932
Chemistry Letters Vol.32, No.10 (2003)
Halogenation of Aromatic Compounds by N-chloro-, N-bromo-, and N-iodosuccinimide
Kiyoshi Tanemura,ꢀ Tsuneo Suzuki, Yoko Nishida, Koko Satsumabayashi, and Takaaki Horaguchiy
School of Dentistry at Niigata, The Nippon Dental University, Hamaura-cho, Niigata 951-8580
yDepartment of Chemistry, Faculty of Science, Niigata University, Ikarashi, Niigata 950-2181
(Received June 10, 2003; CL-030524)
An efficient and mild method for the halogenation of aro-
Table 1. Bromination of toluene with NBS using various catalysts
in CH3CNa
matic compounds using N-chloro-, N-bromo-, and N-iodosucci-
nimide in the presence of NH4NO3 or FeCl3 in acetonitrile was
developed.
Catalyst
Time Conv.
/% p-Bromo- o-Bromo- o,p-Dibromo- Benzyl
Relative yields/%b
toluene toluene
toluene
0
bromide
8
H2SO4
8 h
8 h
8 h
8 h
8 h
8 h
3 h
2h
68
36
56
PyHOTfc
PyHOTs
PyHCld
NH4OTf
NH4NO3
NH4Cl
8219
65
18
4
49
Halogenation of aromatic compounds is one of the most im-
portant reactions in organic synthesis. The most commonly used
reagents for this purpose are bromine and chlorine in the pres-
ence of iron halide. In terms of ease of handling in laboratories,
N-bromo- (NBS) and N-chlorosuccinimide (NCS) will be supe-
rior halogenating reagents if benzylic halogenation is sup-
pressed. Schmid reported that benzene and toluene gave nuclear
brominated derivatives in good yields by the reactions with
NBS and AlCl3 without solvents under long reflux using a large
amount of the catalyst (>1 equiv.), but in unsatisfactory yields
(21–61%) of products together with the polysubstituted prod-
ucts by the reactions using H2SO4, FeCl3, and ZnCl2.1 Lambert
et al. reported that nuclear substituted derivatives were obtained
in good yields from the reactions of aromatic compounds with
NBS in 50% aqueous H2SO4,2 however, this method requires
considerably acidic conditions. Thus, there is a need to develop
a practical procedure for the halogenation of aromatic com-
pounds.
34
29
25
16
18
0
3
41
30
30
49
37
25
27
100
6238
57
0
trace
100
47
36
8
3
4
52
0
e
AlCl3
23
17
e
FeCl3
CANf
20 min 100
40
49
36
11
0
4 h
8 h
8 h
8 h
87
38
15
g
ZnCl2
7235
46
33
0
16
h
Sc(OTf)3
35
4
26
4
0
7
33
85
None
21
aReaction conditions: Toluene 10 mmol, NBS 10 mmol, Catalyst
1 mmol, CH3CN 6.3 mL, Temp. 60 ꢁC. bDetermined by 1H NMR spec-
troscopy. c10% of p-bromobenzyl bromide was obtained. dp- and
o-Bromobenzyl bromide were obtained in 2and 20% yields, respective-
ly. At 25 ꢁC. p- and o-Bromobenzyl bromide were obtained in 8 and
3% yields, respectively. gp- and o-Bromobenzyl bromide were obtained
in 9 and 7% yields, respectively. h6% of p-bromobenzyl bromide was
obtained.
e
f
In this paper, we report that aromatic compounds react with
NCS, NBS, or N-iodosuccinimide (NIS) in the presence of
NH4NO3 or FeCl3 in CH3CN to give the corresponding nuclear
substituted products.
in 40, 49, and 11% relative yields, respectively. Benzyl bromide
was not detected at all. In the case of AlCl3, conversion was low
because NBS was consumed by the reaction with AlCl3. In the
absence of the catalyst, benzylic bromination proceeded very
slowly. For the bromination of aromatic compounds using
NBS, the actual active agent is not free bromine but possibly
the protonated or Lewis acid-coordinated NBS.2 Further study
is necessary to establish the mechanism.
The results of bromination of various substrates with NBS
using NH4NO3 and FeCl3 in CH3CN are summarized in
Table 2.4 The reactions of more active compounds than benzene
with NBS in the presence of 0.1 equiv. of NH4NO3 leaded to
the corresponding monobrominated products in good yields. Di-
phenyl ether, which was sensitive for acids, reacted with NBS
catalyzed by NH4NO3 to give the p-brominated product in
98% yield. When diphenyl ether was treated with bromine at
room temperature without a catalyst in CCl4, the same product
was obtained in a lower yield (63%).5 For benzene and less ac-
tive compounds than benzene, the reactions were performed in
the presence of FeCl3 to give the corresponding brominated
products in good yields. The reaction of nitrobenzene was con-
ducted at 150 ꢁC without the solvent to afford m-bromobenzene
in 95% yield. Bromination at the benzylic positions was hardly
observed in the substrates possessing methyl and ethyl groups.
Furthermore, this method can be applied to the chlorination
First, we examined the bromination of toluene with NBS
using 0.1 equiv. of various protic and Lewis acids at 60 ꢁC
(Table 1). In order to suppress the substitution at benzylic posi-
tion,3 a polar solvent, CH3CN was used. The other solvents such
as DMF and DMSO did not give satisfactory results. Nuclear
brominated products of toluene were obtained together with
the substituted products at the benzylic position. The isomer
distribution of p- and o-bromotoluene varied by the kind of em-
ployed catalyst. Interestingly, the reactions using weak acids
such as NH4NO3, NH4Cl, and PyHOTf proceeded faster than
that using H2SO4, however, the reason is not clear at the present
moment. When toluene was treated with NBS at 60 ꢁC for 8 h in
the presence of NH4NO3, p- and o-bromotoluene were pro-
duced in 62and 38 relative yields, respectively. A trace amount
of benzyl bromide was detected (<1%). The reaction using
NH4Cl gave p- and o-bromotoluene in 57 and 36 relative yields,
respectively within 3 h together with small amounts of o,p-di-
bromotoluene (3%) and benzyl bromide (4%). It was found that
NH4NO3 was the most effective protic acid for nuclear bromi-
nation.
In a series of examined Lewis acids, FeCl3 showed good re-
sults. The reaction completed within 20 min at room tempera-
ture to give p- and o-bromotoluene, and o, p-dibromotoluene
Copyright Ó 2003 The Chemical Society of Japan