Oxidation of substituted toluenes with molecular oxygen in the presence of N,N′,N″-Trihydroxyisocyanuric acid as a key catalyst

Article abstract of DOI:10.1021/jo034313z

N,N′,N″-Trihydroxyisocianuric acid (THICA) was found to be a very efficient catalyst for the oxidation of alkylbenzenes with dioxygen. Thus, a variety of meta- and para-substituted toluenes bearing an electron-withdrawing substituent such as cyanotoluene, chlorotoluene, and toluic acid under O₂ (1 atm) in the presence of THICA (5 mol %) and Co(OAc)₂ (0.5 mol %) at 100 °C were smoothly oxidized to the corresponding benzoic acids in almost quantitative yields. The aerobic oxidation of toluene by THICA was compared with that by N-hydroxyphthalimide. p-Xylene was efficiently oxidized by THICA to telephthalic acid in high yield (over 95%) under mild conditions.

Full text of DOI:10.1021/jo034313z

Oxid a tion of Su bstitu ted Tolu en es w ith Molecu la r Oxygen in th e
P r esen ce of N,N′,N′′-Tr ih yd r oxyisocya n u r ic Acid a s a Key Ca ta lyst
Naruhisa Hirai,† Naoko Sawatari,‡ Norihiro Nakamura,‡ Satoshi Sakaguchi,‡ and
Yasutaka Ishii*,‡
Daicel Chemical Industry, Ltd., Shinzaike, Aboshi-ku, Himeji Hyogo 671-1283, and Department of
Applied Chemistry & High Technology Research Center, Faculty of Engineering, Kansai University,
Suita, Osaka 564-8680, J apan
ishii@ipcku.kansai-u.ac.jp
Received March 10, 2003
N,N′,N′′-Trihydroxyisocianuric acid (THICA) was found to be a very efficient catalyst for the
oxidation of alkylbenzenes with dioxygen. Thus, a variety of meta- and para-substituted toluenes
bearing an electron-withdrawing substituent such as cyanotoluene, chlorotoluene, and toluic acid
under O2 (1 atm) in the presence of THICA (5 mol %) and Co(OAc)2 (0.5 mol %) at 100 °C were
smoothly oxidized to the corresponding benzoic acids in almost quantitative yields. The aerobic
oxidation of toluene by THICA was compared with that by N-hydroxyphthalimide. p-Xylene was
efficiently oxidized by THICA to telephthalic acid in high yield (over 95%) under mild conditions.
In tr od u ction
eventually oxygen-containing products through the redox
decomposition of alkyl hydroperoxides.3 NHPI as the
CRPC is very unique and deserves attention as a new
catalyst for generation of carbon radicals from various
compounds such as alkanes, alkenes, alkynes, alcohols,
ethers, etc. The novel catalytic behavior of NHPI prompted
us to investigate a new class of CRPCs which are capable
of generating carbon radicals from C-H bonds, other
than the NHPI analogues. In the course of our study to
obtain a new CRPC, we have found that N,N′,N′′-
trihydroxyisocianuric acid (THICA) serves as a good
CRPC from alkylbenzenes. In this paper, we have dis-
closed aerobic oxidations of various substituted toluenes
employing THICA as a key catalyst.
Aerobic oxidation of alkylbenzenes is a very important
process in industrial chemistry and is currently carried
out in large scale. These aerobic oxidations, which are
usually called autoxidation, are practiced under the
influence of a small amount of cobalt and manganese
salts in the presence of bromine at higher temperature.1
In particular, conversion of p-xylene to telephthalic acid,
which is an important polymer material for PET resin,
is one of the most important industrial oxidation pro-
cesses. We have recently developed an innovative cata-
lytic method for aerobic oxidation of alkanes using
N-hydroxyphthalimide (NHPI), which serves as a carbon
radical producing catalyst (CRPC) from alkanes.2 Thus,
alkanes such as ethane, isobutene, cyclohexane, and
alkylbenzenes can be efficiently oxidized with dioxygen
to oxygen-containing compounds such as alcohols, ke-
tones, and carboxylic acids under mild conditions. In the
oxidation of alkanes with O2 by NHPI combined with
Co(II), the key step of the oxidation is the generation of
a phthalimide N-oxyl (PINO) radical, which possesses a
strong electrophlic property, from the NHPI by a cobalt-
(III)-oxygen complex generated in situ from Co(II) and
molecular oxygen. The resulting PINO abstracts the
hydrogen atom from the C-H bond of alkanes to lead to
alkyl radicals which are readily trapped by O2 to give
Resu lts a n d Discu ssion
The oxidation of toluene (1) with dioxygen by THICA
in acetic acid under several reaction conditions was
examined and compared with that by NHPI (eq 1, Table
1).
It was found that 1 was oxidized with dioxygen (1 atm)
in the presence of only 1 mol % THICA and 0.5 mol %
Co(OAc)2 at 80 °C for 6 h to give benzoic acid (2) (68%)
along with a small amount of benzaldehyde (3) (3%) (run
1). This indicates that THICA serves efficiently as a
CRPC from 1. Under the same conditions using 1 mol %
NHPI, 1 was only converted to 2 in lower yield (20%) (run
2). Even by the use of 3 mol % NHPI in this oxidation,
the yield (47%) of 2 was lower than that by the use of 1
mol % THICA (run 3). These results show that THICA
is more effective than NHPI for the oxidation of 1. When
3 mol % THICA was used under these conditions, 1 was
oxidized to 2 in high yield (93%) (run 4). In the oxidation
† Daicel Chemical Industry, Inc.
‡ Kansai University.
(1) (a) Parshall, G. W.; Ittel, S. D. Homogeneous Catalysis, 2nd ed.;
Wiley: New York, 1992; p 225. (b) Park, C. J .; Sheehan, R. In Kirk-
Othmer Encyclopedia of Chemical Technology, 4th ed.; Kroschwite, J .
I., Howe-Grant, M., Eds.; J ohn Wiley and Sons: New York, 1996; Vol.
18, p 991. (c) Sheehan, J . R. In Ullmann’s Encyclopedia Industrial
Organic Chemicals; Ullmann, F., Ed.; Wiley-VCH: Weinheim, Ger-
many, 1999; Vol. 8, p 4575. (d) Partenheimer, W. Catal. Today 1995,
23, 69.
(2) Ishii, Y.; Sakaguchi, S.; Iwahama, T. Adv. Synth. Catal. 2001,
343, 393.
(3) Yoshino, Y.; Hayashi, Y.; Iwahama, T.; Sakaguchi, S.; Ishii, Y.
J . Org. Chem. 1997, 62, 6810.
10.1021/jo034313z CCC: $25.00 © 2003 American Chemical Society
Published on Web 07/29/2003
J . Org. Chem. 2003, 68, 6587-6590
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Hirai et al.
TABLE 1. Oxid a tion of 1 w ith O2 (1 a tm ) by NHP I a n d
THICA u n d er Va r iou s Con d ition sa
p-cyanotoluene (4) oxidized by THICA under 1 atm of O2
at 100 °C for 6 h was completely converted into p-
cyanobenzoic acid (5), which is an important pharma-
ceutical precursor (run 1).6 The same oxidation by NHPI
led to 5 in somewhat lower yield (79%) (run 2). Because
of the difficulty in converting 4 to 5 by aerobic oxidation
so far, liquid-phase oxidation by CrO3 with H2SO4 in
acetic acid7 or by NaOCl with H2SO4 in the presence of
RuCl3 catalyst under phase-transfer conditions was
employed for the production of 5.8 Therefore, this is the
first successful aerobic oxidation of 4 to 5. p-Methoxy-
toluene (6), p-chlorotoluene (8), and p-bromotoluene (10)
were also oxidized to the corresponding carboxylic acids
7, 9, and 11 in good to excellent yields, respectively (runs
3-5). It is reported that the aerobic oxidation of 8 by an
immobilized Co(III) catalyst at 130 °C gave 9 in only 25%
yield.9 Therefore, the present method provides a good
route to 9. p-Toluic acid (p-12) was also completely
converted into telephthalic acid (p-13), which is a very
important monomer for PET resin and fiber (runs 6 and
7). We next tried the aerobic oxidation of acetoxytoluenes
14 by both THICA and NHPI (runs 8 and 9). p-Acetoxy-
toluene (p-14) is reported to be oxidized to p-acetoxyben-
zoic acid (p-15) in 50% yield with hydrogen peroxide
catalyzed by RuCl3 on montmorillonite.10 The oxidation
of m- and p-14 by THICA proceeded in relatively good
yields, but o-acetoxytoluene (o-14) was a reluctant sub-
strate for the oxidation to give the corresponding acid
o-15 in very low yield (5.3%) (runs 8-12). Hence, the
oxidation of o-14 was carried out at 150 °C, but the yield
of o-15 was no more than 9% (run 13). Nitrotoluenes 16
having a strong electron-withdrawing substituent showed
a behavior similar to that of acetoxytoluenes 14. THICA
efficiently catalyzed the oxidation of p- and m-16 to form
p- and m-nitrobenzoic acids (p- and m-17) in good yields
(runs 14 and 15). Since THICA is more stable than NHPI
at higher temperature, o-16 could be oxidized at 150 °C
to give o-17 in fair yield (62%) (runs 16 and 17). However,
the same oxidation using NHPI instead of THICA gave
46% yield probably because of the decomposition of NHPI.
On the other hand, toluenes substituted by an electron-
donating group such as p-tert-butyltoluene (18) were
easily oxidized to acids such as p-tert-butylbenzoic acid
(19) in quantitative yield (run 18). Unfortunately, p-
ethyltoluene (20) was difficult to oxidize selectively to
p-methylacetophenone (21) (run 19).
yield (%)
catalyst
(mol %)
temp
(°C)
conversn
(%)
run
2
3
1
2
3
4
THICA (1)
NHPI (1)
NHPI (3)
THICA (3)
THICA (5)
THICA (3)
THICA (5)
NHPI (5)
80
80
80
80
80
100
25
25
71
25
53
>99
>99
>99
1
68
20
47
3
5
3
2
nd
nd
93
5
>99
>99
nd
6
7b
8b
trace
5
39
34
a
1 (3 mmol) was reacted under O2 (1 atm) in the presence of
THICA or NHPI and Co(OAc)2 (0.5 mol %) in AcOH (5 mL) at 25-
b
100 °C for 6 h. 20 h.
of 1 at room temperature by THICA and NHPI, however,
1 was gradually oxidized to 2 by NHPI, but no oxidation
was observed when THICA was used. In a previous paper
on the oxidation of 1 to 2 with O2 by NHPI combined with
Co(II) at room temperature, we showed that the oxidation
is initiated by the hydrogen atom abstraction from the
hydroxyimide group in NHPI by a cobalt(III)-oxygen
complex to form a PINO radical.3 Since the oxidation by
THICA is considered to proceed by a reaction path similar
to that of the oxidation by NHPI, the fact that no
oxidation was observed by THICA at room temperature
indicates that the hydrogen atom abstraction from the
hydroxyimide moiety of THICA by the Co(III)-oxygen
complex has difficulty taking place at up to 25 °C. Minsci
et al. have reported that the O-H bond dissociation
energy of NHPI is evaluated as 88.1 kcal/mol.4 Our ab
initio calculation for the O-H bond dissociation energy
for THICA and NHPI was 91.6 and 88.1 kcal/mol,
respectively.5 These results show that a higher temper-
ature is needed for the generation of an N-oxyl radical
(A) from THICA than from NHPI. Therefore, the oxida-
tion by THICA has difficulty taking place at room
temperature.
It is interesting to compare the time-dependence curves
for the aerobic oxidation of p-xylene (p-22) to p-12 and
p-13 by using THICA (3 mol %) and NHPI (10 mol %)
combined with Co(OAc)2 (0.5 mol %) and Mn(OAc)2 (0.5
mol %) in acetic acid at 100 °C (Figures 1 and 2).
Despite the fact that the oxidation of p-22 by NHPI
occurred very fast up to the formation of a 65% yield of
p-12, the reaction stopped at this stage as shown in
Figure 2. This is believed to be due to the deactivation
of NHPI by decomposition. In contrast, the oxidation of
p-22 by THICA gave p-12, which then undergoes further
On the basis of these results, a variety of substituted
toluenes were allowed to react under O2 in the presence
of THICA combined with Co(OAc)2 (Table 2).
Although alkylbenzenes substituted by electron-with-
drawing groups are reluctant to be oxidized with O2,
(6) (a) Robertson, D. W.; Krushinski, J . H.; Beedle, E. E. J . Med.
Chem. 1987, 30, 552. (b) Koyama, M.; Ohtani, N.; Fumio, K. J . Med.
Chem. 1985, 28, 717.
(4) Amorati, R.; Lucarini, M.; Mugnaini, V.; Pedulli, G. F.; Minisci,
F.; Recupero, F.; Fontana, F.; Astolfi, P.; Greci, L. J . Org. Chem. 2003,
68, 1747.
(5) The O-H bond dissociation energy of THICA and NHPI was
calculated using the PMP2/6-31++G**//HF/6-31G** level of theory.
(7) Levine, M.; Sedlecky, R. J . Org. Chem. 1959, 24, 115.
(8) Sasson, Y.; Zappi, G. D.; Neuman, R. J . Org. Chem. 1986, 51,
2880.
(9) Das, B. K.; Clark, J . H. Chem. Commun. 2000, 605.
(10) Milind, D.; Sudalai, A. Tetrahedron 1999, 55, 5903.
6588 J . Org. Chem., Vol. 68, No. 17, 2003

Oxidation of Substituted Toluenes
a
TABLE 2. Oxid a tion of Su bstitu ted Tolu en es w ith O2 (1 a tm ) by THICA a n d NHP I Com bin ed w ith Co(OAc)2
a
Substrate (3 mmol) was reacted under O2 (1 atm) in the presence of THICA or NHPI and Co(OAc)2 (0.5 mol %) in AcOH (5 mL).
AIBN (1 mol %) and Mn(OAc)2 (0.05 mol %) were added. c Mn(OAc)2 (0.05 mol %) was added. NO2 (20 mol %) and Mn(OAc)2 (0.05 mol
b
d
%) were added. e 4-Acetylbenzoic acid (24%), p-12 (3%), and p-13 (5%) were also obtained.
oxidation to form p-13 in good yield. These results may
indicate that the character of the N-oxyl radical PINO
generated from NHPI is different from that of the N-oxyl
radical A derived from THICA. From consideration of
these two time-dependence curves, it is apparent that
PINO is a more reactive radical species than A. As a
result, the former radical is easily decomposed compared
to the latter during the oxidation of p-22. In fact, the GC
analysis of the reactants after the oxidation of p-22 by
NHPI shows the formation of phthalimide and phthalic
anhydride resulting from the N-O bond cleavage of
NHPI. Owing to the complexity of the reaction process
in the chain reaction, it is difficult to explain why the
phthalimide is formed in the oxidation of p-22 by NHPI.
However, it seems to be related to the violent propagation
step in the oxidation of p-22, which is a reactive substrate
for aerobic oxidation.
Exp er im en ta l Section
Starting materials and catalysts were purchased from
commercial sources and used without further treatment. Yields
were estimated from the peak areas on the basis of the internal
standard technique by using GC. GC analysis was performed
with a flame ionization detector using a 0.2 mm × 30 m
1
capillary column. H and 13C NMR spectra were measured at
270 and 68 MHz, respectively, in chloroform-d with Me4Si as
the internal standard. Infrared (IR) spectra were measured
using NaCl or KBr pellets. GC-MS spectra were obtained at
J . Org. Chem, Vol. 68, No. 17, 2003 6589

Hirai et al.
P r ep a r a tion of N,N′,N′′-Tr ih yd r oxyisocya n u r ic Acid .
THICA was prepared by a modified literature procedure.11
1,1′-Carbonyldiimidazole (165 mmol) was added to a pyridine
(250 mL) solution of O-benzylhydroxylamine (150 mmol) under
Ar. The mixture was stirred for 1 h at room temperature, and
then the temperature was increased to 60 °C for 6 h and 90
°C for 5 h. After the reaction, the solvent was removed under
reduced pressure until the mixture was 100 g. Water (500 mL)
was added slowly to the mixture to give a white precipitate.
The precipitate was filtered and washed with water (50 mL),
AcOH (40 mL), and n-hexane (40 mL). The solid was recrystal-
lized from AcOH (80 mL) and AcOEt (70 mL) and dried under
vacuum to give tribenzyloxy-1,3,5-triaine-2,4,6(1H,3H,5H)-
trione (TBTA) (5.1 g) in 23% yield:
1H NMR (DMSO-d6/TMS) δ 7.52 (m, 2H), 7.42 (m, 3H), 5.10
(s, 2H); 13C NMR (DMSO-d6/TMS) δ 144.8, 133.4, 129.5, 129.0,
128.3, 78.4; IR (KBr) 1740(s), 1401(s), 1197(m), 1001(s), 750(s),
696(s) cm-1
.
F IGURE 1. Time-dependence curves for aerobic oxidation of
p-22 to p-12 and p-13 under O2 (1 atm) in the presence of
THICA (3 mol %) combined with Co(OAc)2 (0.5 mol %) and
Mn(OAc)2 (0.5 mol %).
TBTA (5 mmol) in 100 mL of dioxane was hydrogenated on
10 wt % Pd/C (0.5 g) under normal pressure of hydrogen at
room temperature overnight. After removal of the catalyst by
filtration, the filtrate was evaporated under reduced pressure
to afford THICA, which was recrystallized from acetone in 90%
yield: 1H NMR (DMSO-d6/TMS) δ 11.03 (s, 3H); 13C NMR
(DMSO-d6/TMS) δ 146.6; IR (KBr) 3539(s), 3166(s), 2827(s),
1720(s), 1433(s), 1211(m), 1010(s), 701(s) cm-1. The X-ray
analysis of THICA indicates that three OH groups are situated
at the same plane.
Oxid a tion of Su bstitu ted Tolu en es u n d er a Dioxygen
Atm osp h er e.
An acetic acid solution (5 mL) of substrate (3 mmol), THICA,
and Co(OAc)2 (0.5 mol %) was paced in a 50 mL pear-shaped
flask with a balloon filled with O2. The mixture was stirred at
25-100 °C for 6 h. After the reaction, the solvent was removed
under reduced pressure, and the products were purified by
column chromatography on silica gel to give the corresponding
oxygenated products. The products were identified through
comparison of isolated products with authentic samples.
Ack n ow led gm en t. This work was partially support
by a Grant-Aid for Scientific Research (KAKENHI) (S)
(No. 13853008) from the J apan Society for the Promo-
tion of Science (J SPS).
F IGURE 2. Time-dependence curves for aerobic oxidation of
p-22 to p-12 and p-13 under O2 (1 atm) in the presence of NHPI
(10 mol %) combined with Co(OAc)2 (0.5 mol %) and Mn(OAc)2
(0.5 mol %).
J O034313Z
an ionization energy of 70 eV. All products were known
compounds and were identified by comparison of the isolated
products with authentic samples.
(11) (a) Butula, I.; Takac, M. Croat. Chem Acta 2000, 2, 569. (b)
Staab, H. A.; Benz, W. Angew. Chem. 1961, 73, 657.
6590 J . Org. Chem., Vol. 68, No. 17, 2003