Direct conversion of cyclohexane into adipic acid with molecular oxygen catalyzed by N-hydroxyphthalimide combined with Mn(acac)2 and Co(OAc)2

Article abstract of DOI:10.1021/op980016y

Direct conversion of cyclohexane into adipic acid was achieved by the use of the radical catalyst, N-hydroxyphthalimide (NHPI), in the presence of a small amount of a transition metal. For instance, cyclohexane could be converted into adipic acid in 73% selectivity at 73% conversion under atmospheric oxygen (1 atm) in the presence of NHPI (10 mol %) and Mn(acac)₂ (1 mol %) at 100 °C for 20 h. ESR measurements show that the formation of phthalimide N-oxyl generated from NHPI with O₂ was assisted by Co(II) species. Thus, the oxidation of cyclohexane to adipic acid was found to be enhanced by the addition of a small amount of Co(OAc)₂ to the NHPI/Mn(acac)₂ system. The NHPI-catalyzed oxidation of cyclohexane provides an attractive direct method which has long been desired in the chemical industry for the manufacturing of adipic acid. The present oxidation seems to be the first practical environmentally friendly process, in which nitric acid is not used as the oxidant, for the production of adipic acid from cyclohexane.

Full text of DOI:10.1021/op980016y

Organic Process Research & Development 1998, 2, 255−260
Direct Conversion of Cyclohexane into Adipic Acid with Molecular Oxygen
Catalyzed by N-Hydroxyphthalimide Combined with Mn(acac)2 and Co(OAc)2
Takahiro Iwahama, Kouichi Syojyo, Satoshi Sakaguchi, and Yasutaka Ishii*
Department of Applied Chemistry, Faculty of Engineering and High Technology Research Center, Kansai UniVersity,
Suita, Osaka 564-8680, Japan
Abstract:
worldwide by homogeneous liquid-phase oxidation in the
presence of Co and/or Mn salts, which process is commonly
referred to as autoxidation.6 Autoxidation of cyclohexane
produces a mixture of cyclohexanone/cyclohexanol (K/A oil)
as major products along with a small amount of adipic acid.6
The resulting K/A oil is oxidized to adipic acid which is the
most important compound of all aliphatic dicarboxylic acids
manufactured. Current technology for the industrial produc-
tion of adipic acid involves the two-step oxidation of
cyclohexane,7 i.e., aerobic oxidation of cyclohexane at 150-
170 °C in the presence of a soluble Co catalyst to form a
K/A oil from which subsequent nitric oxidation produces
adipic acid. However, the conversion of cyclohexane in the
first step is necessary to keep only 3-6% in order to obtain
higher selectivity to the K/A oil, and the second step results
in a large amount of undesired NOx which are environmen-
tally critical compounds. Therefore, there has been an
increasing need for the direct one-step conversion of cyclo-
hexane to adipic acid with molecular oxygen due to these
environmental and economical concerns, although the oxida-
tion of cyclohexane to adipic acid has been described under
oxygen pressure using a higher concentration of Co(III)
acetate under the influence of aldehyde or cyclohexanone
which serves as promoter of the autoxidation.8
Direct conversion of cyclohexane into adipic acid was achieved
by the use of the radical catalyst, N-hydroxyphthalimide
(NHPI), in the presence of a small amount of a transition metal.
For instance, cyclohexane could be converted into adipic acid
in 73% selectivity at 73% conversion under atmospheric oxygen
(1 atm) in the presence of NHPI (10 mol %) and Mn(acac)2 (1
mol %) at 100 °C for 20 h. ESR measurements show that the
formation of phthalimide N-oxyl generated from NHPI with
O2 was assisted by Co(II) species. Thus, the oxidation of
cyclohexane to adipic acid was found to be enhanced by the
addition of a small amount of Co(OAc)2 to the NHPI/Mn(acac)2
system. The NHPI-catalyzed oxidation of cyclohexane provides
an attractive direct method which has long been desired in the
chemical industry for the manufacturing of adipic acid. The
present oxidation seems to be the first practical environmentally
friendly process, in which nitric acid is not used as the oxidant,
for the production of adipic acid from cyclohexane.
Introduction
Direct oxygenation of saturated hydrocarbons with mo-
lecular oxygen is a particularly important reaction in
industrial chemistry.1 Several transition-metal-catalyzed
oxidations of alkanes by the combined use of oxygen and
reducing agents such as H2,2 NaBH4,3 RCHO,4 etc., have
been reported. Recently, halogenated metalloporphyrins
have been shown to be efficient catalysts for oxygenation
of alkanes such as isobutane with oxygen without any co-
reductant to give alcohols and/or carbonyl compounds.5
However, the development of new efficient methods for the
catalytic aerobic oxidation of alkanes and cycloalkanes is
one of the most challenging subjects in oxidation chemistry.
The oxidation of hydrocarbons such as cyclohexane and
xylenes is currently carried out on a commercial scale
In previous reports, we have described that N-hydroxy-
phthalimide (NHPI), which serves as the radical catalyst,
(5) (a) Lyons, J. E.; Ellis, P. E., Jr. In Metalloporphyrins in Catalytic Oxidations;
Sheldon, R. A., Ed.; Dekker: New York, 1994, p 291 and references therein.
(b) Ellis, P. E., Jr.; Lyons, J. E. J. Chem. Soc., Chem. Commun. 1989, 1188.
(c) Ellis, P. E., Jr.; Lyons, J. E. J. Chem. Soc., Chem. Commun. 1989, 1190.
(d) Ellis, P. E., Jr.; Lyons, J. E. J. Chem. Soc., Chem. Commun. 1989, 1316.
(e) Ellis, P. E., Jr.; Lyons, J. E. Catal. Lett. 1989, 3, 389. (f) Lyons, J. E.;
Ellis, P. E., Jr. Catal. Lett. 1991, 8, 45. (g) Ellis, P. E., Jr.; Lyons, J. E.
Coord. Chem. ReV. 1990, 105, 181. (h) Lyons, J. E.; Ellis, P. E., Jr.; Durante,
V. A. In Studies in Surface Science and Catalysis; Grasselli, R. Ed.;
Elsevier: New York, 1991; Vol. 67, p 99. (i) Ellis, P. E., Jr.; Lyons, J. E.
Prepr. Petr. DiV. 1990, 35, 174. (j) Lyons, J. E.; Ellis, P. E., Jr.; Wagner,
R. W.; Thompson, P. B.; Gray, H. B.; Hughes, M. E.; Hodge, J. A. Prepr.
Petr. DiV. 1992, 37, 307. (k) Lyons, J. E.; Ellis, P. E., Jr.; Myers, H. K. J.
Catalysis 1995, 155, 59.
(6) (a) Parshall, G, W.; Ittel. S. D. Homogeous Catalysis, 2nd ed.; John Wiley
and Sons: New York, 1992; p 246 and reference cited therein. (b) Simandi,
L. Catalytic ActiVation of Dioxygen by Metal Complexes; Kluwer Academic
Publisher: Dordrecht, The Netherlands, 1992; p 84 and reference cited
therein.
(7) (a) Davis, D. D. In Ullman’s Encyclopedia of Industrial Chemistry, 5th
ed.; Gerhartz, W., Ed., John Wiley and Sons: New York, 1985; Vol. A1,
pp 270-272. (b) Davis, D. D.; Kemp, D. R. In Kirk-Othmer Encyclopedia
of Industrial Chemistry, 4th ed.; Kroschwitz, J. I.; Howe-Grant, M., Eds.;
John Wiley and Sons: New York, 1990; Vol. 1, pp 471-480 and references
therein.
(1) (a) Sheldon, R. A.; Kochi, J. K. Metal-Catalyzed Oxidations of Organic
Compounds; Academic Press: New York, 1981. (b) Hill, C. L. ActiVation
and Functionalization of Alkanes; Academic Press: New York, 1989. (c)
Simandi, L. Catalytic ActiVation of Dioxygen by Metal Complexes; Kluwer
Academic Publisher: Dordrecht, The Netherlands, 1992. (d) The ActiVation
of Dioxygen and Homogeneous Catalytic Oxidation; Barton, D. H. R.,
Martell, A. E., Sawyer, D. T., Eds.; Plenum Press: New York, 1993. (e)
Mennier, B. Chem. ReV. 1992, 92, 1411. (f) Busch, D. H.; Alcock, N. W.
Chem. ReV. 1994, 94, 585.
(2) Tabushi, I.; Yazaki, A. J. Am. Chem. Soc. 1981, 103, 7371.
(3) Tabushi, I.; Yazaki, A. J. Am. Chem. Soc. 1979, 101, 6456.
(4) (a) Kaneda, K.; Haruna, S.; Imanaka, T.; Kawamoto, K. J. Chem. Soc.,
Chem. Commun. 1990, 1467. (b) Yamada, T.; Takai, T.; Rhode, O.;
Mukaiyama, T. Chem. Lett. 1991, 1. (c) Murahashi, S.-I.; Oda, Y.; Naota,
T. J. Am. Chem. Soc. 1992, 114, 7913. (d) Mukaiyama, T. Yamada, T.
Bull. Chem. Soc. Jpn. 1995, 68, 17. (e) Hamamoto, M.; Nakayama, K.;
Nishiyama, Y.; Ishii, Y. J. Org. Chem. 1993, 58, 6421.
(8) (a) Steeman, J. W. M.; Kaarsemaker, S.; Hoftyzer, P. J. Chem. Eng. Sci.
1961, 14, 139. (b) Miller, S. A. Chem. Process Eng. (London) 1969, 50,
63. (c) Onopchenko, A.; Schulz, J, G, D. J. Org. Chem. 1973, 38, 3729. (d)
Tanaka, K. Chem. Technol. 1974, 555 and references therein.
S1083-6160(98)00016-4 CCC: $15.00 © 1998 American Chemical Society and Royal Society of Chemistry
Published on Web 06/16/1998
Vol. 2, No. 4, 1998 / Organic Process Research & Development
•
255

Table 1. Oxidation of cyclohexane (1) with molecular
oxygen catalyzed by NHPI in the presence of various
transition metalsa
Table 2. Oxidation of 1 with molecular oxygen catalyzed by
NHPI in the presence of Mn(acac)2 under various
conditionsa
selectivity (%)
convn
selectivity (%)
convn
run
metal salt
(%)
2
3
run
time (h)
(%)
2
3
1
2b
3c
<1
13
14
<1
36
35
<1
36
40
<1
38
<1
40
14
5
trace
53
65
trace
20
13
trace
35
36
n.d.
33
trace
39
n.d.
20
21
n.d.
46
45
n.d.
35
34
n.d.
25
n.d.
25
1
2
6
14
14
20
20
14
20
20
20
20
36
49
42
65
55
61
73
<5
70
75
20
18
19
2
trace
trace
trace
trace
trace
trace
46
71
65
65
68
71
73
n.d.
60
68
3b
4
4d
5
Mn(acac)2
Mn(acac)2
Mn(OAc)2
Co(acac)2
Co(acac)2
Co(OAc)2
Cr(acac)3
Cr(acac)3
[Rh(OAc)2]2
[Rh(OAc)2]2
Cu(acac)2
Fe(acac)3
Ni(acac)2
Zn(acac)2
Ti(acac)2
5c
6d
7d,e
8f
6
7d
8
9
9g
10h
10d
11
12d
13
14
15
16
17
18
a Compoud 1 (3 mmol) was allowed to react under oxygen (1 atm) in the
presence of NHPI (10 mol %) and Mn(acac)2 (0.5 mol %) in acetic acid (7.5
mL) at 100 °C. b Reaction was carried out at 80 °C. c NHPI (5 mol %) was
used. d Mn(acac)2 (1.0 mol %) was used. e Glutaric acid (5) (9%), succinic acid
(6) (6%), cyclohexyl acetate (7) (up to 2%), and cyclohexanol (4) (up to 1%)
were obtained. f In the absence of NHPI. g Mn(OAc)2 (1 mol %) was used.
h Mn(OBz)2 (1 mol %) was used.
71
99
trace
47
99
12
n.d.
n.d.
4
<1
15
5
n.d.
a Compound 1 (3 mmol) was allowed to react with oxygen (1 atm) in the
presence of NHPI (10 mol %) and transition metal (0.5 mol %) in acetic acid
(7.5 ml) at 100 °C for 6. b Reaction was carried out for 20 h. c Reaction was
carried out under oxygen pressure (10 atm) in CH3CN. d In the absence of NHPI.
cyclohexanone (2) (20%) and 3 (46%) as main products in
higher conversion (36%) compared with that of the conven-
tional autoxidation. The addition of Co(acac)2, Co(OAc)2,
Cr(acac)3, or [Rh(OAc)2]2 to the NHPI-catalyzed oxidation
of 1 resulted in 2 (33-39%) and 3 (25-35%) in 36-40%
conversions (runs 8, 9, 11, and 13, Table 1). In contrast,
Cu(acac)2, Fe(acac)2, Ni(acac)2, Zn(acac)2, and Ti(acac)2 were
less efficient catalysts in the present oxidation. Needless to
say, 1 was difficult to oxidize by either NHPI or a transition
metal alone under these conditions (runs 1, 4, 7, 10, and 12,
Table 1). Although cyclohexanol (4) is expected to be
formed in this oxidation, only a trace amount of 4 was
obtained. In a previous paper, we showed that alcohols can
be oxidized to the corresponding carbonyl compounds by
the NHPI-catalyzed aerobic oxidation.13 Hence, it is believed
that the resulting 4 was easily oxidized to 2 and/or 3 in the
present system, although alcohols are generally difficult to
oxidize to ketones by the conventional autoxidation.
promotes the aerobic oxidation of benzylic compounds,9
cycloalkanes,10 alkylbenzenes,11 polycyclic alkanes,12 and
alcohols13 in the presence or absence of Co(acac)n (n ) 2 or
3) under mild conditions. In this paper, we report in detail
the one-step oxidation of cyclohexane (1) to adipic acid (3)
with molecular oxygen (1 atm) catalyzed by NHPI combined
with transition metal salts (eq 1).
It is interesting to note that manganese salts were more
effective than cobalt salts for the conversion of 1 into 3.
Thus, the oxidation of 1 by NHPI combined with manganese
salts under various conditions was examined (Table 2).
In the oxidation of 1 under atmospheric oxygen (1 atm)
in the presence of NHPI (10 mol %) and Mn(acac)2 (0.5
mol %) at 100 °C for 20 h, 3 was obtained in higher
conversion (65%) and selectivity (65%) (run 4, Table 2).
Even when NHPI was halved under these conditions, 1 was
converted into 3 in 68% selectivity at 55% conversion (run
5, Table 2). Similar results were also obtained when the
oxidation was carried out at 80 °C (run 3, Table 2). By the
use of 1 mol % of Mn(acac)2, 3 was obtained in higher
selectivity (73%) along with small amounts of glutaric acid
(5) (9%), succinic acid (6) (6%), cyclohexyl acetate (7) (up
to 2%), and 4 (up to 1%) in 73% conversion (run 7, Table
2).14 All balance of these oxidation products was 91%, and
the lost selectivity of about 9% is believed to be due to
progressive dehomologation of dicarboxylic acid as well as
Results and Discussions
1. Oxidation of Cycloalkanes by NHPI/Mn(II)-O2
System. Table 1 shows representative results for the
oxidation of 1 with molecular oxygen by NHPI in the
presence of various transition metals. The oxidation of 1
under atmospheric oxygen (1 atm) by NHPI (10 mol %) and
Mn(acac)2 (0.5 mol %) at 100 °C (run 5, Table 1) gave
(9) Ishii, Y.; Nakayama, K.; Takeno, M.; Sakaguchi, S.; Iwahama, T.;
Nishiyama, Y. J. Org. Chem. 1995, 60, 3934.
(10) Ishii, Y.; Iwahama, T.; Sakaguchi, S.; Nakayama, K.; Nishiyama, Y. J. Org.
Chem. 1996, 61, 4520.
(11) Yoshino, Y.; Hayashi, Y.; Iwahama, T.; Sakaguchi, S.; Ishii, Y. J. Org.
Chem. 1997, 62, 6810.
(12) Ishii, Y.; Kato, S.; Iwahama, T.; Sakaguchi, S. Tetrahedron Lett. 1996, 37,
4993.
(13) Iwahama, T.; Sakaguchi, S.; Nishiyama, Y.; Ishii, Y. Tetrahedron Lett. 1995,
36. 6923.
256
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Vol. 2, No. 4, 1998 / Organic Process Research & Development

a
Table 3. Oxidation of various cycloalkanes with molecular oxygen catalyzed by NHPI in the presence of Mn(acac)2
products, %b
temp
(°C)
convn
(%)
run
substrate
cycloalkanone
dicarboxylic acid
1
2
3
cyclooctane (9)
cyclodecane (12)
cyclododecane (15)
100
100
70
83
90
81
cyclooctanone (10), 2
cyclodecanone (13), 2
cyclododecane (16), 3
suberic acid (11), 53
sebacic acid (14), 55
dodecanedioic acid (17), 68
a Substrate (3 mmol) was allowed to react under oxygen (1 atm) in the presence of NHPI (10 mol %) and Mn(acac)2 (1.0 mol %) in acetic acid (7.5 mL) for 14
h. b Yield based on substrate reacted.
complete oxidation.15 The oxidation of 1 by Mn(OAc)2 or
Mn(OBz)2 as a cocatalyst gave almost the same result as
that by Mn(acac)2 (runs 9 and 10, Table 2). The effect of
Mn(II) on the oxidation of 1 by the present system is contrast
to that of manganese derivatives shown by Schulz8c and
Tanaka.8d In these reactions, Co, Cr and Zn salts are reported
to be good catalysts for the conversion of 1 to 3, while Mn
salts have no catalytic activity.16
To gain further information about the effect of Co and
Mn salts on the NHPI-catalyzed oxidation of 1 to 3,
cyclohexanone 2, which would be a precursor of 3, was
oxidized under similar reaction conditions. The oxidation
of 2 by NHPI (10 mol %) in the presence of Mn(acac)2 (0.5
mol %) in acetic acid at 100 °C for 6 h produced 3 as the
major product (64%), glutaric acid (5) (10%), and succinic
acid (6) (5%) (eq 2). However, in the oxidation of 2 using
absence of NHPI. These observations seem to be related to
the formation of a certain Co complex from Co(OAc)2, 2,
and NHPI. In fact, the treatment of Co(OAc)2 (0.5 mmol)
with 2 (10 mmol) in the presence of NHPI (2.5 mmol) in
acetic acid at 100 °C resulted in a dark-brown complex (8)
which appears a mixture of some cobalt complexes. The
aerobic oxidations of 1 and 2 using the complex 8 were
examined, but both substrates were not oxidized by 8 and
recovered unchanged. These results suggest that an unre-
active species which serves as an inhibitor in the aerobic
oxidation of 1 and 2 may be involved in the complex 8.
However, the oxidation of cyclohexanol (4) by the NHPI/
Co(II) system led to 2 (55%) along with 3 (8%) and 7 (27%)
in 69% conversion as reported previously.13
On the basis of these results, the aerobic oxidation of
several cycloalkanes was examined using the NHPI/
Mn(acac)2 system (Table 3). Like 1, cyclooctane (9) and
cyclodecane (12) were oxidized to the corresponding cy-
cloalkanones, cyclooctanone (10) and cyclodecanone (13),
and dicarboxylic acids, suberic acid (11) and sebacic acid
(14), respectively (runs 1 and 2, Table 3). Cyclododecane
(15) was easily oxidized even at 70 °C to give dodecanedioic
acid (17) in good yield along with cyclodecanone (16) (run
3, Table 3). These facts show that the present NHPI-
catalyzed aerobic oxidation can be applied to the production
of cyclic ketones and dicarboxylic acids, which are very
important chemicals, of a wide variety of large-membered
cycloalkanes.
NHPI/Co(acac)2 and NHPI/Co(acac)3 systems, most of the
starting 2 was recovered unchanged (eq 2). In contrast, the
same oxidation of 2 by Co(acac)2 in the absence of NHPI
gave 61% of 3 in 92% conversion (eq 3).
It is interesting to note that, in the oxidation of 2 by
Co(acac)2, the color of the solution changed from pink to
dark-green, which shows the formation of a Co(III) species
in the course of the reaction. However, in the oxidation of
2 in the presence of NHPI and Co(acac)2, the color of the
solution immediately changed from pink to orange and the
color was retained during the reaction.
2. Oxidation of Cyclohexane (1) by NHPI/Mn(II)/Co-
(II)-O2 System. In the NHPI-catalyzed aerobic oxidation
of alkylbenzenes such as toluene or ethylbenzene, we
indicated that the Co(II) species is more effective than the
Mn(II) species as the cocatalyst.10,11 For instance, the
oxidation of ethylbenzene (18) in the presence of NHPI (2
mol %) and Co(II) species (0.5 mol %) afforded acetophe-
none (19) (88% selectivity) and 1-phenylethanol (20) (9%
selectivity) in 75% conversion of 18, while the same
oxidation using Mn(II) in place of Co(II) showed only a
slight effect on the oxidation (26% conversion) (eq 4).
On the other hand, cyclohexanone (2) was smoothly
oxidized to adipic acid (3) by Mn(acac)2 in the presence or
(14) After the reaction, most of the NHPI was found to be converted into
phthalimide. Treatment of the recovered phthalimide with hydroxylamine
gave the NHPI in almost quantitative yield.
(15) To evaluate the extent of decomposition of the resulting adipic acid 3 under
the conditions employed, 3 was allowed to react in the presence of NHPI
(10 mol %) and Mn(acac)2 (1 mol %) in acetic acid at 100 °C for 10 h.
About 90% of 3 was recovered unchanged, and a small amount of 5 (4%)
and 6 (1%) was found to be formed.
(16) In the oxidation of cyclohexane using Co(OAc)2 in the presence of aldehyde
or cyclohexanone as promoter under oxygen pressure, the Co(III) species
formed in situ has been reported to abstract the hydrogen of cyclohexane.8c,d
Vol. 2, No. 4, 1998 / Organic Process Research & Development
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257

Table 4. Oxidation of 1 with molecular oxygen catalyzed by
NHPI in the presence of Mn(acac)2 and Co(OAc)2 under
various conditionsa
selectivity (%)
temp
(°C)
convn
(%)
run
2
3
1
2
90
80
80
80
80
70
70
60
50
49
8
70
58
42
60
17
1
1
trace
trace
trace
11
62
71
trace
71
74
72
68
41
3b
4c
5c,d
6
7c
8
2
48
a Compound 1 (5 mmol) was allowed to react with oxygen (1 atm) in the
presence of NHPI (10 mol %), Co(OAc)2 (0.1 mol %), and Mn(acac)2 (1 mol
%) in acetic acid (10 mL) for 14 h. b In the absence of NHPI. c Reaction was
carried out for 24 h. d In the absence of Co(OAc)2.
Figure 1. Time dependence for the oxidation of cyclohexane
(1) to cyclohexanone (2) and adipic acid (3) by NHPI/Mn(II)
(A) and NHPI/Co(II) (B) system in acetic acid at 100 °C.
Conditions: cyclohexane 1 (3 mmol) was allowed to react with
oxygen (1 atm) in acetic acid (7.5 mL) at 100 °C in the presence
of NHPI (10 mol %) and metal salt (0.5 mol %).
Table 5. Oxidation of 1 with molecular oxygen catalyzed by
NHPI in the presence of Mn(acac)2 and Co(OAc)2 under
various conditionsa
metal (mol %)
Co(II) Mn(II)
selectivity (%)b
convn
(%)
run
2
3
5
1
2
3
0.1
1.0
0.5
0.1
0.05
0.1
70
63
61
41
60
trace
trace
1
34
trace
71
69
66
41
64
9
7
7
1
8
0.05
0.05
0.05
0.05
4
5c,d
a Compound 1 (5 mmol) was allowed to react with oxygen (1 atm) in the
presence of NHPI (10 mol %), Co(OAc)2, and Mn(acac)2 in acetic acid (10 mL)
at 80 °C for 24 h. b Cyclohexanol (4), succinic acid (6), and cyclohexyl acetate
(7) were detected as byproducts. c Reaction was carried out under air pressure
(20 kg/cm2). d Compounds 6 (4%) and 7 (up to 2%) were obtained.
stage of the oxidation (Figure 1). However, when a very
small amount of Co(II) (0.1 mol %) was added to the NHPI/
Mn(II) system, the rapid absorption of O2 was observed
(Figure 2). Since the Co(II) species was found to reduce
the induction period of the oxidation of 1 by NHPI/Mn(II),
the oxidation of 1 using the NHPI/Mn(II)/Co(II) system was
examined (Table 4).
When a very small amount of Co(II) species (0.1 mol %)
was added to the NHPI/Mn(II) system, 1 was oxidized at
80 °C to afford 3 in 71% selectivity at 49% conversion after
14 h and in 71% selectivity at 70% conversion after 24 h
(runs 2 and 4, Table 4). The oxidation of 1 took place even
at 70 °C to form 3 in 68% selectivity (at 60% conversion)
(run 7, Table 4). However, the oxidation at 60 °C gave 2
(48%) and 3 (41%) in lower conversion (17%) (run 8, Table
4). The addition of Co(II) species to the NHPI/Mn(II) system
in the aerobic oxidation of 1 makes it possible to carry out
the oxidation under milder conditions. Thus, the oxidation
of 1 by the NHPI/Mn(II)/Co(II) system was investigated in
detail (Table 5).
Figure 2. O2 uptakes for the oxidation of cyclohexane (1) under
atmospheric pressure of oxygen by catalytic systems. Condi-
tions: cyclohexane 1 was allowed to react with oxygen (1 atm)
in acetic acid (25 mL) at 80 °C in the presence of (A) NHPI (10
mol %) and Mn(acac)2 (1 mol %), (B) NHPI (10 mol %),
Mn(acac)2 (1 mol %), and Co(OAc)2 (0.1 mol %).
To obtain further information concerning the influence
of Co and Mn salts on the reaction rate and selectivity in
the NHPI-catalyzed oxidation of 1, the time-dependence of
the conversion of 1 and the selectivity to 2 and 3 by the
NHPI/Co(II) system were compared with those by the NHPI/
Mn(II) one. The oxidation of 1 by the NHPI/Co(II)
proceeded faster than that by the NHPI/Mn(II) at the early
In contrast to the oxidation of 1 by the NHPI/Mn(II)
system (run 7, Table 2), the amount of Mn(II) could be
reduced from 1 to 0.1 mol % when 0.05 mol % of Co(II)
was added to the NHPI/Mn(II) system (run 3, Table 5).
Although the selectivity of 1 to 3 was lowered to 41% (at
41% conversion) when the concentration of Mn(II) was
258
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Vol. 2, No. 4, 1998 / Organic Process Research & Development

Scheme 1. A possible reaction path for oxidation of cyclohexane (1) by NHPI/Mn/Co-O2 systema
a (i) O2 or Co-oxygen complex; (ii) R-H or NHPI; (iii) R• or 21; (iv) NHPI-O2; (v) NHPI/Mn-O2.
halved from 0.1 to 0.05 mol % (run 4, Table 5), it should be
noted that the aerobic oxidation of 1 to 3 by the NHPI/Mn-
(II) system was significantly accelerated by adding a small
amount of Co(II).
It is very important to employ air instead of oxygen as
the oxidant to carry out the present oxidation in industrial
scale. With this in mind, the aerobic oxidation of 1 using
the NHPI/Mn(II)/Co(II) system was examined under 20 kg/
cm2 of air in acetic acid at 80 °C for 24 h. The reaction
gave 3 (64%), 5 (8%), and 6 (4%) in 60% conversion (run
5, Table 5).
We have previously reported that phthalimide N-oxyl
(PINO) (21) is a key species in the NHPI-catalyzed aerobic
oxidation of hydroaromatic compounds and alkylbenzenes.10
Similarly, 21 was found to be formed in the NHPI-catalyzed
aerobic oxidation of 1 in the presence of a transition metal.
When a benzonitrile solution of NHPI and Co(OAc)2 was
exposed to oxygen at 80 °C for 10 min, the ESR signal
attributed to 21 was observed at g ) 2.0074, aN ) 0.43 mT.17
However, no ESR signal was obtained when a Co(III) species
such as Co(acac)3 was used in place of Co(II) under such
conditions. The Co(II) species is known to react with oxygen
to form a cobalt-oxygen complex (eq 5).18 The resulting
zenes by Co(II)/Mn(II) system, it is reported to be observed
the synergistic effect of Co(II) and Mn(II) leading to the
reduction of the induction period and the acceleration of the
rate in the chain-propagation step.19 Consequently, the Co
salt in the NHPI/Mn/Co system is thought not only to assist
the formation of 21 but also to promote the oxidation of 1
by the similar effect of the Co and Mn system reported above.
Scheme 1 shows a proposed reaction pathway for the
aerobic oxidation of 1 by the NHPI/Mn(II)/Co(II) system.
As 1 was oxidized to 2 and 3 by NHPI alone (runs 2 and 3,
Table 1), the N-oxyl radical 21 is thought to be the key active
species in the present NHPI-catalyzed oxidation of 1. The
Co(II) and Mn(II) species would assist the smooth generation
of 21 from NHPI and molecular oxygen and promote the
redox degradation of the resulting cyclohexyl hydroperoxide
which is eventually converted into adipic acid.
In conclusion, we have developed novel catalytic systems,
NHPI/Mn(acac)2 and NHPI /Mn(acac)2/Co(OAc)2, for the
direct aerobic oxidation of 1 to 3 under mild conditions. This
method, compared with the conventional two-step process
which involves aerobic oxidation and nitric acid oxidation,
has the following features: (1) the one-step oxidation of 1
to 3 with oxygen or air at lower reaction temperature; (2)
high conversion and selectivity to 3; (3) environmental
friendly process not using nitric acid. The present oxidation
provides a novel direct method from cyclohexane 1 to adipic
acid 3 and would play an important role in industrial organic
chemistry.
cobalt-oxygen complex would accelerate the formation of
21 from the NHPI. For the aerobic oxidation of alkylben-
Experimental Section
1H and 13C NMR spectra were measured at 270 and 67.5
MHz, respectively, with tetramethylsilane as the internal
(17) Mackor, A.; Wajer, Th. A. J. W.; de Boer, Th. J. Tetrahedron 1968, 24,
1623.
(18) (a) Wong, C. L.; Switer, J. A.; Balakrishnan, K. P.; Endicott, J. F. J. Am.
Chem. Soc. 1980, 102, 5511. (b) Drago, R. S.; Cannady, J. P.; Leslie, K.
A. J. Am. Chem. Soc. 1980, 102, 6014. (c) Yamada, T.; Mukaiyama, T.
Chem. Lett. 1989, 519 and references therein.
(19) (a) Ravens, D. A. S. Trans. Faraday. Soc. 1959, 55, 1768. (b) Kamiya, Y.;
Nakajima, T.; Sakoda, K.; Bull. Chem. Soc. Jpn. 1966, 39, 519 and
references therein.
Vol. 2, No. 4, 1998 / Organic Process Research & Development
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259

standard. Infrared (IR) spectra were measured using NaCl
or KBr pellets. A GC analysis was performed with a flame
ionization detector using a 0.2 mm × 25 m capillary column
(OV-1). Measurements of oxygen-absorption rates were
performed with an isobaric gas-absorption apparatus under
a closed-flow system (2 ( 0.1 L of oxygen/h) provided with
an electrolyzer. ESR measurements were performed on a
JEOL-FE-1X (X-band).
All starting materials and catalysts were purchased from
commercial sources and used without further treatment. The
yields of products were estimated from the peak areas based
on the internal standard technique.
under reduced pressure gave a dark-brown solid. The
resulting solid was washed with ethyl acetate and dried in
vacuo to form complex 8.
Oxidation of 1 and 2 Catalyzed by NHPI in the
Presence of Co(OAc)2 and Complex 8. To a stirred
solution of NHPI (49 mg, 10 mol %), Co(OAc)2 (3.7 mg,
0.5 mol %), and complex 8 (10 mg, 4 wt %) in acetic acid
(7.5 mL) was added substrate (3 mmol). The mixture was
stirred under oxygen atmosphere at 100 °C for 3 h. The
workup was performed using the same method as described
previously.
Oxidation of 18. An acetic acid (7.5 mL) solution of 18
(3 mmol), NHPI (9.8 mg, 2 mol %), and transition metal
(0.5 mol %) was placed in a three-necked flask equipped
with a balloon filled with O2. The mixture was stirred at
100 °C for 6 h. The resulting solution was extracted with
diethyl ether (20 mL × 3). The combined extracts were dried
over anhydrous MgSO4. Removal of the solvent under
reduced pressure afforded a clean liquid, which was then
purified by column chromatography on silica gel (n-hexane/
AcOEt ) 5/1) to give the corresponding oxygenated
products, acetophenone (19), and 1-phenylethanol (20).
Measurements of the Rate of Oxygen Absorption.
Measurements of oxygen-absorption rates were performed
with an isobaric gas-absorption apparatus under a closed-
flow system (2 ( 0.1 L of oxygen/h) provided with an
electrolyzer using 25 mL of acetic acid containing cyclo-
hexane (840 mg, 10 mmol), NHPI (163 mg, 10 mol %), Co-
(OAc)2 (2.5 mg, 0.1 mol %), and Mn(acac)2 (25 mg, 1 mol
%) at 80 °C. The oxygen absorption was recorded at regular
time intervals.
ESR Measurements. Benzonitrile containing 10-2 mmol
of NHPI and 5 × 10-4 mmol of Co(OAc)2 was exposed to
atmosphere oxygen at 80 °C for 10 min. The air in the ESR
tube was replaced by oxygen gas by means of the freeze-
pump-thaw method. ESR spectra were obtained under the
following conditions: sweep width, 327 ( 2.5 mT; modula-
tion, 0.1 mT; microwave power, 1 mW. The ESR parameter
was determined by using solid Mn2+ (g ) 2.034) as a
standard.
General Procedure for Oxidation of 1. An acetic acid
(7.5 mL) solution of 1 (3 mmol), NHPI (49 mg, 10 mol %),
and transition metal (0.5 mol %) was placed in a three-necked
flask equipped with a balloon filled with O2. The mixture
was stirred at 100 °C for 6 h. After the solvent was removed
under reduced pressure, methanol (25 mL), and a catalytic
amount of concentrated H2SO4 were added to the resulting
mixture, and the solution was stirred at 65 °C for 15 h. The
resulting solution was extracted with diethyl ether (20 mL
× 3). The combined extracts were dried over anhydrous
MgSO4. Removal of the solvent under reduced pressure
afforded a clean liquid, which was purified by column
chromatography on silica gel (n-hexane/AcOEt ) 5/1) to
give the corresponding oxygenated products.
Compounds 2-7, 10, 11, 13, 14, 16, and 17 were
identified through comparison of the isolated products with
authentic samples.
Isolation of 3 on a Preparative Scale. An acetic acid
(250 mL) solution of 1 (8.4 g, 0.1 mol), NHPI (1.63 g, 10
mol %), and Mn(acac)2 (250 mg, 1 mol %) was placed in a
three-necked flask equipped with a balloon filled with O2.
The mixture was stirred at 100 °C for 20 h. After the solvent
was removed under reduced pressure, acetonitrile (100 mL)
was added to the reaction mixture to give a white solid. After
filtration, 4.62 g of 3 was obtained.
Oxidation of 2. An acetic acid (7.5 mL) solution of 1
(3 mmol), NHPI (49 mg, 10 mol %), and transition metal
(0.5 mol %) was placed in a three-necked flask equipped
with a balloon filled with O2. The mixture was stirred at
100 °C for 6 h. The workup was performed using the same
method as previously described.
Acknowledgment
This work was partly supported by Research for the Future
program JSPS.
Preparation of Complex 8. A mixture of 2 (980 mg,
10 mmol), NHPI (408 mg, 2.5 mmol), and Co(OAc)2 (125
mg, 0.5 mmol) in acetic acid (15 mL) was stirred at 100 °C
under an oxygen atmosphere for 3 h. Evaporation of solvent
Received for review February 9, 1998.
OP980016Y
260
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