NaIO4/KI/NaCl: a new reagent system for iodination of activated aromatics through in situ generation of iodine monochloride

Article abstract of DOI:10.1016/j.tetlet.2006.05.062

A new reagent system consisting of NaIO₄/KI/NaCl in aq AcOH has been found to be effective in iodinating a variety of activated aromatic substrates via in situ-generated iodine monochloride, to furnish iodoaromatics in excellent yields. This iodination procedure has been applied successfully for a cost-effective synthesis of 3,3′-diaminobenzidine, a key intermediate for preparing proton conducting membranes for fuel cell applications, with high yield and a purity of 99.7%.

Full text of DOI:10.1016/j.tetlet.2006.05.062

Tetrahedron Letters 47 (2006) 4793–4796
NaIO4/KI/NaCl: a new reagent system for iodination of activated
aromatics through in situ generation of iodine monochloride
Lourdusamy Emmanuvel, Ravi Kant Shukla, Arumugam Sudalai,*
Suryavanshi Gurunath and Swaminathan Sivaram
National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411 008, Maharashtra, India
Received 3 April 2006; revised 1 May 2006; accepted 11 May 2006
Abstract—A new reagent system consisting of NaIO4/KI/NaCl in aq AcOH has been found to be effective in iodinating a variety of
activated aromatic substrates via in situ-generated iodine monochloride, to furnish iodoaromatics in excellent yields. This iodination
procedure has been applied successfully for a cost-effective synthesis of 3,30-diaminobenzidine, a key intermediate for preparing
proton conducting membranes for fuel cell applications, with high yield and a purity of 99.7%.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
easy and environmentally benign method of iodination.
In this letter, we wish to report an efficient, new and
milder procedure for the iodination of activated aroma-
tics under ambient conditions, using the NaIO4/KI/
NaCl/aq AcOH reagent system.
Aromatic iodo compounds are versatile building blocks
for the preparation of organometallic reagents and some
are potential intermediates for the synthesis of pharma-
ceutical and bioactive molecules.1 They are also useful in
metal-catalyzed (e.g., Heck, Stille and Negishi) cross-
coupling reactions, which are widely employed in C–C,
C–N, etc., bond forming reactions.2 Aryl iodides are
usually more difficult to prepare than the other corre-
sponding aryl halides due to the low electrophilic
strength of iodine. Hence, synthetic methods involving
a source of I+ as the reactive species seem to be the most
convenient procedures for the direct iodination of
arenes. Generally, arenes can be iodinated by iodine in
the presence of a Lewis acid, a hydrogen iodide trap
or most commonly in the presence of an oxidizing agent.
Several reagents reported for iodination of aromatic
compounds include iodine–HgO,3 iodine–tetrabutyl-
ammonium peroxydisulfate,4 n-BuLi–CF3CH2I,5 NIS–
CF3SO3H,6 NIS,7 ICl,8 NH4I–oxoneÒ,9 etc.10 Inaddition,
iodination is carried out under harsh conditions in the
presence of powerful oxidants11 such as nitrogen di-
oxide, diiodine pentoxide, Ag2SO4, HgO, NaIO4, HIO4,
KIO3, CrO3, KMnO4, lead acetate, NaOCl, ammonium
hexanitrocerate, nitric acid, or liquid SO3. Since most of
these reagents are complex, costly or involve toxic heavy
metals, it is desirable to provide a quick, inexpensive,
In connection with our ongoing program on NaIO4 med-
iated oxidations12 as well as our interest in providing a
cheaper method for producing 3,30,4,40-tetraaminobi-
phenyl (4, TAB),13 a monomer for fuel cell applications,
we envisioned a simple route, which might involve iodin-
ation of 2-nitroaniline (1) to give 4-iodo-2-nitroaniline
(2), followed by an Ullmann-type homocoupling of 2
and subsequent reduction (Schemes 1 and 3).
When iodination of 2-nitroaniline (1) was carried out
with alkali metal iodides (KI or NaI) as the iodine
source and NaIO4 as the oxidant in aq AcOH, acting
both as solvent and acid source, iodination occurred
to give 2 in 55% yield. Surprisingly, when NaCl (2 equiv)
NH2
NH2
NO2
Reagent
NO2
AcOH:H2O (9:1),
25 oC, 8 h
I
1
2
Reagent: NaIO4-KI
55%
NaIO4-KI-NaCl 98%
NaIO4-I2-NaCl 95%
Keywords: NaIO4; Iodination; Aryl halides; Amines; Phenols.
*
Corresponding author. Tel.: +91 20 25902174; fax: +91 20
25902676; e-mail: a.sudalai@ncl.res.in
Scheme 1. Iodination using the NaIO4–KI–NaCl system.
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.05.062

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L. Emmanuvel et al. / Tetrahedron Letters 47 (2006) 4793–4796
Table 1. Iodination of 2-nitroaniline (1)a
To establish the scope of the methodology, we subjected
Iodine source Additive Yieldb of 2 (%)
a variety of activated aromatic compounds to nuclear
iodination and the results are shown in Table 2. As
can be seen, activated aromatic compounds were con-
verted to mono or poly-iodoaromatics in quantitative
yields within a short period of time at 25 °C. The reac-
tion of phenol with one molar equivalent of KI led to
a mixture of mono and poly-iodinated products. The de-
gree of poly-iodination is temperature dependent, but
attempts to control iodination by conducting the reac-
tion at 0 °C resulted in low conversion (23%; entry 18)
probably because the NaCl was not oxidized at 0 °C.
Similarly, aniline and substituted anilines were extre-
mely active and gave excellent yields of iodoaromatics.
When anilines with deactivating groups such as NO2,
CO2H, Cl and I were subjected to the iodination,
mono-iodination took place. The reaction was exother-
mic, often the temperature of the reaction reached 50–
55 °C during the addition of KI. Easily oxidizable
groups such as hydroxy, aldehyde or amine were not
affected, but sulfides and o-phenylenediamine, when
subjected to the oxidation, gave sulfoxides and ring
opened product, respectively. Also the method failed
in the case of deactivated and weakly activated aromatic
systems such as arenes and alkyl arenes.
Entry Oxidant
1
2
3
4
5
6
7
8
NaIO4
NaIO4
KIO3
KBrO3
Oxone
HIO4
m-CPBAc KI
KI
KI
KI
KI
KI
KI
—
55
98
98
71
47
87
56
32d
NaCl
NaCl
NaCl
NaCl
NaCl
NaCl
NaCl
NaCl
NaCl
NaCl
NaF
LiBr
NCSc
V2O5
KI
9
NaIO4
NaIO4
NaIO4
NaIO4
NaIO4
NaIO4
NaI
n-Bu4NI
I2
KI
KI
84
82
95e
10
11
12
13
14
58
100f (16:84)g
73
KI
a Reaction conditions: Molar equivalents of oxidant:iodine
source:additive = 1:1:2 unless otherwise stated, 10 ml of AcOH:H2O
(9:1), 25 °C, 8 h.
b Isolated yield by column chromatography.
c m-CPBA = 3-chloroperbenzoic acid; NCS = N-chlorosuccinimide.
d The reaction was carried out at 60 °C; the yield at 25 °C was 5%.
e 0.5 equiv of molecular iodine were used.
f The conversion was determined by GC–MS.
g 4-Iodo-2-nitroaniline: 4-bromo-2-nitroaniline in the ratio 1:6 were
formed.
was added to the reaction mixture, both the reactivity as
well as the yield of 2 (98%) increased significantly.
Encouraged by this observation, we screened several
other oxidants which are known to oxidize alkali metal
halides liberating iodine, and the results are shown in
Table 1. The use of a catalytic amount of NaIO4
(30 mol %) and NaCl (30 mol %) was not fruitful and
when LiBr was employed as the additive, nuclear
bromination was a competitive reaction resulting in
the formation of 4-iodo-2-nitroaniline and 4-bromo-2-
nitroaniline in the ratio of 1:6.
The proposed reaction pathway for the iodination is
shown in Scheme 2. It was established in our earlier
studies12 that NaIO4 oxidizes metal halides (e.g., KI,
NaCl) in the presence of acid to liberate halogens (I2,
Cl2) (Eqs. 1–2). Iodine monochloride,14 presumably
formed from the liberated halogens may act as the
electrophile (Eqs. 3–4). The formation of I–Cl was
confirmed by the fact that styrene, under the same
reaction conditions, yielded a mixture of 1-(1-chloro-2-
iodoethyl)benzene (23%) and 2-iodo-1-phenylethyl
acetate (35%).
Table 2. NaIO4/KI/NaCl-mediated iodination of activated arenesa
Entry
Substrate
KI (equiv)
Product
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
Aniline
2-Iodoaniline
4-Iodoaniline
2-Nitroaniline
2-Chloroaniline
4-Chloroaniline
2-Aminobenzoic acid
1H-Benzo[d]imidazole-2(3H)-one
Anisole
1,3-Diethoxybenzene
1-Methoxynaphthalene
Phenol
2
1
1
1
1
1
1
1
1
2
1
3
2
1
2
2
2
2
2,4-Diiodoaniline
2,4-Diiodoaniline
2,4-Diiodoaniline
4-Iodo-2-nitroaniline
4-Iodo-2-chloroaniline
2-Iodo-4-chloroaniline
2-Amino-5-iodobenzoic acid
5-Iodo-H-benzo[d]imidazole-2(3H)-one
4-Iodoanisole
1,5-Diethoxy-2,4-diiodobenzene
2-Iodo-1-methoxynaphthalene
2,4,6-Triiodophenol
2-Chloro-4,6-diiodophenol
2,4-Dichloro-6-iodophenol
1-(2-Hydroxy-3,5-diiodophenyl)ethanone
Methyl 2-hydroxy-3,5-diiodobenzoate
4-Bromo-2,6-diiodophenol
4-Hydroxy-3,5-diiodobenzaldehyde
2
2
2
8
3
3
8
8
97
89
94
98c
95
96
96
90
87
98
95
99d
98
95
97
96
95
95e
9
12
0.5
8
0.5
0.25
6
1
2
0.5
0.25
10
11
12
13
14
15
16
17
18
2-Chlorophenol
2,4-Dichlorophenol
1-(2-Hydroxyphenyl)–ethanone
Methyl 2-hydroxybenzoate
4-Bromophenol
4-Hydroxybenzaldehyde
a Reaction conditions for monoiodination: Substrate (3 mmol), KI (3 mmol), NaIO4 (3 mmol), NaCl (6 mmol), 10 ml of AcOH: H2O (9:1), 25 °C.
b Isolated yield after column chromatographic purification.
c Diiodination was not observed even with 1.2 equiv of KI.
d KI was added portionwise to maintain the temperature around 50 °C.
e The yield was 23% when the reaction was conducted at 0 °C.

L. Emmanuvel et al. / Tetrahedron Letters 47 (2006) 4793–4796
4795
4I2 + 4H2O + 8AcOK + NaI
8KI + NaIO4 + 8AcOH
8NaCl + NaIO4 + 8AcOH
I2 + Cl2
--------1
-------2
4Cl2 + 4H2O + 8AcONa + NaI
AcOH
2I-Cl
O
------3
------4
8I-Cl + NaIO4 + 8AcOH
I
8
+ 4Cl2 + 4H2O + NaI
H3C
O
Scheme 2. Proposed mechanistic pathway for the iodination.
O2N
H2N
ii
i
NH2
NO2
H2N
I
O2N
2
3
N
iv
N
H2N
H2N
NH2
NH2
N
N
n
5, PBI
4
Scheme 3. Reagents and conditions: (i) Pd2(dba)3, Et3N, toluene, 110 °C, 12 h, 89%; (ii) SnCl2Æ2H2O, HCl, 25–40 °C, 2 h, 73%; (iii) isophthalic acid,
polyphosphoric acid, 120–220 °C, 19 h, 92%.
Finally, the procedure has been applied to the synthesis
of poly-benzimidazole (5, PBI), a polymer used for mak-
ing proton conducting membranes in fuel cell applica-
tions. Thus, 4-iodo-2-nitroaniline (2) underwent
homocoupling15 in the presence of a Pd-catalyst to
afford 3,30-dinitrobenzidine (3) in 89% yield. Reduction
of the nitro groups in 3, followed by polymerization of
the tetramine 4 with isophthalic acid produced PBI (5)
in a 92% yield; the inherent viscosity of 5 was found
to be 1.9 dL/g (Scheme 3).
ice-cold water. The solid was extracted with dichloro-
methane, washed twice with water, dried over anhy-
drous sodium sulfate and concentrated under reduced
pressure. The crude product was purified by column
chromatography.
Acknowledgements
L.E. and R.K.S. thank CSIR, New Delhi, for the award
of research fellowships. Financial Grants from DST,
New Delhi (Sanction No SR/S1/OC-22/2002) are grate-
fully acknowledged. The authors thank Dr. B. D. Kulk-
arni, Head, CE-PD Division, for his constant
encouragement and support.
In conclusion, we have developed a simple procedure for
the iodination of activated aromatic compounds under
ambient conditions using NaIO4/KI/NaCl as a mild,
inexpensive and selective iodinating agent. The method-
ology involves the in situ generation of I–Cl which acts
as the electrophile for the iodination. A remarkable fea-
ture of this system, is that even acid sensitive functional-
ities like anilines can be iodinated quantitatively. The
present procedure was successfully employed for an effi-
cient, cost-effective synthesis of 3,30-diaminobenzidine
(4), an important monomer for fuel cell applications,
with an overall yield of 64% and of 99.7% purity.
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