Production of hydrogen peroxide via aerobic oxidation of alcohols catalyzed by N-hydroxyphthalimide

Article abstract of DOI:10.1021/op990082f

An efficient method for production of hydrogen peroxide via aerobic oxidation of alcohols was achieved by the use of N-hydroxyphthalimide (NHPI) as a catalyst. For instance, the oxidation of benzhydrol in the presence of a catalytic amount of NHPI under dioxygen (1 atm) in ethyl acetate at 75 °C gave H₂O₂ in 51% yield along with benzophenone (72%). The production of H₂O₂ from various alcohols was also examined. The reaction proceeds through the formation of an α-hydroxy hydroperoxide as a transient intermediate derived from an alcohol and dioxygen by the action of NHPI.

Full text of DOI:10.1021/op990082f

Organic Process Research & Development 2000, 4, 94−97
Production of Hydrogen Peroxide via Aerobic Oxidation of Alcohols Catalyzed
by N-Hydroxyphthalimide
Takahiro Iwahama, Satoshi Sakaguchi, and Yasutaka Ishii*
Department of Applied Chemistry, Faculty of Engineering & High Technology Research Center, Kansai UniVersity,
Suita, Osaka 564-8680, Japan
Abstract:
process) produces H2O2 and acetophenone, although the
oxidation must be carried out under relatively severe condi-
tions (∼160 °C, 10∼20 atm of air or O2).5a After the isolation
of H2O2, the resulting mixture involving acetophenone is
subjectedtothehydrogenationtoformtheoriginal1-phenylethanol.5a
In previous papers, we reported that N-hydroxyphthal-
imide (NHPI) which serves as a radical catalyst promotes
aerobic oxidations of various hydrocarbons in the presence
or absence of a transition metal under mild conditions.6 The
NHPI-catalyzed aerobic oxidation of alkanes proceeds via a
radical process involving the hydrogen abstraction from
alkanes by phthalimide N-oxyl (PINO) generated in situ from
NHPI and O2, producing hydroperoxides which eventually
are converted into oxygen-containing products such as
alcohols and ketones as well as carboxylic acids. Recently,
we have found that R-hydroxy hydroperoxides I formed in
situ from alcohols and O2 by the action of NHPI can be
applied as oxidants to the selective oxidation of sulfides to
sulfoxides7 and alkenes to epoxides.8 In continuation of our
study on the NHPI-catalyzed autoxidation of alcohols, we
wish to report here a novel approach for the production of
H2O2 by the aerobic oxidation of benzhydrol or 1-phenyl-
ethanol under mild conditions (eq 1).
An efficient method for production of hydrogen peroxide via
aerobic oxidation of alcohols was achieved by the use of
N-hydroxyphthalimide (NHPI) as a catalyst. For instance, the
oxidation of benzhydrol in the presence of a catalytic amount
of NHPI under dioxygen (1 atm) in ethyl acetate at 75 °C gave
H2O2 in 51% yield along with benzophenone (72%). The
production of H2O2 from various alcohols was also examined.
The reaction proceeds through the formation of an r-hydroxy
hydroperoxide as a transient intermediate derived from an
alcohol and dioxygen by the action of NHPI.
Introduction
Hydrogen peroxide (H2O2) is one of the most important
and frequently used oxidants in the laboratory and in industry.
Even many oxidants such as sodium perborate, percarbonate,
potassium hydroperoxy sulfate, and organic peroxy acids are
prepared from hydrogen peroxide.1 In industrial chemistry,
a large amount of H2O2 is used as an oxidant for bleaching
of paper, textiles, and cellulose.2 Recently, H2O2 has become
more and more popular as an environmentally friendly
reagent which leads to only water after the reaction.3
Current technology for the production of H2O2 is based
on the autoxidation of anthrahydroquinones which is known
as the AO process and is extensively employed.3b,4 The
anthraquinones formed are reduced to the original hydro-
quinones with hydrogen. This process, therefore, leads to
the net formation of H2O2 from gaseous hydrogen and
oxygen. In addition to the AO process, the autoxidation of
secondary alcohols is a powerful candidate for the production
of H2O2 via formation of R-hydroxy hydroperoxides (I).3b,5
For instance, the autoxidation of 1-phenylethanol (Arco
Results and Discussion
At the beginning, benzhydrol (1) was chosen as a model
alcohol and allowed to react under various conditions (Table
1). When 1 was reacted under dioxygen (1 atm) in the
presence of a catalytic amount of NHPI (10 mol %) in AcOEt
at 75 °C for 12 h, H2O2 (2) was obtained in 51% yield at
72% conversion of 1 along with benzophenone (3) (72%)
(run 1). This indicates that ∼70% of 1 was oxidized to 3 to
liberate H2O2.9 The formation of H2O2 by the present method
(1) Hess, W. T. In Kirk-Othmer Encyclopedia of Chemical Technology, 4th
ed.; Kroschwitz, J. I., Howe-Grant, M., Eds., John Wily and Sons: New
York, 1995; Vol. 13, p 988. (b) Strukul, G. Catalytic Oxidation with
Hydrogen Peroxide as Oxidant; Kluwer: Dordrecht, 1992.
(2) Hess, W. T. In Kirk-Othmer Encyclopedia of Chemical Technology, 4th
ed.; Kroschwitz, J. I., Howe-Grant, M., Eds., John Wily and Sons: New
York, 1995; Vol. 13, pp 986-988.
(3) Gelbein, A. P. CHEMTECH 1998, 28, 1. (b) Huckins, H. A. CHEMTECH
1999, 29, 2.
(4) Hess, W. T. In Kirk-Othmer Encyclopedia of Chemical Technology, 4th
ed.; Kroschwitz, J. I., Howe-Grant, M., Eds., John Wily and Sons: New
York, 1995; Vol. 13, pp 967-976.
(5) Hess, W. T. In Kirk-Othmer Encyclopedia of Chemical Technology, 4th
ed.; Kroschwitz, J. I., Howe-Grant, M., Eds., John Wily and Sons: New
York, 1995; Vol. 13, pp 976-977. (b) Goor, G.; Kunkel, W. In Ullmann’s
Encyclopedia of Industrial Chemistry, 5th ed.; Elvers, B., Hawkins, S.,
Ravenscroft, M., Schulz, G., Eds., VCH: Weinheim, 1989; Vol. A 13, p
457.
(6) Ishii, Y.; Nakayama, K.; Takeno, M.; Sakaguchi, S.; Iwahama, T.;
Nishiyama, Y. J. Org. Chem. 1995, 60, 3934. (b) Ishii, Y.; Iwahama, T.;
Sakaguchi, S.; Nakayama, K.; Nishiyama, Y. J. Org. Chem. 1996, 61, 4520.
(c) Yoshino, Y.; Hayashi, Y.; Iwahama, T.; Sakaguchi, S.; Ishii, Y. J. Org.
Chem. 1997, 62, 6810. (d) Sakaguchi, S.; Kato, S.; Iwahama, T.; Ishii, Y.
Bull. Chem. Soc. Jpn. 1998, 71, 1237. (e) Iwahama, T.; Syojyo, K.;
Sakaguchi, S.; Ishii, Y. Org. Process Res. DeV. 1998, 2, 255. (f) Sakaguchi,
S.; Takase, T.; Iwahama, T.; Ishii, Y. Chem. Commun. 1998, 2037 and
references therein.
(7) Iwahama, T.; Sakaguchi, S.; Ishii, Y. Tetrahedron Lett. 1998, 39, 9059.
(8) Iwahama, T.; Sakaguchi, S.; Ishii, Y. Chem. Commun. 1999, 727.
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10.1021/op990082f CCC: $19.00 © 2000 American Chemical Society and The Royal Society of Chemistry
Published on Web 02/10/2000

Table 1. Production of H2O2 (2) via oxidation of benzhydrol
Table 2. Production of H2O2 (2) via oxidation of 1 to 3 in
(1) in AcOEt under various conditionsa
various solventsa
yield %
2c
yield (%)
[alcohol]b
(M)
NHPI
(mol %)
time
(h)
conv.
(%)
run
3
run
solvent
time (h)
conv. (%)
2b
3
1
2
3
1
2
2
2
1
1
10
10
5
10
10
10
12
12
12
12
8
72
76
61
71
94
61
51 (70)
48 (64)
37 (62)
60 (85)
21 (22)
33 (55)
72
73
60
70
92
60
1
2
3
4
5
AcOEt
AcOBun
CH3CN
CH3CN
PhCN
PhCN
PhCN
PhCN
PhCN
PhCl
12
12
18
24
18
18
18
3
72
71
48
77
70
79
55
58
82
21
15
51 (70)
44 (62)
42 (87)
55 (72)
42 (60)
43 (54)
38 (69)
34 (60)
34 (41)
14 (60)
<9
72
71
48
76
70
78
54
58
82
21
15
4d
5e
6e,f
6c
7c,d
8e
9e
10
11
12
a 1 (5 mmol) was allowed to react with molecular oxygen in the presence of
NHPI in AcOEt at 75 °C. b Concentration of 1 (mol/L). c Selectivity based on 1
reacted is in paretheses. d 40 mmol of 1 was used. e Co(OAc)2 (0.02 mol %)
was added. f Reaction was conducted at 50 °C.
10
12
12
PhCF3
a 1 (5 mmol) was allowed to react with molecular oxygen in the presence of
NHPI (10 mol %) in solvent (5 mL) at 75 °C. b Selectivity based on 1 reacted
is in paretheses. c PhCN (2.5 mL) was used. d Reaction was carried out at 60
°C. e Reaction was carried out at 85 °C.
Scheme 1
posed through the redox pathway by the cobalt ion. It is well-
known that transition metal ions such as iron and cobalt
prompt the redox decomposition of H2O2 and hydroperox-
ides.11 When the reaction temperature was lowered from 75
to 50 °C, the decomposition of H2O2 was suppressed to some
extent (run 6). The effect of other metal ions such as Cu-
(OAc)2 and VO(acac)2 on the formation of H2O2 was also
examined, but satisfactory results were not obtained by the
addition of these metals.
The choice of solvent is important not only to carry out
efficiently the reaction but also to extract the resulting H2O2
from the solvents. The aerobic oxidation of 1 was run in
several solvents (Table 2). The reaction in AcOBun having
higher lipophilicity than AcOEt tends to decrease the
selectivity to H2O2 (run 2). The oxidation of 1 in CH3CN
led to H2O2 in the highest selectivity (87%) at 48%
conversion, although longer reaction time was needed (runs
3 and 4). For the production of aqueous H2O2, however,
CH3CN may be undesirable, since it is miscible with water.12
Thus, the oxidation of 1 in PhCN which is immiscible with
water was carried out. However, the reaction in PhCN gave
H2O2 in lower selectivity (60%) than that in CH3CN (run
5). The selectivity of H2O2 was somewhat improved at 60
°C (69%) (run 7). The same oxidation at 85 °C for 3 h
resulted in H2O2 (60%) in 58% conversion (60%) (run 8).
The aerobic oxidation of 1 in chlorobenzene or trifluoro-
methylbenzene proceeded slowly to give 2 in poor yields
(runs 10 and 11).
is illustrated by Scheme 1. The reaction using 5 mol % of
NHPI under these conditions gave H2O2 in slightly lower
yield (37%) (run 3). To evaluate whether the present method
can be used as a practical method, it was important to carry
out the reaction in large-scale. Thus, 40 mmol of 1 (7.36 g)
was allowed to react under these reaction conditions, and it
was found that H2O2 was obtained in good selectivity (85%)
and conversion (71%) (run 4). It is interesting to note that
the large-scale reaction gave better results than that on small-
scale.
In a previous paper, we reported that the aerobic oxidation
of various alcohols was markedly enhanced in the presence
of a small amount of a Co species such as Co(OAc)2.10 Thus,
the effect of the Co ion on the formation of H2O2 from 1
was investigated (runs 5 and 6). Despite the higher conver-
sion of alcohol 1 into ketone 3, H2O2 was formed in low
yield. This shows that the formed H2O2 is readily decom-
To extend the present method, various alcohols were
allowed to react under the same reaction conditions (Table
3). From the aerobic oxidation of aromatic alcohols such as
1-phenylethanol (4) and benzoin, H2O2 was obtained in high
(11) Haber, F.; Weiss, J. Proc. R. Soc. London, Ser. A. 1934, 147, 332. (b)
Sheldon, R. A.; Kochi, J. K. Metal-Catalyzed Oxidations of Organic
Compounds; Academic Press: New York, 1981.
(12) The in situ generation of H2O2 seems to be a great advantage in the chemical
industry, because the storage and transportation of explosive hydrogen
peroxide can be omitted. For storage and transportation of H2O2: Goor,
G.; Kunkel, W. In Ullmann’s Encyclopedia of Industrial Chemistry, 5th
ed.; Elvers, B., Hawkins, S., Ravenscroft, M., Schulz, G., Eds., VCH:
Weinheim, 1989; Vol. A 13, pp 461-463.
(9) A part of NHPI was found to be converted into phthalimide during the
reaction. After the evaporation of AcOEt, NHPI and phthalimide were
isolated by filtration and then washed with cold ether. Treatment of the
recovered phthalimide with hydroxylamine gave the NHPI in almost
quantitative yield.
(10) Iwahama, T.; Sakaguchi, S.; Nishiyama, Y.; Ishii, Y. Tetrahedron Lett. 1995,
36, 6923.
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Table 3. Production of H2O2 (2) via Oxidation of Various
Alcohols to Ketones by NHPI-O2 systema
Although we also examined the oxidation of 2-propanol
under these conditions, low yield of H2O2 was obtained (run
6). We believe that the oxidation of secondary alcohols by
the present catalytic system is difficult to occur. From the
practical and synthetic points of view, 2-propanol is not
suited for the production of pure hydrogen peroxide, because
of the complication of isolation of H2O2 from a mixture of
acetone/2-propanol/water/ H2O2.
On the basis of these results, benzhydrol 1 and 1-phen-
ylethanol 4 were found to be good alcohols for the production
of H2O2 by the present method.
To carry out the present reaction in industrial scale, the
employment of air instead of molecular oxygen as the oxidant
is important for economical and safety reasons. With this in
mind, the production of H2O2 by the NHPI-catalyzed
oxidation of benzhydrol 1 and 1-phenylethanol 4 using air
was evaluated (Table 4).
yield (%)b
conv.
(%)
run
alcohol
H2O2
ketone
1
benzhydrol (1)
1-phenylethanol (4)
benzoin
cyclohexanol (6)
6
72
49
54
20
58
51 (70)
40 (81)
40 (74)
14 (70)
12 (21)
<5
72
48
49
19
38
2c
3
4d
5d,e
6d
2-propanol
a Alcohol (5 mmol) was allowed to react with dioxygen (1 atm) in the presence
of NHPI (10 mol %) in AcOEt (5 mL) at 75 °C for 12 h. b Selectivity based on
alcohol reacted is in paretheses. c 18 h. d 20 h. e CH3CN was used as solvent.
Scheme 2
Even under 1 atm of air, the reaction proceeded smoothly
to give H2O2 in 36% yield (63% selectivity) (run 1). When
the same oxidation was conducted under 5 and 10 atm of
air, the yield of H2O2 was improved to 50 and 57%,
respectively (runs 2 and 4). The oxidation at 65 °C under
these conditions produced H2O2 in 35% yield (84% selectiv-
ity) (run 5). Even when the amount of NHPI was halved (5
mol %), 1 afforded H2O2 in 41% yield (run 6). However,
the oxidation at higher temperature (85 °C) resulted in H2O2
in lower selectivity (run 7).
selectivities at moderate conversions (runs 2 and 3).13 The
production of H2O2 from 1-phenylethanol 4 seems to be a
very attractive route, since a large quantity of the 4 is formed
as a coproduct along with propylene oxide during the
epoxidation of propylene with R-hydroperoxy ethylbenzene
by the Halcon process.14
Similarly, the aerobic oxidation of 1-phenylethanol 4 was
examined (runs 8∼10). In all cases, H2O2 was obtained in
satisfactory yields along with acetophenone 5, although the
oxidation took place more slowly than that of 1.
The selectivity of the oxidation of cyclohexanol (6) in
AcOEt was considerably different from that in CH3CN. In
AcOEt, H2O2 was formed in higher selectivity (70%).
However, in CH3CN the selectivity to H2O2 became very
low (21%). This is believed to be due to the fact that the
resulting H2O2 reacted with cyclohexanone (7) leading to
peroxide (9) through R-hydroxy hydroperoxide as shown in
Scheme 2 (runs 4 and 5).15 1H NMR measurement of the
reaction mixture obtained from the aerobic oxidation of
alcohol 4 under the influence of NHPI in CD3CN indicated
a broad peak attributed to the proton of H2O2 at around δ
8.3 and several peaks assigned to 4 and acetophenone (5),
but no peaks assigned to the R-hydroxy hydroperoxides were
In conclusion, we have developed an alternative efficient
route for the production of H2O2 via the aerobic oxidation
of alcohols assisted by the NHPI catalyst. H2O2 could be
prepared by the aerobic oxidation of benzhydrol catalyzed
by NHPI. The resulting H2O2 can be easily separated from
the reaction mixture by extraction with water. Further investi-
gations to extend the present system to the oxidation of vari-
ous substrates with the in situ generated H2O2 are in progress.
Experimental Section
1H and 13C NMR spectra were recorded at 400 and 100
MHz, respectively, using CDCl3 with tetramethylsilane as
the internal standard. Flash chromatography was performed
with use of silica gel (MERCK, Silica gel 60, 70-230 mesh).
Gas chromatography was carried out on Shimazu GC-17A
with a flame ionization detector using a 0.22 mm × 25 m
capillary column (SGE BP-10).
1
observed. In the aerobic oxidation of 6, however, H NMR
of the reactant showed many peaks in the range δ 8.4-9.8
which are assigned to hydroperoxides and peroxides derived
from 7 and H2O2.
All starting materials, solvents and catalysts were pur-
chased from commercial sources and used without further
treatment. The yield of oxidation products except for H2O2
was estimated from the peak areas based on the internal
standard technique.
General Procedure for the Oxidation of 1 and Isolation
of Hydrogen Peroxide. An ethyl acetate (5 mL) solution of
1 (920 mg, 5 mmol), NHPI (82 mg, 0.5 mmol) was placed
in a two-necked flask equipped with a balloon filled with
O2. The mixture was stirred at 75 °C for 12 h. After the
reaction, water (5 mL) and toluene (10 mL) were added to
(13) The Arco process is operated at 140 °C under 21 kg/cm2 of air leading to
30% conversion of 4. On the other hand, the present oxidation of 1 or 4
proceeds smoothly even under 1 atm of O2 or air at moderate tempera-
ture (70∼80 °C) to give H2O2 (71% conversion and 85% selectivity)
comparable to those obtained by the Arco process. Thus, from the safety
point of view, this oxidation method has great advantages in the chemical
industry.
(14) Landau, R.; Sullivan, G. A.; Brown, D. CHEMTECH 1979, 602.
(15) Brown, N.; Roedel, M. J.; Anderson, A. W.; Schweitzer, C. E. J. Am. Chem.
Soc. 1955, 77, 1756. (b) Kharasch, M. S.; Sosnovsky, G. J. Org. Chem.
1958, 23, 1322. (c) De La Mare, H. E.; Kochi, J. K.; Rust, F. F. J. Am.
Chem. Soc. 1963, 85, 1437. (d) Sauer, M. C. V.; Edwards, J. O. J. Phys.
Chem. 1971, 75, 3377. (e) Zhou, X.; Lee, Y. N. J. Phy. Chem. 1992, 96,
265.
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Table 4. Production of H2O2 (2) via aerobic oxidation of 1 or 4 to 3 or 5 in AcOEt under air pressurea
yield (%)
select. (%)
air
(atm)
[alcohol]b
(M)
NHPI
(mol %)
temp.
(°C)
time
(h)
conv.
(%)
run
alcohol
2
3
2
3
1
2
3
4
5
1
1
1
1
1
1
1
4
4
4
1
5
10
10
5
5
5
5
10
5
1
1
1
1
1
2
2
2
2
1
10
10
10
10
10
5
75
75
75
75
65
75
85
75
75
75
12
12
8
12
12
12
8
24
24
24
57
66
63
75
42
50
45
42
51
40
36
50
51
57
35
41
33
35
40
35
48
66
63
75
42
50
63
76
81
76
84
82
73
83
78
86
84
99
99
99
99
99
6c
7c
8c
9c
10
5
45
99
10
10
10
42d
50d
40d
99d
98d
99d
a 1 (5 mmol) was allowed to react in the presence of NHPI under pressure of air in AcOEt (5 mL). b Concentration of alcohol employed. c Alcohol (10 mmol) was
used. d Acetophenone 5.
the reactant, and then the aqueous phase was separated. The
quantity of hydrogen peroxide in the aqueous solution was
determined by iodometry.16 The slight amount of AcOEt was
found to be involved in aqueous H2O2 by GC analysis. The
organic layer was dried over MgSO4 and analyzed by GLC
with an internal standard. The products were separated from
the solvent under reduced pressure and purified by column
chromatography on silica gel (n-hexane/AcOEt ) 5/1) to
give the corresponding ketones. Ketones were identified
through the comparison of their 1H and 13C NMR with those
of authentic samples.
Oxidation of 1 on a Large Scale. An ethyl acetate (20
mL) solution of 1 (7.36 g, 40 mmol), NHPI (0.652 g, 4
mmol) was placed in a two-necked flask (100 mL) equipped
with a balloon filled with O2. The mixture was stirred at 75
°C for 12 h. The workup was performed using the same
method as previously described.
mL) placed in a 50 mL stainless steel autoclave was added
NHPI (82 mg, 0.5 mmol). The autoclave was pressured with
5 or 10 atm of air, with stirring, at 75 °C. After 12 h, the
autoclave was cooled in an ice bath, and then the residual
air was ventilated. The workup was performed using the same
method as previously described.
1H NMR Measurement in the Oxidation of 4. A
CD3CN (2 mL) solution of 4 (244 mg, 2 mmol), NHPI (32
mg, 0.2 mmol) was placed in a two-necked flask equipped
with a balloon filled with O2. The mixture was stirred at 75
°C for 24 h. After the reaction, the mixture was subjected to
1
the H NMR measurement.
Acknowledgment
This work was partly supported by Research for the Future
program JSPS.
General Procedure for Oxidation of 1 under Air
Pressure. To a solution of 1 (1.84 g, 10 mmol) in AcOEt (5
Received for review October 1, 1999.
OP990082F
(16) Ricciuti, C.; Coleman, J. E.; Willits, C. O. Anal. Chem. 1955, 27, 405.
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