An efficient copper-catalysed aerobic oxybromination of arenes in water

Article abstract of DOI:10.1039/c0gc00328j

An aerobic oxybromination of arenes catalysed by Cu(NO₃) ₂ was achieved using HBr as a bromine source, molecular oxygen as the oxidant and water as solvent with high selectivity. The catalyst shows not only high chemoselectivity for monobromination, but also a remarkable regioselectivity for para-isomers.

Full text of DOI:10.1039/c0gc00328j

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An efficient copper-catalysed aerobic oxybromination of arenes in water†
Jian Wang, Wei Wang and Jing-Hua Li*
Received 15th July 2010, Accepted 4th October 2010
DOI: 10.1039/c0gc00328j
Table 1 Oxybromination of phenol with HBr catalysed by different
An aerobic oxybromination of arenes catalysed by
Cu(NO3)2 was achieved using HBr as a bromine source,
molecular oxygen as the oxidant and water as solvent with
high selectivity. The catalyst shows not only high chemos-
electivity for monobromination, but also a remarkable
regioselectivity for para-isomers.
metal saltsa
Entry
Metal salt
Time/h
Conversionb (%)
1
2
3
4
5
6
7
8
Ni2SO4
MnSO4
Co(OAc)2
NaNO2
FeCl2
FeSO4
Fe2(SO4)3
CuSO4
2
2
2
2
2
2
2
2
2
2
2
2
2
3
3
3
3
<1
<1
<1
7
<1
<1
<1
37
Bromoarenes are versatile reagents in synthetic chemistry that
are useful in carbon–carbon bond and carbon–hetero atom
bond formation via Ullmann, Heck, Stille and Suzuki reactions.1
At the same time, they are also used widely in the manufac-
ture of flame retardants, disinfectants, antibacterial drugs and
many other products.2 Traditional methods for the synthesis
of bromoarenes involve aromatic halogenations using various
brominating agents such as bromine,3 NBS,4 hypobromite,5
bromate6 and organic perbromide.7 Recently, tribromide ionic
liquids have been developed as greener and more highly selective
brominating agents.8 However, the Br atom economy is less than
50%.
An alternative solution is oxybromination using bromide
anions as a bromine resource. Typically, oxybrominations of aro-
matic compounds are carried out with a combination of bromide
anion and a variety of oxidants.9 All of these systems require
stoichiometric oxidizing agents, which leads to environmental
problems due to undesirable by-products.
9
Cu(Ac)2
CuBr
CuCl2
50
<1
30
10
11
12
13
15
16
17
18
CuCl
<1
85
Cu(NO3)2
Cr(NO3)3
KNO3
Fe(NO3)3
Pb(NO3)2
100c
81c
21c
100c
a Aerobic oxybromination conditions were as follows: phenol (5 mmol),
HBr (5.5 mmol, 8 mol L-1 aqueous solution), at 100 ◦C. b Conversion and
selectivity were determined by GC. c Some by-products were detected
besides brominated phenols.
scope of application. Only 1 mol% of Cu(NO3)2 is used as a
catalyst in this research.
Among the reports of aerobic oxybromination, there are
some common features of the catalyst (Scheme 1). (1) It can
oxidize Br- to Br2 and itself turn into a protosalt simultaneously.
(2) The protosalt can be oxidized by O2 and then repeat the
preceding reaction until the Br- is exhausted. Therefore, in
our initial study, we tested the activity of various multivalent
inorganic metal salts in oxybromination reactions (Table 1). In
this experiment, phenol was chosen as the substrate to screen
for the best catalyst. Among all of the metal salts tested, Cu2+
salts, especially Cu(NO3)2, showed the best catalytic efficiency,
which prompted us to further optimize the reaction conditions.
Compared with that as described above, hydrogen peroxide-
based oxybromination is a mild and environmentally friendly
system, in which the only byproduct is water.10 However, the
relatively high cost of hydrogen peroxide and its undesirable
decomposition during the reaction at elevated temperatures
cannot be avoided.
Oxybromination has become more and more atom-
economical and environmentally friendly in recent years since
H2O2 was replaced by O2, the most abundant and cheapest
oxidant.11 Several examples of aerobic oxybromination have
appeared that all use VOCs (volatile organic compounds) as
solvents and metal salts (more than 5 mol%) as catalysts. These
cause waste that is hazardous to the environment. Recently, the
oxyhalogenation of aromatic compounds was examined in ionic
liquids (ILs) to overcome these problems.12 Apart from their
low selectivity, the methods involve the use of stoichiometric
amounts of oxidative IL as co-solvent and the applicable scope
of aromatic substrates is very narrow.
Scheme 1 The valence state of catalyst during the oxybromination.
Herein, we report an aerobic oxybromination using HBr as
the bromine source in water with a high selectivity and extensive
The conditions of oxybromination catalysed by Cu(NO3)2
are presented in Table 2. The influence of temperature is
apparent (Table 2, entries 1–4). Despite the increase of Cu(NO3)2
significantly accelerating the reaction, it also produces quite a
few by-products besides brominated phenols (Table 2, entries 3–
6). According to results of our experiments, 1 mol% of catalyst
College of Pharmaceutical Sciences, Zhejiang University of Technology,
310032, Hangzhou, China. E-mail: lijh@zjut.edu.cn
† Electronic supplementary information (ESI) available: Analytical data
and NMR spectra. See DOI: 10.1039/c0gc00328j
2124 | Green Chem., 2010, 12, 2124–2126
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Table 2 Optimization of reaction conditionsa
Table 4 Selectivity in this oxybromination systema
Entry T/◦C Conditionsb Time/h Catalyst (mol%) Conversionc (%)
Entry
Substrate
Time/hb
Selectivityc
1
2
3
4
5
6
7
8
40
60
80
1
1
1
20
20
4
3.5
2.5
3.5
6
7
10.5
8
10
10
10
10
15
5
1
1
1
1
<10
70
1
2
3
4
5
6
7
8
Phenol
o-Cresol
m-Cresol
p-Cresol
p-Chlorophenol
Hydroquinone
Anisole
9
8
5.5
5
21
4
97 (92)
97 (92)
97 (93)
92
95
90
98d
98d
99d
98d
98
Reflux 1
80
80
80
80
80
80
1
1
1
2
3
4
9
20
98 (97)
98 (93)
98
98
97
Toluene
9
10
a Aerobic oxybromination conditions were as follows: aromatic com-
pound (5 mmol), HBr (5.5 mmol, 8 mol L-1 aqueous solution), Cu(NO3)2
(0.05 mmol), at 80 ◦C. The reaction was carried out until the substrate
was totally exhausted. b The reaction time at which the substrate was
totally consumed. c The selectivity for the monobrominated products
(the number in the parentheses are the selectivity for the para-bromo
products) were determined by GC in comparison with authentic
samples.
a Aerobic oxybromination conditions were as follows: phenol (5 mmol),
HBr (5.5 mmol, 8 mol L-1 aqueous solution), at 100 ◦C. b Conditions:
1. O2 balloon; 2. O2 pumped into the mixture; 3. air pumped into the
mixture with an air compressor; 4. reaction carried out in an open
system. c Conversion and selectivity were determined by GC. d Some
by-products were detected besides brominated phenols.
is desirable, which almost completely converts the phenol into
bromophenol and avoids the formation of by-products (Table
2, entries 6–10). Compared with pure O2, air is much cheaper,
more easily available and more desirable.
should be followed by regular GC analysis so as to stop the
reaction as soon as the substrate is nearly consumed, in order to
avoid further transformations of the monobrominated products.
The conversion of compounds 1–8 increased up to 100% by
prolonging the reaction time. However, they showed diverse
chemoselectivity and regioselectivity, as presented in Table 4.
It is interesting that the compounds that had the para-position
occupied (Table 4, entries 4–6) show less monoselectivity than
those where the para-position was unoccupied (Table 4, entries
1–3, 7 and 8). Compared with the other arenes in this study,
anisole showed the best regioselectivity (Table 4, entries 1–3, 7
and 8).
The optimum reaction conditions (5 mmol of substrate,
5.5 mmol of 8 mol L-1 aq. HBr and 0.05 mmol of Cu(NO3)2) were
used for the oxybromination of various aromatic compounds
(Table 3). From Table 3, we find that the arenes with electron
donating groups can be easily brominated in this system (Table 3,
entries 1–4, 6 and 7). Phenols with electron withdrawing groups
can also be successfully brominated by prolonging the reaction
time (Table 3, entry 5). However, electron-deficient arenes did
not react with HBr in this system (Table 3, entries 9 and
10). Different from all the methods of aerobic oxybromination
previously reported, toluene, a weaker active arene, can be
effectively transformed into its monobromide (Table 3, entry
8). All substrates showed good (>93%) para-regioselectivities
(Table 3, entries 1–3, 7 and 8) and ortho-regioselectivities in
cases where the para-position was occupied (Table 3, entries
4–6). The high chemoselectivity (99%) of this reaction for
monobromination products is remarkable. However, it should
be emphasized that if the reaction is allowed to progress further,
di- and multibrominated products appear. Thus, the reaction
A possible mechanism for the copper-catalysed oxybromi-
nation is presented in Scheme 2, which can be described as a
sequential cascade of double-cycle redox reactions.13 Cu2+/NO3
-
react with HBr to form Br2, while Cu2+/NO3 themselves
-
transform to Cu+/NO, which can be re-oxidised by oxygen and
undergo the next oxidation of HBr. It is worth mentioning that 1
mol% Cu(NO3)2 catalyses the reaction smoothly, different from
all of the other aerobic oxybrominations reported.
In summary, we have developed a copper-catalysed oxidative
bromination of aromatic compounds under mild aerobic condi-
tions. HBr is used as a Br source and only 1% metal catalyst is
Table 3 The aerobic oxybromination of various arenesa
Productb (%)
c
Entry
Substrate
Time/h
Conversion (%)b
o-
p-
Sm
1
2
3
4
5
6
7
8
9
Phenol (1)
8
7
5
4
18
3
8
15
24
24
98
97
97
92
94
92
98
95
<1
<1
5
2
4
94
99
o-Cresol (2)
97 (2a)
95 (3a)
—
—
—
99
94
—
—
99(92)
99(91)
99(90)
99(91)
99(90)
99(95)
99
m-Cresol (3)
p-Cresol (4)
p-Chlorophenol (5)
Hydroquinone (6)
Anisole (7)
Toluene (8)
Chlorobenzene (9)
Nitrobenzene (10)
99 (4a)
99 (5a)
99 (6a)
—
5
—
—
—
10
—
a Aerobic oxybromination conditions were as follows: aromatic compound (5 mmol), HBr (5.5 mmol, 8 mol L-1 aqueous solution), Cu(NO3)2
(0.05 mmol), air was pumped into the reactor at 80 ◦C. b Conversion and selectivity were determined by GC in comparison with authentic samples.
c Selectivity for monobrominated products (the numbers in the parentheses are the isolated yields of the main product).
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