Organic Process Research & Development 1999, 3, 451−454
Oxidative Bromination in a Liquid-Liquid Two-Phase System to Synthesize
Organic Intermediates: 2-Bromophenol, 2,6-Dibromophenol, and
2
-Bromo-4-methylphenol
,
†
Sudip Mukhopadhyay,* S. Ananthakrishnan, and Sampatraj B. Chandalia
Chemical Engineering DiVision, UniVersity Department of Chemical Technology, UniVersity of Mumbai, Matunga,
Mumbai - 400 019 India
Abstract:
mentally friendly separation of the desired product from the
An alternative manufacturing process-scheme was developed
to synthesize 2-bromophenol and 2,6-dibromophenol involving
oxidative bromination of a substrate protected in the para
position in a two-phase system followed by deprotection involv-
ing decarboxylation. Thus, selective oxidative bromination of
reaction mixture. 4-Hydroxybenzoic acid and 4-methylphenol
were brominated selectively by using HBr-H O in a two-
2 2
phase system, and the resultant bromocarboxylic acids, in
case of 4-hydroxybenzoic acid, were decarboxylated in
quinoline to obtain the products. In case of 4-methylphenol
after the oxidative bromination, the product was isolated by
fractional distillation. (Scheme 1).
2 2
4-hydroxybenzoic acid in ethylenedichloride with HBr-H O ,
and subsequent decarboxylation in quinoline gave 90-95%
yield to the mono- or dibromophenol depending upon the mol
ratio of HBr:H
2
O
2
employed in the oxidative bromination.
Experimental Section
Similarly, 4-methylphenol under identical reaction conditions
gave 99.6% selectivity to 2-bromo-4-methylphenol at 89%
conversion ratio of 4-methylphenol.
Oxidative Bromination. Experimental Procedure. The
experiments were carried out in a 250-mL borosilicate glass
reactor equipped with six-blade turbine impeller, four baffles,
a dropping funnel, and a water condenser. The outgoing gases
were passed through a caustic scrubber. The assembly was
kept in a constant-temperature bath. For large-scale industrial
production, it is worth considering the use of a glass- or
titanium-lined reactor.
In a typical reaction, 0.0435 mol of substrate and 0.174
mol of 40% hydrobromic acid were added to 50 mL of
ethylenedichloride, and the reaction mixture was kept at 45
°C. Then, 0.039 mol of 30% hydrogen peroxide was added
dropwise to the reaction mixture over 2.5 h. The reaction
mixture was stirred for another 0.5 h at 45 °C. The layers
were separated when the reaction was over. In the case of
Introduction
2
-Bromophenol, 2,6-dibromophenol, and 2-bromo-4-
methyl phenol have great relevance in organic process
industries as intermediates for fine-chemicals and pharma-
ceuticals. In general, these are synthesized by direct bromi-
nation of the reactant. But there is always a chance of getting
an isomeric mixture1,2 of 2- and 4-halo substituted products
with some di- or trihalo compounds from which, the
separation of the desired product itself is a problem.
2 2
Oxidative halogenation by using HCl or HBr and H O of a
4
-methylphenol, the product, 2-bromo-4-methylphenol, was
isolated by fractionation of the organic layer (isolated yield,
7%; bp, 109-114 °C at 29-31 mm), but in the case of
para-blocked substrate followed by deprotection involving
desulphonation or decarboxylation is reported.3
-5
2,6-Di-
9
bromophenol has been produced by bromination of 4-hy-
6
-7
4-hydroxybenzoic acid, the products, 3-bromo-4-hydroxy-
benzoic acid or 3,5-dibromo-4-hydroxybenzoic acid, were
isolated by distilling out the organic solvent under atmo-
spheric pressure. The acids were then dried and taken for
the decarboxylation step. The decarboxylation mixture was
distilled under reduced pressure to isolate 2-bromophenol
droxybenzoic acid and subsequent decarboxylation. The
above halogenations were carried out in homogeneous
conditions or in aqueous acidic solution, where the separation
of the desired product from the highly corrosive aqueous
hydrochloric or hydrobromic acid solution is a major
problem. In this work, oxidative bromination is done in a
liquid-liquid two-phase system to get an easy and environ-
(isolated yield, 88%; bp, 93-97 °C at 31-32 mm) and 2,6-
dibromophenol (isolated yield, 92%; bp, 174-178 °C at 30-
*
Corresponding author.
Present address: Casali Institute of Applied Chemistry, The Hebrew
3
3 mm).
†
Analytical Procedure. The reaction mixture was analyzed
University of Jerusalem, Givat Ram Campus, Jerusalem 91904, Israel.
(
1) Kirk-Othmer Encyclopedia of Chemical Technology, 2nd ed.; Wiley:
London, 1964; Vol. 5, p 329.
by HPLC. Column used: MERCK50983, Lichrosphere 100
RP-18, 5 µm. 254 × 4 mm.
(
(
2) Ullmann’s Encyclopedia of Industrial Chemistry; 1986; Vol. A6, p 342.
3) Seikel, M. K. Organic Syntheses; Wiley: London, 1963; Collect. Vol. III,
p 262.
Conditions: mobile phase, water-acetonitrile, (3:2); flow
rate, 1 mL/min; wavelength, 254 nm.
(4) Mukhopadhyay, S.; Chandalia, S. B. Org. Process Res. DeV. 1999, 3, 10-
Decarboxylation. Experimental Procedure. A 100-mL
autoclave was used for the decarboxylation reactions. In a
typical reaction, 5 g of bromo-substituted benzoic acid, 0.5
g of cuprous oxide, and 50 mL of quinoline were charged
1
6.
(
5) Mukhopadhyay, S.; Chandnani, K. H.; Chandalia, S. B. Org. Process Res.
DeV. 1999, 3, 196-200.
(6) Pope, F. G.; Wood, A. S. J. Chem. Soc. 1912, 101, 1827.
7) Blicke, F. F.; Smith, F. D.; Powers, J. L. J. Am. Chem. Soc. 1932, 54, 1465.
(
1
0.1021/op990035n CCC: $18.00 © 1999 American Chemical Society and The Royal Society of Chemistry
Vol. 3, No. 6, 1999 / Organic Process Research & Development
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451
Published on Web 11/02/1999