Use of sodium bromate for aromatic bromination: Research and development

Article abstract of DOI:10.1021/op9901947

Sodium bromate is a powerful brominating agent for aromatic compounds that contain deactivating substituents. A bromination process, in which sodium bromate was utilized, was optimized on laboratory scale. Addition of a strong acid into a stirred aqueous solution, or slurry, of the substrate and bromate salt at 40-100°C, leads to the decomposition of the bromate ions and production of the active brominating species. Substrates such as nitrobenzene, benzoic acid, and benzaldehyde were brominated in high yields (85-98%) and specificity. The reaction is especially useful for the bromination of disubstituted benzenes, such as 4-nitrofluorobenzene or 4-fluorobenzoic acid. Several substrates, such as dinitrobenzenes or nitrobenzoic acids, did not undergo bromination at all. The main parameters of the reaction and some of its synthetic potential are discussed.

Full text of DOI:10.1021/op9901947

Organic Process Research & Development 2000, 4, 30−33
Use of Sodium Bromate for Aromatic Bromination: Research and Development
Amiram Groweiss
TAMI (IMI) Institute for Research and DeVelopment, P.O.Box 10140, Haifa-Bay 26111, Israel
Abstract:
(vide infra) where neither mild reagents (like DBDMH or
NBS) nor Br gives satisfactory results.
Initial work on bromination with KBrO
Sodium bromate is a powerful brominating agent for aromatic
compounds that contain deactivating substituents. A bromina-
tion process, in which sodium bromate was utilized, was
optimized on laboratory scale. Addition of a strong acid into a
stirred aqueous solution, or slurry, of the substrate and bromate
salt at 40-100°C, leads to the decomposition of the bromate
ions and production of the active brominating species. Sub-
strates such as nitrobenzene, benzoic acid, and benzaldehyde
were brominated in high yields (85-98%) and specificity. The
reaction is especially useful for the bromination of disubstituted
benzenes, such as 4-nitrofluorobenzene or 4-fluorobenzoic acid.
Several substrates, such as dinitrobenzenes or nitrobenzoic
acids, did not undergo bromination at all. The main parameters
of the reaction and some of its synthetic potential are discussed.
2
3
was carried out
2
by Harrison and co-workers, who prepared bromonitroben-
zene and also bromobenzoic and phthalic acids. In another
study Banerjee described the bromination of several other
3
-6
substrates by the same method.
Thus far, the use of
NaBrO for such aromatic bromination has never been
3
7
reported. Despite all of the similarities between the alkali
+
metals, there are several differences in action between Na
+
and K ions, and in many processes the use of the more
2 3
delicate KOH and K CO is preferred over the often sluggish
NaOH and Na CO . In bromination, however, our study has
2
3
proven that sodium and potassium bromate act very similarly,
thus giving a commercial advantage to the less expensive
sodium salt.
The functionalization of aromatic compounds through
brominated intermediates is a very useful synthetic method.
Many reagents are used for the bromination step, including,
Results and Discussion
As shown in eq 1, sodium bromate was used to prepare
2
besides Br itself (with or without a catalyst), such com-
pounds as NBS, 1,3-dibromodimethylhydantoin (DBDMH),
benzyltrimethylammonium tribromide, etc. Most of these
agents are used for the bromination of aromatic substrates
that contain ring-activating groups, for example, toluene,
aniline, and phenol. Very few reagents can be used to
brominate compounds with strong electron-withdrawing
groups, such as nitrobenzene, benzoic acid, or benzene-
sulfonic acid. The lack of an efficient and economical method
for such bromination is probably one of the reasons meta-
substituted compounds are less common in many applications
than their ortho- or para-substituted isomers. This study deals
with meta bromination and recommends the utilization of
NaBrO for the bromination of aromatic substrates that
3
contain one or two such deactivating groups.
Severe regulations on the use of sodium and potassium
bromate were imposed, in the past few years, by health and
environmental protection authorities. Some of their regular
brominated aromatic substrates with one- and two-electron
2
withdrawing groups (X ) NO , COOH, COOMe, CHO, F,
CF , etc.) (R ) H, F, Cl, etc.) in the meta position, in high
3
yields and good regioselectivities. The reactions were carried
out by mixing the substrate, a mineral acid (usually concen-
trated H SO ) and NaBrO . Since NaBrO and H SO are
2 4 3 3 2 4
not compatible, the brominations were performed by gradu-
ally adding one of the two reagents into the reaction mixture
(
a semi-batch process). In this instance there were three
possible modes of reaction:
a) Addition of concentrated H
of substrate and bromate in water.
b) Addition of solid NaBrO , in small portions, into a
solution of the substrate in aqueous H SO .
(
2 4
SO into a stirred slurry
(
3
3
uses (like KBrO as a flour improver in baking processes)
1
were banned. In this atmosphere of diminishing markets and
declining demands, other uses are being sought. One such
potential utilization is in bromination and oxidation reactions.
Price-wise, however, none of the brominating reagents,
2
4
(
2) Harrison, J. J.; Pellegrini, J. P.; Selwitz, C. M J. Org. Chem. 1981, 46,
169-2171.
(3) Banerjee, A.; Banerjee, S.; Samaddar, H. J. Ind. Chem. Soc. 1979, 56, 985-
87.
2
9
2
including bromates, can compete with Br , and usually the
(
(
(
(
4) Banerjee, A.; Banerjee, S.; Samaddar, H. J. Ind. Chem. Soc. 1979, 56, 988-
price of KBrO is twice as much as that of bromine.
3
990.
5) Banerjee, A.; Banerjee, G. C.; Dutt, S.; Banerjee, S.; Samaddar, H. J. Ind.
Chem. Soc. 1980, 57, 640-642.
6) Banerjee, A.; Banerjee, G. C.; Adak, M. M.; Banerjee, S.; Samaddar, H. J.
Ind. Chem. Soc. 1981, 58, 985-988.
3
7) Two recent reports on bromination by NaBrO : (a) bromination of N,N-
Therefore, the use of bromate salts in processes may be
economically justified only when they provide substantial
advantages in the yield and reaction conditions over the use
2
of Br . The best example is the bromination of nitrobenzene
disubstituted benzamides: Dong, C.-H.; Julia, M.; Tang, J. Eur. J. Org.
Chem. 1998, 1689-1696. (b) Benzylic bromination of alkylbenzenes:
Kikuchi, D.; Sakaguchi, S.; Ishii, Y. J. Org. Chem. 1998, 63, 6023-6026.
(1) Chem. Ind. (London) 1989, 22, 734.
3
0
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10.1021/op9901947 CCC: $19.00 © 2000 American Chemical Society and The Royal Society of Chemistry
Published on Web 12/28/1999

(
c) As in method b, but the added reagent was in solution.
The latter mode was less successful because the low
solubility of NaBrO in water (365 g/L at 20 °C) led to
Table 1: Comparison of methods for the bromination of
nitrobenzene
3
sodium bromate
bromine
140 °C
dilution of the acid and hence reduced the yield of the
obtained brominated products.
To optimize the yields, the main parameters of the reaction
have been studied and determined as herein discussed.
Bromate to Substrate Molar Ratio. For many substrates
temperature
reaction time
catalyst
“Br” amount
yield
45 °C
2 h
none
stoichiometric
85-88%
96-99%
8 h
Fe (10% w/w)
60% excess
60-75%
94%
regioselectivity
3
it was found that even when excess of NaBrO was used,
the conversion still did not reach 100%, and addition of more
bromate resulted only in higher quantities of dibrominated
derivatives. Therefore, in most cases an optimal ratio of
The Acid. A strong acid was needed to convert NaBrO
to the “bromonium” active species. The first choice is H
SO
other strong acids (HCl, HBr, HNO
reduction reactions with bromate salts. H
only in a very few cases (e.g., benzaldehyde). The preferred
concentration of H SO was 30-65% (w/w), depending on
the substrate, and inter-related with the reaction temperature.
The advantages of NaBrO over Br in the bromination
of nitrobenzene are shown in Table 1. The table clearly
demonstrates that with NaBrO milder conditions were
required and a higher yield and improved regioselectivity
were obtained. Even the price advantage of Br over NaBrO
3
2
-
0
.95-0.97 was taken. This yielded maximum conversion
4
which is involved only in the desired reaction, while
) undergo oxidation-
PO was useful
(usually >90%) and a limited amount (usually <4%) of
3
dibromo compounds. Only for disubstituted substrates were
there cases where an excess of bromate was essential (e.g.,
3
4
4-fluoronitrobenzene).
2
4
Regioselectivity and Specificity. The regioselectivity is
herein defined as the quantity of the desired product (a meta
isomer) divided by the total amount of brominated products.
Our observations have revealed that the selectivity for
monobromination is between 85% and >99%, and is
3
2
8
3
2
definitely comparable to the action of Br . Two extreme cases
2
3
were nitrobenzene, with a selectivity of >96% and benzoic
acid, which yielded more dibromo isomers, and the regio-
selectivity was only 80-85%, depending on the temperature
employed. The latter molecule indeed gave inferior selectivity
was diminished by the need for a large excess of bromine.
Another advantage was the easy purification of the product
by either extraction or crystallization from the aqueous
medium.
compared with the traditional bromination with Br
2
and a
2
It was pointed out that a gas evolved in the bromination
Lewis acid catalyst. In a few cases of 1,4-disubstituted
substrates, where the combined orientation effect of both
substituents point to the same carbon, for example, 4-fluo-
ronitrobenene, the specificity was literally 100%.
Temperature. As expected, the temperature played a
major role in the reaction, affecting both the conversion and
the selectivity. Benzoic acid, again, served as an indicative
example: up to 50 °C, the conversions were very low but
changed from 8% at 35 °C to ∼96% at 90-100 °C.
The strongly exothermic reaction made it very difficult
to control the temperature inside the reactor, which fluctuated
of nitrobenzene and contained not only O
CO . Since the only source of carbon is the starting material,
it was assumed that CO was produced by the oxidation of
a small amount of substrate. Our study has shown that this
oxidation is not general and was detected in only a few
substrates.
The reaction was also utilized for the preparation of
3-bromo-4-fluoronitrobenzene, a potential intermediate for
ciprofloxacin (Cipro, Ciloxan) and other fluoroquinolone
antibiotic drugs. The bromination step was carried out at 65
2
, but also some
2
2
3
°C with 1.2 equiv of NaBrO . The yields varied between
when the reagents (either NaBrO
3
or H
2
SO
4
) were added.
85-98%, and the regioselectivity was 100%.
Therefore, in this investigation, three temperature ranges were
defined: 40-50, 60-65, and 85-100 °C, and for each
substrate, one of these ranges was selected. This approach
was well-illustrated in the bromination of 4-fluoronitroben-
zene when the product to starting material ratio was improved
from 47:53 at 35 °C to 81:19 at 65 °C and remained almost
the same (80:19) when the temperature was elevated to 85
There were several nitro-containing substrates, such as
1,3-dinitrobenzene or m-nitrobenzoic acid, for which bro-
mination did not occur. In these cases an excess of bromine
was liberated, which could be observed visually and indicated
that no reaction had taken place, even before it was proven
by analysis.
The bromination of benzoic acid was performed at 85-
1
00 °C with an H
afforded a yield of 92%, but with a regioselectivity of only
5%. A much higher selectivity was obtained when methyl-
benzoate was brominated. This reaction was carried out at
5-40 °C, and 99% conversion was reached after 4 h. The
2 4
SO concentration of 30-65% and
°C. Not just the conversion, but also the regioselectivity was
dependent on the temperature, as the amounts of the
accompanying ortho and para isomers and especially dibro-
minated products increased at higher temperatures (above
8
3
80 °C).
isolated yield was 91%, and two dibromo derivatives were
also formed, comprising 5% of the product mixture. At 40
Stirring. This reaction is a two-phase system, and efficient
stirring (725 rpm or higher) was essential for mixing the
hydrophobic aromatic compounds with the aqueous inorganic
medium and for preventing local high concentrations of the
active bromo species.
(
8) The procedure for the latter reaction was taken from: Johnson, J. R.;
Gauerke, C. G. Organic Syntheses, 2nd ed.; Wiley: New York, 1944;
Collect. Vol. I, pp 123-124.
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31

Scheme 1: Bromination of benzaldehyde
The oxidation is visually observed by the liberation of
bromine by the following reaction:
-
-
+
5
Br + BrO3 + 6H f 3 Br + 3 H O
2 2
To improve the extent of bromination and minimize oxida-
tion, the addition of solid bromate into the reactor was
commenced only at 80 °C. Even then, before the first crystals
3
of NaBrO were added, there was already 5% of benzoic
acid in the reaction mixture (probably due to air oxidation).
When optimized, the benzaldehyde conversion was >95%,
giving a mixture of 70:20 bromobenzaldehyde/bromobenzoic
acid. The other reaction products were benzoic acid and two
isomers of dibromobenzaldehyde.
°
C no hydrolysis of the ester was observed, despite the
Conclusions
strongly acidic conditions. Only when the temperature was
elevated to 60 °C was the rate of hydrolysis increased and
the reaction mixture then contained brominated products of
both methyl-benzoate and of benzoic acid.
The use of NaBrO
the following advantages over other methods were found:
1) Bromates are efficient brominating agents for aromatic
substrates with one and two deactivating groups.
2) Unlike other efficient agents, for example, dibromo-
3
for bromination was investigated, and
(
The bromination of 4-fluorobenzoic acid was the first step
used for the preparation of 3-phenoxy-4-fluorobenzoic acid,
an intermediate for the synthesis of fluoro-pyrethroids. In
this bromination, the combined orientation by both substit-
uents toward C-3 results in a >97% regioselectivity. The
effective temperature range is wide (50-80 °C), and the
average yield, 90%. In contrast, bromination of other
bifunctional carboxylic derivatives with stronger deactivating
groups, for example, phthalic or 4-nitrobenzoic acid, was
found to give low yields, usually between 5 and 40%.
The most surprising result in this study was obtained when
the bromination of benzaldehyde was attempted. 3-Bro-
mobenzaldehyde is an intermediate for the preparation of
the synthetic pyrethroids, deltametrin and cypermetrin, and
converted to 3-phenoxy-benzaldehyde by the Ullmann reac-
tion (Scheme 1). Usually 3-bromobenzaldehyde is prepared
(
9
isocyanuric acid, this reagent is commercially available.
(3) Unlike bromine, bromates are easy-to-handle solids.
(4) There is no evolution of HBr in the reactions.
(5) The reactions are performed in aqueous solution,
without the use of expensive or hazardous solvents.
6) The reaction medium (excess of acid) is mostly
(
recyclable in the process.
There are a few disadvantages that should be mentioned
if large-scale implementation of the reaction is desired:
(1) Sodium bromate is more expensive than bromine.
(
2) Hazard: bromates are strong oxidizing agents and
oxygen is liberated during the reactions.
4
3) The effluents of the bromination are NaHSO and the
(
excess sulfuric acid, which need to be treated.
2 3
by bromination with Br and a large excess of AlCl , and it
Experimental Section
was surprising that a reaction of an aldehyde with a strong
oxidizing agent could lead to anything other than benzoic
acid. Indeed, Banerjee showed that when benzaldehyde was
General Procedures. The yields, conversions, and se-
lectivities were determined by GC, HPLC, and NMR
quantitative and qualitative methods, and the products were
identified by comparison with authentic standards. GC were
measured with HP-5890 equipped with HP-3992-A integra-
tor, on capillary phenyl-silicone (5 or 12 m) columns. GC/
MS were obtained with HP-5890 GC, equipped with HP-
3 2 4
reacted with KBrO in H SO (4 N), a mixture of benzoic
4
and 3-bromobenzoic acids were obtained. We have found,
however, that upon careful selection of the reaction condi-
tions it was possible to prepare a mixture of 3-bromobenz-
aldehyde and 3-bromobenzoic acid in a ratio of 7:2. The
bromination and oxidation are competitive; to increase the
fraction that undergoes bromination one must work at 90-
5
970 mass selective detector, on a capillary column. HPLC
were measured with a Varian model Vista 5500 liquid
chromatograph on a fully end-capped Regis Val-U-Pak 25
3 4
100 °C and in concentrated acid (90% H PO ). Milder
cm × 4.6 µm ODS column with a UV detector operating at
temperatures or more diluted acids led eventually to oxida-
tion. The reason for the temperature differences is explained
by the fact that while oxidation occurred at the whole range
of temperatures, bromination took place only above 60-70
1
2
30 nm. H NMR spectra were taken on a Bruker WP-200-
3 6
SY in CDCl or d -DMSO solutions and TMS as internal
standard for calibration. Amounts of inorganic bromides, acid
concentration, water content and other wet analyses were
determined in conventional titrametric methods.
°C. Therefore attempts to “protect” the aldehyde by employ-
ment of a lower temperature resulted in the increased
Bromination of Benzoic Acid by Addition of H
2 4
SO
production of benzoic acid instead. Another disadvantage
(Method a). A 1 L, four-necked flask, equipped with a
1
arises from the stoichiochemistry of the reaction; only /
3
mechanical stirrer, a reflux condenser, a digital thermometer,
and a dropping funnel, was charged with 61.0 g of benzoic
equiv of bromate is sufficient to oxidize all of the aldehyde:
3
ArCHO + NaBrO f 3 ArCOOH + NaBr
3
(9) Gottardi, W. Monatsh. Chem. 1968, 99, 815-822.
32
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Vol. 4, No. 1, 2000 / Organic Process Research & Development

acid (0.5 mol), 71.7 g of finely ground NaBrO
00 mL of water, and 1 g of K SO . The reactor was warmed
to 85-90 °C, and then 122 mL of concentrated H SO was
added dropwise over 1 h. The stirring and temperature were
maintained for another 30 min. The mixture was allowed to
cool to room temperature, water was added, and the product
was filtered under reduced pressure, washed with cold water,
and dried in a vacuum oven at 60 °C; 92.3 g (yield ) 93.7%)
of a light-yellow material was obtained.
Bromination of Nitrobenzene by Addition of Solid
3
NaBrO (Method b). A 2 L four-necked flask, equipped with
a mechanical stirrer, a reflux condenser, a digital thermom-
eter, and a funnel, was charged with 123.1 g of nitrobenzene
3
(0.475 mol),
temperature was kept at 40-50 °C with an ice bath. When
the addition was completed, stirring was maintained for
another 1 h, the mixture was then cooled, and the crystalline
product was filtered, washed with cold water, and dried in a
vacuum oven at 55 °C; 186.2 g of a light yellow material
was obtained, which still contained 9% humidity. The
product (net weight: 169.4 g, yield ) 85.6%) contained
96.1% 3-nitrobromobenzene.
3
2
4
2
4
Acknowledgment
The excellent technical assistance of Orly Cohen and
Muhammad Jamal is gratefully acknowledged. The author
expresses special thanks to Dr. A. Kampf (Bromine Com-
pounds Ltd.) for a generous gift of sodium bromate.
(
1.0 mol), 500 mL of concentrated H
and 1.5 g of K SO . The reactor was warmed to 40-45 °C,
and then 143.3 g of NaBrO (0.95 mol) was added in portions
of 4-5 g over 1 h. During the bromate addition, the
2 4
SO , 500 mL of water,
2
4
Received for review April 30, 1999.
OP9901947
3
Vol. 4, No. 1, 2000 / Organic Process Research & Development
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33