Novel bromination method for anilines and anisoles using NH 4Br/H2O2 in CH3COOH

Article abstract of DOI:10.1081/SCC-120038491

A simple, efficient, regioselective, environmentally safe, and economical method for the oxybromination of anilines and anisoles without catalyst is reported. The electrophilic substitution of bromine generated in situ from ammonium bromide as a bromine source and hydrogen peroxide as an oxidant for the first time.

Full text of DOI:10.1081/SCC-120038491

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Novel Bromination Method for Anilines and Anisoles
Using NH4Br/H2O2 in CH3COOH
K. V. V. Krishna Mohan a , N. Narender a , P. Srinivasu a , S. J. Kulkarni a & K. V. Raghavan
a
a Catalysis Group, Indian Institute of Chemical Technology, Hyderabad, 500 007, India
Published online: 17 Aug 2006.
To cite this article: K. V. V. Krishna Mohan , N. Narender , P. Srinivasu , S. J. Kulkarni & K. V. Raghavan (2004): Novel
Bromination Method for Anilines and Anisoles Using NH4Br/H2O2 in CH3COOH, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 34:12, 2143-2152
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 12, pp. 2143–2152, 2004
Novel Bromination Method for Anilines
and Anisoles Using NH4Br/H2O2
in CH3COOH#
K. V. V. Krishna Mohan, N. Narender, P. Srinivasu,
*
S. J. Kulkarni, and K. V. Raghavan
Catalysis Group, Indian Institute of Chemical Technology,
Hyderabad, India
ABSTRACT
A simple, efficient, regioselective, environmentally safe, and economical
method for the oxybromination of anilines and anisoles without catalyst is
reported. The electrophilic substitution of bromine generated in situ from
ammonium bromide as a bromine source and hydrogen peroxide as an
oxidant for the first time.
Key Words: Bromination; Anilines; Anisoles; NH4Br; H2O2.
#IICT Communication No. 01/X/07.
*
Correspondence: S. J. Kulkarni, Catalysis Group, Indian Institute of Chemical
Technology, Hyderabad 500 007, India; Fax: þ91-40-7160387/7160757; E-mail:
sjkulkarni@iict.ap.nic.in.
2143
DOI: 10.1081/SCC-120038491
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

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INTRODUCTION
Halogenated aromatic compounds are a useful class of intermediates as
they are precursors to a number of organo metallic species useful in the
synthesis of natural products and pharmaceutically important compounds.
The manufacture of a range of bulk and fine chemicals, including flame
retardants, disinfectants, and antibacterial and antiviral drugs, involve
bromination.[1] Consequently, a variety of methods for the bromination of
aromatics have been reported in the literature.[1–10]
Traditional methods of aromatic bromination involve the use of
non-selective hazardous acidic reagents, such as mineral acids and metal
halides that can lead to separation difficulties and unacceptable levels of toxic
and corrosive waste. The classical direct bromination of aromatic systems
suffers from being wasteful in the bromine employed. One-half ends up as
hydrogen bromide. In large-scale operations this is an environmental as well as
an economical problem. In oxybromination,[11–14] HBr is being used as a
bromine source and H2O2/TBHP are as oxidants was thought to be a possible
solution to overcome these difficulties met with partial success, since HBr is
highly toxic and corrosive and is as harmful as molecular bromine to the
environment.
Recently, we developed a highly para-selective method for the oxybro-
mination of aromatic compounds using KBr as a bromine source and
H2O2/Oxonew as oxidants.[15,16] However, an adoption of these methods
involving potassium salts (potassium hydroxide) are side products would
not be suitable for large-scale eco-friendly processes. We have, therefore,
sought to develop an eco-friendly, highly para-selective (regioselective)
method for bromination of aromatic compounds based on the use of NH4Br
as a bromine source and H2O2 as an oxidant.
Herein, we report a new method for the selective mono-bromination of
anilines and anisoles using NH4Br as a bromine source and H2O2 as an oxidant
for the first time. The results are summarized in Tables 1 and 2. Efficient
bromination of aromatic substrates with good yields and regioselectivity
observed with acetic acid as solvent (Sch. 1).
The bromination is highly para-selective for aniline itself as well as for
ortho- and meta-substituted anilines. Para-substituted anilines were brominated
in the ortho-position. The yields were generally good to excellent (Table 1).
Introduction of an electron-withdrawing group on the aromatic ring slows
down the reaction (substantially decreased the rate of ring bromination).
In this paper, we describe the high regioselectivity achieved in the ring
bromination of several methoxy derivatives of benzene and naphthalene,
and the results are summarized in Table 2. These systems yield selectively
para-brominated aromatics unless the para-position is substituted. The

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Scheme 1.
para-substituted anisole was brominated in the ortho-position in the case of
only p-methylanisole. The electron withdrawing groups presented on para-
position of anisoles failed to undergo bromination under the same reaction
conditions. 2-Methoxynaphthalene gives 1-bromo-2-methoxynaphthalene.
Anisoles give more selective para-brominated products than anilines.
The products obtained under these conditions resulted exclusively from ring
bromination. When benzylic positions (susceptible to radical bromination) were
present,[17,18] no benzyl bromides were detected in the crude reaction mixtures.
Since we had observed large increase in the ring bromination rate using this
system, we decided to study the behavior of methylanisoles and methylanilines
in order to determine whether the NH4Br/H2O2 system could achieve ring bromi-
nation without competition from benzylic bromination. The results are shown in
Table 1 (entries 3 and 9) and Table 2 (entry 5). Even ortho-bromination was
favored over side chain bromination in the reaction of 4-methylanisole and
4-methylanilines.Theabsenceofsidechainbrominationproductsinreactioncon-
ductedin acetic acid suggests a substantial increasein therate oftheionic process.
While less reactive aromatics such as bromo benzene, nitrobenzene, toluene,
benzoic acid failed to undergo bromination under the same reaction conditions.
In contrast to what is reported in the oxidative bromination using
hydrogen peroxide, the presence of vanadate or molybdate catalyst[19–21] is
not required to obtain good selectivities and good yields of brominated
materials using NH4Br/H2O2 system. A wide range of solvents have been
employed in these reaction including, carbon tetrachloride, hexane, methanol,
acetonitrile, and acetic acid. The best results were obtained when acetic acid
was used as a solvent compared to others. The role of hydrogen peroxide was
confirmed by conducting a blank experiment where the formation of bromo
compound was not observed.
It is assumed that hydrogen peroxide oxidizes the Brꢀ (NH4Br) to Brꢁ
(HOBr), which reacts in the presence of acetic acid (Bronsted acid) with
organic substrate to give brominated compounds (Sch. 2).
The brominated aromatic products were analyzed by GC and isolated
1
products were analyzed by H NMR and mass spectroscopy
In conclusion, we developed an efficient new method using ammonium
bromide as an interesting alternative to HBr and KBr in the oxidative

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2151
Scheme 2.
bromination of anilines and anisoles. The present method which is more attrac-
tive than the earlier methods, offers the additional advantages such as the com-
mercial availability of the reagents, simple reaction conditions, no evolution of
hydrogen bromide, high yield, economical, easy setup and workup, selective
mono-bromination with high regioselectivity, inexpensive, and environmentally
friendly process makes our method valuable from a preparative point of view.
The absence of side chain brominated products in reactions conducted in
CH3COOH suggests a substantial increase in the rate of the ionic process.
General Procedure for the Bromination of Anilines and
Anisoles
A 25 mL two-necked round bottomed flask was charged with the substrate
(2 mmol) and ammonium bromide (2.2 mmol) in acetic acid (4 mL). A 30%
H2O2 (2.2mmol) was added dropwise to the reaction mixture and the contents
allowed to stir at room temperature. The reaction was monitored by thin layer
chromatography (TLC). After the completion of the reaction, the reaction
mixture was treated with saturated sodium bicarbonate solution and extracted
with dichloromethane. The organic extract was dried over anhydrous sodium
sulfate and solvent evaporated under reduced pressure. The products were
purified by column chromatography and confirmed by 1H NMR and mass spectra.
ACKNOWLEDGMENTS
We are thankful to Department of Science and Technology, New Delhi
for funding, DST, Project No.: SP/S1/H07/97. PS thanks to CSIR, New
Delhi for the award of a Senior Research Fellowship.

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Received in India January 3, 2004

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