An instant and facile bromination of industrially-important aromatic compounds in water using recyclable CaBr2-Br2 system

Article abstract of DOI:10.1039/c1gc15359e

Various industrially-important brominated intermediates have been instantly synthesized using aq. CaBr₂-Br₂ system as an efficient and recyclable brominating reagent under aqueous conditions at room temperature without the need for metal catalysts or acidic additives. Structurally-diverse phenol and aniline derivatives with strong electron-withdrawing groups such as carboxylic, nitro and formyl show remarkable reactivity to the brominating reagent and brominated in 92-98% yield with high purity (>99%) in a very short reaction time. Organic solvent-free conditions, a feature of the green chemistry, were successively used not only for the reactions but also for the isolation of products at the end of the reaction. The recycling of HBr by its neutralization, thereby generating additional amounts of industrially-important CaBr₂ has been designed and developed. The brominating reagent has been recycled and regenerated, and the process was repeated up to 4 cycles after the fresh batch using the regenerated brominating reagent having almost identical selectivity and isolated yields, which seems to be the most promising methodology from the viewpoint of the green approach to organic synthesis.

Full text of DOI:10.1039/c1gc15359e

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PAPER
An instant and facile bromination of industrially-important aromatic
compounds in water using recyclable CaBr –Br system
2
2
Lalit Kumar,* Tanu Mahajan and D. D. Agarwal
Received 3rd April 2011, Accepted 18th May 2011
DOI: 10.1039/c1gc15359e
Various industrially-important brominated intermediates have been instantly synthesized using
aq. CaBr –Br system as an efficient and recyclable brominating reagent under aqueous conditions
2
2
at room temperature without the need for metal catalysts or acidic additives. Structurally-diverse
phenol and aniline derivatives with strong electron-withdrawing groups such as carboxylic, nitro
and formyl show remarkable reactivity to the brominating reagent and brominated in 92–98%
yield with high purity (>99%) in a very short reaction time. Organic solvent-free conditions, a
feature of the green chemistry, were successively used not only for the reactions but also for the
isolation of products at the end of the reaction. The recycling of HBr by its neutralization, thereby
generating additional amounts of industrially-important CaBr has been designed and developed.
2
The brominating reagent has been recycled and regenerated, and the process was repeated up to 4
cycles after the fresh batch using the regenerated brominating reagent having almost identical
selectivity and isolated yields, which seems to be the most promising methodology from the
viewpoint of the green approach to organic synthesis.
Introduction
that do not use harmful organic solvents are encouraged
6
7
and are in great demand today. A recent report on “green
solvents” concluded that the use of solvents like dioxane,
acetonitrile, 1-butanol, propanol, acids, acetone, ethyl acetate,
formaldehyde and THF are not recommended from an
environmental perspective. Water, on the other hand, is a
promising solvent because it is readily available, non-flammable,
non-toxic and could offer the easy separation of reagents
or catalysts from many organic products. To date, published
research on bromination of aromatic compounds in water
Bromination of aromatic compounds has been a subject
1
of great interest in recent years due to the commercial
2
importance of brominated compounds in the manufacture
of pharmaceuticals, fine chemicals, agrochemicals and other
specialty chemicals like fire retardants, pesticides, herbicides, etc.
Although bromination of aromatic compounds by elemental
3
bromine is a well-known organic reaction, bromination
using elemental bromine usually results in a complex mixture
4
of mono-, di-, tri-, and even tetra-brominated products.
8
is rare and limited to only few examples. Ganchegui et al.
reported the oxybromination of phenol and aniline derivatives
Hence to date, there has been no simple, inexpensive, instant,
easily available, and high yield method developed that
can be commercialized for the said purpose. A number of
using NaBr–H
2
O
2
in H
2
O/scCO biphasic system, albeit low
2
◦
conversions, high temperature (40 C), longer duration (from 4
to 20 h) and use of excess amount of reagent (substrate : NaBr :
5
a
‘
bromine’ based reagents are available, such as Br
2
/Ag
2
SO ,
4
5b
5c
5d
Br
Br
Br
2
2
2
/SO
/zeolite, Br
/H /LDH-WO
2
Cl
2
/zeolite,
Br
2
/Lewis acid,
Br
2
5f
/SbF
3
/HF,
/H O ,
H
2
2
O ; 1 : 3 : 3) are some of the concomitant shortcomings.
5e
5g
2
/silica or clay-supported ZnBr
2
, Br
2
2
2
Moreover, experiments using compressed gases must only
be conducted in suitable equipment and under appropriate
5h
2
O
2
4
,
Br
2
/CTAB/heteropolyacid cesium
5i
5j
salt, Br
2
/tetrabutylammonium peroxydisulfate, Br
2
(for
9
safety precautions. Recently, Podgorsek et al. described an
5k
lithiated haloarenes), etc.. Still, the use of toxic and expensive
reagents, catalysts, volatile organic solvents, low yields and
discharge of corroding HBr waste circumvent these processes
from industrial application. Clean organic reaction processes
interesting oxidative bromination of activated arenes using
H
2
2
O –HBr/“on water” system. This system is beneficial since
water is the only by-product; however, a very long reaction time
10
(
from 8 h to 28 h) and the various hazards associated with
H
2
2
O make this method of limited industrial utility. The highly
toxic 48% aqueous HBr reacts violently with many metals with
the generation of highly flammable hydrogen gas, which may
explode, which further limits its use. Other reported “on water”
Department of Industrial Chemistry, Jiwaji University, Gwalior, 474011,
Madhya Pradesh, India. E-mail: lalitkumar0108@gmail.com;
Tel: +91-9993267029
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and “in water” brominating systems are limited only to the
and loss of solvent during the recycling procedure that makes
the present reaction more convenient, (2) no addition of water is
required after completion of reaction as the brominated product
too is insoluble in water while in case of acetonitrile solvent,
15 mL water has to be added for 10 mL acetonitrile solvent
to separate the precipitated product. This increases the overall
volume of filtrate thereby increasing the cost of recovery of
11
12
13
synthesis of bromohydrins, a-bromoketones, iodination
14
and benzylic bromination.
Literally hundreds of Br
2
-based and oxidative bromination
reagents have been reported for the bromination of organic
compounds, some recent reports are given in Table 1. There
are some other reagents that have been developed as a sub-
stitute for Br
2
, including, but not limited to, NBS/[Bmim]-
CaBr from the aqueous medium at the end of the reaction,
(3) the reaction is operationally- simple, requires no heating or
cooling and is easy to workup, (4) the brominated compound
2
15a
15b
15c
15d
Br,
ZrBr
4
/diazene,
[K·18-crown-6]Br
3
,
[BMPy]Br
3
,
15e
15f
[
Hmim]Br
3
,
[Bmim]Br
3
,
poly(4-vinylpyridinium tribro-
15g
15h
15i
mide), DABCO-bromine, pentylpyridinium tribromide,
and CaBr recovered at the end of reaction are in pure form as
2
15j
ethylene bis(N-methylimidazolium)ditribromide. The bromi-
nation of polymer latex has been carried out using bromine
there is no organic solvent in the reaction mixture for their
contamination and also the only HBr byproduct present in
emulsion which is prepared by dissolving Br
2
into an aqueous
the aqueous filtrate has to be converted to CaBr , (5) the
present reaction leads to zero organic waste and zero effluent
discharge to the environment, since from the three components
2
16
solution of anionic surfactant. However, no such reagent
is commercialized to date, because of their expensive nature,
poor recovery and recycling of spent reagent, disposal of large
amounts of HBr waste and that the reagents are also not so
stable and weaken during long periods of storage; hence they
are meant only for laboratory-scale preparations with limited
applications.
of the reagent, i.e., CaBr
was transferred to organic substrate and the other half-forming
HBr is again utilized back to CaBr by its neutralization with
Ca(OH) . The CaBr of the fresh reaction and the additional
CaBr generated from HBr neutralization was recovered as a
crystalline solid by concentrating the aqueous filtrate (14 g
2
, Br
2
and water; one atom of Br
2
2
2
2
2
After execution of the kilogram-scale synthesis of
tetrabromobisphenol-A (largest-selling flame retardant) using
1
9
CaBr
recovered CaBr
2
in 20 mL H
2
O similar to literature procedure ). The
1
7
20
KBr
for bromination of organic compounds in terms of yield and
reaction conditions. Very recently, we have reported aq. CaBr
3
,
we found that Br
2
in aq. CaBr
2
is a good choice
2
has potential industrial value (such as in
drilling fluids, neuroses medication, freezing mixtures, food
preservatives, photography and fire retardants) and has also
been utilized effectively to regenerate the brominating reagent
for bromination in subsequent batches without any significant
loss of reactivity. Henceforth, at the end of the reaction we have
nothing to dispose to the environment which is justifiable in view
of green chemistry.
2
–
18
Br system in MeCN as a highly efficient brominating agent
2
which provided an instantaneous bromination of industrially-
important compounds in excellent yields and purity. The
method is advantageous due to the cost-effective nature of the
brominating reagent and high purity of the desired products,
whereas the use of organic solvent acetonitrile and the additional
step for recovery of the solvent (MeCN) makes this method of
limited industrial utility. Subsequently, to make the system more
industrially-oriented and environmentally-friendly, we tried the
The use of aqueous CaBr
2
–Br system as the most inexpensive
2
brominating agent and water as a reaction medium represents
the most logical choice of brominating reagent to satisfy the need
of cheaper, cleaner and most efficient system for the instant
synthesis of commercially-important brominated compounds.
A comparison of the brominating ability of the present system
bromination of liquid substrates using aq. CaBr
2
–Br solution
2
in water as a solvent. In this system, organic compound is
insoluble and bromination was tried in aqueous suspension.
(aqueous CaBr
2
–Br system) with those of recently published
2
+
21a–o
The thought was that the electrophile (Br ) can diffuse through
methods
is reported in Table 1 which clearly indicates the
the droplets of aniline leading to bromination. This reaction
proceeded well and the bromine color disappeared immediately
resulting the instantaneous synthesis of 2,4,6-tribromoaniline
in 96% yield (HPLC purity 99.7%) within 15 min of reaction
time (Table 2, entry 19). This result encouraged us to brominate
the solid substrate (4-nitroaniline) under the same conditions.
We observed an immediate disappearance of reddish-brown
color in the flask and whole of the bromine get consumed
within 2–3 min of stirring indicating that an instant interaction
between the bromine and 4-nitroaniline has occurred in the
aqueous system. Yellow crystalline powder of 2,6-dibromo-4-
nitroaniline was obtained in 98% yield with an HPLC purity
of 99.03% (Table 2, entry 16). Encouraged by these results, we
have successfully carried out the bromination of industrially-
advantages of the present system over existing methods. In this
current study, we are presenting, for the first time, a simple
and direct bromination of phenol and aniline derivatives with
strong electron-withdrawing groups such as carboxylic, nitro
and formyl as examples of pharmaceutical intermediates under
purely aqueous conditions (Scheme 1).
important compounds using aq. CaBr
2
–Br solution under
2
aqueous conditions at room temperature using no organic
solvent before and after the completion of reaction (Table 2).
When bromination was carried out in water using aq. CaBr
Br system, it offers the following advantages: (1) absence of
organic solvent (MeCN) minimizes the solvent recovery step
2
–
2
Scheme 1 Bromination of substituted aromatics using aq. CaBr –Br2
system.
2
2
188 | Green Chem., 2011, 13, 2187–2196
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2 2
Table 1 A comparison of the results of present system (aq. CaBr –Br solution) with the literature precedents of some recently published brominating
systems in the synthesis of pharmaceutical intermediates
a
Entry Substrate
1
Product
aq CaBr
2
–Br
2
(present system)
Recently published brominating systems
Hexaminethylene tetramine–bromine/CH
◦
b
21a
93%, 15 min, 25 C (96.2%)
2
Cl
2
30%,
5
min, rt
◦
b
21b
2
3
93%, 20 min, 25 C (96.6%)
4
NBS/NH OAc/MeCN 89%, 1 h, rt
21c
◦
NBS/MeCN/hn 88%, 30 min, 32 C
21d
NBS/SO
3
H-functionalized silica 73%, 3 h, rt
◦
b
21e
96%, 15 min, 25 C (99.9%)
LiBr/CAN/MeCN 99%, 7 h, rt
21f
KBr/BTPPMS/MeCN 90%, 4 h, rt
21g
TEATB/H
2
O–DMF 65%, 1 h, rt
21h
◦
KBr/H
2
O
2
/CuPcF16-APSG/AcOH 87%, 2.2 h, 60 C
◦
b
b
21i
4
5
92%, 15 min, 25 C (99.2%)
NH
HBr/H
NBS/SO
4 2 2
Br/H O /AcOH 73%, 4 h, rt
2
21j
◦
2
O /MeOH 99%, 12 h, 0 C to rt
21d
3
H-functionalized silica 91%, 3 h, rt
◦
21i
94%, 15 min, 25 C (98.4%)
4 2 2
NH Br/H O /AcOH 95%, 2.5 h, rt
21g
TEATB/MeCN 46%, 1.5 h, rt
2
1k
EBMIDTB/CH
H O
2 2
2
Cl
2
50%, 4.5 h, rt
21l
–HBr/‘on water’ 75%, 24 h, rt
◦
b
21j
◦
6
7
98%, 20 min, 25 C (99.03%)
2 2
HBr/H O /MeOH 95%, 10 h, 0 C to rt
21l
H
2
O
2
–HBr/‘on water’ 95%, 28 h, rt
◦
b
21j
92%, 10 min, 25 C (96.23%)
HBr/H
KBr/H
2
2
O
O
2
2
/MeOH 93%, 15 h, rt
21m
/AcOH/zeolite 45%, 5 h, rt
KBr/BTPPMS/MeCN 92%, 2 h, rt
21f
21h
◦
2 2
KBr/H O /CuPcF16-APSG/AcOH 75%, 2 h, 60 C
21l
H
2
O
2
-HBr/‘on water’ 90%, 8 h, rt
◦
b
21j
8
9
97%, 25 min, 25 C (96.5%)
HBr/H
2
O
2
/MeOH 84%, 20 h, rt
◦
b
21j
◦
96%, 15 min, 25 C (99.7%)
HBr/H
2
O
2
/MeOH 96%, 8 h, 0 C to rt
21g
2
TEATB/H O–DMF 63%, 1.5 h, rt
21n
TBATB/50% aq. DMF 65%, 15 min, rt
◦
b
21l
1
1
0
1
94%, 30 min, 25 C (97.5%)
H
2
O
2
–HBr/‘on water’ 95%, 24 h, rt
◦
b
21o
96%, 15 min, 25 C (99.67%)
HBr/iso-amyl nitrite/CH
2
Cl
2
100%, 16 h, rt
a
b
Conditions: Substrate (10 mmol), mol. equiv. of substrate : CaBr
2
: Br
2
; 1 : 1 : 1 (mono-Br), 1 : 2 : 2 (di-Br) and 1 : 3 : 3 (tri-Br), water (10 mL). HPLC
purity
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2 2
Table 2 Bromination of various aromatic compounds using aq. CaBr –Br system
Solvent system
a
b
Water
Acetonitrile
c
c
◦
Entry Substrate
1
Product
Time/min Yield (%) Time/min Yield (%) Mp/ C (lit.)
Application
22a
20
15
20
15
20
92
94
96
93
93
20
—
10
15
30
91
—
94
97
95
226 (226–229
)
Bactericide when
incorporated into topical
ointments
28
2
2b
29
2
3
4
5
270–273 (271–274 ) Medical intermediate
2
2a
80–82 (80–84
183 (181–185
)
)
Pharmaceutically
acceptable salt as inhibitor
of stearoyl-CoA
desaturase useful for the
30
treatment of obesity
2
2b
Intermediate for the
production of medicines,
agricultural chemicals or as
31
flavors
2
2b
163-166 (164-166
) In pharmaceutical flavor,
32a
pesticide chemical and
organic synthetic
32b
industries
2
2a
2b
33
6
7
15
20
96
98
10
20
99
96
166 (165–169
200–202 (202
)
)
Analgesic, antipyretic
2
Pharmaceutical intermediate
A potent antifungal,
22b
8
15
96
15
95
200 (198–200
)
34
antiamoebic
2
2b
9
15
20
94
92
15
30
93
97
235 (235–237
114 (116–117
)
)
Pharmaceutical intermediate
22b
1
0
Anthelmintic or in
combination with
parasiticides and
35
antibacterials
2
2b
1
1
1
2
30
15
94
92
30
15
95
91
145 (145
)
Used in wood treatment
22b
108 (110–113
)
Fine organic and
custom intermediate
2
190 | Green Chem., 2011, 13, 2187–2196
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Table 2 (Contd.)
Solvent system
a
b
Water
Acetonitrile
c
c
◦
Entry Substrate
Product
Time/min Yield (%) Time/min
Yield (%) Mp/ C (lit.)
Application
2
2b
36
1
3
15
15
96
97
15
96
127-129 (129-133 ) Pharmaceutical intermediate
2
2b
1
4
15
96
100-102 (102–103 ) Precursor for substituted
thiazoles used as fungicides
37
2
2b
2b
1
1
5
6
15
20
94
98
15
10
95
98
102–104 (104
206 (206–208
)
)
Intermediate for dyestuffs
2
38
A potent antifungal, in the
preparation of diazonium
salts used in the synthesis of
oligomeric disperse dyes
2
2b
39
1
1
7
8
10
25
92
97
5
97
98
83–84 (84
)
Antibacterial, antifungal
and anthelmintic (for
hookworm infection)
22b
39
30
103–104 (105–107 ) Antibacterial, antifungal
22a
1
9
15
96
5
97
120 (120–121
)
Intermediate for
agrochemicals,
pharmaceuticals, and
fire-extinguishing agents
a
b
◦
Conditions: Substrate (10 mmol), mol. equiv. of substrate : CaBr
Conditions: Substrate (10 mmol), mol. equiv. of substrate : CaBr
5 mL), 25 C. Yield of isolated pure product
2
: Br
2
; 1 : 1 : 1 (mono-Br), 1 : 2 : 2 (di-Br) and 1 : 3 : 3 (tri-Br), water (10 mL), 25 C.
2
: Br ; 1 : 1 : 1 (mono-Br), 1 : 2 : 2 (di-Br) and 1 : 3 : 3 (tri-Br), MeCN (10 mL), water
2
◦
c
(
Results and discussion
Screening of reaction conditions
dependent on the mole ratio of Br
2
/4-NA. It has been found
that the optimum yield (98%) of DBNA and the desired
◦
22b
◦
melting point of 206 C (lit., 206–208 C) are obtained at
the mole ratio of Br /4-NA = 2/1 in the bromination of 4-
NA using aq. CaBr –Br solution as brominating agent. The
yield of the product becomes stagnant if we further increase
The dibromination of para-substituted substrate reduces the
possible complex mixture of mono- and dibrominated species,
thus in order to simplify the analytics, 4-nitroaniline 16 (4-NA)
was used as a typical substrate in a first-screening for suitable
reaction conditions. To optimize the yields and purity, effects
2
2
2
the mole ratio from Br
2
/4-NA = 2.0 to 2.2. The yield of the
◦
product drops to 93% with a melting point 198–200 C (not
within the required standards) if we decrease the mole ratio
of the concentration of Br
2
and CaBr on the yield and melting
2
point of 2,6-dibromo-4-nitroaniline (DBNA) were examined in
the dibromination of 4-NA.
of Br
2
/4-NA from 2.0 to 1.8. An under-brominated product
◦
(yield: 88%) is obtained which melts from 160–170 C when
we further decrease the mole ratio from 1.8 to 1.65. It is
Effect of mole ratio of Br
DBNA. Fig. 1 describes that quality of the product is strongly
2
on yield and melting point of
noted that at mole ratio of Br
brominated 4-nitroanilines were obtained that melt at 102 C
2
/4-NA = 1.5 and 1.25, mono-
◦
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nating reagent (aq. CaBr
2
–Br
2
solution) over a recently reported
15a
brominating system (NBS/[Bmim]Br or dioxane) that phenol
and aniline derivatives with strong electron-withdrawing groups
such as carboxylic, nitro and formyl were instantly brominated
regioselectively in excellent yields and purity. The same reported
15a
system, however, yields a complex mixture of mono- and di-
bromo products. In the present system, salicylic acid 1 and
4-hydroxybenzoic acid 2 were transformed with quantitative
conversion resulting in clean synthesis of 3,5-dibromosalicylic
acid (92% yield; 96.2% HPLC purity) and 3,5-dibromo-4-
hydroxybenzoic acid (94% yield; 99.2% HPLC purity) after
2
0 min and 15 min, respectively. Pharmaceutically-important
aromatic aldehydes (Table 2, entries 3,4,5) were also instanta-
neously synthesized using aq. CaBr –Br system in excellent
yields. Under these conditions, acetanilide 6 and benzanilide
were regioselectively transformed to their mono-brominated
Fig. 1 Effect of mole ratio of Br
melting point of 2,6-dibromo-4-nitroaniline in the bromination of
2
/4-nitroaniline on the yield and
4
(
-nitroaniline using aq. CaBr
10 mmol), CaBr
2
–Br
2
solution. Conditions: Substrate
2
2
◦
2
(20 mmol), water (10 mL) at 25 C for 20 min.
7
◦
and 100–101 C, respectively (mp of 2-bromo-4-nitroaniline is
products in very good yields. The regioselectivity observed in
these reactions matches to that expected for an electrophilic
bromination pathway modulated by steric effects. We found that
oxine 8 and sulfanilamide 9 could also be effectively brominated
affording pharmaceutically-important 5,7-dibromooxine (96%
yield; 99.67% HPLC purity) and 3,5-dibromosulfanilamide
◦
22b
1
04 C ).
Effect of mole ratio of CaBr on yield and melting point of
2
DBNA. Fig. 2 illustrates an identical pattern in the increase of
mole ratio of CaBr /4-NA from 0.25 to 2.0 in the bromination
of 4-NA using aq. CaBr –Br solution as brominating agent;
the optimal yield and desired melting point are obtained at
mole ratio of CaBr /4-NA = 2/1. The melting point does not
change considerably but the yield of the product increases from
1 to 98% when we increase the mole ratio of CaBr /4-NA
was justified by conducting
as the
2
2
2
(94% yield; 96.6% HPLC purity) within 15 min. Another
anthelmintic or antibacterial, 2,4-dibromo-6-nitrophenol was
isolated in good yield within 20 min from 2-nitrophenol
2
(
Table 2, entry 10). The less reactive 4-nitrophenol 11 shows
9
2
excellent reactivity resulting 2,6-dibromo-4-nitrophenol (94%
yield; 97.5% HPLC purity) within 30 min using 2 equivalent
of reagent. Bromination of the same substrate with H
HBr/‘on water’ gave 2,6-dibromo-4-nitrophenol over a period
of 24 h. The strong feature of the present method is an efficient,
facile, rapid and regioselective bromination of deactivated
anilines (Table 2, entries 12 to 16) in excellent yields at room
from 0.25 to 2.0. The role of CaBr
2
◦
a blank reaction for 1 h at 25 C using molecular Br
2
2
O -
only brominating agent which resulted in a complex mixture of
under-brominated species that melts from 160 to 190 C. Thus,
the results obtained from Fig. 1 and Fig. 2 concluded that the
optimum mole ratio of 4-NA to CaBr
2
21l
◦
2
to Br (i.e., 1 : 2 : 2) was
2
found to be ideal for the dibromination of 4-NA.
temperature upon simple admixing with aq. CaBr
which is somewhat difficult by other methodologies.
2
–Br
2
2
solution
1d,21g,21i–21l
1
-Bromo-2-naphthol 17 (92% yield; 96.2% HPLC purity) was
instantaneously obtained under identical reaction conditions in
good yield within 10 min, while for 1,6-dibromo-2-naphthol
18 (97% yield; 96.5% HPLC purity), 25 min of reaction time
and 2 equivalents of aq. CaBr –Br solution were essential.
2
2
This indicates that the position of the electrophilic attack as
well as the number of entering bromine atoms can be regulated
by controlling the ratio of substrate: aq. CaBr
2
–Br solution,
2
i.e., 1 : 1 for mono-, 1 : 2 for di-, and 1 : 3 for tribromination
of aromatic compounds. Under these reaction conditions, the
deactivated substrates like nitrobenzene and benzoic acid did
not show any conversion at all. Table 2 reveals that the reaction
time and yields of brominated products are comparable in water
and acetonitrile as solvents, respectively. The only limitation
associated with the reaction using water as a solvent is that
granular and scaly substrates have to be pulverized and ground
prior to reactions to convert them into fine powders. Since the
reaction operates completely in water and generates absolute
zero effluent; it seems valuable to extend this system for the
bromination of other compounds of industrial use.
Fig. 2 Effect of mole ratio of CaBr
and melting point of 2,6-dibromo-4-nitroaniline in the bromination
2
/4-nitroaniline on the yield
of 4-nitroaniline using aq. CaBr
10 mmol), Br
2
–Br
2
solution. Conditions: Substrate
◦
(
2
(20 mmol), water (10 mL) at 25 C for 20 min.
Stirring. As the reaction was instantaneous, an efficient stir-
ring (725 rpm or higher) was needed for mixing the hydrophobic
aromatic substrate with the aqueous inorganic medium and for
preventing local high concentrations of the active bromo species.
The general applicability of this method was established
when bromination of structurally-diverse activated aromatic
compounds substituted with electron-withdrawing groups were
assayed (Table 2). It is the advancement of the present bromi-
Next, a desirable “green” approach to the present method
is followed by an environmentally-friendly recycling procedure.
The absence of organic waste and organic solvent in the reaction
enabled simple isolation procedure comprised of filtration
2
192 | Green Chem., 2011, 13, 2187–2196
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of solid brominated product and the addition of powdered
Ca(OH) to the filtrate for the neutralization of HBr waste so
that the bromine atom of HBr thus fixed as CaBr
This process generates additional amount of CaBr
Table 4 Maximum absorbance wavelengths in reaction media for
different possible brominating species of interest
2
2
(Scheme 2).
in the filtrate
Species
lmax. (nm)
Ref.
2
[
eqn (1) and 2].
Br
Br
Br
2
3
5
390
265
315
284, 350
329
24a
24a
25
40
41
-
-
Substrate(s/l) + aq. CaBr
2
–Br2(sol.) → Br–substrate + HBr +
(
2
1)
CaBr
HOBr
BrO-
Acetanilide
p-Bromoacetanilide
240
252
42
42
2
HBr + Ca(OH)
The aqueous filtrate was reused in the next cycle. The
molecular Br was added to the filtrate containing recycled
CaBr , and the regenerated brominating agent was then used
2
→ CaBr
2
+ 2H
2
O
(2)
effectively, and at the end of reaction, we discharge zero oranic
waste and zero effluent to the environment.
2
2
to brominate the substrate subsequently in the next run. In
this way, the dibromination of 4-nitroaniline has been carried
out successfully for 4 cycles after the fresh batch using 4-NA:
+
Br transfer mechanism
As far the mechanism of bromination using bromine is con-
cerned, possible brominating species that can be formed in aq.
bromine solutions are HOBr, BrO , Br
Table 4 gives the UV-VIS spectral characteristics for various
brominating species of interest. The UV-VIS studies were carried
23
Br (1 : 2) mole ratio in each run without addition of the fresh
2
-
-
-
CaBr
2
to afford 2,6-dibromo-4-nitroaniline within 20 min at
3
and Br
5
respectively.
◦
25 C. Recycling experiments (Table 3) show that for at least
4
cycles followed by the fresh batch, there is no significant
loss of reactivity of the regenerated brominating reagent. When
the concentration of CaBr increases in the filtrate, the filtrate
was concentrated by evaporation which causes the CaBr to
precipitate as a crystalline solid, and an additional amount (7
mol) of CaBr was recovered after fresh batch + 4 cycles: 1 mol of
CaBr generated additionally in each cycle by the neutralization
of HBr using Ca(OH) . Thus, starting with 2 mol of CaBr wrt
mol of 4-NA in the fresh batch, we have regenerated 7 mol
out to find out the role of CaBr
2
in the faster polarization of Br
solution was prepared by mixing
and Br , and was standardized
2
2
molecule. Aqueous CaBr
–Br
2
2
2
equimolar amounts of CaBr
2
2
spectrophotometrically that gives an intense band of tribromide
-
24a–c
2
ion (Br ) at 266 nm. In agreement with many literature data,
3
2
the appearance of the band at 266 nm can be readily attributed
to the formation of a charge-transfer complex, CTC, between
2
2
1
bromine and CaBr
band is due to tribromide ion, Br
region and which could arise as shown via the formation of a
: 1 CaBr –Br complex, [eqn (3)].
2
(Scheme 3). It is likely that the 266 nm
-
24a
of CaBr in the end. Thus, the byproduct HBr has been utilized
2
3
which absorbs in the same
1
2
2
+
-
+
-
CaBr ·Br + Br
2
↔ CaBr ·Br
3
(3)
When equimolar amounts of Br
2
and CaBr
2
were employed,
the formation of tribromide is substantial and no formation of
-
pentabromide ion (Br
Br
also confirmed by UV-VIS spectrum of aq. bromine solution
5
) was detected at such concentrations of
25
2
as it required a higher amount of Br in solution. This was
2
(
Br
with added bromide) that does not show any absorption of
-
25
5
ion (lmax. = 315 nm ). In order to study the UV-VIS, the
solution of acetanilide in MeCN was added to aq. CaBr
2
–Br
2
solution and a UV-VIS spectrum was recorded. There was an
instant disappearance of band at 266 nm which reveals that
the Br molecule has been polarized and dissociated in the
2
+
presence of added metal bromide and the generated Br has
been transferred to the acetanilide. This was confirmed by the
appearance of a peak (lmax. = 252 nm), which corresponds
Scheme 2 Complete bromination cycle showing regeneration and
reusability of CaBr
2
.
a
Table 3 Recycling experiments for the dibromination of 4-nitroaniline
b
◦
22b
◦
c
Recycle
Appearance
Yield (%)
Mp/ C (lit., 206–208 C)
Purity (%)
Fresh batch
Recycle 1
Recycle 2
Recycle 3
Recycle 4
Yellow powder
Yellow powder
Yellow powder
Yellow powder
Yellow powder
98.0
97.8
97.6
97.3
97.5
206
206
204–206
205–206
205–206
99.03
99.00
98.67
98.89
98.86
a
Conditions: 10 mmol 4-NA, 20 mmol Br
C for 20 min (each cycle). Isolated yields. Purity determined by HPLC
2
(4-NA and Br
2
2
moles charged in each cycle) and 20 mmol CaBr (charged only in the fresh batch) at 25
◦
b
c
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Green Chem., 2011, 13, 2187–2196 | 2193

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+
activated ring. This results in the transfer of Br to the substrate
+
-
d+
d-
from a tribromide ion-pair intermediate Ca[Br Br (Br –Br )]
+
and ring-bromination by a Br -transfer mechanism occurs.
Conclusions
We have reported a quick, mild and facile method for the
efficient and selective synthesis of pharmaceutically-important
brominated intermediates using aq. CaBr
2
–Br system as an
2
instant brominating agent under aqueous conditions. The green
features of this protocol include no use of organic solvent and
an effective utilization of HBr byproduct which lead to zero
organic waste and zero effluent discharge to the environment,
thus applicable for large scale bromination.
Scheme
3 Bromonium ion mechanism involving bromonium-
tribromide ion pair intermediate.
-
to p-bromoacetanilide (Fig. 3). This shows that Br
3
is the
Experimental
active brominating species in the reaction that generates the
electrophile Br and ruled out the formation of HOBr and BrO
+
-
Reagents and analytics
species as no characteristic absorption bands of these species
were observed before and after the reaction. Such species are
rather formed under the conditions of oxidative bromination
Reagents and starting material were purchased from Acros,
Aldrich and Merck and were used as received. Granular and
scaly substrates were ground and converted into fine powder
prior to reactions. Doubly distilled water was used all through
the study. HPLC analyses were conducted using Waters 2695
instrument with PDA detector, column C18 (250 mm ¥ 4.6 mm ¥
21h,m
described elsewhere.
Fig. 3 discloses that the bathochromic
shift operates in which the absorption maxima at 240 nm (lmax.
of acetanilide) was shifted towards longer wavelength at 252
nm (lmax. of p-bromoacetanilide), owing to the consumption
-
5 m), solvent system of 70% CH
3
OH + 30% H
1 mL min . HPLC purity is reported by area%. H NMR spectra
were recorded at 400 MHz in DMSO and CDCl solutions on
2
O, and flow rate of
of substrate and Br
3
ions. The water being polar solvent also
-
1
1
26
increases the rate of bromination by solvolysis, in which charge
separation in the bromine molecule by solvation is facilitated
due to the specific electrophilic solvation of the leaving bromide
anion by hydrogen bonding.
3
a Bruker Avance II 400 NMR spectrometer and are reported
in ppm using tetramethylsilane (TMS) as an internal standard.
Mass spectra were recorded on Micromass Quattro Micro API
triple quadrupole MS equipped with a standard APCI ion
source. IR spectra were recorded on a Shimadzu Prestize 21 FT-
-
1
IR Spectrometer (KBr, 3500–440 cm ). The UV spectra were
recorded on a Chemito Spectrascan UV-2600 double beam UV-
visible spectrophotometer in the wavelength range of 200–400
nm. Isolated compounds were identified on the basis of physical
1
determination and spectroscopic data ( H NMR, IR and MS)
while in case of known compounds comparison with literature
data was made; yields were calculated by the weight.
Typical procedure for the synthesis of 2,6-dibromo-4-nitroaniline
(16)
Fig. 3 UV study showing disappearance of acetanilide peak and
formation of p-bromoacetanilide using aq. CaBr
brominating agent at 25 C.
2
–Br
2
solution as a
To a solution of CaBr (3.99 g, 20 mmol) in water (10 mL)
2
◦
was added bromine (3.2 g, 20 mmol) and the resulting mixture
◦
was stirred at 25 C to form a dark reddish-brown clear
27
Bellucci et al. have proposed a mechanism for the addition
of Br to olefins using tetrabutylammonium tribromide as a
solution. This solution was added rapidly to a fine powder of
4-nitroaniline (1.3813 g, 10 mmol) taken in a 100 mL round-
bottom flask equipped with a magnetic stirring bar utilizing a
pressure-equalizing funnel within 2 to 3 min. The bromine color
disappeared immediately and yellowish thick precipitates of 2,6-
dibromo-4-nitroaniline were obtained within 20 min (monitored
2
brominating agent. This mechanism explains the catalytic effect
of added bromide salts by the fact that they are involved in the
rate-determining step. Looking into the UV-visible results of the
present study and also considering the scheme of Bellucci et al.,
◦
it can be proposed that the binding of CaBr
2
to Br
2
molecule
by TLC) at 25 C. The precipitated mass was separated by
involves the cleavage of a bromine-bromine bond to give a
bromonium-tribromide ion pair intermediate (Scheme 3). In this
vacuum filtration utilizing a Buchner funnel, and then washed
with Na
2
S
2
O solution (10%, 10 mL ¥ 3) and dried in oven at
5
◦
reaction, the added CaBr
2
acts as a catalyst that instantaneously
100 C. The filtrate was saved for the next run. The product was
obtained as yellow powder (2.9001 g, 98% yield, and 99.03%
HPLC area purity). mp: 206 C (lit., 206–208 C). H NMR
(DMSO, 400 MHz): d 8.21 (s, 2H, ArH), 6.79 (s, 1H, NH ). IR
polarized the Br molecule and generates bromonium ion.
2
◦
22b
◦
1
Scheme 3 shows a transition state suggested for the reaction in
+
which the electrophile Br attacks the electron-rich p-system of
2
2
194 | Green Chem., 2011, 13, 2187–2196
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(
1
KBr): n 3480, 3372, 3084, 2922, 2666, 2363, 1605, 1501, 1474,
383, 1300, 1270, 1126, 943, 897, 821, 737, 695, 575, 532, 457
1595, 1452, 1425, 1385, 1300, 1229, 1180, 1130, 876, 789, 714,
-
1
681, 658, 600, 552, 471 cm ; MS (APCI): calcd for C
294.8434, found 294.
7
H
4
Br
2
3
O :
-
1
cm . MS (APCI): calcd for C
6
H
4
Br
2
N
2
O
2
: 295.9; found 295.2.
Procedure for recycling of HBr as CaBr
brominating reagent (recycle 1)
2
and regeneration of
4-Bromoacetanilide (6)
1
White crystals, H NMR (DMSO, 400 MHz): d 2.1 (s, 3H), 7.25
(d, J = 8.4 Hz, 2H), 7.52 (d, J = 8.8 Hz, 2H), 9.73 (s, 1H). IR
(KBr): n 3293, 3260, 3186, 3115, 3052, 1668, 1644, 1601, 1586,
1532, 1487, 1394, 1309, 1290, 1255, 1007, 831, 819, 740, 687, 504
The filtrate originating from the above reaction was neutralized
by adding Ca(OH) (0.7409 g, 10 mmol) to convert HBr into
CaBr . Subsequently, bromine (3.2 g, 20 mmol) was added to the
aqueous solution containing recycled CaBr to regenerate the
brominating reagent. The regenerated aq. CaBr –Br solution
2
2
-
1
2
cm . MS (APCI): calcd for C H BrNO: 216.07, found 216.
8
8
2
2
was then added rapidly within 5 min to a fine powder of 4-
nitroaniline (1.3813 g, 10 mmol) taken in a 100 mL round-
bottom flask equipped with a magnetic stirring bar utilizing
a pressure-equalizing funnel. Immediately after addition, the
bromine color disappeared and yellowish thick precipitates
of 2,6-dibromo-4-nitroaniline were obtained within 20 min of
5,7-Dibromo-8-hydroxyquinoline (8)
1
Light beige powder; H NMR (CDCl
3
, 400 MHz): d 7.437 (d,
J = 0.514 Hz, 1H), 8.422 (ddd, J = 8.783, J = 1.826, J = 0.514
Hz, 1H), 7.223 (dd, J = 8.783, J = 4.678 Hz, 1H), 8.823 (dd, J =
4.678, J = 1.826 Hz, 1H). IR (KBr): n 3071, 1738, 1583, 1491,
◦
1459, 1389, 1333, 1273, 1202, 1138, 1045, 934, 868, 808, 787,
reaction time at 25 C. The product was separated from the
-
1
725, 686, 652, 617, 594, 563, 500 cm . MS (APCI): calcd. for
mother liquor by vacuum filtration and then washed with
◦
C
9
H
5
2
Br NO: 302.95, found 302.2.
Na
2
S
2
O
5
solution (10%, 10 mL ¥ 3) and dried in oven at 100 C.
Yellow powder of 2,6-dibromo-4-nitroaniline was obtained in
◦
2,4,6-Tribromoaniline (19)
2
.894 g (97.8%) yield with mp 206 C and purity 99%. The
characteristic data recorded for the isolated product were found
to be same as given in the above typical procedure. The HBr
evolved was again neutralized and the aqueous solution was
successively reused in the next run with an additional amount
1
Shining-white fine needles; H NMR (CDCl , 400 MHz) d: 7.5
3
(
1
s, 2H, Ar), 4.54 (br. s, 2H, NH
383, 1285, 1225, 1063, 858, 729, 706, 673, 546, 486 cm . MS
2
). IR (KBr): n 3414, 3293, 1452,
-1
(
APCI): calcd. for C
6
H
4
Br N: 329.816; found 328.8.
3
of Br .
2
Acknowledgements
Procedure for recycle 2, 3 and 4
The authors gratefully acknowledge Dept. of Industrial Chem-
istry, Jiwaji University, Gwalior for providing University Re-
search Fellowship. We are also thankful to Kapil Kumar, SRF
Ltd. and Director, Sophisticated Analytical Instrumentation
Facility, Punjab University, Chandigarh in carrying out the LC-
MS and NMR analyses of the compounds.
Similar to the above procedure of recycle 1, bromine (3.2 g,
2
0 mmol) was added to the aqueous solution containing
recycled CaBr obtained after the separation of 2,6-dibromo-
-nitroaniline and the reaction progressed in a like manner with
-nitroaniline (1.3813 g, 10 mmol) in each cycle.
2
4
4
Experimental procedure for UV-visible measurements
◦
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–Br
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