Practical and regioselective halogenations of aromatic compounds using tetrabutylammonium peroxydisulfate

Article abstract of DOI:10.1080/10426500590911395

The halogenated aromatic compounds have been important intermediates for various synthetic methods. Electron-rich aromatic compounds were easily iodinated using tetrabutylammonium peroxydisulfate (1) and iodine in mild conditions with excellent yields. Bromination was achieved using 1 and bromine, and regioselective bromination of highly activated aromatic compounds was also achieved using 1 and lithium bromide in mild conditions with excellent yields. Copyright Taylor & Francis Inc.

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Phosphorus, Sulfur, and Silicon
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Practical and Regioselective
Halogenations of Aromatic
Compounds Using
Tetrabutylammonium
Peroxydisulfate
Yong Hae Kim a , Min Young Park a & Seung Gak Yang
a
a School of Molecular Science, Department of
Chemistry, Korea Advanced Institute of Science and
Technology, Daejon, Korea
Published online: 16 Aug 2006.
To cite this article: Yong Hae Kim , Min Young Park & Seung Gak Yang (2005) Practical
and Regioselective Halogenations of Aromatic Compounds Using Tetrabutylammonium
Peroxydisulfate, Phosphorus, Sulfur, and Silicon and the Related Elements, 180:5-6,
1235-1240, DOI: 10.1080/10426500590911395
To link to this article: http://dx.doi.org/10.1080/10426500590911395
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Phosphorus, Sulfur, and Silicon, 180:1235–1240, 2005
Copyright © Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500590911395
Practical and Regioselective Halogenations of Aromatic
Compounds Using Tetrabutylammonium Peroxydisulfate
Min Young Park
Seung Gak Yang
Yong Hae Kim
School of Molecular Science, Department of Chemistry, Korea Advanced
Institute of Science and Technology, Daejon, Korea
The halogenated aromatic compounds have been important intermediates for var-
ious synthetic methods. Electron-rich aromatic compounds were easily iodinated
using tetrabutylammonium peroxydisulfate (1) and iodine in mild conditions with
excellent yields. Bromination was achieved using 1 and bromine, and regioselec-
tive bromination of highly activated aromatic compounds was also achieved using
1 and lithium bromide in mild conditions with excellent yields.
Keywords Bromination; iodination; regioselective halogenation; tetrabutylammonium
peroxydisulfate
INTRODUCTION
Halogenated aromatic compounds have been used as intermediates for
a number of natural products and bioactive materials1 and also proved
as important and useful reagents in organic syntheses by functionaliza-
tion through carbon-carbon bond formation of diarenes and ethylenic
or acetylenic condensations using transition metals.2 Especially dur-
ing the past decade, numerous methods for the direct introduction of
halogen atoms into aromatic molecules have been intensively devel-
oped. Iodination of aromatic compounds needs additives to activate the
less-reactive iodine sources such as iodine, NaI, and KI. Various meth-
ods have been investigated and reported.3 However, because most of
these methods require a hazardous or toxic reagent, or high reaction
temperature for a long reaction time, it is difficult to control the regios-
electivity of iodination. Aryl bromides often are also used in synthe-
ses of aryl esters, aryl olefins, and other useful classes of compounds.
Received July 9, 2004; accepted October 5, 2004.
Address correspondence to Yong Hae Kim, School of Molecular Science of M. O. E.,
Department of Chemistry, Korea Advanced Institute of Science and Technology, Daejon,
305-701, Korea. E-mail: Kimyh@kaist.ac.kr
1235

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M. Y. Park et al.
There are many published cases. It is well known that bromine is more
reactive than iodine in aromatic halogenation, but it is difficult to con-
trol mono bromination using elemental bromine only, especially for the
electron rich aromatic compounds. There have been numerous bromi-
nation reagents reported.4 However, many of them suffer from regiose-
lectivity of bromination of activated aromatic compounds, so the control
over the degree of bromination and the regioselectivity still has been
needed.
Recently, we have reported an efficient iodination system for acti-
vated aromatic compounds using iodine and tetrabutylammonium per-
oxydisulfate [(n-Bu4N)2S2O8] 1.5 Here we describe a new practical and
regioselective iodination and bromination of activated aromatic and
heterocyclic compounds under mild reaction conditions as shown in
Scheme 1.
SCHEME 1 Halogenation of aromatic compounds with tetrabutylammonium
peroxydisulfate as an oxidant.
The peroxide 1 turned out to be a useful source of the tetrabutylam-
monium sulfate radical, which shows oxidizing ability and can be read-
ily converted to sulfate anion by one electron transfer from substrate.6
In contrast to K2S2O8, Na2S2O8, or (NH4)2S2O8, 1 is easily soluble
in various organic solvents such as acetonitrile, acetone, methanol,
and methylene chloride and therefore it can be easily used in general
organic reactions. Regioselective iodination of various aromatic com-
pounds can be successfully achieved using 1 and iodine. To prevent
polybromination, aromatic bromination with complete regioselectivity
has been achieved using lithium bromide and 1 under mild conditions.
The results obtained are reported herein.
RESULTS
The compound 1 was successfully prepared by mixing two equivalent of
tetrabutylammonium hydrogensulfate and potassium persulfate in wa-
ter. After stirring for 30 min at 25◦C, the desired product was extracted
with methylene chloride, washed with distilled water, dried over an-
hydrous MgSO4, and concentrated under reduced pressure to give the
pure precipitate solid, which met elemental analysis.6a The white solid
1 is stable for a couple months at 25◦C and can be stored in the refrig-
erator almost permanently.

Halogenations of Aromatic Compounds
1237
In order to check the regioselectivity in the iodination reaction, a va-
riety of methoxy arenes and aniline derivatives were iodinated. Various
activated aromatic compounds were reacted with iodine in the presence
of 1 at room temperature in acetonitrile or methylene chloride to give
mono iodinated products. The products obtained showed the complete
regioselective p-oriented iodination with respect to electron donating
group of –OMe or N(Me)2. The results obtained are summarized in
Scheme 2.
SCHEME 2 Iodination reaction of aromatic compounds with iodine and tetra-
butylammonium peroxydisulfate.
The regioselectivity can be deduced from the results that iodination
occurred at a more electron-rich and less sterically hindered position.
Methoxybenzenes were iodinated with selectivity of p-position, whereas
o-iodination only occurred when the p-position was blocked with a sub-
stituent (3b). Although the iodination of aniline derivatives (6a and 7a)
is slower as compared to dimethoxybenzenes, only p-iodinated prod-
ucts were obtained in excellent yields under the same mild conditions.
It is noteworthy that an aromatic compound 8a bearing aldehyde moi-
ety, which can be readily oxidized, was iodinated at p-position with
regioselectivity in high yield (87%) without oxidizing aldehyde moiety.
It was observed that there was no iodination of aromatic compounds
bearing electron-withdrawing substituents, such as nitrobenzene and
acetophenone, under the same reaction conditions: starting material
was recovered almost quantitatively.
We applied this oxyhalogenation reaction to the bromination of
electron-rich aromatic compounds. Various electron-rich aromatic com-
pounds were brominated with bromine in the presence of 1 at 25◦C
in methylene chloride to give mono brominated products with high
regioselectivity. The results obtained are summarized in Scheme 3.
Mono brominations exclusively occurred at the p-position of methoxy

1238
M. Y. Park et al.
SCHEME 3 Bromination reaction of aromatic compounds with bromine and
tetrabutylammonium peroxydisulfate.
or amino group. When p-position of methoxy group was blocked with a
substituent, o-bromination occurred only. Because bromination of ani-
line and methoxybenzene proceeded more slowly as compared with that
of dimethoxybenzene, the reaction appears to be related to the electron
density of the aromatic compounds.
Complete regioselectivity of mono bromination of 1,2,3-trimetho-
xybenzene (12a) with bromine and 1 failed: a mixture of mono- and
dibrominated products was obtained in the ratio of 6:1. The elongated
reaction time (6 h) with 2a also caused the formation of small amount
of dibrominated product (monobrominated 2c: approximately 90%, di-
brominated product: approximately 10%). To overcome this problem, a
milder bromination system was designed using lithium bromide and
1. The direct use of hazardous molecular bromine can be avoided by
the use of the neutral salt of LiBr. Various activated aromatic com-
pounds reacted with lithium bromide and 1 in acetonitrile at 25◦C to
give the corresponding monobrominated products in excellent yields
with complete regioselectivity. The results obtained are summarized in
Scheme 4.
In comparison to the system using bromine and 1, this system needed
longer reaction time but resulted in high yields and complete regiose-
lectivity in monobrominations. m-Methoxyanisole (2a) gave o-bromo-m-
methoxyanisole (2c) in quantitative yield (98%). A large-scale bromi-
nation reaction (12a: 4.33 g, 25.7 mmol; 1: 43.5 g, 64.2 mmol; LiBr: 5.6
g, 64.2 mmol) was performed for the practical purpose of giving 12c in
high yield (82%). The bromination occurred at only the p-position of
the electron-donating group: o-brominated isomers were not detected.
In the case of m-methoxyphenol (13a), only p-bromo-m-methoxyphenol

Halogenations of Aromatic Compounds
1239
SCHEME 4 Bromination reaction of aromatic compounds with LiBr and tetra-
butylammonium peroxydisulfate.
(13c, p-position was brominated toward OH group) was obtained. Some
heterocycles (16a and 17a) were also successfully brominated with
lithium bromide and 1 at 25◦C in acetonitrile in high yields. However,
less-activated aromatic compounds such as anisole or toluene did not
give brominated products under the same reaction conditions.
We have developed highly regioselective iodination and bromination
of activated aromatic compounds under the mild conditions using 1 as
an oxidant. The stable peroxydisulfate 1 can be readily prepared and
can be handled easily and safely. Thus, it can be practically used for
oxyhalogenation reaction. Bromination and iodination with bromine
and iodine in the presence of 1 gave the monobrominated and iodinated
products, respectively, in high to excellent yields as the major products
in short reaction time. In contrast to using bromine, bromination with
lithium bromide and 1 resulted in only monobrominated products with
complete regioselectivity in good to excellent yields under neutral and
mild conditions. In this reaction, lithium bromide proves to be a better
alternative than hazardous molecular bromine.
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