Nitrile-promoted alkene epoxidation with urea-hydrogen peroxide (UHP)

Article abstract of DOI:10.1080/00397911.2012.699578

An efficient method for alkene epoxidation has been studied systematically using benzonitrile and the complex urea-hydrogen peroxide (UHP), which is an anhydrous form of hydrogen peroxide and has the potential to release hydrogen peroxide in a controlled manner and thus avoid the need to slowly add aqueous H₂O₂ to the reaction mixture. The absence of water in the reaction media was also beneficial, because it minimized undesired reactions of the oxidized products. A range of alkenes was epoxidized by this method, providing yields ranging from 79% to 96%. Copyright

Full text of DOI:10.1080/00397911.2012.699578

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Nitrile-Promoted Alkene Epoxidation
with Urea–Hydrogen Peroxide (UHP)
Li Ji a , Ya-Na Wang a , Chao Qian a & Xin-Zhi Chen a
a Department of Chemical and Biological Engineering , Zhejiang
University , Hangzhou , China
Accepted author version posted online: 26 Jan 2013.Published
online: 03 Jun 2013.
To cite this article: Li Ji , Ya-Na Wang , Chao Qian & Xin-Zhi Chen (2013): Nitrile-Promoted Alkene
Epoxidation with Urea–Hydrogen Peroxide (UHP), Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 43:16, 2256-2264
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Synthetic Communications1, 43: 2256–2264, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2012.699578
NITRILE-PROMOTED ALKENE EPOXIDATION
WITH UREA–HYDROGEN PEROXIDE (UHP)
Li Ji, Ya-Na Wang, Chao Qian, and Xin-Zhi Chen
Department of Chemical and Biological Engineering, Zhejiang University,
Hangzhou, China
GRAPHICAL ABSTRACT
Abstract An efficient method for alkene epoxidation has been studied systematically using
benzonitrile and the complex urea–hydrogen peroxide (UHP), which is an anhydrous form
of hydrogen peroxide and has the potential to release hydrogen peroxide in a controlled
manner and thus avoid the need to slowly add aqueous H2O2 to the reaction mixture.
The absence of water in the reaction media was also beneficial, because it minimized unde-
sired reactions of the oxidized products. A range of alkenes was epoxidized by this method,
providing yields ranging from 79% to 96%.
Supplemental materials are available for this article. Go to the publisher’s online edition
of Synthetic Communications1 to view the free supplemental file.
Keywords Alkenes; nitrile; oxidation; Payne epoxidation; peroxycarboximidic acid;
urea–hydrogen peroxide (UHP)
INTRODUCTION
Epoxides, very important chemicals in synthetic organic chemistry as well as in
industry, are largely used for the synthesis of key intermediates and in many impor-
tant organic transformation reactions.[1] Most important, these chemicals are widely
used in industry for manufacturing various types of important products, ranging
from perfumery chemicals[2] to therapeutically active substances.[3] Many reagents
have been utilized to epoxidize olefins, and among them peracids are the most widely
used. Unfortunately, the highly corrosivity and potential for explosions make the use
of traditional peroxy acids undesirable and the by-product carboxylic acids must
then be recovered for reuse or disposal. Thus, there is a continuing and increasing
Received April 9, 2012.
Address correspondence to Chao Qian, Department of Chemical and Biochemical Engineering,
Zhejiang University, No. 38, Zheda Road, Hangzhou, 310027, China. E-mail: chemtec@163.com
2256

NITRILE-PROMOTED ALKENE EPOXIDATION
2257
Scheme 1. Alkene epoxidation with RCN=UHP.
demand for procedures that could help overcome these challenges, and it is necessary
to develop a mild, efficient, and selective means of epoxides. The nitrile=H2O2 system
(Payne epoxidation)[4,5] has the advantage of being useful for both large- and
small-scale reactions. The primary epoxidazing agent peroxyimidic acid[6,7] is gener-
ated in situ from the addition of hydrogen peroxide to a nitrile. Recently, the R-CN=
H2O2 system has been studied experimentally and theoretically by von Holleben et al.
and employed to prepare epoxide from unfunctionalized olefins.[8]
In the work reported here we have re-examined the use of the nitrile=H2O2
system under conditions where the H2O2 is delivered as the urea–H2O2 (UHP)
complex, which has been employed in organic reactions as an anhydrous source of
H2O2 for more than 20 years.[9–12] Usually, UHP is used in oxidation in the presence
of acid anhydride (acetic anhydride, trifluoroacetic anhydride, etc.) or catalyzed by
expensive metallic catalyst (methyl trioxorhenium, etc.). These conditions we
reported here give excellent yields of epoxides in a range of unsaturated substrates
(Scheme 1.). Additionally, UHP provides a number of advantages as a source of
H2O2.[13,14] Its stability at room temperature, high hydrogen peroxide content, and
the potential for releasing it in a controlled manner, as well as its solubility in organic
solvents, make it a good and safe substitute for anhydrous hydrogen peroxide.
RESULTS AND DISCUSSION
Effect of Nitrile
Initially, to optimize the reaction conditions, various nitriles available were
employed in the model reaction of epoxidation of cyclohexene with UHP (Table 1).
As compared with acetonitrile (entry 1), benzonitrile (entry 2) showed better results,
which was probably because of the stableness of peroxyimidic acid from benzene
ring’s conjugative effect. Several benzonitrile derivatives with electron-donating
groups (entry 3 and 4) and electron-withdrawing group (entries 5–8) were also exam-
ined. Unfortunately, none of them gave more yields as compared with benzonitrile.
Meanwhile, because of poor solubility in most solvents, pentachlorobenzonitrile
and tetrafluoroterephthalonitrile, which are important intermediates in the syntheses
of pyrethroids, afforded poor yields.
Effects of Solvent
The epoxidation of phenyl cyclohexene with peroxyimidic acid in situ from
benzonitrile=UHP was studied in different solvents (Table 2). In general, poor yields

2258
L. JI ET AL.
Table 1. Effects of nitrile during the epoxidation of cyclohexene with nitrile=UHPa
Entry
Nitrile
Conversionb (%)
Yieldb(%)
1
2
3
4
5
6
7
8
Acetonitrile
Benzonitrile
65
95
38
28
77
82
15
10
44
90
22
20
64
77
5
2-Methylbenzonitrile
4-Methoxybenzonitrile
2-Chlorobenzonitrile
2-Fluorobenzonitrile
Pentachlorobenzonitrile
Tetrafluoroterephthalonitrile
3
aThe substrate cyclohexene was treated with UHP (3.50 equiv.), nitrile (1.10
equiv.), and KHCO3 (0.2 equiv.) at 30 ꢀC in MeOH.
bConversion and yield determined by GC.
were observed when using hydrocarbon (entries 1 and 2), halohydrocarbon (entries 3
and 4) or EtOAc (entry 5), as solvents and good yields were observed when using
highly polar solvents such methanol (entry 7) and ethanol (entry 8), except in the case
of dimethylformamide (DMF) (entry 6). It could be attributed to UHP’s low solu-
bility in weak polar solvents, and hydrogen bond formed in alcohols could promote
the stability of reactive intermediate peroxyimidic acid. Therefore, methanol was
selected as solvent because of its low boiling point, ability to dissolve many substrates,
and production of the greatest yield of product.
Effects of the Alkalies
Although in Payne’s original article, sodium hydroxide[4] was selected to afford
basic condition, potassium bicarbonate was employed later.[5–8] We investigated the
epoxidation of cyclohexene with different kinds and different amounts of alkalies
such as sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium
bicarbonate systematically, and the results showed that greatest yield was obtained
by adding potassium bicarbonate and 0.20 equiv. to cyclohexene was enough
(Table 3).
Table 2. Effects of solvent in the epoxidation of cyclohexene with benzonitrile=UHPa
Entry
Solvent
Dielectric constant
Conversionb(%)
Yieldb(%)
1
2
3
4
5
6
7
8
n-C6H14
PhMe
1.88
2.38
10
27
21
8
4
14
10
3
CHCl3
CH2Cl2
EtOAc
DMF
4.81
8.93
6.02
19
43
96
90
4
36.70
32.70
25.80
21
89
77
MeOH
EtOH
aThe substrate cyclohexene was treated with UHP (3.50 equiv.), benzonitrile (1.10
equiv.), and KHCO3 (0.2 equiv.) at 30 ꢀC.
bConversion and yield determined by GC.

NITRILE-PROMOTED ALKENE EPOXIDATION
2259
Table 3. Yields of epoxidation of cyclohexene with different kinds and different
amounts of alkaliesa
Entry
Alkalies
Amount (equiv.)
Conversionb (%)
Yieldb (%)
1
2
3
4
5
6
7
8
Na2CO3
NaHCO3
K2CO3
0.20
0.20
0.20
0.05
0.10
0.20
0.30
0.40
60
45
84
82
90
96
97
98
49
30
73
78
83
89
88
88
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
aThe substrate cyclohexene was treated with UHP (3.50 equiv.) and benzoni-
trile (1.10 equiv.) at 30 ꢀC in methanol, 4 h.
bConversion and yield determined by GC.
Effects of the Amount of UHP
The amount of UHP was varied from 1.0 to 5.0 eq. to study its effect on the
epoxidation of cyclohexene with benzonitrile=UHP (Table 4). The yield of cyclohex-
ene oxide was measured after 4 h of stirring the reaction mixture at 50 ꢀC. It was
observed that the yield increases rapidly as the amount of UHP was increased (up
to 3.5 eq.) and then remained about the same even when slightly slowed down. There-
fore, we decided to use 3.5 eq. of UHP for further experiments.
Effects of the Reaction Temperature
The reaction temperature was varied from 10 to 60 ꢀC to study its effect on the
epoxidation of cyclohexene (Table 5). We observed that the yield increases rapidly as
the temperature was increased (up to 50 ꢀC) and the reaction time was significantly
shortened when the temperature was higher than 60 ꢀC. In view of operation of
reaction and generality of the method, 50 ꢀC was chosen for further experiments.
Table 4. Yields of epoxidation of cyclohexene with different amounts of UHPa
Entry
UHP (eq.)
Conversionb (%)
Yieldb (%)
1
2
3
4
5
6
7
8
1.0
1.5
2.0
2.5
3.0
3.5
4.0
5.0
35
61
32
55
71
81
86
90
91
90
79
85
90
96
98
>99
aThe substrate cyclohexene was treated with benzonitrile (1.10 equiv.) and
KHCO3 (0.2 equiv.) at 30 ꢀC in MeOH, 4 h.
bConversion and yield determined by GC.

2260
L. JI ET AL.
Table 5. Yields of epoxidation of cyclohexene at different reaction temperaturesa
Entry
Temperature (ꢀC)
Time (h)
Conversionb (%)
Yieldb (%)
1
2
3
4
5
6
7
8
10
15
20
25
30
40
50
60
72.0
40.0
24.0
12.0
8.0
77
81
66
75
78
83
90
84
82
76
86
88
96
98
6.0
3.5
>99
>99
2.0
aThe substrate cyclohexene was treated with UHP (3.50 equiv.), benzonitrile (1.10
equiv.), and KHCO3 (0.2 equiv.).
bConversion and yield determined by GC.
Comparison of Epoxidation of Cyclohexene with UHP and
Aqueous H2O2
In Table 6, the results of the epoxidation with our method were recompared
with conventional Payne epoxidation reagent PhCN=H2O2.[5] As can be seen, this
method is superior to some previously reported methods in terms of chemoselectivity,
yields, and reaction times.
Epoxidation of Different Alkenes with Benzonitrile/UHP
To explore the generality and scope of the method, various alkenes were
epoxidation with benzonitrile=UHP using the optimized reaction conditions, and
the results are listed in Table 7.
a
Table 6. Comparison of epoxidation of cyclohexene with UHP and aqueous H2O2
Yieldb (%)
Entry
Reagent
PhCN=UHP
PhCN=30%H2O2
Time (h)
Epoxide
1,2-Diol
Others
Ref.
1
2
3.5
8.0
90.1
54.8
60.0
76.0
95.0
75.0
55.0
65.0
85.0
78.4
0.8
13.6
—
3.7
5.8
—
—
—
—
—
—
—
—
This work
This work
[15]
3
CCl3CN=30%H2O2
CCl3CN=30%H2O2
DCC=UHP
6.0
[8]
4
24.0
4.0
—
—
[6]
5
[16]
[16]
[17]
[18]
[19]
6
CCl3CN=30%H2O2 ultrasonic
PhCN=30%H2O2 ultrasonic
70%mCPBA
24.0
24.0
1.5
—
—
7
8
—
—
9
10
Magnesium monoperphthalate
Acetone=oxone
7.0
3.0
—
aThe substrate (10.0 mmol) was treated with UHP (3.50 equiv.) or 30% H2O2 (4.00 equiv.), benzonitrile
(1.10 equiv.), and KHCO3 (0.2 equiv.).
bYield determined by GC.

NITRILE-PROMOTED ALKENE EPOXIDATION
2261
Table 7. Epoxidation of different alkenes with benzonitrile=UHPa
Entry
1
Alkene
Epoxide
Time (h)
Yieldb (%)
90
8.0
2
3
8.0
6.0
96
96
4
6.0
82
5
6
7
6.0
5.0
9.0
95
84
85
8
9
9.0
9.0
90
93
79
10
12.0
11
12
10.0
10.0
84
89
aThe substrate (10.0 mmol) was treated with UHP (3.50 equiv.), benzonitrile (1.10 equiv.),
and KHCO3 (0.2 equiv.).
bIsolated yield.
CONCLUSION
In summary, an efficient method for alkene epoxidation based on the peroxyi-
midic acid generated in situ has been studied systematic using benzonitrile and the
complex UHP. With the increasing tight legislation on the release of waste and
use of hazardous substances as a measure to control environmental pollution, the

2262
L. JI ET AL.
usage of UHP as a safe source of H2O2 and the slightly basic reaction condition
make it environmentally friendly. Because of the characteristics of UHP, the present
method avoids the need to add the aqueous H2O2 slowly to the reaction mixture and
undergoes fewer side reactions than conventional Payne epoxidation with
RCN=H2O2. In addition, the by-product benzamide can be recovered as valuable
compound, and thus this method is suitable for industrial applications.
EXPERIMENTAL
All chemicals were of reagent grade and used without further purification. All
yields refer to isolated products after purification. Products were characterized by
comparison with authentic samples and by spectroscopy data (1H NMR and 13C
NMR spectra). 1H NMR and 13C NMR spectra were recorded at 400 MHz (for 1H)
and 100 MHz (for 13C) on a Bruker AC-P400 spectrometer. The spectra were mea-
sured in CDCl3, relative to tetramethylsilane (TMS) (0.00 ppm). Gas chromato-
graphic (GC) analysis was run with GC Agilent 1705A. Melting-points were
determined on a WSR-2 capillary melting-point apparatus and are uncorrected. All
reactions were carried out in predried glassware (150 ꢀC, 5 h) cooled under vacuum.
General Procedure for the Epoxidations
Into a reaction vessel with a reflux condenser were successively placed cyclohex-
ene (10.0 mmol, 0.82 g), benzonitrile (11.0 mmol, 1.13 g), KHCO3 (2.0 mmol, 0.20 g),
MeOH (50 mL) and UHP (35.0 mmol, 3.29 g). The resulting mixture was stirred at
50 ꢀC for 3.5 h. Water (10 mL) was added to the reaction mixture, and the mixture
was extracted with dichloromethane (3 ꢁ 20 mL). The extract was dried over anhy-
drous sodium sulfate, concentrated under reduced pressure, and subjected to a
column chromatography using a mixture of n-hexane=EtOAc (10:1, v=v) as an eluent
to give cyclohexene oxide (0.884 g, 90.1% yield) and benzamide (1.16 g, 87.1% yield).
In a large-scale preparation, cyclohexene (1.0 mol, 82.1 g), benzonitrile (1.1 mol,
113.4 g), KHCO3 (0.2 mol, 20.0 g), and MeOH (1000 mL) were placed in a reaction
vessel, and UHP (3.5 mol, 329.2 g) was added in four portions. The resulting mixture
was stirred at 50 ꢀC for 5.0 h. Water (1000 mL) was added to the reaction mixture, and
the mixture was extracted with dichloromethane (3 ꢁ 300 mL). The extract was
dried over anhydrous sodium sulfate and then concentrated under reduced pressure.
Cyclohexene oxide (85.2 g, 86.8% yield) was obtained by reduced pressure distillation
(58–59 ꢀC at 15 mmHg), and benzamide (98.7 g, 81.5% yield) was obtained from
residue by recrystallization in water–EtOH (3:1, v=v).
Cyclohexene Oxide[19]
IR (KBr) t=cmꢂ1: 3030, 2924, 2895, 1423, 1251, 1065, 787, 760, 668; 1H NMR
(400 MHz, CDCl3): d 3.11 (s, 2H), 1.77–1.94 (m, 4H), 1.15–1.40 (m, 4H); 13C NMR
(100 MHz, CDCl3): d 52.2 (2CH), 24.5 (2CH2), 19.5 (2CH2).
Benzamide
1
White solid, mp: 126.2–128.5 ꢀC ; H NMR (400 MHz, CDCl3): d 7.84 (t,
J ¼ 7.6 Hz, 2H), 7.55 (d, J ¼ 7.6 Hz, 1H), 7.48 (t, J ¼ 8.0 Hz, 1H), 6.11 (brs, 1H),

NITRILE-PROMOTED ALKENE EPOXIDATION
2263
13
=
5.90 (brs, 1H); C NMR (100 MHz, CDCl3): d 169.5 (C ONH2), 135.1 (C), 132.0
(CH), 129.1 (2CH), 128.4 (2CH)
Please see the Supplemental Material, available online, for complete
experimental details.
ACKNOWLEDGMENTS
We thank the National Natural Science Foundation of China (21076183,
21006087), the Fundamental Research Funds for the Central Universities
(2011QNA4018), and the Key Innovation Group of Zhejiang Province
(2009R50002) for financial support.
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