Biomimetic models of nitric oxide synthase for the oxidation of oximes to carbonyl compounds catalyzed by water-soluble manganese porphyrins in aqueous solution

Article abstract of DOI:10.1142/S1088424611003173

A mild green and efficient approach for hydrogen peroxide oxidative converting oximes to the corresponding carbonyl compounds with a water-soluble manganese porphyrin as catalyst in water/acetone mixture has been developed. The water-soluble manganese porphyrin showed an excellent activity for the oxidative deoximation reactions of various oximes under ambient conditions in the absence of any additive. The oxidative deoximation was through the formation of high valent oxo-manganese species, which was confirmed by in situ UV-vis spectroscopy.

Full text of DOI:10.1142/S1088424611003173

Journal of Porphyrins and Phthalocyanines
J. Porphyrins Phthalocyanines 2011; 15: 211–216
DOI: 10.1142/S1088424611003173
Published at http://www.worldscinet.com/jpp/
Biomimetic models of nitric oxide synthase for the
oxidation of oximes to carbonyl compounds catalyzed
by water-soluble manganese porphyrins in
aqueous solution
Qing-Gang Ren, Xian-Tai Zhou and Hong-Bing Ji*
School of Chemistry and Chemical Engineering, The Key Laboratory of Low-Carbon Chemistry & Energy
Conservation of Guangdong Province, Sun Yat-Sen University, Guangzhou 510275, P.R. China
Received 24 December 2010
Accepted 5 April 2011
ABSTRACT: A mild green and efficient approach for hydrogen peroxide oxidative converting oximes
to the corresponding carbonyl compounds with a water-soluble manganese porphyrin as catalyst in
water/acetone mixture has been developed. The water-soluble manganese porphyrin showed an excellent
activity for the oxidative deoximation reactions of various oximes under ambient conditions in the absence
of any additive. The oxidative deoximation was through the formation of high valent oxo-manganese
species, which was confirmed by in situ UV-vis spectroscopy.
KEYWORDS: oxime; oxidation; water-soluble porphyrin; hydrogen peroxide.
of various organic compounds. However, most of the
INTRODUCTION
metalloporphyrins-mediated oxidations are conducted
In the chemical industry, organic solvents should be
in organic solvents [7]. Therefore, the oxidations cata-
avoided wherever possible [1]. Compared with organic
lyzed by metalloporphyrins in water will be of great
solvents, water is a readily available, economic, safe, and
significance, which is closer to simulate the environ-
environmentally-benign solvent [2]. Although the most
ments of the enzyme-mediated process [8]. A suc-
complex form of organic compounds requires the con-
cessful example of efficient controllable oxidation of
struction of chemical bonds in an aqueous environment,
alcohols to aldehydes or acids catalyzed by metallopor-
water as a solvent was ruled out from organic reactions
phyrins in water has been developed in our previous
during the preceding decades [3].
works [9].
Oximes are useful protecting groups and are widely
We have reported the aerobic deoximation to the cor-
used for the purification and characterization of carbonyl
responding carbonyl compounds with manganese por-
compounds [4]. Since oximes can also be prepared from
phyrin in organic solvent with benzaldehyde as sacrificial
non-carbonyl compounds, the generation of carbonyl
reductant [10]. In order to avoid using organic solvent
compounds from them provides an alternative method
and sacrificial reductant for the deoximation, herein we
for the preparation of aldehydes and ketones [5]. The
report the aqueous oxidation of oximes catalyzed by
reactions require organic solvent, drastic conditions and
tedious procedures [6].
meso-tetrakis(N-ethyl-4-pyridyl)manganese porphyrin
(MnTEPyP) with hydrogen peroxide as oxidant
Metalloporphyrins as chemical models of cyto-
(Scheme 1). The catalytic system has proved to be effec-
chrome P450 and related monooxygenases have been
tive for the oxidation of oximes, which are commonly
used to carry out oxygenation and oxidation reactions
used as chemical models of nitric oxide synthase (NOS).
Meanwhile, the process also provides a possible way
for mimicking the aqueous oxidations of the numerous
nitrogenous organic compounds in living organisms.
*Correspondence to: Hong-Bing Ji, email: jihb@sysu.edu.cn,
tel: +86 20-8411-3658, fax: +86 20-8411-3654
Copyright © 2011 World Scientific Publishing Company

212
Q.-G. Ren et al.
significant difference was observed both for the
conversion of cyclohexanone oxime and selec-
tivity of cyclohexanone (entries 3–6). Also, no
increased yield of cyclohexanone was obtained
by prolonging reaction time to 45 min (entry 7).
Therefore, the optimal amount of catalyst for
the deoximation reaction was 1.0 × 10-3 mmol
and the appropriate reaction time was 30 min.
In addition, almost no reaction took place when
the catalyst was replaced by manganese acetate
with the same catalytic amount as metallopor-
phyrins (entry 8).
N
Mn
N
N
N
N
N
N
N
OH
N
Effect of organic solvent on the oxidation of
cyclohexanone oxime
O
C
C
R1
R2
R1
R2
H2O2, water/acetone = 5/1(v/v)
As shown in Table 2, the conversion of cyclo-
hexanone oxime was only 33% when the reac-
tion was conducted in aqueous medium, which
Scheme 1. The oxidation of oximes to carbonyl compounds catalyzed
by MnTEPyP
could be attributed to the poor solubility of oxime in
water (entry 1). Oxime might be dispersed well in the
reaction media by adding one kind of organic solvent.
Therefore, different organic solvents were checked for
choosing the optimal reaction media. From Table 2, ace-
tone was more favorable for the reaction compared with
dimethylformamide, acetonitrile, methanol and ethanol
(entries 2–5). It seems that the deoximation is related
with the dielectric constant of solvent, in which solvent
with large dielectric constant is not suitable for the oxida-
tion in the presence of water-soluble manganese porphy-
rin. In addition, the mixture between water and organic
solvent, that is homogeneously mixed or not, is impor-
tant for the reaction. Although the dielectric constant of
toluene is very low, the yield of cyclohexanone was only
RESULTS AND DISCUSSION
Effect of MnTEPyP amount on the oxidation of cyclo-
hexanone oxime
The catalytic activity of MnTEPyP with different
amounts for oxime oxidation was investigated by using
cyclohexanone oxime as the model substrate. The results
are summarized in Table 1.
As shown in Table 1, only 12% of cyclohexanone
oxime was converted in the absence of catalyst (entry
1). It was also observed that the conversion of cyclo-
hexanone oxime was considerably enhanced when
MnTEPyP was used. The conversion could reach up to
81% even if the amount of catalyst was only 0.5 × 10-3
mmol (entry 2), which indicated manganese porphy-
rin is crucial in oxidation reaction. With the increasing
amount of catalyst from 1 × 10-3 to 5 × 10-3 mmol, no
Table 2. Effect of organic solvent on the oxidation of oximes
to carbonyl compoundsa
Entry
Solvent
Dielectric
constant
Conv.,
%
Yield,
%
b
Table 1. Effect of the amount of catalyst on the oxidation of
oximes to carbonyl compoundsa
1
2
—
acetonitrile
dimethylformamide
methanol
ethanol
—
33
24
32
35
34
90
27
78
82
75
57
19
19
19
25
25
83
24
63
76
73
53
Entry
Amount of
catalyst
Conv.,
%
Yield,
%
Selectivity,
37.5
36.7
32.6
24.3
20.5
2.4
b
%
3
(× 10-3 mmol)
4
1
0
12
81
90
92
92
93
91
1
10
72
83
84
85
84
82
1
83
89
5
2
0.5
1.0
2.0
3.0
5.0
1.0
1.0
6
acetone
3
92
7
toluene
8c
9d
10e
11f
acetone
20.5
20.5
20.5
20.5
4
91
5
92
acetone
6
90
acetone
7c
8d
90
acetone
>99
a
Oxime (1 mmol), MnTEPyP (1 × 10-3 mmol), H2O (5 mL),
organic solvent (1 mL), H2O2 (3 mmol), 60 °C, 30 min. b The
by-product was benzonitrile. c-f The volume of acetone is 0.5, 2,
3 and 5 mL, respectively.
a Oxime (1 mmol), acetone/water (1 mL/5 mL), H2O2 (3 mmol),
b
c
60 °C, 30 min. The by-product was benzonitrile. Reaction
time was 45 min. d Manganese acetate was used as catalyst.
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213
27% when the reaction was carried out in water/toluene
peroxide, and the typical results are summarized in
Table 4.
mixture medium (entry 7). It could be attributed to the
formation of two phase system by adding toluene into the
mixture, which is unfavorable to contact between catalyst
and substrate.
The conversion of cyclohexanone oxime decreased
with the increasing volume of acetone from 2 to 5 mL in
the reaction system, coupled with the enhanced selectiv-
ity of cyclohexanone (entries 9–11). When 5 mL acetone
was added to the mixture, only 57% of the substrate was
converted. It could be understood that oxime might be
enriched in acetone with the increasing amount, which
retarded the interaction between catalyst and oxime.
As shown in Table 4, the oxidations of most oximes
occurred smoothly to afford the corresponding carbonyl
compounds by MnTEPyP in the presence of hydrogen
peroxide selectively. Among the cyclic oximes, cyclo-
hexanone oxime was more efficiently oxidized than other
cyclic oximes such as cyclooctanone and cyclopentanone
oximes, which required longer reaction time or higher
reaction temperature (entries 1–3).
The catalytic system also presented high activity for
the conversion of aromatic oximes to carbonyl com-
pounds. For example, 82% of benzaldoxime could be
converted to the corresponding benzaldehyde (76%) in
5 h at 90 °C (entry 4). It seems that the oxidation effi-
ciency for this catalytic system was dependent on the elec-
tronic property of substrates. The main product obtained
was nitrile for the substrates with electron-withdrawing
groups at ortho-position (entries 6,7). However, the oxi-
dation efficiency was not affected by electron-denoting
group of substrate (entry 5). Such extremely different
results should be attributed to different electronic atmo-
sphere of C=N bond [10]. Steric structure almost has no
effect on the conversion of oximes, while it is favorable
for the selectivity of carbonyl compound (entries 8,9).
Effect of temperature on the oxidation of cyclo-
hexanone oxime
Effect of reaction temperature on the oxidation of
cyclohexanone oxime to cyclohexanone catalyzed by
MnTEPyP was also investigated. Results are summarized
in Table 3.
As shown in Table 3, the conversion of cyclohexanone
oxime is closely related with the reaction temperature.
Almost no cyclohexanone oxime was converted to its cor-
responding product in the experiment that was carried out
at 20 °C (entry 1). It was also observed that the conversion
of cyclohexanone oxime was considerably enhanced with
the increasing reaction temperature from 30 °C to 60 °C.
However, the selectivity of cyclohexanone is minimally
influenced by reaction temperature. With the elevated
temperature from 60 °C to 70 °C, no obvious increase was
observed for the conversion of cyclohexanone oxime, but
it exhibited a slight decrease of cyclohexanone selectivity.
Such results indicated that 60 °C was the optimal reaction
temperature for the deoximation reaction catalyzed by
MnTEPyP in the presence of hydrogen peroxide.
Plausible mechanism for the oxidation of oxime cata-
lyzed by MnTEPyP
For the selective oxidation of hydrocarbons or other
organic compounds, the application of iron porphyrins in
combination of hydrogen peroxide is particularly exten-
sive [11]. It is suggested that reaction of hydrogen per-
oxide with iron(III) porphyrins results in the formation
of an iron(IV) oxo species or iron(IV) π-radical cations,
which are the active species for the oxidation [12]. In the
present deoximation catalyzed by manganese porphyrins,
as mentioned above, water-soluble manganese porphyrin
(MnTEPyP) is essential for the reaction in the presence
of hydrogen peroxide. The presence of manganese-oxo
porphyrin was confirmed by in situ UV-vis spectra for the
oxidation of cyclohexanone oxime. The spectrophotom-
eter was programmed to acquire UV-vis spectrum every
5 min.
Oxidation of various oximes catalyzed by MnTEPyP
in the presence of H2O2
Different substrates were examined for the oxidation
catalyzed by the MnTEPyP in the presence of hydrogen
Table 3. Effect of temperature on the oxidation of oximes to
carbonyl compoundsa
As shown in Fig. 1, the initial characteristic absorp-
tion peaks of MnTEPyP were at 464 and 562 nm. After
adding H2O2 and cyclohexanone oxime into the reaction
system, in situ determination revealed that the character-
istic absorption peak of MnTEPyP weakened gradually,
suggesting the consumption of oxidant active species
(MnIV=O) by substrate [13]. In addition, color changes of
the reaction mixture from dark green to tinge also indicate
valence change of manganese. GC analysis of these reac-
tive products revealed the formation of cyclohexanone,
indicative of the presence of active oxidation species.
In the metalloporphyrins-catalyzed oxidation of oxi-
mes with various oxidants, the formation mechanism of
Mn-oxo active species is quite different. For the aerobic
Entry
T, °C
Conv.,
%
Yield,
%
Selectivity,
b
%
1
2
3
4
5
6
20
30
40
50
60
70
5
37
49
73
90
91
5
30
43
68
83
81
100
81
88
93
92
89
a
Oxime (1 mmol), MnTEPyP (1 × 10-3 mmol), acetone/water
b
(1 mL/5 mL), H2O2 (3 mmol), 30 min. The by-product was
benzonitrile.
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Q.-G. Ren et al.
Table 4. Oxidation of various oximes catalyzed by MnTEPyP in the presence of H2O2a
Entry
Oxime
Product
T, °C
Time, h
Conv., %
Yield, %
83
O
OH
N
1
60
0.5
90
OH
N
O
2
3
4
60
90
90
2.5
5
96
96
82
87
82
76
OH
N
O
OH
H
O
N
5
H
OH
N
O
OH
5
90
5
91
87
OH
O
NO2
22
30
OH
N
NO2
6
90
5
52
N
NO2
O
19
N
OH
N
7
90
5
47
N
N
26
98
95
N
OH
O
N
8
90
90
5
5
98
95
HO
O
N
9b
a Oxime (1 mmol), MnTEPyP (1 × 10-3 mmol), acetone/water (1 mL/5 mL), H2O2 (3 mmol). b Acetone (2 mL).
Copyright © 2011 World Scientific Publishing Company
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BIOmImetIC mODelS Of nItRIC OxIDe SynthaSe fOR the OxIDatIOn Of OxImeS
215
tend to be protonated firstly, followed to yield nitrile via
dehydration step.
The metalloporphyrins-catalyzed aerobic oxidations
are always carried out with sacrificial additives under
atmospheric pressure. To avoid using additives, the oxi-
dations should be conducted under high pressures [15].
The present deoximation was conducted not only under
ambient conditions, but also conducted in the absence of
any additives. The reaction could also provide some evi-
dences to explore the metabolism of nitrogenous organic
compounds in living organisms.
EXPERIMENTAL
Fig. 1. In situ UV-vis spectra of MnTEPyP in the solution of
cyclohexanone oxime oxidation in the presence of hydrogen
peroxide (time scan: 5 min). Cyclohexanone oxime (1 mmol),
H2O2 (3 mmol), MnTEPyP (1 × 10-3 mmol), acetone/water
(1 mL/5 mL), 60 °C
Oximes with analytical grade were obtained from
Aldrich or Fluka Chemical Company without further
purification unless indicated. Pyrrole was purified before
use. UV-vis spectrum was recorded on a Shimadzu
UV-2450 spectrophotometer. Mass spectra were obtained
on a Shimadzu LCMS-2010A. Elemental analysis data
were obtained on Vario EL III. Other solvents were all of
analytical grade.
deoximation catalyzed by MnTPPCl as reported previ-
ously [10], the active species (MnIV=O) was generated
via a radical process coupled with the sacrifice of ben-
zaldehyde as a reductant. While, for the deoximation
reaction of hydrogen peroxide with MnTEPyP, Mn(IV)
oxo species was generated by the homolytic cleavage
of Mn(III) hydroperoxide species, which was formed
by the reaction of hydrogen peroxide with manganese
porphyrins [14].
MnTEPyP (meso-tetrakis(N-ethylpyridinium-4-yl)man-
ganese porphyrin) catalysts were prepared according to
previously reported procedures [9, 16]. The structure of
MnTEPyP was confirmed by elementary analysis, mass
spectra and UV-vis spectra, respectively.
[MnTEPyP]4+. EI-MS: m/z 787. UV-vis (H2O): λmax
,
Based on these observations, a plausible reaction
mechanism for the deoximation with water-soluble man-
ganese porphyrin (MnTEPyP) as catalyst was proposed
(Fig. 2). The reaction mechanism could involve the use of
oxo-manganese intermediate generated from the reaction
between manganese porphyrin and hydrogen peroxide.
An adduct (a) could be generated from the nucleophilic
attack of the high-valent oxo species to C=N bond, which
produces the corresponding carbonyl compounds by
decomposition. For the oximes with electron-withdraw-
ing groups at ortho-position (entries 6,7, Table 4), nitrile
was obtained as another main product. Such oximes may
nm (log ε) 464 (2.48), 559 (1.25), 675 (0.87), 769 (0.54).
Anal. calcd. for [MnTEPyP]4+: C, 44.50; H, 3.42; N, 8.65.
Found: C, 44.67; H, 3.51; N, 8.49.
General procedures for the catalytic oxidation of oxi-
mes to carbonyl compounds. All reactions were carried
out in a 25 mL flask equipped with a magnetic stirrer bar
under air. Water (5 mL), acetone (1 mL), oxime (1 mmol),
MnTEPyP (1 × 10-3 mmol), and 30% H2O2 (3 mmol) were
mixed at 60 °C while stirring for 30 min. The product for
each reaction was analyzed with GC (Shimadzu GC-2010
plus) and GC-MS (Shimadzu GCMS-QP2010 plus) with
naphthalene as an internal standard after the extraction
with ethyl acetate at an interval of 5 min.
OH
H+
N
O
PorMnV
OH
CONCLUSION
R
H
H2O2
In summary, an environmentally friendly pro-
tocol has been developed for the catalytic oxida-
tion of oximes to give carbonyl compounds. The
MnTEPyP-based catalytic system has proven to
be effective in the deoximation with hydrogen
peroxide as a terminal oxidant. The oxidation
of cyclohexanone oxime by MnTEPyP in water/
acetone mixture (5/1, v/v) gave oxidative prod-
uct up to 83% yield. Various oximes could be
successfully converted. The oxidative deoxima-
tion was through the formation of high valent
oxo-manganese species, which was confirmed
PorMnIII
OH
OH
+
R
C
H
N OH2
MnVPor
O
C
H
N O
R
R
C N
PorMnII
O
R
H2O
(a)
H
Fig. 2. Plausible reaction mechanism of the deoximation catalyzed by
MnTEPyP in the presence of hydrogen peroxide
Copyright © 2011 World Scientific Publishing Company
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216
Q.-G. Ren et al.
by in situ UV-vis spectroscopy. A plausible mechanism
for the oxidative deoximation has been proposed. The
reaction is conducted under atmospheric pressure in the
absence of any additive, which has the application pros-
pects and provides a possible way to explore the aque-
ous oxidations of the nitrogenous organic compounds in
living organisms.
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Acknowledgements
The authors thank the National Natural Science
Foundation of China (Nos. 21036009 and 20976203),
Higher-Level Talent Project for Guangdong provincial
universities, the Fundamental Research Funds for the
Central Universities and Guangdong Province 211 Proj-
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