Epoxidation by sodium chlorite with aldehyde-promoted chlorine dioxide formation

Article abstract of DOI:10.1016/j.tetlet.2010.09.102

An improved method is described for selective room temperature epoxidation of alkenes by sodium chlorite in a solvent mixture of ethanol, acetonitrile, and water buffered at pH 7. In addition, the use of aldehydes as promoters in chlorite oxidations is described for the first time. The amount of sodium chlorite, the solvent mixture, and the addition of formaldehyde as a practical promoter were optimized. Styrene was used as a test substrate in the optimization studies and the generality of the method was assessed by using a variety of nucleophilic and electrophilic substrates. Yields up to 89% were obtained with styrene and other nucleophilic alkenes are readily converted into epoxides.

Full text of DOI:10.1016/j.tetlet.2010.09.102

Tetrahedron Letters 51 (2010) 6481–6484
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Epoxidation by sodium chlorite with aldehyde-promoted chlorine
dioxide formation
⇑
Ashok Jangam, David E. Richardson
Center for Catalysis, Department of Chemistry, University of Florida, Gainesville, FL 32605, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
An improved method is described for selective room temperature epoxidation of alkenes by sodium chlo-
rite in a solvent mixture of ethanol, acetonitrile, and water buffered at pH 7. In addition, the use of alde-
hydes as promoters in chlorite oxidations is described for the first time. The amount of sodium chlorite,
the solvent mixture, and the addition of formaldehyde as a practical promoter were optimized. Styrene
was used as a test substrate in the optimization studies and the generality of the method was assessed by
using a variety of nucleophilic and electrophilic substrates. Yields up to 89% were obtained with styrene
and other nucleophilic alkenes are readily converted into epoxides.
Received 6 August 2010
Accepted 20 September 2010
Available online 25 September 2010
Keywords:
Epoxidation
Chlorite
Chlorine dioxide
Aldehyde
Ó 2010 Elsevier Ltd. All rights reserved.
The uses of sodium chlorite in synthetic organic chemistry have
been reviewed.1 Under certain conditions, the byproducts of chlo-
rite oxidations, in particular hypochlorous acid, can lead to the for-
mation of other reactive chlorine species, such as chlorine dioxide
(ClO2). Chlorine dioxide is a stable free radical that functions as a
one-electron oxidant in reactions with reducing substrates, such
as amines,2–7 sulfides,8 and phenols.9–13 A radical mechanism has
been proposed for the reactions of ClO2 with allylic and benzylic
substrates.14–16 In addition, it has been proposed that epoxides
can be formed in ClO2 reactions with alkenes via a radical addi-
tion–elimination mechanism.14,17 Although ClO2 has potentially
useful properties as a selective radical reagent for organic transfor-
mations, it must be produced immediately prior to its use via di-
rect synthesis since it is an explosive gas18 and is unstable when
stored in solution. Sodium chlorite, on the other hand, is readily
obtained, relatively stable in storage as a strongly oxidizing solid,
and can serve as a source of ClO2 in situ under appropriate
conditions.
We report herein an improved method for the selective, room
temperature epoxidation of alkenes by sodium chlorite in a solvent
mixture of ethanol, acetonitrile, and water buffered at pH 7. In
addition, we describe the use of aldehydes as promoters for the
first time. In this investigation we have optimized the amount of
sodium chlorite, the solvent mixture, and the use of formaldehyde
as a practical and simple promoter. Styrene was used as a test sub-
strate in the optimization studies and the generality of the method
was assessed with a variety of nucleophilic and electrophilic sub-
strates. By using high concentrations of chlorite ion, neutral pH
conditions, and selected solvent combinations, we are able to ob-
tain high conversion levels (99+ %) and epoxidation selectivities
up to 89% at room temperature for styrene.
Table 1 summarizes a survey of results for the epoxidation of
styrene by sodium chlorite under various conditions. Initially, the
room temperature epoxidation of styrene was carried out by using
different concentrations of sodium chlorite in ethanol/water (3:1,
v/v; 100 mM styrene, 15 mL ethanol, 5 mL water (phosphate buf-
fer, pH 7, 100 mM)). Neutral pH conditions were used to reduce
hydrolysis of the desired epoxide product. Yields increased to
88% at the higher concentrations of sodium chlorite (as a result
of both higher conversions and selectivities), and based on these
results, 10 equiv of chlorite was used in subsequent experiments.
In all reactions, there was a significant induction period before
the reaction achieved the maximum rate. With 1.0 M chlorite,
the induction period is ꢀ1 to 1.5 h and the maximum reaction rate
is observed at ꢀ2 h (Fig. 1). As the reactions progress, we observe
the accumulation of dissolved ClO2, as observed by Kolar and Lind-
gren17 and Geng et al.19
Geng et al.19 reported sodium chlorite as an oxidant for epoxi-
dation of alkenes to their corresponding epoxides in an acetoni-
trile/water mixture at 55–65 °C. The authors found that chlorine
dioxide is responsible for the epoxidation of alkenes and that chlo-
rite generates chlorine dioxide at the elevated reaction tempera-
ture. Previously, Kolar and Lindgren17 had observed styrene oxide
as a product of the ClO2 reaction with styrene but their acidic con-
ditions did not favor epoxide formation and only low yields were
obtained.
We also screened various solvent combinations (Table 1). No
reaction was observed in pure water, presumably due to the
insolubility of styrene and/or slow formation of ClO2. Among the
⇑
Corresponding author. Tel.: +1 352 392 0545; fax: +1 352 392 3255.
E-mail address: der@ufl.edu (D.E. Richardson).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.09.102

6482
A. Jangam, D. E. Richardson / Tetrahedron Letters 51 (2010) 6481–6484
Table 1
added to yield ClO2 and initiate the reaction, we have found that
the addition of aldehydes is a particularly convenient method for
producing the requisite amounts of chlorine dioxide in situ. In par-
ticular, formaldehyde is an attractive promoter because the end
product in its oxidation by a large excess of chlorite is carbon diox-
ide.20 In this way, the promoter byproduct is effectively removed
from the reaction mixture during the reaction and does not inter-
fere with the isolation of product. The oxidation of aldehydes by
chlorite ion is well known21 and a few recent studies have investi-
gated the mechanism of ClO2 formation.20,22 In the absence of sub-
strate, ClO2 is produced in a few minutes via the reaction of
chlorite with formaldehyde in our reaction conditions.
The promotional effect of HCHO was investigated for styrene
epoxidation using various concentrations of the promoter (Fig. 1).
The induction period is reduced with the increasing amounts of
promoter and essentially eliminated at 25 mM HCHO. It is note-
worthy that the addition of HCHO minimized or effectively elimi-
nated the initial induction period but did not reduce the
maximum rate of the reaction.
Along with HCHO, we have also checked other aldehydes, such
as glyoxal, benzaldehyde, and glucose and the results are pre-
sented in Table 2. With the exception of glucose, which reacts
slowly with chlorite ion,23,24 there is a significant decrease in the
required runtime of the reaction with the addition of small
amounts of these aldehydes due to the decrease of the induction
period. The ultimate yields are generally almost unchanged but
addition of the highest amounts of aldehyde (50 mM) results in re-
duced styrene oxide yield, presumably due to the rapid generation
of large amounts of HOCl, which reacts with styrene to produce
chlorinated byproducts.17 Based on these results, we settled on a
standard of 25 mM for the aldehyde promoter concentration.
The convenience and relatively high yields of the aldehyde-pro-
moted reaction led us to examine a variety of alkenes to assess the
generality of the method. Since ethanol/water is not a good solvent
for many substrates, we have broadened the applicability of the
method by replacing some of the ethanol co-solvent with acetoni-
trile. The effect of the solvent change on the styrene prototype
reaction is nil and we obtained an 89% styrene oxide yield in 5 h
with an acetonitrile/ethanol ratio of 2:1. Consequently, the optimal
reaction system was composed of 10 equiv of sodium chlorite in
acetonitrile/ethanol/pH 7 aq buffer (2:1:1, by volume) promoted
by 25 mM HCHO at room temperature (25 °C).
Solvent and temperature effects in epoxidation of styrene by sodium chlorite
[NaClO2] (M)
Solventa
Runtime (h)
Reaction
temp (°C)
Yield of
epoxideb (%)
0.3
0.5
1.0
1.5
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
EtOH/H2O
EtOH/H2O
EtOH/H2O
EtOH/H2O
7
6
5
4.5
5
8
22
18
22
24
5
4
3
20
20
2
25
25
25
25
25
25
25
25
25
25
25
25
25
25
15
35
60
70
88
88
81
80
64
64
70
60
83
80
76
82
83
81
MeOH/H2O
1-PrOH/H2O
1-BuOH/H2O
i-PrOH/H2O
t-BuOH/H2O
Acetonitrile/H2O
EtOH/H2O (4:1)
EtOH/H2O (2:1)
EtOH/H2O (1:1)
EtOH (100%)
EtOH/H2O
EtOH/H2O
a
Solvent/water ratio is 3:1, unless otherwise noted. Water is buffered to pH 7,
100 mM phosphate buffer. [styrene] = 100 mM.
b
Yields are based on GC analysis and are equal to conversion ꢁ selectivity.
Figure 1. Kinetics of epoxidation of styrene to styrene oxide using sodium chlorite
(1.0 M in 3:1 ethanol/H2O pH 7 phosphate buffer) with varying concentrations of
formaldehyde (legend). Open markers: styrene; filled markers: styrene oxide.
Addition of formaldehyde up to
induction period but does not reduce the selectivity for the epoxide product.
a final concentration of 25 mM reduces the
The method was tested on substituted aliphatic and aromatic
alkenes (Table 3) under the optimized conditions. The reactions
were done with and without formaldehyde promoter for compari-
son. For this wide variety of alkenes, the rates, conversions, and
selectivities were in general fair to very good for the promoted
solvent systems we studied, ethanol/water resulted in the highest
yield, with 100% conversion and 88% selectivity. Higher molecular
weight alcohols maintained relatively high conversions (at longer
reaction times) but produced significantly lower selectivities.
We also tested the influence of the solvent to water ratio and
noted that 3:1 ethanol/water gives the highest yield. At ethanol/
water ratios of less than 2:1, yields and selectivities were <80%.
Relatively small changes in selectivity occurred over the range of
15–35 °C but the required reaction time decreased significantly
at 35 °C.
Although chlorite is the ultimate source of oxidant in the epox-
idation reaction, the mechanism of chlorite epoxidation is believed
to involve the intermediate formation of chlorine dioxide and a
chain reaction as described by Kolar and Lindgren.17 We observed
that the induction period can be eliminated by direct addition of
chlorine dioxide (ꢀ15 mM), reducing the reaction time substan-
tially. However, synthesis of pure chlorine dioxide solutions is
time-consuming and must be done carefully to avoid explosions
and the resulting stock solutions have limited storage lifetimes.
We, therefore, sought a convenient method for producing chlorine
dioxide in situ by rapid conversion of a small portion of the chlorite
to chlorine dioxide. Although oxidants such as bromine can be
reactions but tend to be better for nucleophilic alkenes (a-methyl-
styrene was an exception, where the increased rate in the
Table 2
a
Promotional effect of aldehydes on epoxidation of styrene with NaClO2
Aldehyde
Amount of
aldehyde
(mM)
Run
time (h)
Conversion (%)
Yield of styrene
oxideb (%)
Unpromoted
HCHO
HCHO
HCHO
Glyoxal
Glyoxal
Glyoxal
Benzaldehyde
Glucose
—
5
4
3
2
3
2
2
3
4
99
88
88
88
78
82
87
81
85
87
10
25
50
10
25
50
50
50
100
100
96
100
100
100
99
99
a
Ethanol/water 3:1. Water is pH 7 100 mM phosphate buffer.
Yields are based on GC analysis and are equal to conversion ꢁ selectivity.
b

A. Jangam, D. E. Richardson / Tetrahedron Letters 51 (2010) 6481–6484
6483
Table 3
induction period at pH 8 was effectively eliminated with 25 mM
formaldehyde.
Comparison of promotional effect of HCHO in epoxidation of alkenes by sodium
chloritea
The electrophilic nature of this oxidant system was further
investigated by an examination of the substituent effects in styrene
epoxidations (Table 4). Several para-substituted styrenes were
investigated and compared to the results for styrene. It is observed
that the rate of the reaction is in the order R = –OCH3 > –CH3 >
–H > –Cl > –NO2, which shows the electrophilicity of this epoxida-
tion reagent. Interestingly, the overall conversion remains high
given the sufficient reaction time for all substrates but the selectiv-
ities decline for the two most nucleophilic substrates (R = Me,
Substrate
Results with and without promoterb
Runtime (h)
Conv. (%)
Selectivityc (%)
7
5
99
99
89
89
8
4
99
100
85 trans
84 trans
OMe), as also observed for a-methylstyrene (Table 3).
According to Kolar and Lindgren,17 the direct reaction of styrene
with the stable free radical ClO2 in the presence of chlorite yields
styrene oxide via the chain reaction of Eqs. (1)–(3), where SO = sty-
rene oxide. HOCl formed as an intermediate in
23
23
61
85
63 trans 18 cis
72 trans 11 cis
ClO2 þ S ! SO þ ClO
ð1Þ
ð2Þ
ð3Þ
ClO þ ClO2 þ H2O ! HOCl þ ClOꢂ þ Hþ
15
5
98
96
76
72
3
HOCl þ 2ClOꢂ2 þ Hþ ! 2ClO2 þ Clꢂ þ H2O
Eq. 2 is responsible for the formation of chlorinated byproducts via
side reactions. In the presence of excess sodium chlorite, the forma-
tion of ClO2 via the complex reaction of HOCl with chlorite25 (Eq. 3)
is favored over the formation of byproducts. This competition ex-
plains why styrene oxide yields increase with increasing [NaClO2]
(Table 1).
4
2
99
99
83
44
24
18
67
98
59
50
The loss of stereochemistry at the double bond (as illustrated by
the cis-stilbene reaction) is consistent with a radical addition
mechanism for Eq. 1 in which the intermediate (e.g., a substituted
benzyl radical in the case of styrene, 1) can undergo free rotation
around the C–C bond prior to the elimination of ClO radical and
closure of the epoxide ring. With radical addition as the rate deter-
mining step, substrate reactivity will tend to follow the radical
stability for the addition product, thereby explaining the high
reactivity of phenyl alkenes and the effect of substituents on rates
(Table 4). It is notable that ClO2 is isoelectronic with ROÅ2ꢃ and
intermediate 1 is analogous to that shown by Brill to account for
the formation of epoxides in the autoxidation of alkenes.26 The
elimination of ClOÅ (Eq. 1) is analogous to the elimination of ROÅ
in the autoxidation mechanism.
24
18
76
80
81
78
28
22
90
95
65
68
OH
HO
HO
28
22
58
77
77
85
O
24
24
32
65
78
84
O
a
1.0 M sodium chlorite in acetonitrile/ethanol/aq buffer (2:1:1, by volume) at
room temperature (25 °C) and at pH ꢀ7.
b
For each compound, the first entry is for no promoter and the second is for
H
25 mM formaldehyde promoter.
H
c
Yields are based on GC analysis and are equal to conversion ꢁ selectivity.
Cl
O
O
H
promoted reaction is accompanied by markedly reduced selectiv-
ity). Unfortunately, linear aliphatic alkenes such as 1-hexene and
5-decene are not usefully converted into the epoxide as the reac-
tions are slow and non-selective (ꢀ20% yield with reaction times
of 25 and 30 h, respectively). Similarly, selectivity in cyclohexene
oxide formation was ꢀ50%, although the cyclooctene reaction
was relatively selective. Overall, the reactivity pattern indicates
that this is an electrophilic oxidant system, although the electro-
philic alkene trans -1,2-dibenzoylethylene was converted slowly
into epoxide with good selectivity.
1
The induction period in the absence of the promoter (Fig. 1) is
associated with the slow initial conversion of small amounts of
chlorite to form chlorine dioxide, most likely through the reactions
involving alcohol and/or the aqueous buffer. Once ClO2 is produced
Table 4
a
Epoxidation of para-substituted styrenes with NaClO2
It was observed that the epoxidation of trans-stilbene gives
trans-stilbene oxide alone whereas cis-stilbene yields trans-stil-
bene oxide as the major product. This result shows the non-stereo-
specificity of the reaction and is in good agreement with an earlier
report on sodium chlorite epoxidations by Geng et al.19
We also examined pH effects in the range of 6–8 for the oxida-
tion of styrene and found that yields of the epoxide remain >80% in
that range, although at pH 8 the induction period is lengthened
substantially in the absence of the promoter (to ꢀ6 h). This long
para-Substituent
Runtime (h)
Conversion (%)
Yield of epoxide (%)b
–OCH3
–CH3
–H
–Cl
–NO2
1
3
5
6
23
100
100
99
99
96
51
60
89
78
86
a
1.0 M sodium chlorite in acetonitrile/ethanol/aq buffer (2:1:1, by volume)
promoted by 25 mM HCHO at room temperature (25 °C) and at pH ꢀ7.
b
Yields are based on GC analysis and are equal to conversion ꢁ selectivity.

6484
A. Jangam, D. E. Richardson / Tetrahedron Letters 51 (2010) 6481–6484
10. Hoigne, J.; Bader, H. Water Res. 1994, 28, 45–55.
in sufficient amounts, the chain reaction (Eqs. (1)–(3)) becomes
self-sustaining and the reaction rapidly reaches its maximum rate.
To bypass the slow initiation and to improve the practicality of the
reaction, direct addition of reactants that form ClO2 via the reac-
tion with chlorite can reduce the induction period and decrease
the reaction times. It has been long known that sodium chlorite
can oxidize aldehydes to their respective acids and chlorine diox-
ide is produced during this process.20–22 According to Chinake
et al.20 the overall stoichiometry for chlorite oxidation of formalde-
hyde to formic acid is given by Eq. 4,
11. Nam, K. C.; Kim, J. M. Bull. Korean Chem. Soc. 1994, 15, 268–270.
12. Tratnyek, P. G.; Hoigne, J. Water Res. 1994, 28, 57–66.
13. Ganiev, I. M.; Ganieva, E. S.; Kabal’nova, N. N. Russ. Chem. Bull. 2004, 53, 2281–
2284.
14. Lindgren, B. O.; Svahn, C. M. Acta Chem. Scand. 1965, 19, 7–13.
15. Chen, A. S. C.; Larson, R. A.; Snoeyink, V. L. Environ. Sci. Technol. 1982, 16, 268–
273.
16. Silvestre, S. M.; Salvador, J. A. R. Tetrahedron 2007, 63, 2439–2445.
17. Kolar, J. J.; Lindgren, B. O. Acta Chem. Scand. B 1982, 36, 599–605.
18. Jin, R. Y.; Hu, S. Q.; Zhang, Y. G.; Bo, T. J. Hazard. Mater. 2009, 166, 842–847.
19. Geng, X. L.; Wang, Z.; Li, X. Q.; Zhang, C. J. Org. Chem. 2005, 70, 9610–9613.
20. Chinake, C. R.; Olojo, O.; Simoyi, R. H. J. Phys. Chem. A 1998, 102, 606–611.
21. Launer, H. F.; Tomimatsu, Y. Anal. Chem. 1959, 31, 1385–1390.
22. Lehtimaa, T.; Kuitunen, S.; Tarvo, V.; Vuorinen, T. Ind. Eng. Chem. Res. 2010, 49,
2688–2693.
3ClOꢂ2 þ HCHO þ 2Hþ ! HCOOH þ 2ClO2 þ Clꢂ þ H2O
ð4Þ
and in the presence of excess chlorite, formic acid is further
oxidized to CO2 in a second net reaction (Eq. 5).
23. Launer, H. F.; Tomimatsu, Y. J. Am. Chem. Soc. 1954, 76, 2591–2593.
24. Launer, H. F.; Wilson, W. K.; Flynn, J. H. J. Res. Nat. Bur. Stand. 1953, 51, 237–
245.
25. Kormanyos, B.; Nagypal, I.; Peintler, G.; Horvath, A. K. Inorg. Chem. 2008, 47,
7914–7920.
3ClOꢂ2 þ HCOOH þ 2Hþ ! CO2 þ 2ClO2 þ Clꢂ þ 2H2O
ð5Þ
Under our aldehyde-promoted conditions,30 ClO2 is formed
rapidly by reactions analogous to Eq. 4 with reactive aldehydes
(plus Eq. 5 in the case of formaldehyde) and the chain reaction that
produces epoxide is initiated without a significant induction period
(Fig. 1). The promotion reaction need not achieve the stoichiome-
tric limits in Eqs. 4 and 5 to be effective.
26. Brill, W. F. J. Am. Chem. Soc. 1963, 85, 141.
27. Jia, Z. J.; Margerum, D. W.; Francisco, J. S. Inorg. Chem. 2000, 39, 2614–2620.
28. Furman, C. S.; Margerum, D. W. Inorg. Chem. 1998, 37, 4321–4327.
29. Masschelein, W. J. J. Am. Water Works Assoc. 1984, 76, 70–76.
30. All alkenes and reagents were purchased from commercial suppliers and used
without further purification. Technical grade sodium chlorite (80%) was
purchased from Fisher Scientific and recrystallized as described previously.27
The purity of sodium chlorite was determined by the ion chromatography
(Model ICS-1500, Dionex Corporation, CA, USA). General procedures for
epoxidations and product analysis.
A 50 mL of round-bottomed flask was
Acknowledgments
charged with a solvent mixture (10 mL acetonitrile, 5 mL ethanol and 5 mL
water (pH 7, 100 mM phosphate buffer) for reactions listed in Table 3). To this
solvent mixture 100 mM of alkene and 50 mM of naphthalene (when used as a
GC standard) were added and stirring was continued for 1 h to dissolve the
alkene completely. To this mixture recrystallized sodium chlorite was added to
give a 1 M solution. The reaction starts as soon as the sodium chlorite was
added. The solution turned from colorless to yellow during the reaction.
The authors thank Mr. Alex Weppelmann for assistance in the
synthesis of chlorine dioxide. Funding was provided by the Univer-
sity of Florida and the Army Research Office.
Product analysis was done at regular intervals. A 250 lL aliquot of the reaction
References and notes
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e
= 1250 Mꢂ1 cmꢂ1). Purity was assessed by using
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