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Sharma / Chemistry International 1(1) (2015) 60-70
60
Article type:
Research article
Article history:
Received 13 October 2014
Accepted 27 December 2014
Published 05 January 2015
January 2015 Issue
Keywords:
Halogenation
Oxidative bromination
Molecular bromine
Aqueous medium
Green chemistry
A fast, efficient, simple, eco-friendly, regioselective, controllable and economical
method for the bromination of aromatic compounds using AlBr3-Br2 system was
invetigated. The direct bromination of anilines and phenols with molecular bromine in
solution frequently results in polybromination, and when brominated in the existence
of oxidants, they also get oxidized rather than experiencing substitutions and in some
cases, require fortification of the amino (-NH2) group.
nitroaniline, and 0.06 per cent starting material (Table 3, entry
4).
The bromination of acetanilide (1a) and benzanilide
(1b), under these conditions, took place selectively and only p-
brominated products with no detectable o-bromo or
dibromocompounds were inaccessible in excellent yields.
Aniline 1e and phenol 1d were tribrominated to their consistent
bromo-derivations in outstanding yields (97 per cent with
1:3:3 molar ratio of substrate:AlBr3:Br2). In case if both
meta- and o.p-directing functional groups are present on the
hetrocyclic aromatic ring, only the o.p-directing group will
directs the incoming bromination ion as perceived in case of o-
nitrophenol 1e. Anilines comprising an electron-withdrawing
group can also brominate using brominating system at ambient
temperature. An aquous solution of AlBr3/Br2 can be
effectively used for the bromination of several deactivated
anilines 1g-11 proficiently and promptly upon admixing these
with it, which is somewhat tedious by other methodologies
(Das et al., 2007). It was observed that oxine (1m) and
sulphanilamide (1n) could also be successfully brominated
using 5,7-dibromo-oxine and 3,5-dibromosulphanilamide of
pharmaceutically importance, in yield of 95 and 93 per cent,
correspondingly, within 15 minutes of the reactions time.
I t w a s a l s o f o u n d t h a t s ubstrates 1p and 1q
showed good reactivity that results in a clean synthesis of 2,4-
dibromo-1-naphthol (97 per cent) and 3,5-dibromosalicylic acid
(91per cent) after 15 and 20 minutes, respectively. Similarly,
the aldehydes (1o and 1r) were also efficiently brominated in
outstanding yield (97 and 94 per cent) with the use of 2
counterparts of aquous AlBr3-Br2 solution. Bromination of β-
Sharma / Chemistry International 1(1) (2015) 60-70
66
Table 2: Bromination of various aromatic compounds using aqueous AlBr3-Br2 systema
Entry Substrate Product Time
(Min)
Yieldb
(%)
Mp
(°C (lit.))
Applications
1a NHCOPh
NHCOPhBr
18 97 (202)
200-202
Pharmaceutical intermediate
1b
OH
OH
Br
Br
Br
12 96 (92)
92-94
Reactive flame retardant
1c OH
NO 2
OH
NO2
Br
Br
25 97 114 (116-
117)
Anthelmintic or in combination with
parasiticides and antibacterials
1d
NH2
NO 2
NH2
NO 2
Br
15 90 108 (110-
113)
Fine organic and custom intermediate
1e NH2
NO 2
NH2
NO 2
Br
Br
16 95 127-129 (129-
133)
Pharmaceutical intermediate
1f NH2
O2N
NH2
O2N
Br
25 91 126-130 (128-
132)
Organic intermediate
1g NH2O2N
NH2O2N
Br
17 94 102-104 (104) Intermediate for dyestuff
1h
NH2O2N
NH2O2N
Br
Br
12 99 206 (206-
208)
A potent antifungal in the preparation
of diazonium salts used in the
synthesis of oligomeric disperse dyes
1i SO2NH2NH2
SO2NH2NH2
Br
Br
15 94 235 (235-
237)
Pharmaceutical intermediate
Sharma / Chemistry International 1(1) (2015) 60-70
67
Naphthol (1s) under identical reactions resulted in
excellent yield (97 percent) within 5 minutes, while for 1t,
two equivalents of aqueous AlBr3-Br2 and 30 minutes of
reaction time were essentially required. Similarly 5-
bromovanillin 1u, an industrially-important compound, was
also obtained from vanillin in good yield within 30 minutes.
This substrate undergoes bromination f o r a longer p e r i o d
o f time and resulted in low yields (Deshmukh et al., 1998).
The selective contact herbicide bromoxynil 1v was also
achieved in 98 per cent yield in 15 minutes of reaction time.
Table 3 shows the High Performance Liquid
Chromatography (HPLC) purity of few representatives
brominated products that determined that the high yields of
mono-, di-, and tribrominated products can be regioselectively
achieved by simply incresesing the molar equivalents of
substrate/AlBr3/Br2, in the ratio of 1/3/3 for mono-, 1/2/2 for
di- and 1/3/3 for tribromination of aromatic compounds. By
implementing an eco-friendly workup procedure, further we
have modified our green approach to bromination. The reaction
supported a simple isolation procedure composed of filtration
of solid brominated products due to absence of organic waste
and chlorinated organic solvent. This process generates an
added amount of Aluminium tribromide in the filtrate. The
solvent obtained in filtrate was distilled-off and reclaimed in
the next run of process. From the filtrate the solvent was
distilled out and can be used in the subsequent brominations. In
this way, 7 mol of AlBr3 was isolated in the end after four runs,
starting with 2 mol of Aluminium tribromide wrt 1 mol of 4-NA
in the fresh batch. By this the problem of conventional
methods associated with discharge of Hydrogen bromide
byproducts waste was successfully elliminated which otherwise
is very toxic, corrosive, and cause great pollution in the
environment. As far the mechanism of bromintion using
bromine is concerned, probable brominating classes which can
be made in aq. bromine solutions are HOBr, BrO-, Br3
-
correspondingly. The UV-vis spectral characteristics are
reported in Table 2 for numerous brominating species. The UV-
vis studies were carried out to identify the dynamic brominating
species. Equimolar solution of 1 molar equivalent aluminium
tribromide and 1 molar equivalent Br2 was prepared. The UV-
vis spectrum for this was recorded that gives a powerful
band at 266 nm wavelength. In agreement with available
studies, the band that appears at 266 nm wavelength can be
attributed due to the formation of a charge-transfer complex
between Br2 and aluminium tribromide. It is possible that
266 nm wavelength band was mainly due to tribromide ion
(Br3) that absorbs in the same region and which could arise as
depicted thruough the formation of a 1/1 AlBr3-Br2 complex.
Water that is used for the preparation of aqueous AlBr3-Br2 solution also support the formation of tribromide through the
well-defined H2O-Br2 reaction discharging bromide ion and as
found in UV- vis study. When equimolar amounts of Br2 and
AlBr3 were employed, the formation of tribromide is
considerable and no formation of pentabromide ion (Br5-) was
discovered such concentrations of Br2 as it required a higher
Table 2: Continuous….
1j CHOOH
CHOOH
Br
Br
17 98 183 (181-
185)
Pharmaceutical Intermediate
1k COOH
OH
COOH
OH
Br
Br
22 92 225 (224-
227)
Bactericide when incorporated in to
topical ointments
1l CHO
OH
CHO
OH
Br
Br
14 95 80 (80-84) Pharmaceutically acceptable salt as
inhibitor of stearoyl-CoA desaturase
useful for the treatment of obesity
1m
CHO
H3CO
OH
CHO
H3CO
OH
Br
25 96 166 (164-
166)
In pharmaceutical flavor pesticide
chemical and organic synthetic
industries
a Confirmed by comparative study of some authentic samples. All the reactions were carried out on 10 millimole scale; molar equivalents of substrate:
AlBr3:Br2 =1/1/1 (monobromination), 1/2/2 (dibromination-) and 1/3/3 (tribromination); Acetinitrile 10 mL; water 5 mL; room remperature and b Yield of final products
Sharma / Chemistry International 1(1) (2015) 60-70
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Table 3: The selectivity of Product from starting material in the bromination of various aromatic compounds
using aqueous AlBr3-Br2 system
Entry
Substrate
Substrate
AlBr3:Br2
Product Yielda
(%)
Product Purityb (%)
Main
product
Others
1.
SO2NHNH2
1:2:2
SO2NHNH2
Br
Br
94 97.93 2.07
2.
COOH
OH
1:2:2
COOH
OH
Br
Br
90 96.80 3.20
3.
CHO
OH
1:2:2
CHO
OH
Br
Br
95 95.85 4.15
4.
NH2O2N
1:2:2
NH2O2N
Br
Br
97 99.00 1.00
5.
NH2O2N
1:1:1 NH2O2N
Br
95 98.20 1.80
6.
NH2
No2
1:2:2
NH2
No2
Br
Br
96 93.20 6.80
7.
NH2
No2
1:1:1 NH2
No2
Br
91 98.90 1.10
8.
OH
1:3:3
OHBr
Br
Br
98 99.10 0.90
a Isolated Product Yields and b Purity of end products by High Performance Liquid Chromatograph (HPLC)
Sharma / Chemistry International 1(1) (2015) 60-70
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amount of Br2 as it required a higher amount of Br2 in
solution. This was also confirmed by UV-vis spectrum of
aqueous bromine solution (with added bromide) that does not
show any absorption of Br5-
ion (λmax = 315 nm). The
acetanilide solution wa s dissolved in Acetonitrile (ACN)
then added to aqueous AlBr3-Br2 solution and UV-vis spectrum
was documented. The prompt desertion of Br3-
peak shows that
bromine molecule (Br2) has been polarized and dissociated in
presence of added metal bromide and the produced
Brominium ion (Br+)
has been relocated to the acetanilide.
This was confirmed by the presence of a peak (λmax = 252
nm), which resembles to p-bromoacetanilide. This shows that
Br3-
is the active brominating class involved in the reaction that
generates the eletrophile Br+ and ruled out the formation of
HOBr and BrO- species as no characteristics absorption bands
of these species were witnessed before and after the reaction.
Such species are somewhat formed under the condition of
oxidative bromination defined elsewhere. Bellucci et al. have
suggested a mechanism for the addition of Br2 to olefins using
tetrabutylammonium tribromide as a brominating agent. This
mechanism clarifies the catalytic effect of added bromide salts
by the fact that they are involved in the rate-datermining step.
Considering the UV-vis results of the present study and
also considering the result pattern of Bellucci et al., it can be
projected that the binding of AlBr3 to Br2 molecule involves
the breakage of a Br-Br bond to give a bromonium-
tribromide (Br3-) intermediate ion pair. In this reaction, the
added AlBr3 acts as a catalyst that instantaneously polarized the
Br2 molecule and produces bromonium ion (Br3-). A transition
state reflects brominium ion mechanism which shows the
nucleophilic attack at the bromine by the electron-rich Π-
system of activated ring was suggested. This reports a
relocation of Brominium ion (Br+)
to the substrate from a
tribromide ion-pair intermediate Al[Br+Br
-(Br
δ+---Br
δ-)] and
ring-bromination occurs by brominium ion, Br+-relocation
mechanism. The ―salting out effect of ions over bromine (Br2),
effects in the establishment of ion-dipole complex increases the
activity-factor of Br2 in solutions of metal halides. At the end,
transition state breakup to give brominated end product and
hydrogen bromide (HBr) as reaction byproduct.
CONCLUSIONS
A new, cost effective, efficient, and simple bromination
protocol is determined and disclosed for mono-, di-, and
tribromination. The features of this –green process includes the
use of cost efficient aqueous AlBr3-Br2 solution as a effective
brominating agent which can be invigorated simply even at
commercial level applications. This method is free from strong
acids, organic solvent and HBr- byproducts waste during the
reactions, which are very common in old and existing protocol,
which makes this protocol eco-friendly because of zero effluent
discharge to the environment, consequently, a good choice to
existing bromination methods.
The categorization data (1H NMR, Infrared and Mass
Spectroscopy) achieved for various representative compounds
are given below:
2,6-Dibromo-4-nitophenol (1f): Off white powder; 1H-NMR