Efficient and eco-friendly synthesis of iodinated aromatic building blocks promoted by iodine and hydrogen peroxide in water: A mechanistic investigation by mass spectrometry

Article abstract of DOI:10.1016/j.tetlet.2012.07.102

The reaction of aromatic and heteroaromatic compounds with molecular iodine in the presence of aqueous hydrogen peroxide using water without any co-solvent at 50 °C for 24 h produced versatile iodinated organic molecules with potential application in organic synthesis and medicine in very good yields. In addition, a mechanistic investigation for the iodination process was carried out by mass spectrometry.

Full text of DOI:10.1016/j.tetlet.2012.07.102

Tetrahedron Letters 53 (2012) 5372–5375
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Efficient and eco-friendly synthesis of iodinated aromatic building blocks
promoted by iodine and hydrogen peroxide in water: a mechanistic
investigation by mass spectrometry
Rafael D. C. Gallo a, Irlon M. Ferreira a, Gleison A. Casagrande a, Lucas Pizzuti a, Diogo Oliveira-Silva b,
,
⇑
Cristiano Raminelli b,
⇑
a Universidade Federal da Grande Dourados, Faculdade de Ciências Exatas e Tecnologia, Rodovia Dourados-Itahum, Km 12, Dourados 79804-970, MS, Brazil
b Universidade Federal de São Paulo, Departamento de Ciências Exatas e da Terra, Rua Prof. Artur Riedel, 275, Diadema 09972-270, SP, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
The reaction of aromatic and heteroaromatic compounds with molecular iodine in the presence of aque-
ous hydrogen peroxide using water without any co-solvent at 50 °C for 24 h produced versatile iodinated
organic molecules with potential application in organic synthesis and medicine in very good yields. In
addition, a mechanistic investigation for the iodination process was carried out by mass spectrometry.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 21 June 2012
Revised 17 July 2012
Accepted 24 July 2012
Available online 28 July 2012
Keywords:
Iodination reaction
Iodinated compounds
Water as solvent
Mechanistic investigation
Mass spectrometry
Iodinated organic compounds can be considered versatile build-
ing blocks in synthetic organic chemistry finding application as
electrophilic partners in several cross-coupling processes, includ-
ing, for example, Sonogashira,1 Stille,2 Suzuki,3 and Buchwald–Har-
twig4 reactions. Besides, iodinated organic substrates have found
use in iodine–lithium5 and iodine–magnesium6 exchange reac-
tions. The aforesaid transformations are useful in the construction
of carbon-carbon and carbon-heteroatom bonds,1–6 which are
broadly employed in total syntheses of complex molecules7 and
in the production of polymers of importance in materials science.8
Furthermore, a significant number of iodinated organic compounds
are biologically active substances with different sorts of activities9
and have found applications in targeted molecular radiotherapy10
and as contrast media for diagnostic imaging.11 In this context,
turning our attention to the approaches to the synthesis of iodin-
ated molecules one can mention the diazotization–iodination reac-
tion sequence12 and the electrophilic iodination using iodine or
iodide in combination with an oxidizer13 as important alternatives.
Following the growing concern over environmental pollution and
sustainable development, oxidative iodination methods in aqueous
media have experienced a remarkable growth.14 One of the most
useful protocols that uses molecular iodine and hydrogen peroxide
in aqueous medium has been employed in the iodofunctionaliza-
tion of relatively simple aromatic compounds.15 To the best of
our knowledge, the I2/H2O2 (30%) system in the absence of an
acidic catalyst using water without any co-solvent has not been ex-
plored in the preparation of partially and completely iodinated aro-
matic and heteroaromatic compounds. Accordingly, having in
mind the requirement for iodinated aromatic and heteroaromatic
compounds for synthetic purposes, along with the great applicabil-
ity of iodinated compounds in medicine, we focused on the devel-
opment of an efficient and eco-friendly methodology which uses
molecular iodine as the iodine source of choice, aqueous hydrogen
peroxide as a safe and environmentally accepted oxidizer and
water as a non-flammable and innocuous solvent, in order to pro-
duce partially and completely iodinated aromatic and heteroaro-
matic compounds with potential application in organic synthesis
and medicine. In this communication we also present findings
about a mechanistic investigation by mass spectrometry involving
the iodination process developed.
Initially, for producing triiodinated aromatic and heteroaro-
matic compounds, we allowed the reaction of phenol (1a) with
1.5 equiv of iodine and 3 equiv of hydrogen peroxide (30%) in
water at 50 °C for 24 h and obtained 2,4,6-triiodophenol (2a) in a
65% yield (Table 1, entry 1).16 In an attempt to improve the ob-
tained yield (entry 1), we performed the same transformation
⇑
Corresponding authors. Tel.: +55 11 3319 3474; fax: +55 11 4043 6428.
E-mail address: raminelli@unifesp.br (C. Raminelli).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.07.102

R. D. C. Gallo et al. / Tetrahedron Letters 53 (2012) 5372–5375
5373
Table 1
Synthesis of iodinated aromatic and heteroaromatic compounds (2) by the reaction of aromatic and heteroaromatic compounds (1) with iodine and hydrogen peroxide in water at
50 °C for 24 ha
Entry Aromatic and heteroaromatic
Iodinated aromatic and heteroaromatic
compound (2)
I2/H2O2
equivalents
Mp (oC) [Mp (oC) from
literature]
Isolated yield
(%)
compound (1)
I
OH
153–154 [152–153]17
153–154 [152–153]17
175–176 [177–179]17
65
83
80
0
I
I
I
I
OH
OH
NH2
Br
1
1.5/3
2/4
1a
2a
2a
2b
I
I
OH
2
1a
I
I
NH2
3
2/4
1b
I
I
Br
4
2/4
1c
2c
I
N
N
I
N
5
2/4
180–183 [180–183]18
97
I
I
H
N
H
1d
2d
H3CO
H3CO
198–199 [200–201]19
198–199 [200–201]19
93
96
OCH3
OCH3
I
OCH3
6
7
1/2
2/4
1e
1e
2e I
2e I
H3CO
H3CO
I
OCH3
I
I
I
S
2f
8
9
S
1f
1/2
2/4
0.5/1
1/2
2/4
2/4
31–32 [38]20
32
90
<5
50
97
82
I
I
S
2f
S
1f
31–32 [38]20
OCH3
OCH3
OCH3
OCH3
NHBoc
10
11
12
13
41–42 [43–45]15c
41–42 [43–45]15c
41–42 [43–45]15c
134–136 [143.7–147.0]21
1g
1g
1g
1h
2g
OCH3
OCH3
NHBoc
I
I
I
2g
2g
2h
OCH3
OH
OCH3
OH
O
H
O
H
14
15
2/4
2/4
179–180 [179–180]22
140–142 [140–141]23
90
70
1i
I
2i
N
N
I
N
N
Ts
Ts
1j
2j
a
Reaction conditions: 2 mmol of 1, the indicated amount of I2, the indicated amount of H2O2 (30%) and 10 mL of H2O were maintained under stirring at 50 °C for 24 h.
using 2 equiv of iodine and 4 equiv of hydrogen peroxide (30%). In
83% (entry 2). In order to examine the scope and limitations of the
this case, the triiodinated phenol 2a was isolated in a good yield of
process, we carried out the reaction of aniline (1b) with 2 equiv of

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R. D. C. Gallo et al. / Tetrahedron Letters 53 (2012) 5372–5375
iodine and 4 equiv of hydrogen peroxide (30%) using water as sol-
vent at 50 °C. After 24 h, we obtained 2,4,6-triiodoaniline (2b) in an
80% yield (entry 3). As can be seen in Table 1, entry 4, 2-bromo-
1,3,5-triiodobenzene (2c) was not obtained and the starting mate-
rial 1c was recovered. This experiment shows that the success of
our reaction depends dramatically on the electronic effects pro-
moted by the substituent attached to the aromatic ring. On the
other hand, when we carried out the transformation employing
imidazole (1d), triiodoimidazole (2d) was produced in an almost
quantitative yield of 97% (entry 5). Afterwards, for producing diio-
dinated aromatic and heteroaromatic compounds, we allowed the
reaction of the electron-rich 1,3-dimethoxybenzene (1e) with
1 equiv of iodine and 2 equiv of hydrogen peroxide (30%) in water
at 50 °C for 24 h and obtained 1,5-diiodo-2,4-dimethoxybenzene
(2e) in an excellent yield of 93% (entry 6). No significant improve-
ment in the isolated yield of compound 2e was obtained when we
allowed 1,3-dimethoxybenzene (1e) to react with 2 equiv of iodine
and 4 equiv of hydrogen peroxide (30%) in water at 50 °C for 24 h
(entry 7). By performing the reaction between thiophene (1f) and
1 equiv of iodine and 2 equiv of hydrogen peroxide (30%) in water
at 50 °C for 24 h, 2,5-diiodothiophene (2f) was prepared in only
32% yield (entry 8). In order to improve the yield of this reaction
(entry 8), we carried out the same transformation using 2 equiv
of iodine and 4 equiv of hydrogen peroxide (30%) and obtained
2,5-diiodothiophene (2f) in a very good yield of 90% (entry 9). Ulti-
mately, for producing monoiodinated aromatic and heteroaromatic
compounds, we allowed anisole (1g) to react with 0.5 equiv of io-
dine and 1 equiv of hydrogen peroxide (30%) in water at 50 °C for
24 h and obtained 4-iodoanisole (2g) in a very low yield (<5%) (en-
try 10). Trying to improve the yield of this iodofunctionalization
(entry 10), we performed the same transformation using 1 equiv
of iodine and 2 equiv of hydrogen peroxide (30%) and produced
4-iodoanisole (2g) in only 50% yield (entry 11). Next, we allowed
anisole (1g) to react with 2 equiv of iodine and 4 equiv of hydrogen
peroxide (30%) in water at 50 °C. After 24 h, we obtained 4-iodoan-
isole (2g) in an excellent 97% yield (entry 12). We did not observe
the formation of ortho-iodinated anisoles in the reactions pre-
sented in entries 10–12. These experiments show that our reaction
is rather sensible to the steric effect exerted by the substituent
bonded to the aromatic ring. In agreement with this finding, when
we subjected N-Boc-aniline (1h) to the reaction with 2 equiv of io-
dine and 4 equiv of hydrogen peroxide (30%) in water at 50 °C for
24 h, 4-iodo-N-Boc-aniline (2h) was isolated in an 82% yield (entry
13). Treatment of vanillin (1i) with excesses of molecular iodine
and hydrogen peroxide (30%) in water at 50 °C for 24 h led to the
formation of iodovanillin (2i) in a very good yield of 90% (entry
14). When 1-tosyl-imidazole (1j) was treated with 2 equiv of io-
dine and 4 equiv of hydrogen peroxide (30%) in water at 50 °C for
24 h, 2-iodo-1-tosyl-imidazole was produced in a 70% yield (2j)
(entry 15).
mechanistic investigations.25 Thus, ‘ion fishing’ mass spectrome-
try experiments were carried out to identify the transient species
and to follow the progress of our reaction. However, when ESI-MS
analyses were conducted in the positive mode (ESI+), no species
containing I+ was identified, even when we performed experi-
ments employing only molecular iodine (1 equiv) and hydrogen
peroxide (30%) (2 equiv) in water. On the other hand, the iodide
ion (IÀ, m/z = 127) and other negative structures (I3À, m/z = 381;
[IÀH2O]À, m/z = 145 and [IÀH2O2]À, m/z = 161) were detected in
the negative mode (ESIÀ). The monitoring assays of the ions were
realized during the iodination process (0, 1, 3 and 18 h) and it
was observed for the continuous increase of abundance of the an-
ions. Nearly the same profile of intermediates containing iodine
was observed in similar experiments employing phenol (1a) as
nucleophile. In all entries the reaction mixtures presented pH
ꢀ4.26 By these results we cannot overrule the most accepted reac-
tion pathway for electrophilic iodination of organic compounds,
which involves electrophilic iodine species,13–15 once the by-
product for the oxidation process of I2 by H2O2 in water (pH
ꢀ4) would presumably be IÀ and species bearing this negative
ion. Further investigations are being conducted in order to char-
acterize other involved intermediates and elucidate the reaction
mechanism.
In summary, an efficient and eco-friendly reaction for the prep-
aration of iodinated aromatic and heteroaromatic compounds has
been developed and versatile organic molecules with potential
application in organic synthesis and medicine were produced in
very good yields, under relatively mild reaction conditions, which
include molecular iodine, hydrogen peroxide (30%) and water as
solvent. Additionally, a mechanistic investigation by ESI-MS was
carried out. Although no species containing I+ has been detected,
the iodide ion (IÀ) and some negative species related with this
ion (I3À, [I-H2O]À and [I-H2O2]À) were detected. These results are
important findings concerning the reaction mechanism for electro-
philic iodination of organic compounds.
Acknowledgments
We gratefully acknowledge the Conselho Nacional de Desen-
volvimento Científico e Tecnológico (CNPq), the Fundação de
Amparo à Pesquisa do Estado de São Paulo (FAPESP) and the Fun-
dação de Apoio ao Desenvolvimento do Ensino, Ciência e Tecnolo-
gia do Estado de Mato Grosso do Sul (FUNDECT) for financial
support. We also acknowledge Shimadzu do Brasil for the
partnership.
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black solid; mp 31–32 °C (lit.20 mp 38 °C); 1H NMR 300 MHz (DMSO-d6, ppm):
7.1 (s, 2H); 13C NMR 75 MHz (DMSO-d6, ppm): 138.9, 79.4; IR (KBr, cmÀ1):
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off-white solid; mp 140–142 °C (lit.23 mp 140-141 °C); 1H NMR 500 MHz
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7.1 (d, J = 1.8 Hz, 1H), 2.5 (s, 3H); 13C NMR 125 MHz (CDCl3, ppm): 146.7, 133.8,
132.9, 130.2, 128.4, 123.3, 84.3, 21.8; IR (KBr, cmÀ1): 3440, 3150, 1383, 1079,
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16. General procedure for iodination of aromatic and heteroaromatic compounds (2):
To a suspension of the appropriate aromatic or heteroaromatic compound (1a–
j) (2 mmol) and molecular iodine (1–4 mmol) in distilled water (10 mL) was
added hydrogen peroxide 30% (m/v) (2–8 mmol). The mixture was maintained
under stirring at 50 °C for 24 h. Afterwards, a saturated sodium thiosulfate
aqueous solution (10 mL) was added to the mixture, which was extracted with
ethyl acetate (3 Â 20 mL). The organic phase was dried over MgSO4. After
filtration, the solvent was evaporated under reduced pressure. The residue was
purified by column chromatography on silica gel using an appropriate eluent,
affording the desired product (2a–j). 2,4,6-Triiodophenol (2a) (CAS number: 609-
23-4): Yield 0.7831 g (83%); yellowish solid; mp 153–154 °C (lit.17 mp 152–
153 °C); 1H NMR 300 MHz (CDCl3, ppm): 7.9 (s, 2H), 5.8 (s, 1H); 13C NMR
75 MHz (CDCl3, ppm): 153.7, 146.4, 83.3, 83.2; IR (KBr, cmÀ1): 3439, 3053,
1435, 1370, 1136, 533; EI-MS (m/z,%): 472 (100.0), 218 (8.3), 127 (7.3). 2,4,6-
Triiodoaniline (2b) (CAS number: 24154-37-8): A 10% NaHCO3 solution (20 mL)
was added to the mixture before extraction; yield 0.7536 g (80%); brownish
solid; mp 175–176 °C (lit.17 mp 177–179 °C); 1H NMR 500 MHz (DMSO-d6,
ppm): 7.9 (s, 2H), 5.2 (s, 2H); 13C NMR 125 MHz (DMSO-d6, ppm): 146.9, 145.3,
82.8, 78.6; IR (KBr, cmÀ1): 3396, 3295, 1606, 1436, 860, 536; EI-MS (m/z,%): 471
(100.0), 344 (12.5), 217 (7.3), 127 (8.0). 2,5-Diiodothiophene (2f) (CAS number:
625-88-7): To a mixture of thiophene (2f) (2 mmol) in distilled water (10 mL)
26. General procedures for mass spectrometry experiments: experiment I: A solution
of molecular iodine (4 mmol) and hydrogen peroxide 30% (m/v) (8 mmol) in
distilled water (10 mL) was subjected to magnetic stirring and four samples
were collected: t = 0 h (prior to heating); t = 1 h (50 °C); t = 3 h (50 °C) and
t = 18 h (50 °C). Each sample was immediately analysed by ESI-MS. Experiment
II:
A solution of phenol (1a) (2 mmol), molecular iodine (4 mmol) and
hydrogen peroxide 30% (m/v) (8 mmol) in distilled water (10 mL) was
subjected to magnetic stirring and four samples were collected: t = 0 h (prior
to heating); t = 1 h (50 °C); t = 3 h (50 °C) and t = 18 h (50 °C). Each sample was
immediately analysed by ESI-MS. The samples collected from the reaction
mixtures presented pH ꢀ4 in all experiments. ESI-MS analyses: The samples
were analysed on a triple-quadrupole mass spectrometer LCMS-8030 equipped
with electrospray ionization and coupled to a UFLC-XR Prominence liquid
chromatography system (Shimadzu). The injection volume was 0.1
lL and
ultrapure water used as mobile phase (50 L/min). The ion source was set as
l
follows: DL = 100 °C, heat block = 200 °C, nebulizing gas = 3 L/min, drying
gas = 15 L/min, voltage = 2.5 kV and À2.0 kV (ESI+ and ESIÀ, respectively).
The mass/charge ratios were detected in scan (m/z = 100-700) and product ion
scan (m/z = 50–700) modes, in both ESI polarities.