OOxidative bromination of activated aromatic compounds using aqueous nitric acid as an oxidant

Article abstract of DOI:10.1021/op030055w

Oxidative bromination of activated aromatic compounds using alkali metal bromide salts and aqueous nitric acid to the corresponding bromo-derivatives is achieved in a liquid-liquid, two-phase system under ambient conditions. Nitric acid offers a dual function of an oxidant as well as a proton donor, which is essential for oxidative bromination using metal bromide salts. Bromination as well as chlorination could be accomplished with this simple system.

Full text of DOI:10.1021/op030055w

Organic Process Research & Development 2004, 8, 568−570
0Oxidative Bromination of Activated Aromatic Compounds Using Aqueous Nitric
Acid as an Oxidant
Ashutosh V. Joshi,† Mubeen Baidossi,† Sudip Mukhopadhyay,*,‡ and Yoel Sasson*,†
Casali Institute of Applied Chemistry, Hebrew UniVersity, Jerusalem, 91904, Israel, and
Chemical Engineering Department, UniVersity of California, Berkeley, California 94720
Abstract:
hand, there is evidence that the rate of reaction increases
significantly in the presence of a phase-transfer catalyst in
conjunction with H2O27a,b or tert-butylhydroperoxide7c,d and
alkali perborate.7e Oxidative halogenations using enzymes
such as haloperoxidases were also described.8 Yet, large-
scale halogenations using enzymes have not been com-
mercialized; one of the reasons is that such reactions need
to be performed in dilute solutions, rendering it less attractive
from the economic point of view.9
Oxidative bromination of activated aromatic compounds using
alkali metal bromide salts and aqueous nitric acid to the
corresponding bromo-derivatives is achieved in a liquid-liquid,
two-phase system under ambient conditions. Nitric acid offers
a dual function of an oxidant as well as a proton donor, which
is essential for oxidative bromination using metal bromide salts.
Bromination as well as chlorination could be accomplished with
this simple system.
We have studied recently the nitration of phenolic
compounds with dilute nitric acid using tetrabutylammonium
bromide as a phase transfer catalyst.10 Interestingly, when
we extended the same protocol to the nitration of anisole,
bromoanisoles were obtained as the major product. We
attributed this phenomenon to the oxidative bromination of
anisole where tetrabutylammonium bromide catalyst had
provided the source of bromine in dilute nitric acid solution
(eq 1).
Introduction
Halogenation is usually used as a tool for providing
complex functionality to achieve the desired structure and
activity of the end compound. Aryl halides are intermediates
for the preparation of organometallic reagents, numerous bulk
and fine chemicals, and pharmaceuticals.1 Classical direct
halogenation of aromatic compounds using Cl2 or Br2 suffers
from the major drawbacks that only half of the halogen is
utilized and the other half ends up as a halogen acid.2 A
possible solution to this limitation is oxidative halogenation
where a halogen acid or salts of acid are used in combination
with an oxidant.3 The commonly used oxidant is 30% H2O2.
The reaction proceeds well without adding any catalyst
particularly in liquid phase;4 however, several reports on
oxidative halogenation, using catalysts such as V2O5,5a,b,c
NH4VO3, or Na2MO4,5d,e and heteropolyanion compounds5f
have appeared. Chemoselective oxybromination of methoxy
arenes in acidic media using oxone,6a alkali bromates,6b or
sodium chlorite6c have been recently reported. On the other
Oxidative bromination of aromatic substrates utilizing a
KBr-nitric acid mixture in the presence of phase transfer
catalysts is performed in this study. Nitric acid offers a dual
function of an oxidant as well as a proton donor, which is
essential for oxidative halogenation using alkali metal halide
salts. Using a metal halide-H2O2 system requires a sto-
ichiometric amount of mineral acids.5b Bromination of
aromatic compounds was studied using KNO3/KBr/aq CF3-
COOH or KBr/O2/CF3COOH in the presence of a catalytic
amount of NaNO2 or NO2Br/aq CF3COOH, where it was
suggested that the nitrite species formed is deoxidized.11
Selective monobromination of arenes with KBr/NaNO3/H2-
* Corresponding author. E-mail: sudip.mukhopadhyay@honeywell.com.
† Hebrew University.
‡ University of California, Berkeley.
(1) (a) Ullmann’s Encyclopedia of Industrial Chemistry, 6th ed.; Wiley-VCH:
2002. (b) Davis, S. G. Organotransition Metal Chemistry: Application to
organic synthesis; Pergamon Press: Oxford, 1982.
(2) Sasson, Y. In The chemistry of functional group Suppl. D2: The Chemistry
of halides, pseudo-halides and azides Part 1; Patai, S., Rappoport, Z., Eds.;
John Wiley & Sons: 1995.
(3) Bray, W. C.; Livinston, R. S. J. Am. Chem. Soc. 1928, 50, 1654.
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J. H.; Green Chem. 2000, 2, 248. (c) Bora, U.; Bose, G.; Chaudhari, M. K.;
Dhar, S. S.; Gopinath, R.; Khan, A. T.; Patel, B. K. Org. Lett. 2000, 2,
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(e) Conte, V.; Di Furia, F.; Moro, S. Tetrahedron Lett. 1996, 37, 8609. (f)
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Kurkalli, B. Org. Process Res. DeV. 2000, 4, 509. (c) Barhate, N. B.; Gajare,
A. S.; Wakharkar, R. D.; Bedekar, A. V. Tetrahedron 1999, 55, 11127. (d)
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Lett. 2003, 44, 4085. (e) Deshmukh, A. P.; Padiya, K. J.; Jadhav, V. K.;
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Res. DeV. 2003, 7, 95.
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Published on Web 05/25/2004

SO4 (60%)12a or bromination of strongly deactivated com-
pounds with NaBr/HNO3 (65%)/H2SO4 (100%)12b have also
been reported. There are some prior reports where concen-
trated nitric acid was used as an oxidant with halogen acids.13
Lately, bromination using dilute nitric acid in microemulsion
has also been reported,14 utilizing stoichiometric amounts
of the relatively expensive quaternary ammonium bromide
(QBr) salts as a bromide source.
In this work, we report a simple method for the oxidative
bromination of some activated aromatic substrates using
dilute aqueous nitric acid and readily available potassium
bromide in the presence of a phase transfer catalyst under
ambient conditions. Active substrates such as substituted
phenols, though, reacted under similar conditions to give
nitro-brominated products. This is an interesting observation
as one can use this protocol to make nitro-bromo substituted
aromatic compounds in one step.
Table 1. Oxidative bromination of various activated
aromatic bubstratesa
molar ratio of
bromide salt/
%
entry
substrate
anisole
substrate
time, h conversion
1
2
2
1.2
2
1.5
4
3
99
4-methylanisole
99
85
98
25
40
33
99
70
89
35
51
32
42
52
1.2
1.2
2
2
1.2
2
1.2
1.2
2
6
22
2
20
22
3
6
22
5
3
4
5
toluene
mesitylene
o-xylene
2
20
6
22
2
1.2
1.2
2
6
naphthalene
Results and Discussions
In a typical experiment, 5 mmol of 4-methylanisole (0.611
g) was stirred with 20 mmol of nitric acid (21% w/w; 1.80
g of 70%HNO3 acid diluted with a desired amount of water
to obtain a particular concentration of nitric acid), 10 mmol
of potassium bromide (1.19 g), 3 mol % tetrabutylammonium
chloride (0.15 mmol, 41 mg) (TBAC) as a phase transfer
catalysts, and 10 mL of dichloroethane (EDC) at 25 °C for
3 h. GC analysis of the final mixture exhibited full conversion
of the substrate to yield 2-bromomethylaniosle (eq 2) (see
Experimental Section for isolation of the product).
a Reaction conditions: substrate 5 mmol; KBr 6 or 10 mmol (0.714 or 1.19
g); HNO3 20 mmol (21% w/w; 1.80 g of 70% HNO3 diluted with calculated
amount of water to obtain the particular concentration of nitric acid); TBAC
3-mol % of the substrate; EDC 10 mL; temperature, 25 °C.
reasonable conversions were obtained with these substrates
(Table 1). Reaction was executed in the absence of light
(covered vessel) with substrates such as toluene, o-xylene,
and mesitylene to curb side chain bromination. In the case
of toluene, o-xylene, and naphthalene, only moderate conver-
sions were obtained even when a 100% molar excess of KBr
was utilized in the reaction. In each of the cases, the yield
of the corresponding mono-bromo derivative exceeded 95%.
High regioselectivity was observed during the oxidative
bromination of 4-methylanisole, mesitylene, and o-xylene.
4-Bromoanisole was formed in high regioselectivity. In the
case of naphthalene, 1-bromonaphthalene was the only
isomer detected by GC-MS and confirmation by its
comparison with the standard. However, toluene gave a
mixture of isomers, o/p 34:66.
The presence of nitrite anion, namely potassium nitrite
in the aqueous phase of the reaction mixture (eq 3) was
qualitatively assayed with potassium permanganate solution.15
To ascertain the in situ formation of Br2 species, a blank
reaction was conducted with KBr-HNO3 using dichloroet-
hane in the absence of substrate. The layers were separated,
and styrene was added to the dark brown organic layer. GC
analysis of the organic phase revealed formation of dibro-
mostyrene, indicating the presence of Br2.
The above procedure was extended for the oxidative
bromination of several other substrates, and the reaction
products were confirmed by GC-MS. The results are
enlisted in Table 1.
When a 100% molar excess of KBr was employed, a full
conversion to the corresponding bromo derivatives was
achieved using anisole, mesitylene, and 4-methylanisole as
the substrate (eq 3). With a 20% molar excess of KBr,
We also attempted to chlorinate aromatic substrates such
as anisole employing a similar protocol using a 100% molar
excess of NaCl as a chloride source and 30% HNO3. The
reaction was executed at 45 °C. Complete conversion of the
substrate was achieved. Ortho- and para-chloroanisoles were
obtained in the ratio of 3:1 with more than 97% selectivity.
In another set of experiments, we employed a modified
KNO3-HBr system to brominate a substrate such as anisole.
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Org. Khim. 1988, 24, 248.
(12) (a) Iqbal, S.; Anwar, M.; Munawar, M. A.; Siddiq, M. J. Chem. Soc. Pak.
1992, 14, 212. (b) Marterer, W.; Prikoszovich, W.; Wiss, J.; Prashad, M.
Org. Process Res. DeV. 2003, 7, 318 and references therein.
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L.; Chatterjee, N. R. J. Am. Chem. Soc. 1916, 38, 2545.
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Anisole was successfully brominated as well as chlorinated
(NaNO3-HCl) to the corresponding haloanisoles.
Different behavior was observed when substituted phenols
were exposed to the above reagents. Reaction of substituted
phenols such as 4-chlorophenol, p-cresol, and 4-cumylphenol
was carried out using 5 mmol of the substrate, 20 mmol of
11% nitric acid, 6 mmol of KBr, and 5-mol % TBAC. In all
these instances, 100% conversion of the substrate was
achieved.
We expected to obtain bromophenols in high yields, but
surprisingly we observed a different route of the consecutive
nitration and bromination process (eq 4). Yields of bromo-
nitro derivatives of these substrates were in the range of 30-
45%.
column (25 m). Reaction products were characterized by
GC-MS or comparison of their GC spectra with standard
samples.
General Procedure for Oxidative Bromination: A.
Preparation of 2-Bromomethylaniosle. In a typical pro-
cedure, KBr (40 mmol, 4.76 g) was added to 80 mmol of
nitric acid (21% w/w, 7.2 g of 70% nitric acid diluted with
a calculated amount of water to obtain the particular
concentration of nitric acid), to which were added 40 mL of
dichloroethane, 20 mmol of 4-methylanisole (2.44 g), and
TBAC 3-mol % of the substrate (166 mg) and stirred together
in a 100-mL closed glass reactor at 25 °C. The progress of
the reaction was monitored by GC. After the completion of
the reaction, the organic layer was separated from the
aqueous layer. It was then washed with 3 × 30 mL water
and finally with 30 mL of 2% K2CO3, and the organic layer
was separated and dried over magnesium sulfate. The dried
organic layer was concentrated under reduced pressure to
obtain an oil (3.57 g, 89% yield) of 2-bromomethylanisole
of 97% purity (GC and GC-MS analysis).
B. Preparation of Bromo-Nitro Phenols. In a typical
procedure, KBr (6 mmol, 0.74 g) was dissolved in 20 mmol
of nitric acid (11% w/w, 1.8 g of 70% nitric acid diluted
with a calculated amount of water to obtain the particular
concentration of nitric acid), to which was added 10 mL of
dichloroethane, 5 mmol of 4-chlorophenol (0.643 g), and
TBAC 5 mol % of the substrate (69 mg). The mixture was
stirred together in a 50-mL closed glass reactor at 25 °C for
2 h. GC analysis revealed that the yield to bromo-nitro
product was around 40%.
The presence of 100% molar excess of KBr and higher
concentration of nitric acid (21% HNO3) resulted in almost
similar yields of bromo-nitro derivatives of these substrates.
GC analysis of the samples drawn at periodic intervals
indicated that the rate of nitration is 2 orders of magnitude
faster than that of the bromination, and consequently nitro
intermediates, which are instantly formed, are finally oxy-
brominated to the end product.
Conclusion
We have demonstrated a simple reaction protocol that
could be utilized for oxidative bromination of activated
aromatic substrates using a readily available source of an
oxidant (aqueous nitric acid) and halide source such as a
metal halide.
Acknowledgment
We thank Mrs. Marcela Haimberg and Mr. Michael
Mogilnitsky from the MS laboratory at Makhteshim Chemi-
cal Works, Beer Sheva, for GC-MS analysis and interpreta-
tion of several products in this study. A.V.J. acknowledges
the Israeli Ministry of Science and Technology for financial
support.
Experimental Section
Materials and Instrumentation. All the chemicals were
purchased from a commercial firm (of high purity) and used
without further purification. GC analyses were performed
using a HP-5890 gas chromatography with a RTX-5 capillary
Received for review December 11, 2003.
OP030055W
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