Aerobic oxidative bromination of arenes using an ionic liquid as both the catalyst and the solvent

Article abstract of DOI:10.1016/j.tetlet.2015.09.150

A method for the bromination of alkoxy-substituted benzenes and naphthalenes was developed by using the residual oxygen in the reaction tube as the oxidant, and [Bmim]NO₃ (1-butyl-3-methylimidazolium nitrate) ionic liquid as both the catalyst and the solvent. No other reagent apart from the ionic liquid and molecular bromine was used in the reactions, and basically all the bromine atoms in the bromine source were transferred to the bromination products, showing that the presented protocol is highly atom economic and practical.

Full text of DOI:10.1016/j.tetlet.2015.09.150

Accepted Manuscript
Aerobic Oxidative Bromination of Arenes Using an Ionic Liquid as both the
Catalyst and the Solvent
Yun-Lai Ren, Binyu Wang, Xin-Zhe Tian, Shuang Zhao, Jianji Wang
PII:
S0040-4039(15)30191-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.09.150
TETL 46822
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
3 August 2015
27 September 2015
30 September 2015
Please cite this article as: Ren, Y-L., Wang, B., Tian, X-Z., Zhao, S., Wang, J., Aerobic Oxidative Bromination of
Arenes Using an Ionic Liquid as both the Catalyst and the Solvent, Tetrahedron Letters (2015), doi: http://dx.doi.org/
10.1016/j.tetlet.2015.09.150
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Aerobic Oxidative Bromination of Arenes Using an Ionic Liquid
as both the Catalyst and the Solvent
Yun-Lai Ren, Binyu Wang, Xin-Zhe Tian, Shuang Zhao, Jianji Wang*
School of Chemical Engineering & Pharmaceutics, Henan University of Science and Technology,
Luoyang, Henan 471003, P. R. China.
School of Chemistry and chemical Engineering, Key Laboratory of Green Chemical Media and
Reactions, Ministry of Education, Henan Normal University, Xinxiang, Henan 453007, P. R.
China.
ABSTRACT
A method for the bromination of alkoxy-substituted benzenes and naphthalines was
developed by using the residual oxygen in the reaction tube as the oxidant, and
[Bmim]NO3 (1-butyl-3-methylimidazolium nitrate) ionic liquid as both the catalyst
and the solvent. No other reagent apart from the ionic liquid and molecular bromine
was used in the reactions, and basically all the bromine atoms in the bromine source
were transferred to the bromination products, showing that the presented protocol is
highly atom economic and practical.
Keywords:
Bromination
Arenes
Ionic liquid
Catalysis.
* Corresponding author. Tel.: 86-379-64232156 ; Fax: 86-379-64210415.
E-mail address: Jwang@henannu.edu.cn (J. Wang).

Bromination of arenes is an important chemical transformation1 because the
resulting products often serve as the electrophilic coupling partner for the
cross-coupling reactions to synthesize various classes of organic compounds.2
Therefore, considerable effort has been devoted to the development of various
effective
brominating
reagent
systems,
e.g.
bromide
salts/oxidant,3
N-bromosuccinimide4 as well as other fantastic and expensive bromonium
equivalents.5 By all appearances, the use of bromide salts as the brominating reagent
leads to low atom economy due to the fact that metal elements in bromide salts cannot
transfer to the bromination product. The reactions using the bromonium equivalents
such as N-bromosuccinimide also suffer from the inherent disadvantages including
low atom economy and expensive brominating reagent.
Another alternative brominating reagent is the inexpensive and readily available
molecular bromine.6 However, the classical bromination methods with molecular
bromine suffer from poor atom economy: up to 50% bromine atoms is transferred to
the bromination product and the resulting HBr by-product not only wastes raw
material, but also pollutes the environment. One of the effective solutions to this
situation is the oxidative strategy where the resulting HBr by-product is in-situ
oxidated to reactive bromine species in the presence of oxidant.7 From the
environmental and economic perspectives, molecular oxygen (especially in its diluted
form, air) is the most ideal oxidizer,8 which prompts chemists to develop various
aerobic methods for the bromination of arenes using Fe2O3/zeolite,8 CeO2
nanoparticles,9 copper salts,10 9-mesityl-10-methylacridinium ion,11 sodium nitrite,12
2

15
RuCl3·xH2O,13 H5PMo10V2O4014 or NH4VO3 as the catalyst. In a previous work, we
have developed an aerobic method for the iodination with nitrogen dioxide as the
catalyst and acetonitrile as the solvent.[12b] Considering the fact that the use of toxic
nitrogen dioxide catalyst and the evaporable solvent is easy to lead to environmental
pollution, our attention is turned to developing a more clean procedure for the aerobic
bromination of arenes by using ionic liquid as both the catalyst and solvent, and the
results are herein reported. Compared with the previous procedure for the ionic liquid
or sodium nitrite-catalyzed aerobic bromination of arenes,[7a,7b,3a] the notable
advantage of this procedure is the absence of corrosive acid condition.
Bromination of methoxybenzene was selected as a model reaction to initiate our
investigation. As shown in Table 1 (entry 1), bromination of methoxybenzene gave
4-bromoanisole in 44% yield in the case of 0.5 equiv. Br2 and 1.5 mL acetonitrile
solvent. Subsequently, various reaction conditions including reaction temperature,
time and solvent were changed to increase the yield, but these attempts were
unsuccessful because 50% of bromine atoms in the molecular bromine was
theoretically converted to the unreactive Br- ion.16 In order to obtain a higher yield,
we tried to add a catalytic amount of [Bmim]NO3 to catalyze the oxidation of the
resulting unreactive Br- ion to reactive bromine species (Table 1, entries 3-5). For
example, an addition of 10 mol% [Bmim]NO3 increased the yield from 44% to 90%.
The residual oxygen in the reaction tube seemed to play a role of the oxidizing reagent.
Indeed, the removal of oxygen from the reaction system led to a remarkable decrease
in the yield (Table 1, entries 7,10). Since [Bmim]NO3 is often regarded to be a greener
3

solvent,17 acetonitrile was replaced by this ionic liquid as the solvent. The results
shown in Table 1 (entry 6) revealed that [Bmim]NO3 was an effective solvent, and 86%
yield was obtained by using this ionic liquid as the solvent.
After discovering a suitable catalyst and solvent, we optimized other reaction
conditions such as the loading of brominating reagent, the reaction temperature and
time. It was shown that 0.5 equiv. Br2 was sufficient for the complete
monobromination of methoxybenzene, and an increase of the brominating source
loading amount led to a decrease of the monobromination yield due to the increase of
dibromination by-product yield. The reaction required at a temperature as high as 80
o
oC, and the yield of the desired product was decreased to 81% in the case of 60 C.
Under the optimal condition, the monobromination of methoxybenzene occurred at
the p-position related to the methoxy group with excellent selectivities (Scheme 1),
and only small amount of ortho-bromination product was observed. Such an excellent
regioselectivity was also observed in previous literatures16 where NaNO2-catalyzed
bromination of arenes was investigated. The main by-products were
2,4-dibromoanisole (<2% yield) from the dibromination as well as 2-bromoanisole
from the ortho-bromination. Another by-product was from the nitration of the benzene
ring.
A variety of representative phenyl rings were tested to examine the scope and
limitation of the new bromination method. As seen from Table 2, many phenyl rings
with alkoxy group underwent the bromination in moderate to high yields with
excellent selectivities. Although the bromination of toluene often gives benzyl
bromide in previous literature,18 no benzyl bromide product was observed under our
4

experimental condition (Table 2, entries 2,4,5). Benzene, alkylbenzenes and several
electron withdrawing group-substituted benzenes were less reactive (Table 2, entries
13,14,15). These results reveal that the scope of the presented bromination method
was limited to more electron-rich phenyl rings in the case of the bromination of
phenyl rings. Surprisingly, the benzene ring with amino group gave the bromination
product in lower yield (Table 2, entry 12) although amino groups are also stronger
electron-donating group. This result can be rationalized by assuming that the
bromination reaction is incompatible with the alkaline character of amino groups.
Indeed, the bromination of methoxybenzene gave the bromination product in poor
yield in the presence of alkaline substances (Table 1, entry 11). We tried to examine
the reaction with isobutylbenzene, phenylamine and phenol as the substrate, but the
desired bromination products were obtained in low yields.
Alkoxy group-substituted naphthalenes are also a kind of good substrates for the
bromination, but naphthalene without activating group was not smoothly converted
into α-bromonaphthalene (Table 2, entry 16). Bromination of 1-methoxynaphthalene
occurred at the 4-position, while 2-ethoxynaphthalene was brominated at its
1-position (Table 2, entries 17, 18). The same site-selectivity was also reported in
previous literatures19 where the electrophilic substitution of naphthalene rings was
examined. Next, the bromination of several disubstituted or trisubstituted benzenes
was investigated to extend the scope of the presented bromination method. As seen
from Table 2, a series of ortho-, meta- and para-substituted alkoxybenzenes were
brominated in moderate to high yields (Table 2, entries 3-8). The bromination
occurred selectively at para-position of alkoxy group in the case of ortho- and
meta-substituted alkoxybenzenes (Table 2, entries 3, 4), while para-substituted
alkoxybenzene underwent ortho-bromination related to alkoxy group (Table 2, entry
5

5). The present procedure for bromination also allowed 1,2,3-trimethoxybenzene to be
brominated with high selectivity (Table 2, entry 8).
Interestingly, the bromination selectively occurred at the alkoxy-substituted
benzene ring in the coexistence of alkoxy and alkyl benzene rings (Scheme 2).
1-Alkoxynaphthalene was preferentially brominated over naphthalene without
substituted group. When the alkoxy-substituted benzene encountered the
alkoxy-substituted naphthalene, the latter was selectively brominated. This offers an
opportunity to the selective bromination of one alkoxy-substituted benzene or
naphthalene ring in the case of the substrate containing two aromatic rings. For
example, when benzyl phenyl ethers were employed as the substrates (Table 2, entries
9-11), only phenyl rings bonded to oxygen were functionalizated and no bromination
occurred at the phenyl side of the benzyloxy moiety.
Subsequently, our investigation was focused on the recycling of the catalyst with
bromination of methoxybenzene as a model reaction. At the end of the reaction, the
desired product was extracted with diethyl ether (3 × 5 mL). After the organic layer
containing the product was separated, the recovered [Bmim]NO3 catalyst could be
reused for seven times without a significant change relative to the catalytic activity
(see Table S4 in the supporting information ).
Finally, we were lost in thought about the reaction mechanism. It is known that
molecular bromine is more reactive towards electron-rich aromatic compounds,6
which was also confirmed by the following experimental result: methoxybenzene was
reacted with 0.5 equiv. molecular bromine to give 4-bromoanisole in 44% yield in the
absence of catalyst (Table 1, entry 1). Thus it is reasonable to assume that the
bromination starts with the reaction between benzene ring and molecular bromine to
give the bromination product and HBr (Scheme 3).6 The resulting HBr is then
6

oxidated by the residual oxygen in the reaction tube to give reactive molecular
bromine21 where [Bmim]NO3 possibly plays a role of catalyst precursor (Scheme 3).
Indeed, bromination of methoxybenzene with HBr as the brominating reagent
smoothly proceeded (Table 1, entry 7), while the bromination did not occur in the
absence of [Bmim]NO3 (Table 1, entry 2). At the present stage, we can not confirm
the real catalytic species, but it is possible that the real catalytic species was formed
-
from the NO3 anion of [Bmim]NO3 because the bromination did not occur in some
-
ionic liquids without NO3 anion (Table 1, entries 8,9). It is also possible that NO2/NO
or NO+/NO pair served for the catalytic cycle upon the basis of previous
literatures.20,21
In conclusion, a new procedure for the bromination of alkoxy-substituted
benzenes and naphthalines was developed by using the residual oxygen in the reaction
tube as the oxidant, and [Bmim]NO3 ionic liquid as both the catalyst and solvent. The
presented method for the bromination has a highly atom economic character since
basically all the atoms in the brominating reagent could be transferred to the
bromination product. No other reagent apart from the ionic liquid and molecular
bromine was used in the reactions, which suggests that the presented protocol is
practical. The presented method allowed a series of alkoxy-substituted benzenes and
naphthalines to be smoothly brominated in moderate to high yields with excellent
selectivities. Compared with the previous procedure for ionic liquid or sodium
nitrite-catalyzed aerobic bromination of arenes,[7a,7b,3a] the notable advantage of this
procedure is that the corrosive acid is absent. Preliminary mechanistic investigation
suggests that the bromination possibly starts with the reaction between benzene ring
7

and molecular bromine to give the bromination product and HBr. Then the resulting
HBr is oxidated by the residual oxygen in the reaction tube to give reactive molecular
bromine where [Bmim]NO3 possibly plays a role of catalyst precursor.
Acknowledgments
This work is sponsored by the Program for Science＆Technology Innovation
Talents in Universities of Henan Province (Grant No.15HASTIT004) and the National
Natural Science Foundation of China (Grant No. 21002023).
Supplementary data
Supplementary data associated with this article can be found, in the online version,
at doi:
.
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10

22 General experimental procedure for the bromination: 1 mL [Bmim]NO3, 0.5 mmol substrate
and 0.25 mmol Br2 were added to a dried 45 mL tube equipped with a magnetic stirring (note:
the air in the tube was not removed). Then the reaction tube was sealed to perform the reaction
o
at 80 C for 24 h. Once the reaction time was reached, the mixture was cooled to room
temperature and 3 mL water was added. Then the desired product was extracted with CH2Cl2 (3
× 10 mL). GC analysis of the mixture provided the GC yield of the product. The product in
another parallel experiment was purified by column chromatography, and identified by
1H-NMR and 13C-NMR.
11

MeO
Br
Br
< 2%
Residual air in the reaction tube
[Bmim]NO3
Br +
MeO
+ Br2
MeO
80 oC, 24 h
0.5 equiv
MeO
Br
86%
<3%
Scheme 1 Bromination of methoxybenzene with [Bmim]NO3 as the catalyst and solvent.
12

0.5 equiv Br2
MeO
MeO
MeO
MeO
Br
Br
+ Cl
Cl
Br
1mL [Bmim]NO3
trace
81%
90%
0.5 equiv Br2
Me
Br
Me
+
1mL [Bmim]NO3
2%
OMe
OMe
OMe
0.5 equiv Br2
+
Br
MeO
MeO
+
+
1mL [Bmim]NO3
5%
Br
65%
OMe
Br
0.5 equiv Br2
+
1mL [Bmim]NO3
90%
Br
1%
Br
0.5 equiv Br2
1mL [Bmim]NO3
O
O
78%
Scheme 2 Several competition reactions between different aromatic rings.
13

MeO
+ Br2
MeO
Br
+ HBr
1
Catalytic species from [Bmim]NO3
1
2
1
Br2 + H2O
2
HBr + O2
4
Scheme 3 Considerations on the mechanistic pathway.
14

Table 1 Bromination of methoxybenzene a
Catalyst
Solvent, 80 oC, 24 h
+ 0.5Br2
MeO
MeO
Br
Entry
Catalyst
Solventc
Bromine
source
Conversion
(%)b
Yield (%)b
1
2
3
-
-
Acetonitrile
Acetonitrile
Acetonitrile
Br2
HBr
Br2
51
0
44
0
[Bmim]NO3
72
68
(2 mol%)
[Bmim]NO3
(5 mol%)
4
5
Acetonitrile
Acetonitrile
Br2
Br2
84
98
86
90
[Bmim]NO3
(10 mol%)
6
-
-
-
-
-
-
[Bmim]NO3
[Bmim]NO3
[Bmim]Cl
Br2
97
99
0
86
90
0
7
HBr
HBr
HBr
HBr
Br2
8
9
[Bmim]BF4
[Bmim]NO3
[Bmim]NO3
0
0
10d
11e
61
33
53
18
o
a Reaction conditions: 0.5 mmol methoxybenzene, 0.25 mmol Br2 or 0.5 mmol HBr, 80 C, 24 h,
the air in the tube was not removed.
b Determined by GC with 1,2,4,5-tetramethylbenzene as an internal standard.
c 1.5 mL.
d The air inside the tube was replaced with N2 gas by six vacuum/gas cycles.
e 0.25 mmol NaCO3 was added.
15

Table 2
Bromination of various substituted benzenes and naphthalines a
[Bmim]NO3
80 oC, 24 h
Residual air in the reaction tube
ArBr
ArH
+ 0.5 Br2
Entry
Substrate
Product
MeO
GC yield(%)b Isolated yield(%)
MeO
1
2
Br
86
87
70
72
O
Br
O
MeO
H3C
MeO
H3C
Br
Br
3
83
53
MeO
MeO
4
5
81
64
68
61
Me
Me
Me
MeO
Br
MeO
MeO
Me
Br
MeO
MeO
6
7
8
72
80
97
-
MeO
MeO
MeO
Br
77
80
OMe
OMe
MeO
MeO
MeO
MeO
MeO
MeO Br
O
O
Br
9
78
76
86
40
6
72
60
70
33
-
O
O
O
Br
10
11
12
13
14
15
16
NC
F
NC
F
O
Br
N
N
Br
Br
Me
Cl
Me
Cl
Br
trace
6
-
Br
Br
Br
-
Br
13
-
16

OMe
OMe
17
18
98
87
80
85
Br
Br
OEt
OEt
a Reaction conditions: 0.5 mmol methoxybenzene, 0.25 mmol Br2, 1 mL [Bmim]NO3, 80 oC, 24 h,
the air in the tube was not removed.
b Determined by GC with an internal standard.
17

Graphical Abstract
Aerobic Oxidative Bromination of Arenes Using an Ionic Liquid
as both the Catalyst and the Solvent
Yun-Lai Ren, Binyu Wang, Xin-Zhe Tian, Shuang Zhao, Jianji Wang*
[Bmim]NO3
Ar H + 0.5 Br2
Ar Br
A method for the bromination of alkoxy-substituted benzenes and naphthalines was
developed by using the residual oxygen in the reaction tube as the oxidant, and
[Bmim]NO3 (1-butyl-3-methylimidazolium nitrate) ionic liquid as both the catalyst
and solvent. No other reagent apart from the ionic liquid and molecular bromine was
used in the reactions, and basically all the bromine atoms in bromine source were
transferred to the bromination products, showing that the presented protocol is highly
atom economic and clean.
18

Research Highlights
► Greener and readily available ionic liquid was used as both the solvent and
catalyst. ► The reaction is highly atom-economic and practical. ► Clean and
inexpensive air was used as the oxidant.
19