.1
25.1
22.8
3.1
3.6
3.1
1.0
1.0
0.7
90.3
84.5
85.7
7.3
2.4
11.4 3.4
11.7 2.6
a
o
3
0 mmol scale, 0.01 mol% T(o/m/p-Cl)PPM, O2 (1.8 MPa), 140 C, 6.0 h.
b
By HPLC analysis.
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Based on the high activities and selectivities for T(p-Cl)PPNi and T(p-Cl)PPMn (Table 4,
entry 5 and Table 5, entry 5), the electron-withdrawing group, -Cl, was employed firstly to
examine the substituent position effect (Table 7). All the Fe(III)-, Co(II)-, Mn(II)- and Zn(II)-
porphyrins exhibited improved reaction activities with an order of T(p-Cl)PPM < T(m-Cl)PPM <
T(o-Cl)PPM. The selectivities for all the T(o/m/p-Cl)PPM were over 85.0%, especially, the T(o-
Cl)PPZn also demonstrated a selectivity of over 90.0%, comparable to that of the T(p-Cl)PPMn.
Moreover, compared to the activities, the selectivities showed an opposite trend for the T(o/m/p-
Cl)PPMn (Table 7, entries 7-9). These results indicated that the large steric hindrance of the
phenyl groups on the T(o/m/p-Cl)PPM could significantly promote their reaction activities, but
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
had little effect on the selectivity. This could be attributed to greater steric hindrance preventing
the self-aggregation of the metalloporphyrins to stimulate their activities.28
The substituent position effect of the electron-donating group for the T(o/m/p-OMe)PPM
was also examined (Table 8). Unlike the previous results for the T(o/m/p-Cl)PPM, the T(o/m/p-
OMe)PPM showed an activities order of T(o-Cl)PPM < T(m-Cl)PPM < T(p-Cl)PPM. Their
selectivities were in a range of 81.1-88.3%, which were relatively lower than these of the
T(o/m/p-Cl)PPM. Moreover, the selectivities of the T(o/m/p-OMe)PPCo exhibited similar trend
to their activities (Table 8, entries 4-6), however, the T(o/m/p-OMe)PPZn gave an opposite result
(Table 8, entries 10-12).
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2
2
2
2
3
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3
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3
3
4
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4
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5
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Table 8. Aerobic Oxidation of 4-Ethylnitrobenzene Promoted by T(o/m/p-OMe)PPMa
entry T(o/m/p-OMe) conversionb
b
b
yield (%)
selectivity (%)
PPM
(%)
ketone alcohol acid ketone alcohol
acid
1
2
3
T(o-OMe)PPFeCl
T(m-OMe)PPFeCl
T(p-OMe)PPFeCl
42.6
50.6
55.1
36.8
44.7
47.7
3.0
3.3
4.0
2.8
2.6
3.4
86.4
88.3
86.6
5.9
6.5
7.3
5.5
5.1
6.2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
4
5
6
T(o-OMe)PPCo
T(m-OMe)PPCo
T(p-OMe)PPCo
34.2
42.7
44.5
28.3
35.5
38.8
3.8
4.4
2.9
2.1
2.8
2.8
82.7
83.1
87.2
11.1
10.3
6.5
6.1
6.6
6.3
7
8
9
T(o-OMe)PPMn
T(m-OMe)PPMn
T(p-OMe)PPMn
20.7
50.2
51.3
17.3
40.7
42.6
2.6
6.2
3.4
0.8
3.3
5.3
83.6
81.1
83.0
12.6
12.4
6.6 10.3
3.9
6.6
1
1
12
a
0
1
T(o-OMe)PPZn
T(m-OMe)PPZn
T(p-OMe)PPZn
15.5
42.3
40.4
13.5
36.3
34.1
2.0
3.6
3.9
0.0
2.4
2.4
87.1
85.8
84.4
o
12.9
8.5
9.7
0.0
5.7
5.9
3
0 mmol scale, 0.01 mol% T(o/m/p-OCH3)PPM, O2 (1.8 MPa), 140 C, 6.0 h.
b
By HPLC analysis.
9
9
9
9
5
4
3
2
T(p-Cl)PPMn
T(p-Br)PPFeCl
T(o-Cl)PPZn
T(p-Et)PPFeCl
T(o-Cl)PPCo
T(p-CN)PPFeCl
91
90
89
88
87
86
85
30
35
40
45
50
55
60
65
70
Conversion (%)
Figure 3. The activities and selectivties comparison of T(p-Cl)PPMn, T(p-Br)PPFeCl, T(o-
Cl)PPZn, T(p-Et)PPFeCl, T(o-Cl)PPCo and T(p-CN)PPFeCl.
On the basis of the above results, it is demonstrated that the T(p-CN)PPFeCl and T(o-
Cl)PPCo exhibited very high activities with conversion yields over 60% (Figure 3). Moreover,
most of the metalloporphyrins showed high selectivites over 80.0%, and over 90.0% selectivities
could be achieved for the T(p-Br)PPFeCl, T(p-Cl)PPMn, T(o-Cl)PPZn and T(p-Et)PPFeCl
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(
Figure 3). Especially, the T(p-Cl)PPMn demonstrated a selectivity and conversion of up to
9
3.6%, 51.9% respectively, and a yield of 48.6% for ketone, with only a little acid (6.4%) and no
alcohol observed. This high selectivity makes us confidently to scale up the reaction.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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0
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0
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3
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0
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2
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1
2
3
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5
6
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8
9
0
1
2
3
4
5
6
7
8
9
0
Reaction time effect and large-scale experiment. Reaction time effect was also carefully
investigated on the aerobic oxidation promoted by 0.01 mol% T(p-Cl)PPMn in 30.0 mmol scale
(4.53 g) in a 100 mL pressure reactor. The selectivity continues to increase in the first six hours,
and then begins to decline (Figure 4a). This is attributed to the increase of the over-oxidation
product 5 (Figure 4b). The 1-(4-nitrophenyl) ethanol (3) can be obviously detected only in the
first five hours. The isolated yields after column chromatography for the desired ketone 2 were
consistent with the conversion yields obtained from the HPLC analyses (Table 9 entries 6-8).
(
a) 100
(b)
90
4-ethylnitrobenzene (1)
-nitroacetophenone (2)
1-(4-nitrophenyl) ethanol (3)
4-nitrobenzoic acid (5)
70
60
9
0
0
4
80
8
70
60
70
60
50
4
1
-nitroacetophenone (2)
-(4-nitrophenyl)ethanol (3)
4-nitrobenzoic acid (5)
40
30
20
50
40
30
50
40
3
0
0
20
10
0
10
2
10
0
2
3
4
5
6
7
8
9
10 11 12
2
3
4
5
6
7
8
9
10 11 12
Time (h)
Time (h)
Figure 4. (a) Product selectivties and (b) conversion and product yields versus reaction time for
the aerobic oxidation of 1 in a 30.0 mmol scale promoted by 0.01 mol% T(p-Cl)PPMn under O2
o
(1.8 MPa) at 140 C in a 100 mL pressure reactor.
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1
1
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1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Table 9. Reaction time effect of the aerobic oxidation of 4-ethylnitrobenzene promoted by T(p-
Cl)PPMn
conversionb
%)
b
b
entry
time
(h)
yield (%)
alcohol acid
selectivity (%)
(
ketone
ketone alcohol acid
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
2.0
3.0
4.0
5.0
6.0
7.0
8.0
9.0
10.0
16.5
31.3
37.0
38.8
51.9
52.0
59.8
60.5
61.9
64.0
83.1
12.6
26.1
32.5
34.8
48.6
3.1
0.8
1.5
2.1
4.0
3.3
5.4
6.6
7.3
76.4
83.4
87.8
90.0
93.6
89.6
89.0
87.9
18.8
11.8
9.2
0.0 10.3
0.0 6.4
4.8
4.8
5.7
3.7
3.4
0.0
0.0
46.6 (49.2)c 0.0
53.2 (54.3)c 0.0
53.2 (55.1)c 0.0
0.0 10.4
0.0 11.0
0.0 12.1
53.9
55.8
0.0
0.0
8.0
8.2
87.1
87.1
78.1
0.0 12.9
0.0 12.8
0.0 21.9
1
0
11
11.0
12.0
64.9 (66.0)c 0.0
18.2
a
c
o
b
3
0 mmol scale, 0.01 mol% T(p-Cl)PPMn, O2 (1.8 MPa), 140 C, 6.0 h. By HPLC analysis.
Isolated yields after column gromatography in the parentheses.
Before scaling up the experiment, the safety was further evaluated with a real reaction
mixture (1.0 g) and additional T(p-Cl)PPMn (0.24 mg) (Figure 5). The ARC test curves also
o
showed an exotherm event and pressure raising at about 250 C. This result is similar to the
curves of the ARC test temperature and pressure history for a mixture of 1 (0.24 g), 2 (0.24 g)
and 5 (0.01 g), which was discussed above. However, the pressure is much bigger, attributing to
the more reaction mixture and the additional T(p-Cl)PPMn.
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Testing termination
Temperature
Pressure
3.0
2.5
5
4
3
2
00
00
00
00
Self-heating up
2
1
.0
.5
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0
1
2
3
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8
9
0
Exotherm event
1.0
.5
0.0
100
0
0
Gas generate
10
0
20
30
40
50
Time (h)
Figure 5. ARC test temperature and pressure history for a real reaction mixture (1.0 g) and T(p-
Cl)PPMn (2.4 mg).
Figure 6. (left) Large-scale experiment. (right) 100 g 1 in a 250 mL pressure reactor (A); a
mixture of 100 g 1 and 0.01 mol% T(p-Cl)PPMn (B); reaction mixture under O (1.8 MPa) at
2
o
1
40 C for 6 h (C); the 39.21 g product 2 obtained by crystallization (D).
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6
Large-scale experiment was set up in 661.6 mmol scale (100 g) in a 250 mL pressure
reactor. The reaction could proceed smoothly with a 48.2% conversion and 93.5% selectivity
(Figure 6, left) and gave a yellow reaction mixture (Figure 6, right, C). The desired product
0
1
2
3
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9
0
ketone 2 (39.21 g, >99.0% purity) could be easily separated by crystallization in ethanol in a
light yellow solid (Figure 6, right, D). Another 5.35 g ketone 2 could be obtained by adding
some hexane to the mother solution to give a total isolated yield of 40.8% (see Supporting
information for details). Compared with the above result, this lower conversion and the
generation of alcohol 3 were due to the relatively smaller contact area between the reactants and
the O gas.
2
It should be noted that the metalloporphyrin, T(p-Cl)PPMn, completely decomposed
through the color change before and after the reaction (Figure 6, right, A-C). Similar phenomena
were also observed in aerobic oxidation promoted by other metalloporphyrins discussed above.
Also, the bleach or degradation of the metalloporphyrins in reaction systems were reported by
Cunningham,47-49 Nasrollahi and Khazaei's group. The composition of the reaction mixture
50
51
was also confirmed by a UV-Vis spectra analyses (Figure 7). The high energy strong absorption
1
bands below 450 nm are assigned to (π-π*) transitions of the phenyl groups of in the 4-
ethylnitrobenzene, T(p-Cl)PPMn and T(p-Cl)PP. It can be seen clearly that the strong absorption
band for Soret band at 477 nm and two reletively weak absorption bands for the Q bands at 582
and 617 nm. Also, the porphyrin T(p-Cl)PP exhibits four Q bands at 514, 549, 588 and 647 nm.
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However, after reaction, all the characteristic absorption bands of 450-700 nm for the T(p-
Cl)PPMn and T(p-Cl)PP disappeared, indicating the decompsition of the T(p-Cl)PPMn, and also
the porphyrin rings are not existing. The reaction could continue if the reaction time was
prolonged (Table 9). These results demonstrated that the metalloporphyrins were not catalysts,
but acted as initiators in our reaction system.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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3
3
3
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0
1
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0
1
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9
0
1
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0
1
2
3
4
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8
9
0
1
2
3
4
5
6
7
8
9
0
4
-Ethylnitrobenzene
4
3
2
1
0
T(p-Cl)PPMn
T(p-Cl)PP
Before reaction
After reaction
3
00
400
500
600
700
Wavelength (nm)
-5
Figure 7. UV-Vis spectra of 4-ethylnitrobenzene (0.3 M), T(p-Cl)PPMn (3.0×10 M), T(p-
Cl)PP (3.0 × 10-5 M), and mixture of before reaction and after reaction. Wherein the
-5
concentrations of 4-ethylnitrobenzene (0.3 M) and T(p-Cl)PPMn (3.0×10 M) in the mixture
before reaction are the same with their pure samples.
CONCLUSION
A solvent-free process for the oxidation of 4-ethylnitrobenzene to 4-nitroacetophenone promoted
by metalloporphyrins was developed in pressure reactor using O as clean oxidant. This process
2
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2
2
2
2
2
2
2
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is environment-friendly and can also avoid the loss of the raw material and O . More than 60
2
metalloporphyrins had been employed to systematically explore the central metal ion effect and
the ligand effect on the reaction activities and selectivities. Generally, the Fe(III)- and Mn(II)-
porphyrins exhibited higher activities than these of the Co(II)-porphyrins, and Ni(II)- and Zn(II)-
porphyrins usually showed poor activities. Moreover, the Fe(III)-, and Co(II)-porphyrins with
electron-withdrawing substituents on the para-positions of the phenyl rings showed activities
with an order of T(p-Br)PPM < T(p-Cl)PPM < T(p-F)PPM. The substituent position effect on the
reaction activities of T(o-Cl)PPM > T(m-Cl)PPM > T(p-Cl)PPM, and T(o-OMe)PPM < T(m-
OMe)PPM < T(p-OMe)PPM were observed, where the M could be Fe(III), Co(II), Mn(II) or
Zn(II). The T(p-CN)PPFeCl and T(o-Cl)PPCo exhibited very high activities with conversion
yields over 60% (Figure 2). Furthermore, most of the metalloporphyrins showed high selectivites
over 80.0%, and over 90.0% selectivities could be achieved for the T(p-Br)PPFeCl, T(p-
Cl)PPMn, T(o-Cl)PPZn and T(p-Et)PPFeCl (Figure 2). Especially, the T(p-Cl)PPMn
demonstrated a selectivity and conversion of up to 93.6%, 51.9% respectively, and a yield of
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
4
8.6% for ketone, with only a little acid (6.4%) and no alcohol observed, and the selectivity was
nearly keeping the same for a large-scale experiment (100 g). TON of up to 5370 could be
achieved for the desired ketone promoted by T(p-CN)PPFeCl, which was over 20 times higher
42
than the best reported catalysts. Several efficient metalloporphyrins with high selectivities were
developed for the aerobic oxidation of the of 4-ethylnitrobenzene, which could provide an
efficient alternative process for the preparation of the 4-nitroacetophenone.
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ASSOCIATED CONTENT
Supporting Information
1
1
1
1
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1
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1
2
2
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2
2
2
2
2
2
2
3
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0
The Supporting Information is available free of charge on the ACS Publications website.
Details of sampling and analytical methods, NMR and HRMS spectra of the products (PDF).
AUTHOR INFORMATION
Corresponding Author
*
E-mail: guijieli@zjut.edu.cn; sheyb@zjut.edu.cn.
ORCID
Guijie Li: 0000-0002-0740-2235
Yuanbin She: 0000-0002-1007-1852
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was financially supported by the National Natural Science Foundation of China
(21776259, 21602198, 21878276 and 21476270). We gratefully acknowledge Prof. Wenhan Liu
and Dr. Yuanjie Teng for their help of the HPLC analysis.
REFERENCES
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