Chemo- and regioselective direct hydroxylation of arenes with hydrogen peroxide catalyzed by a divanadium-substituted phosphotungstate

Article abstract of DOI:10.1002/anie.201201605

Peroxide in, phenol out: The catalyst [-PW₁₀O₃₈V ₂(μ-OH)₂]^3- showed high activity in the hydroxylation of various aromatic compounds with aqueous H₂O ₂. The system was regioselective, producing para-phenols from monosubstituted benzene derivatives. Furthermore, alkylarenes with reactive side-chain Ca spa 3-H bonds could be chemoselectively hydroxylated without significant formation of side-chain oxygenated products. Copyright

Full text of DOI:10.1002/anie.201201605

Angewandte
Chemie
DOI: 10.1002/anie.201201605
Polyoxometalate Catalysis
Chemo- and Regioselective Direct Hydroxylation of Arenes with
Hydrogen Peroxide Catalyzed by a Divanadium-Substituted
Phosphotungstate**
Keigo Kamata, Taiyo Yamaura, and Noritaka Mizuno*
Phenols with one or more functional groups are valuable
organic intermediates related to resins, plastics, pharmaceut-
icals, and agrochemicals in the chemical industry.[1] Most of
these phenols are industrially produced by multistep process-
es. Therefore, the direct catalytic hydroxylation of arenes to
phenols with green oxidants, such as H2O2,[2] N2O,[3] and O2, in
combination with reductants[4] has attracted much attention.[5]
Whereas the catalytic oxidation of benzene to phenol has
been extensively investigated, little is known about the
selective direct hydroxylation of substituted derivatives.
Numerous metal catalysts, such as Ti, V, Mn, Fe, Co, Cu,
Ru, Pt, and polyoxometalates (POMs), have been developed
for the oxidation of arenes with H2O2.[2] However, hydroxyl-
ation of arenes with functional groups usually leads to
a mixture of ortho-, meta-, and para-substituted phenols.
hydroxylation of various structurally diverse arenes to
phenols. The present system shows unique chemo- and
regioselectivity for the formation of para-phenols from
monosubstituted benzenes. This study provides the first
example of a synthetic catalyst that can chemoselectively
hydroxylate alkylarenes with reactive secondary and tertiary
À
aromatic side-chain C H bonds without significant formation
of the corresponding side-chain oxygenated products.
Hydroxylation of anisole (1a) was carried out under
various reaction conditions using an excess of 1a with respect
to H2O2 (1a/H2O2 = 10:1; Table S1). In the presence of I,
hydroxylation of 1a in CH3CN/tBuOH (1:1, v/v) efficiently
proceeded to give the corresponding methoxyphenols (2a) in
70% yield based on H2O2. The formation of phenol by the
oxidative demethylation of 1a was not observed. Notably, the
para-hydroxylation of 1a preferentially proceeded, and the
ortho-/meta-/para-2a ratio was 3: < 1:96. The present regio-
selectivity (96%) for para-2a was much higher than those
reported for stoichiometric reagents, such as peroxytrifluoro-
acetic acid (21%)[9a] and hydroxyl radical (10%),[9b] or H2O2
based catalytic systems, such as sterically hindered metal-
loporphyrins (23–90%),[2c,10a] TS-1 (a titanium silicate zeolite;
71–75%),[2a] [Fe(tpaa)(ClO4)2] (tpaa = tris-[N-(2-pyridyl-
methyl)-2-aminoethyl]amine; 51%),[10b] [(dppe)Pt(CF3)-
(CH3)(CH2Cl2)](ClO4) (dppe = 1,2-bis(diphenylphosphino)-
ethane; 15%),[2h] and K7NiV13O38·16H2O (0%; Table S2).[2i]
Hydroxylation efficiently proceeded even at 298 K without
significant changes in catalytic performance. Furthermore,
the yield and regioselectivity for hydroxylation of 1a under
air were almost the same as those under argon, showing that
the possibility of participation by molecular oxygen in air can
be excluded. Compound I was much more active than
[g-SiW10O38V2(m-OH)2]4À.[8] Mono- and trivanadium-substi-
tuted phosphotungstates, [a-PVW11O40]4À and [a-H2P-
V3W9O40]4À, and monoprotonated [g-HPV2W10O40]4À (which
has an {OV-(m-O)(m-OH)-VO} core) were inactive, suggesting
Furthermore, most systems for the oxidation of alkylarenes
3
À
preferentially oxidize the aromatic side-chain sp C H bonds
2
À
rather than the aromatic ring sp C H bonds, because the
bond dissociation energies (BDEs) of the ArCR2 H bonds
À
À1
À
(ca. 375 kJmol ) are much lower than those of the Ar H
bonds (ca. 470 kJmolÀ1).[5,6] Natural enzymes can chemo- and
regioselectively hydroxylate alkylarenes through molecular
recognition.[7] However, synthetic catalysts have scarcely
achieved highly chemo- and regioselective hydroxylation of
alkylarenes, especially with reactive secondary and tertiary
3
À
aromatic side-chain sp C H bonds.
Recently, we have reported the formation of non-free-
radical and electrophilic oxidants with high steric hindrance,
such as [g-PW10O38V2(m-OH)(m-OOH)]3À and [g-PW10O38V2-
(m-O2)]3À, by the reaction of a divanadium-substituted phos-
photungstate, [g-PW10O38V2(m-OH)2]3À (I; Supporting Infor-
mation, Figure S1) with H2O2.[8] Such oxidants can efficiently
catalyze various oxidative functional group transformations.
Herein, we apply the I-catalyzed oxidation system to direct
[*] Dr. K. Kamata, T. Yamaura, Prof. Dr. N. Mizuno
Department of Applied Chemistry, School of Engineering
The University of Tokyo
À À
=
that the active sites are not the V O W and V O sites, but
rather the bis-m-hydroxo site of {OV-(m-OH)2-VO} in I. In the
presence of tungstates and HClO4, hydroxylation did not
proceed.[11] Simple vanadium compounds, including [VO(O2)-
(pic)(H2O)2] (pic = picolinate) and TBA[VO3]/PCA (TBA =
[(n-C4H9)4N]+, PCA = pyrazine-2-carboxylic acid), which
have been reported to be active for the hydroxylation of
arenes with H2O2,[12] hardly catalyzed hydroxylation under the
present reaction conditions.[13]
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656 (Japan)
E-mail: tmizuno@mail.ecc.u-tokyo.ac.jp
Homepage: http://park.itc.u-tokyo.ac.jp/mizuno/
[**] This work was supported in part by the Japan Society for the
Promotion of Science (JSPS) through its Funding Program for
World-Leading Innovative R&D on Science and Technology (FIRST
Program) and a Grant-in-Aid for Scientific Research from the
Ministry of Education, Culture, Science, Sports, and Technology of
Japan.
Hydroxylation of 1a efficiently proceeded, even when
using I at a loading of 0.16 mol%, to give 2a in 67% yield
based on H2O2 [Eq. (1)]. The regioselectivity was not affected
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201201605.
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Table 1: Regioselective hydroxylation of arenes with H2O2 catalyzed by
I.[a]
Entry Substrate
YS
YO
Product
(Selectivity [%])[d]
[%][b] [%][c]
(>99)
o/m/p=5:<1:95
1
2
85
by reduction of the catalyst loading. In this case, the turnover
number (TON) reached up to 405 and the turnover frequency
(TOF) was 540 hÀ1. These values were much larger than those
reported for the catalytic systems based on H2O2 (TON =< 1–
80, TOF =< 1–53 hÀ1; Table S2).[2,10,13]
2[e]
1a
2
2
92
93
56
2a
2a
2a
(99)
o/m/p=3:<1:97
(99)
o/m/p=3:<1:97
(91)
3[e.f] 1a
4[g]
1a
1b
14
o/m/p=1:<1:99
Hydroxylation of various arenes was carried out with an
excess of substrate relative to H2O2 (Table 1). Reactivities of
monosubstituted benzenes were dependent on the electronic
effects of the substituents on the aromatic rings. Benzenes
with electron-donating substituents (1a, 1d, and 1e) were
efficiently hydroxylated to the corresponding phenols in 56–
86% yield based on H2O2 (Table 1, entries 1, 10, and 11),
whereas hydroxylation of bromobenzene gave bromophenols
in 7% yield based on H2O2 under the same reaction
conditions. These reactivities indicate the formation of
active electrophilic oxygen species. After the hydroxylation
of 1a was complete (Table 1, entry 2), 30% aqueous H2O2
(100 mmol) was added to the resulting reaction solution.
Hydroxylation again proceeded with almost the same yield
based on H2O2 (93%) and regioselectivity for para-2a (97%)
as those observed for the first run (92% yield based on H2O2
and 97% regioselectivity for para-2a; Table 1, entries 2 and
3). Thus, I is intrinsically recyclable.[14] Regioselectivities for
the hydroxylation of various arenes with H2O2 were then
investigated. As monosubstituted benzenes with electron-
donating groups show predominantly ortho/para orientation
for electrophilic hydroxylation, organometallic complexes
without bulky ligands and stoichiometric oxidants give
a mixture of ortho- and para-substituted phenols.[2,9,10] On
5[h]
6
5
2
50
78
(>99)
(>99)
2b
7[h]
8
80
(>99)
8
1c
1c
2
16
93
64
2c
2c
(>99)
(>99)
9[g]
(99)
10
1
56
o/m/p= <1:25:74
(85)
11[h,i]
2
86
85
o/m/p=5:<1:95
12[g,j] 1e
18
2e
(81)
o/m/p= <1:<1:99
13[h]
6
63
(>99)
[a] Reaction conditions: TBA4[g-HPW10V2O40] (2.5 mmol), HClO4
(2.5 mmol), substrate (5 mmol), CH3CN/tBuOH (1:1, 2 mL), aqueous
H2O2 (30%, 0.1 mmol), 333 K, 60 min, under Ar (1 atm). Yields and
selectivities were determined by GC analysis. [b] YS (%)=[products
(mol)/initial substrate (mol)]ꢀ100. [c] YO (%)=[products (mol)/initial
H2O2 (mol)]ꢀ100. [d] Selectivity for formation of hydroxylated products.
[e] 298 K. [f] Recycling experiment (see the Supporting Information).
[g] Reaction conditions: TBA4[g-HPW10V2O40] (2.5 mmol), HClO4
(2.5 mmol), substrate (0.4 mmol), CH3CN/tBuOH (1:1, 2 mL), aqueous
H2O2 (30%, 0.1 mmol), 298 K, 240 min, under Ar (1 atm). [h] Substrate
(1 mmol). [i] 1,4-Benzoquinone (8% selectivity), muconaldehyde (2%
selectivity). [j] 1,4-Benzoquinone (18% selectivity), muconaldehyde (1%
selectivity).
À
the other hand, the C H bonds at the para position of
monosubstituted benzenes were regioselectively hydroxy-
lated, with 74–95% of para-phenol versus total phenol
produced (Table 1). The high regioselectivity for para-
phenol formation is likely due to the ortho-hydroxylation
being suppressed by the steric crowding between the POM
framework and the substituents. Similarly, the high stereo-
specificity and diastereo- and regioselectivities for I-catalyzed
epoxidation are explained by the steric constraints of the
active site.[8,15,16] Not only monosubstituted benzenes, but also
disubstituted ones (1b and 1c) were regioselectively hydroxy-
lated, and 1c gave the less sterically hindered 2,4-dimethox-
yphenol (2c) with > 99% selectivity (Table 1, entries 5–8).
The substrate 1-methoxynaphthalene (1 f) was also regiose-
lectively hydroxylated to give 4-methoxy-1-naphthol (2 f;
Table 1, entry 13). Hydroxylation of 1a, 1c, and 1e with
relatively low substrate/H2O2 ratios (4:1) was also carried out.
Yields based on substrate could be increased to 14–18%
without significant changes in regioselectivity (Table 1,
entries 4, 9, and 12).[17]
without significant formation of side-chain oxygenated prod-
ucts, such as benzyl alcohol, benzaldehyde, and benzoic acid
(Table 2, entry 1). The ring/chain ratio (ring-oxygenated
products/side-chain-oxygenated products) was 98:2, and the
value was quite different from those of vanadium complexes
such as [V2O3(sha)3(H2O)3] (sha = N-Salicyl hydroxamate),
[V(O)(Cl) (pbha)2] (pbha = N-phenyl benzohydroxamate),
and [VO(acac)2] (acac = acetylacetonate) (0:100–25:75;
Table S3).[2b,18] Ethylbenzene (1h), cumene (1i), and diphe-
nylmethane (1j), which all possess more reactive secondary
This system could also be applied to the chemoselective
oxidation of various kinds of alkylarenes to phenols (Table 2).
Toluene (1g) was chemoselectively oxidized to cresols (2g)
2
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Table 2: Chemoselective hydroxylation of alkylarenes with H2O2 catalyzed by I.[a]
chemoselectively oxidized to the corresponding
phenols (Table 2, entries 6–8).
Entry Substrate
YS
YO [%][c]
Product
(Selectivity
[%])[d]
[%][b] (R/C)
The kinetic isotope effect (kH/kD) was deter-
mined by the I-catalyzed competitive hydroxylation
of 1g and [D8]toluene (1g-d8) with H2O2. The
intramolecular kH/kD value for aromatic ring hy-
droxylation was 1.0, indicating that the
(86)
o/m/p
=7:16:77
60
1
1[e]
(98:2)
(77)
o/m/p
=5:20:75
À
C H bond cleavage is not included in the rate-
66
1
2[f]
determining step for this hydroxylation. The value is
smaller than that of hydroxyl radical (1.7)[21] and
comparable to those of [VO(O2)(pic)(H2O)2] (0.95–
1.05), peroxytrifluoroacetic acid (ca. 1), and cyto-
chrome P450 enzymes (0.95–1.27).[12a,22–24] The addi-
tion of a radical scavenger, 2,6-di-tert-butyl-4-meth-
ylphenol (5 equiv vs. I), did not affect the reaction
rate, selectivity, or total yield for the hydroxylation of
1a. No formation of coupling products, such as
biphenyls, was observed. Furthermore, the reactivity
order for the hydroxylation of a series of monosub-
(86:14)
(88)
o/m/p
=2:20:77
55
1
3[g]
(93:7)
(97)
o/m/p
=9:20:71
47
1
4[h]
(97:3)
43
4
5[i]
(87)
(87:13)
(98)
2,3/3,4
=5:95
stituted
benzenes
(OH ꢀ OMe > Me > Br)
61
1
6[j]
(98:2)
decreased in the opposite order of that of the
hydroxyl radical system.[21] All these results, includ-
ing chemo- and regioselectivities, suggest that non-
free-radical, electrophilic, metal-based oxidants play
an important role in the present hydroxylation
method.
In summary, divanadium-substituted phospho-
tungstate I showed high catalytic activity and unique
chemo- and regioselectivities for the direct hydrox-
ylation of various arenes with aqueous H2O2.
(96)
2,4/3,5/2,6
=90:9:<1
71
1
7[k]
(96:4)
98
2
8[l]
(45)
(88:12)
[a] Reaction conditions: TBA4[g-HPW10V2O40] (2.5 mmol), HClO4 (2.5 mmol), sub-
strate (5 mmol), CH3CN/tBuOH (1:1, 2 mL), 30% aqueous H2O2 (0.1 mmol),
333 K, 60 min, under Ar (1 atm). Yields and selectivities were determined by GC.
[b] YS (%)=[products (mol)/initial substrate (mol)]ꢀ100. [c] YO (%)=[products
(mol)/initial H2O2 (mol)]ꢀ100. R/C=ring/chain ratio=[(phenols (mol) + qui-
nones (mol)]/side-chain oxygenated products (mol). [d] Selectivity for formation of
hydroxylated products. [e] Benzyl alcohol (2% selectivity), 2-Methyl-1,4-benzoqui-
none (12% selectivity). [f] 1-Phenylethanol (13% selectivity), 2-ethyl-1,4-benzoqui-
none (9% selectivity). [g] 2-Phenyl-2-propanol (7% selectivity), 2-isopropyl-1,4-
benzoquinone (5% selectivity). [h] Benzhydrol (2% selectivity), benzophenone (1%
selectivity). [i] 1k (1 mmol). Xanthydrol (2% selectivity), xanthone (11% selectivity).
[j] 2-Methylbenzyl alcohol (2% selectivity). [k] 3-Methylbenzyl alcohol (4% selec-
tivity). [l] 3-Methylbenzyl alcohol (8% selectivity), 4-methylbenzaldehyde (4%
selectivity), 2,5-dimethyl-1,4-benzoquinone (43% selectivity).
Received: February 28, 2012
Revised: April 10, 2012
Published online: && &&, &&&&
Keywords: arenes · hydrogen peroxide · hydroxylation ·
.
polyoxometalates · vanadium
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Angew. Chem. Int. Ed. 2012, 51, 1 – 5
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Rogge, T. Gierahn, B. G. Fox, Proc. Natl. Acad. Sci. USA 2003,
100, 3784 – 3789.
[11] a) K. Kamata, K. Yonehara, Y. Sumida, K. Yamaguchi, S.
Hikichi, N. Mizuno, Science 2003, 300, 964 – 966; b) K. Kamata,
T. Hirano, S. Kuzuya, N. Mizuno, J. Am. Chem. Soc. 2009, 131,
6997 – 7004.
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Weiss, J. Am. Chem. Soc. 1983, 105, 3101 – 3110; b) G. B.
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1989, 54, 4368 – 4371.
[13] Although the TON (405) of I was smaller than that of
K7NiV13O38·16H2O (942), the TOF of I (540 hÀ1) was much
larger than that of K7NiV13O38·16H2O (135 hÀ1).[2i] Furthermore,
the K7NiV13O38·16H2O/H2O2 system is not applicable to the
chemoselective hydroxylation of toluene because of the signifi-
cant formation of benzaldehyde and benzoic acid.
[24] The NIH shift value was investigated for hydroxylation of
4-deuterotoluene (1g-d1). Hydroxylation proceeded with 67%
retention and/or migration of deuterium in the formation of
para-2g. This high NIH shift value is in the same range as those
observed for hydroxylation of 1g-d1 by [VO(O2)(pic)(H2O)2]
(70%), [VO(acac)2]/O2/aldehyde (50%), pyridine N-oxide/hn
(59%), and natural enzymes (68–78%).[12a,22,23]
[14] The 51V NMR spectrum of I after hydroxylation showed a strong
À580 ppm signal for I, as well as a À671 ppm signal for
VO(OtBu)3 (integrated signal intensity; 1% with respect to I).
4
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ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
These are not the final page numbers!

Angewandte
Chemie
Communications
Polyoxometalate Catalysis
Peroxide in, phenol out: The catalyst [g-
PW10O38V2(m-OH)2]3À showed high activ-
ity in the hydroxylation of various aro-
matic compounds with aqueous H2O2.
The system was regioselective, producing
para-phenols from monosubstituted
benzene derivatives. Furthermore, alky-
À
K. Kamata, T. Yamaura,
N. Mizuno*
&&&& — &&&&
Chemo- and Regioselective Direct
Hydroxylation of Arenes with Hydrogen
Peroxide Catalyzed by a Divanadium-
Substituted Phosphotungstate
larenes with reactive side-chain Csp3
bonds could be chemoselectively
H
hydroxylated without significant forma-
tion of side-chain oxygenated products.
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!