Biomimetic Cleavage of Aryl–Nitrogen Bonds in N-Arylazoles Catalyzed by Metalloporphyrins

Article abstract of DOI:10.1007/s10562-018-2446-9

The cleavage of C–N single bonds of N-containing compounds provides either an excellent nitrogen source or an excellent carbon source. In this study, an efficient metalloporphyrins/H₂O₂ cleavage of C–N bonds of arylpyrazoles was investigated. The effects of different factors, including different catalysts, catalyst dosages, H₂O₂ dosages, reaction temperature and reaction time were studied. The experimental results showed that the optimal catalyst was FeTPPCl, and the yield of pyrazole derivatives could reach up to 12.3%, which was fourfold higher than hemin catalyzed reaction and closed to ceric ammonium nitrate catalyzed reaction, respectively. Compared with transition-metal-catalyzed and strong-oxidization cleavage of C–N bonds, this protocol is characterized by environmentally-friendly, stable, mild reaction conditions and simplified operation procedures. Graphical Abstract: [Figure not available: see fulltext.].

Full text of DOI:10.1007/s10562-018-2446-9

Catalysis Letters
https://doi.org/10.1007/s10562-018-2446-9
Biomimetic Cleavage of Aryl–Nitrogen Bonds in N-Arylazoles
Catalyzed by Metalloporphyrins
Zongjiang Yu1 · Guoqing Zhai1,2 · Mo Xian1 · Ming Lu3 · Pengcheng Wang3 · Tao Jiang2 · Chao Xu1 · Weizhi Sun1
Received: 22 March 2018 / Accepted: 3 June 2018
© Springer Science+Business Media, LLC, part of Springer Nature 2018
Abstract
The cleavage of C–N single bonds of N-containing compounds provides either an excellent nitrogen source or an excellent
carbon source. In this study, an efficient metalloporphyrins/H2O2 cleavage of C–N bonds of arylpyrazoles was investigated.
The effects of different factors, including different catalysts, catalyst dosages, H2O2 dosages, reaction temperature and reac-
tion time were studied. The experimental results showed that the optimal catalyst was FeTPPCl, and the yield of pyrazole
derivatives could reach up to 12.3%, which was fourfold higher than hemin catalyzed reaction and closed to ceric ammonium
nitrate catalyzed reaction, respectively. Compared with transition-metal-catalyzed and strong-oxidization cleavage of C–N
bonds, this protocol is characterized by environmentally-friendly, stable, mild reaction conditions and simplified operation
procedures.
Graphical Abstract
Keywords Biomimetic · Metalloporphyrins · Cleavage of C–N bonds
1 Introduction
* Chao Xu
xuchao@qibebt.ac.cn
The C–N bond is one of the most abundant chemical bonds
* Weizhi Sun
and widely exists in many organic molecules and biomac-
romolecules [1]. The formation and cleavage of C–N bonds
play a crucial role in the process of organic reaction and
biochemistry. For example, the process from proteins to
α-amino acids via the amide C–N bond cleavage in the pres-
ence of enzymes are essential for life [2–5].
sunwz@qibebt.ac.cn
1
Key Laboratory of Bio-based Materials, Institute
of Biotechnology, Qingdao Institute of Biomass Energy
and Bioprocess Technology, Chinese Academy of Sciences,
Qingdao 266101, China
2
3
Key Laboratory of Marine Drugs, Ministry of Education
of China, School of Medicine and Pharmacy, Ocean
University of China, Qingdao 266003, China
Recently, the cleavage of C–N single bonds has become
a hot topic, because it provides either an excellent nitrogen
source or an excellent carbon source from readily avail-
able and simple N-containing compounds to form useful
School of Chemical Engineering, Nanjing University
of Science and Technology, Nanjing 210094, Jiangsu, China
Vol.:(0123456789)
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Z. Yu et al.
molecules [6]. However the high C–N bond dissociation
energy and the stability of unactivated N-containing com-
pounds have made them the most prevalent and unreactive
classes of organic compounds in synthetic organic chemistry
[7]. Although cleavage of inert chemical bonds such as C–H,
C–C, and C–O bonds is an area of utmost importance in
organic chemistry and organometallic chemistry, the cleav-
age of C–N bonds is less explored [8–13]. Therefore, it is
conceivable that the C–N bond cleavage will remain a great
challenge and will attract more attention in future chemistry.
Many papers on the cleavage of C–N bonds from transi-
tion-metal-catalyzed reaction and strong oxidization have
been published over the recent years [14–18]. But these cata-
lysts need tough experimental conditions and pollute the
environment, which limit their application to some special
conditions. In recent years, the field of biomimetic catalysis
has led to the development of a number of highly efficient
and selective new catalysts [19]. Research in this field has
also indirectly led to the development of organocatalysis,
which is an active research area that has achieved tremen-
dous success [20].
purchased from commercial sources, and used without fur-
ther purification.
Gas chromatography (GC) was performed using by an
Agilent Technologies Series 7890B system and Agilent
19091J-413 analytical column (30 m×0.32 mm) was used
in separation and quantification of the arylpyrazoles, pyra-
zole derivatives and benzoquinone. All arylpyrazoles were
analyzed by NMR (Agilent, AVANCE-III 600 MHz) and
gas chromatography–mass spectrometer (GC–MS, Agilent,
7890A–5975C) and all metalloporphyrins were analyzed by
NMR and IR (The Nicolet iN10 IR Microscope).
2.2 General Procedure of the Synthesis
of Porphyrins (Scheme 1)
Porphyrins were synthesized by the modified typical
Adler reaction. The benzaldehyde or substituted benzalde-
hyde (40 mmol) was heated to reflux with propionic acid
(300 mL), and pyrrole (40 mmol) was added drop-wise for
30 min under N2 atmosphere. The reaction continued to
reflux for 20 min. The temperature was brought to 90 °C and
the dark precipitates were filtered. The residue was washed
with hot DCM (35 °C) and deionized water and dried under
vacuum to obtain the crystal of porphyrins.
Herein, we have synthesized four metalloporphyrins as
catalysts, to catalyze the cleavage of C–N bonds of arylpyra-
zoles. Then a study on the catalytic ability under various
reaction conditions have been done. Under optimal reaction
conditions, arylpyrazoles with the conversion rate of 23.3%
was achieved, and N containing compounds with the yield
of 12.3% were obtained. The catalytic activity was fourfold
higher than that of hemin catalyzed reaction and closed to
that of ceric ammonium nitrate (15%) catalyzed reaction
[21]. The effects of hemin and horse radish peroxidase
(HRP) have also been investigated as controls.
2.3 General Procedure of the Synthesis
of Metalloporphyrins (Scheme 2)
Metalloporphyrins were synthesized according to a
known procedure described in the literature. Porphyrins
(0.33 mmol) were dissolved in 100 mL of dimethylforma-
mide (DMF), FeCl2, CoCl2, or MnCl2 (1.9 mmol) was added
and the reaction was refluxed for 1 h at 150 °C. The reaction
mixture was cooled to room temperature and quenched with
6 M HCl solution (40 mL). The precipitate was filtered and
washed with 3 M HCl solution and then dried under vacuum.
2 Experimental Section
2.1 Materials and Instrumentations
2.4 General Procedures for the Preparation
of Arylpyrazoles (Scheme 3)
All of the arylpyrazoles [22, 23] and metalloporphyrins [24]
synthesized in this research were known compounds and
the data accorded with those given in the references. Diam-
monium cerium(IV) nitrate (CAN), hemin and horse radish
peroxidase were obtained from Aladdin Industrial Corpora-
tion. Other reactants, solvents and standard samples were
4-Methoxyphenylhydrazine hydrochloride (6 mmol) and
sodium acetate trihydrate (6 mmol) with ethanol (5 mL) were
added to a round bottom flask fitted, and stirring for 30 min
at 50 °C. The reaction was cooled to room temperature and
Scheme 1 Synthesis of por-
phyrins
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Biomimetic Cleavage of Aryl–Nitrogen Bonds in N-Arylazoles Catalyzed by Metalloporphyrins
Scheme 2 Synthesis of metal-
loporphyrins
Scheme 3 Synthesis of arylpyrazoles
added to the solution containing arylpyrazoles (0.5 mmol),
acetonitrile (4 mL) and distilled water (1 mL), and this mix-
ture continued to be stirred.
The reaction was quenched with distilled water (3 mL),
concentrated, extracted with CH2Cl2, dried over MgSO4,
dried under vacuum, identified and quantitatively analyzed
by GC, LC–MS, and HPLC.
Scheme 4 Enzymatic cleavage of aryl–nitrogen bonds
3 Results and Discussion
3.1 Arylpyrazoles and Catalyst Preparation
Three arylpyrazoles, including Me-PMP, Ph-PMP and
F-PMP were synthesized by using benzoquinone derivatives
and acetylacetone derivatives as template compounds. The
yields were 86.4, 75.6 and 78.3%, respectively, which were
about twofold higher than the traditional Ullmann synthetic
method. Three arylpyrazoles were identified by NMR and
MS.
Scheme 5 metalloporphyrins cleavage of aryl–nitrogen bonds
filtered. Filtrate was added to 2 mL of ethanol solution with
diketone (6 mmol), and the reaction was refluxed for 2 h
at 90 °C. Reaction mixtures were neutralized with satu-
rated NaHCO3 solution, extracted with CH2Cl2, dried over
MgSO4, concentrated, and the crude residue obtained was
purified by column chromatography.
Four metalloporphyrins with different structures and
different kinds of metal ions were synthesized by classical
Adler reaction. The yields of all the four metalloporphyrins
were about 20%, and the metalloporphyrins were identified
by NMR and IR.
2.5 General Procedure of Metalloporphyrins
Cleavage of Aryl–Nitrogen Bonds (Schemes 4, 5)
3.2 Effects of Different Catalysts
To a solution of metalloporphyrins (0.1 mmol) in dimethyl-
sulfoxide (5 mL), phosphate sodium buffer (1 mL, pH 4.87)
and 30% H2O2 (0.3 mmol) were added. The reaction was
initiated by adding horse radish peroxidase (1 mg), and after
stirring at room temperature, qualitative analyzation is per-
formed though GC–MS.
The effect of different catalysts on the catalytic cleavage
of C–N bonds of arylpyrazoles were investigated under the
following conditions: arylpyrazoles (0.1 mmol), metallopor-
phyrins (0.1 eq), H2O2 (3.0 eq), 12 h at 25 °C. The results
(Fig. 1) indicated that the C–N bonds of arylpyrazoles could
not be cleaved by H2O2 without mimic enzymes, and all
Metalloporphyrins (0.05 mmol) and 30% H2O2
(0.05 mmol) were dissolved in acetonitrile (2 mL), then
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Z. Yu et al.
Effects of different catalystsa
Effects of the amount of catalysta
10
8
8
6
4
2
0
Ph-PMP
Me-PMP
F-PMP
Ph-PMP Me-PMP F-PMP
6
4
2
0
Blank
control
HRP
CAN
Hemin FeTPPCl FeTCPPCl MnTPPCl CoTPPCl
0.01 eq
0.05 eq
0.1 eq
0.2 eq
Catalysts
The amount of catalyst Catalyst
Fig. 1 The yield of pyrazolyl derivatives with different substrates
catalyzed by different catalysts. aReaction conditions: 3.0 eq of H2O2,
reaction temperature at 25 °C, 0.1 eq of catalysts and 12 h of reaction
time
Fig. 3 The yield of pyrazolyl derivatives with different substrates
a
catalyzed by different amount of catalyst. Reaction conditions: FeT-
PPCl as catalysts, 3.0 eq of H2O2, reaction temperature at 25 °C and
12 h of reaction time
of the metalloporphyrins showed the catalytic activity. As
shown in Fig. 2, HRP and CAN showed the higher conver-
sion rate, although no or a little pyrazole derivatives were
obtained, and probabaly due to the high oxidative activity of
HRP and CAN, the products were further oxidized.
As shown in Fig. 1, compared with other three metal-
loporphyrins, FeTPPCl showed higher catalytic activity in
this reaction for the three arylpyrazoles. The yield of pyra-
zole derivatives were closed to the reaction catalyzed by
CAN, and FeTPPCl had better application prospects in the
field of catalysis.
3.4 Effects of the Amount of H2O2 on the Catalytic
Performance
It was known that the amount of H2O2 was very important
to the biomimetic catalysis. Therefore, the catalytic perfor-
mance of FeTPPCl to cleave the C–N bonds of arylpyra-
zoles was tested. The amount of H2O2 varied from 1.0 to
10.0 eq, while other optimized parameters were unchanged.
As shown in Fig. 4, the yields were decreased by increasing
or decreasing the amount of catalysts while the conversion
rate of arylpyrazoles increased with increasing amounts of
H2O2 (Fig. 5). Which might result from low activity of met-
alloporphyrins with a small quantity of H2O2 and oxidation
of arylpyrazoles or products of pyrazolyl derivatives with
excessive H2O2. These findings demonstrated that the opti-
mal amount of H2O2 was 3.0 eq.
3.3 Effects of the Amount of Catalyst
on the Catalytic Performance
The role of catalyst amount during the cleavage of C–N
bonds of arylpyrazoles were assessed by varying the amount
of FeTPPCl from 0.01 to 0.2 eq, while other optimized
parameters were unchanged. It can be seen from Fig. 3, the
yields increases with the amount of catalyst in the range of
0.01–0.1 eq and then decreases with the amount of catalyst
in the range of 0.1–0.2 eq. The results indicated that when
the catalyst dosages were too low or too high, the yields of
pyrazole derivatives decrease. These findings suggest that
regarding the three arypyrazoles, 0.1 eq of catalyst was the
optimal dosage.
3.5 Effect of Reaction Temperature on the Catalytic
Performance
Reaction temperature also influences catalytic perfor-
mance, hence, a study was carried out by varying the reac-
tion temperate from 0 to 50 °C for cleaving C–N bonds
of arylpyrazoles while other optimized parameters were
unchanged. It can be seen from Fig. 6 that when the reac-
tion temperature was 0 °C, the metalloporphyrins activity
Coversion of different catalystsa
Fig. 2 The conversion of dif-
ferent substrates catalyzed by
different catalysts. aReaction
120
Ph-PMP
Me-PMP
F-PMP
conditions: 3.0 eq of H2O2,
reaction temperature at 25 °C,
0.1 eq of catalysts and 12 h of
reaction time
100
80
60
40
20
0
Blank
control
HRP
CAN
Hemin FeTPPCl FeTCPPCl MnTPPCl CoeTPPCl
Catalysts
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Biomimetic Cleavage of Aryl–Nitrogen Bonds in N-Arylazoles Catalyzed by Metalloporphyrins
Effects of the timea
a
Effects of the amount of H2O2
14
Ph-PMP Me-PMP F-PMP
Ph-PMP Me-PMP F-PMP
10
8
12
10
8
6
6
4
4
2
2
0
0
1.0 eq
3.0 eq
5.0 eq
10.0 eq
1 h
2 h
6 h
12 h
24 h
48 h
The amount of H2O2
Time
Fig. 4 The yield of pyrazolyl derivatives with different substrates
Fig. 7 The yield of pyrazolyl derivatives at different reaction time.
aReaction conditions: 3.0 eq of H2O2, 0.1 eq of FeTPPCl, reaction
temperature at 25 °C
a
catalyzed by different amount of H2O2. Reaction conditions: 0.1 eq
of FeTPPCl, reaction temperature at 25 °C and 12 h of reaction time
a
3.6 Effects of the Reaction Time on the Catalytic
Performance
Conversion of the different amount of H2O2
Ph-PMP
Me-PMP
F-PMP
100
80
60
40
20
0
It is known that the reaction time is of vital importance for
oxidation reactions. In order to obtain the optimal condition
of the reaction, the reaction time were assessed by varying
the time from 1 to 48 h. The results (Fig. 7) showed that
within 12 h (Ph-PMP and F-PMP) or 24 h (Me-PMP) the
yields were gradually increased with the reaction time. After
that, the yields decreased with increasing reaction time. The
optimal reaction time were 12 h for Ph-PMP and F-PMP as
raw material, while the optimal reaction time (yield: 12.3%)
was 24 h for Me-PMP as raw material.
1.0 eq
3.0 eq
5.0 eq
10.0 eq
The amount H2O2
Fig. 5 The conversion of different substrates catalyzed by the differ-
a
ent amount of H2O2. Reaction conditions: 0.1 eq of FeTPPCl, reac-
tion temperature at 25 °C and 12 h of reaction time
The optimal reaction conditions of C–N bonds cleavage
were obtained by studying the effects of reactions time, reac-
tion temperature, ratio of H2O2 and catalyst. As shown in
Figs. 1 and 8, the yields and conversions rates were fourfold
higher than that of the hemin catalysis and closed to that of
the ceric ammonium nitrate (CAN) catalysis.
Effects of the temperaturea
10
Ph-PMP Me-PMP F-PMP
8
6
4
2
0
3.7 The Catalytic Mechanism
This metalloporphyrin mediates the reaction of arylpyra-
zoles substrates in a three-step catalytic cycle (Fig. 9). As
depicted in Fig. 9, the ground-state iron(III)-porphyrins were
oxidized by H2O2 in the first step to obtain an oxoiron(IV)
porphyrin radical cation (compound I), which abstracts
an electron from the arylpyrazoles substrate in the second
step to become another oxoiron(IV) porphyrin intermediate
(compound II) and produce a arylpyrazoles radical (com-
pound III). In the third step, compound II interacts with
compound III to produce cationic compound IV and at this
time the metalloporphyrin converts back to the ground state.
Compound IV can react with H2O to produce benzoquinone
and substituted pyrazol.
0°C
25°C
37°C
50°C
Temperature
Fig. 6 The yield of pyrazolyl derivatives at different reaction temper-
a
ature. Reaction conditions: 3.0 eq of H2O2, 0.1 eq of FeTPPCl and
12 h of reaction time
was lower. It is observed that as reaction temperature
increases from 25 to 50 °C, the yield of pyrazole deriva-
tives gradually decreases due to the increasing dosages of
the catalysts at the higher reaction temperature and side
reaction increases. To our observation, best results were
obtained by maintaining the reaction temperature at 25 °C
to achieve an optimal activity of the catalyst for cleavage
of all of the three arylpyrazoles.
The differences in yields of three arylpyrazoles can be
explained by the reaction mechanism. As the substrate, at
optimum reaction conditions the yield of Me-PMP was
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Z. Yu et al.
Fig. 8 The yield and conver-
sion of pyrazolyl derivatives at
optimal reaction conditions
Catalyzed by FeTPPCl
Catalyzed by FeTPPCl
15
10
5
50
40
30
20
10
0
0
Ph-PMP
Me-PMP
F-PMP
Ph-PMP
Me-PMP
F-PMP
Substrate
Substrate
Fig. 9 Mechanism for cleavage of aryl–nitrogen bonds with metalloporphyrins
twofold higher than that of Ph-PMP and that of F-PMP
(Fig. 8). The results showed that electron-donating group
(–Me) were beneficial to C–N bonds cleavage, and electron-
withdrawing group (–CF3) or steric hindrance increasing
group (–Ph) were disadvantageous to the reaction.
conditions, Me-PMP was catalyzed by FeTPPCl, the yield of
dimethylpyrazole could reach up to 12.3% and was fourfold
higher than that of the HRP catalyzed reaction and closed
to that of the CAN catalyzed reaction. This system has the
advantages of being mild in reaction conditions, high in
efficiency, easy to operate and environmentally friendly has
great potential for wide application.
4 Conclusions
Acknowledgements This work was supported by the Research Project
of Post-doctoral application of Qingdao.
In this study, an efficient metalloporphyrins/H2O2 cleavage
of C–N bonds of the arylpyrazoles system under mild condi-
tions has been developed. The effects of different catalysts,
the amount of catalyst, the amount of H2O2, the reaction
temperature and the reaction time were also investigated.
The optimal reaction conditions were 0.1 eq of FeTPPCl,
3.0 eq of H2O2 at 25 °C for 24 or 12 h. Under the optimal
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