Comparative study of the reactivity of iodinating agents in solution and solid phase

Article abstract of DOI:10.1007/s11178-005-0256-1

The results of reactions of a series of aromatic substrates with iodine, iodine(I) chloride, and N-iodosuccinimide in solution and solid phase were compared for the first time. In all cases, the general relations holding in the iodination process were similar. Iodine(I) chloride was found to chlorinate anthracene. A high efficiency of solid-phase iodination of β-diketones was demonstrated using dibenzoylmethane as an example.

Full text of DOI:10.1007/s11178-005-0256-1

Russian Journal of Organic Chemistry, Vol. 41, No. 6, 2005, pp. 855–859. Translated from Zhurnal Organicheskoi Khimii, Vol. 41, No. 6, 2005,
pp. 876–880.
Original Russian Text Copyright © 2005 by Krasnokutskaya, Lesina, Gorlushko, Filimonov.
Comparative Study of the Reactivity of Iodinating Agents
in Solution and Solid Phase
E. A. Krasnokutskaya, Yu. A. Lesina, D. A. Gorlushko, and V. D. Filimonov
Tomsk Polytechnical University, pr. Lenina 30, Tomsk, 634050 Russia
e-mail: e_krasnokutskaya@mail.ru
Received May 27, 2004
Abstract—The results of reactions of a series of aromatic substrates with iodine, iodine(I) chloride, and
N-iodosuccinimide in solution and solid phase were compared for the first time. In all cases, the general
relations holding in the iodination process were similar. Iodine(I) chloride was found to chlorinate anthracene.
A high efficiency of solid-phase iodination of β-diketones was demonstrated using dibenzoylmethane as
an example.
Aromatic iodides are indispensable building blocks
in organic synthesis, and some their derivatives are
important drugs and diagnostics [1]. A promising line
in modern organic synthesis includes carrying out
chemical reactions in a solid phase without a solvent,
i.e., so-called solvent-free processes. However, ex-
amples of such processes in the field of electrophilic
aromatic iodination are almost unknown. Only re-
cently, some information has been published on the
solid-phase iodination of aromatic compounds with
tetramethylammonium dichloroiodate (Me4N+ ICl2–) [2]
and iodine in the presence of bismuth(III) nitrate [3].
Unfortunately, there are no data on general relations
holding in the solid-phase iodination and on the
behavior under these conditions of iodinating agents
commonly used in liquid-phase processes.
with highly nucleophilic phenoxides (see, e.g., [4]). In
fact, sodium phenoxide effectively reacted with iodine
in the solid phase to afford 2,4,6-triiodophenol (IIIa)
in nearly quantitative yield. More active iodine(I)
chloride vigorously reacted with durene (I) in the
absence of a solvent. The reaction was exothermic, so
that the mixture melted, and gaseous HCl and ICl
evolved. The process terminated in 15–20 min, and
subsequent grinding of the mixture in a mortar did not
lead to an appreciable change in its composition. How-
ever, the conversion of initial arene I was incomplete
even when the ICl:I ratio was 2:1, and the yield of
iododurene (Ia) did not exceed 40%. We have found
that preliminary mixing ICl with silica gel and sub-
sequent contact of the resulting mixture with durene (I)
ensures smooth iodination and high conversion of the
substrate and prevents loss of ICl. In this way, iodo-
durene (Ia) was isolated in 88% yield.
The goal of the present work was to elucidate gen-
eral relations holding in solid-phase iodination at room
temperature and under mechanochemical activation
with such iodinating agents as molecular iodine,
iodine(I) chloride, and N-iodosuccinimide (NIS). As
substrates we used durene (I), biphenyl (II), phenol
(III), carbazole (IV), and anthracene (V), i.e., com-
pounds for which the results of liquid-phase iodination
with the same reagents have been well documented.
The results of our comparative experiments are given
in table.
The reaction of carbazole (IV) with ICl both in the
presence and in the absence of silica gel was accom-
panied by oxidation to produce an inseparable mixture
of products among which 3-iodo- and 3,6-diiodocar-
bazoles were detected by thin-layer chromatography.
Solid-phase reaction of anthracene (V) with ICl
attracted a specific interest, taking into account that
iodine(I) chloride in organic solvents or sulfuric acid
acts as chlorinating rather than iodinating agent [5, 6].
When anthracene (V) was brought into a contact with
ICl, the latter instantaneously decomposed with evolu-
tion of iodine vapor, while the substrate was converted
into a mixture of 9-chloro- and 9,10-dichloroanthra-
cenes Va and Vb (TLC data). The same result was
Molecular iodine turned out to be inactive with
respect to all the examined substrates in the solid
phase. Analogous behavior in the absence of an oxi-
dant is typical of reactions in solution. On the other
hand, it is well known that iodine is capable of reacting
1070-4280/05/4106-0855 © 2005 Pleiades Publishing, Inc.

KRASNOKUTSKAYA et al.
856
Iodination of arenes I–VII with ICl and NIS in solution and under solvent-free conditions
Time, Tempera- Substrate–reagent
Substrate/reagent
Solvent
No solvent
Product, yield, %
ture, °C
molar ratio
h
Phenol (III)/I2, NaOH
Durene (I)/ICl
0.5
2.5
20
0.1:3.6
2,4,6-Triiodophenol (IIIa), 70
Iododurene (Ia), 76
Aqueous H2SO4,
10 vol % [16]
10:10
1000
Durene (I)/ICl
Durene (I)/ICla
No solvent
" "
1.0
1.0
1.5
0.5
20
20
20
20
1:2
.01:1.4
.01:1.5
1:2
Iododurene (Ia), 40
Iododurene (Ia), 88
Carbazole (IV)/ICl
Carbazole (IV)/ICl
Acetonitrile [11]
No solvent
3-Iodocarbazole (IVa), 63
Mixture of 3- and 3,6-diiodo-
carbazoles; strong tarring
Anthracene (V)/ICl
Anthracene (V)/ICl
Acetonitrile [6]
2.5
3.0
20
1.26:1.00
10:40
9-Chloroanthracene (Va), 66.8;
9,10-dichloroanthracene (Vb), 4.52
Aqueous H2SO4,
10 vol % [5]
1000
9,10-Dichloroanthracene (Vb), 37
Anthracene (V)/ICl
Phenol (III)/ NIS
No solvent
EtOH–H2SO4
No solvent
0.5
0.5
0.5
20
20
20
20
20
20
20
25
1:4
1:3
9,10-Dichloroanthracene (Vb), 55
2,4,6-Triiodophenol (IIIa), 64
2,4,6-Triiodophenol (IIIa), 75
Iododurene (Ia), 76
Phenol (III)/ NIS
1:3
Durene (I)/NIS
AcOH–H2SO4 [9] 0.5
1:1
Durene (I)/NIS–H2SO4
Biphenyl (II)/NIS
Biphenyl (II)/NIS–H2SO4
Carbazole (IV)/NIS
No solvent
0.5
3.0
1.5
2.0
.01:1.2
1:2
Iododurene (Ia), 75
AcOH/H2SO4 [9]
No solvent
4,4'-Diiodobiphenyl (IIa), 75
4-Iodobiphenyl (IIb), 65
.01:1.2
1:2
CHCl3–AcOH,
3:1 [10]
6-Iodocarbazole (IVa), 35;
3,6-diiodocarbazole (IVb), 65
Carbazole (IV)/NIS–H2SO4
Biphenyl (II)/NIS–TsOH
No solvent
0.5
20
1:4
Mixture of 3- and 3,6-diiodo-
carbazoles; strong tarring
" "
2.0
2.0
0.5
20
20
20
.01:1.2
.01:1.1
.01:1.2
4-Iodobiphenyl (IIb), 60
Naphthalene (VI)/NIS–TsOH " "
Acetanilide (VII)/NIS–TsOH " "
1-Iodonaphthalene (VIa), 50
p-Iodoacetanilide (VIIa), 93
a
In the presence of silica gel.
obtained in the presence of silica gel. In the reaction
of V with 4 equiv of ICl we succeeded in isolating
compound Vb in 55% yield (see table). Thus iodine(I)
chloride acts as chlorinating agent with respect to
anthracene (V) both in solution and in solid phase,
which is important for understanding the mechanism
of this reaction.
derivative IIIa (yield 75–80%). For comparison, we
also examined the reaction of phenol (III) with
N-bromosuccinimide (NBS) under analogous condi-
tions. The reaction with NBS was much more
vigorous, and bromine vapor instantaneously evolved.
To make the process smoother, a required amount of
NBS was added in three portions; 2,4,6-tribromo-
phenol was isolated in 85–90% yield.
N-Iodosuccinimide (NIS) has long been known as
iodinating agent. It is effective toward a wide spectrum
of substrates, from phenols and anilines to nitroben-
zene which is deactivated to electrophilic substitution.
It is also known that NIS exhibits the maximal activity
in strongly acidic medium, e.g., in trifluoromethane-
sulfonic acid [7] and sulfuric acid [8]. Phenol reacts
with NIS under solvent-free conditions to give triiodo
N-Iodosuccinimide turned out to be inactive toward
substrates I, II, IV, and V in the solid phase, and the
initial compounds were recovered from the reaction
mixtures. However, addition of a catalytic amount of
sulfuric acid strongly activated the iodinating agent.
By reactions of durene (I) and biphenyl (II) with NIS
preliminarily ground with three drops of H2SO4 we
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COMPARATIVE STUDY OF THE REACTIVITY OF IODINATING AGENTS
857
obtained 75% of iododurene (Ia) and 65% of 4-iodo-
biphenyl, respectively. Under analogous conditions,
anthracene was slowly oxidized to anthraquinone.
proposed procedure. Iodide VIIIa prepared by iodo-
debromination of the corresponding bromo-β-diketone
[12] or by electrochemical iodination [13] spontane-
ously loses iodine at an appreciable rate when contacts
with a number of solvents (acetone, benzene, chloro-
form, methylene chloride). The solid-phase procedure
allows us to minimize operations in solvents and
isolate pure product VIIIa.
Despite acid activation, the reactivity of N-iodo-
succinimide under solvent-free condition was lower
than in solution. Nitrobenzene and p-nitrotoluene
remained unchanged upon grinding with NIS in the
presence of H2SO4, whereas nitroarenes were success-
fully iodinated with NIS in sulfuric acid solution at
room temperature [8, 9]. In addition, the system NIS–
H2SO4 showed a low selectivity with respect to carba-
zole (IV). Treatment of carbazole with an equimolar
amount of NIS afforded a mixture of 3-iodo- and
3,6-diiodocarbazoles, the substrate conversion was not
complete (TLC), and the reaction was accompanied by
tarring. It should be noted that iodination of carbazole
in solution is often characterized by low selectivity as
well [10, 11].
O
O
VIII
O
O
NIS, 20°C, 97%
I
VIIIa
We were the first to demonstrate that N-iodo-
succinimide can be activated by p-toluenesulfonic acid
(molar ratio 1:1) under solvent-free conditions. In
doing so, we succeeded in reducing side tar formation
to an appreciable extent, while the efficiency of the
iodinating system remained unchanged. The other
relations also did not change: anthracene underwent
slow oxidation rather than iodination, biphenyl was
smoothly converted into 4-iodobiphenyl, and carbazole
gave rise to a mixture of iodo derivatives which were
difficult to separate (see table).
The results of our study led us to conclude that
general relations holding in the iodination with I2, ICl,
and NIS in solution are also typical of reactions
performed under solvent-free conditions. These are the
following: (1) molecular iodine is capable of iodinat-
ing only phenoxide and is inactive toward arenes;
(2) ICl reacts with anthracene to give chloro rather
than iodo derivative; and (3) the iodinating power of
NIS increases in the presence of strong acids. More-
over, in some cases the solid-phase iodination proce-
dure is obviously more advantageous due to its
simplicity, mild conditions, high reaction rate, and
minimization of operations involving organic solvents.
The solvent-free iodination of naphthalene (VI)
with NIS in the presence of p-toluenesulfonic acid
gave 50% of 1-iodonaphthalene (VIa); this reaction
cannot be effected under catalysis by sulfuric acid. The
reaction was highly selective: according to the 13C
NMR data, the ratio of 1- and 2-iodonaphthalenes was
about 95:5. It should be noted that spontaneous libera-
tion of iodine was observed while recording the NMR
spectra of VIa in CDCl3 and CHCl3. Under analogous
conditions, the iodination of acetanilide (VII) gave
93% of 4-iodoacetanilide (VIIa) with high para
selectivity.
EXPERIMENTAL
The progress of reactions was monitored, and the
purity of products was checked, by TLC on Sorbfil
PTsKh-P-A-UF and Silufol UV-254 plates; spots were
visualized under UV light; the following solvents were
used as eluents: hexane (anthracene, durene), benzene
(biphenyl, p-nitrotoluene, phenol, dibenzoylmethane),
and hexane–diethyl ether (2:1) (carbazole).
1
The H and 13C NMR spectra were recorded on
N-Iodosuccinimide was highly effective in the
monoiodination of dibenzoylmethane (VIII) in the
absence of acid catalyst. Grinding of compound VIII
with NIS over a period of 10 min resulted in almost
complete conversion of the substrate, and pure diben-
zoyl(iodo)methane (VIIIa) was isolated in 97% yield.
This reaction is the first example of solid-phase
iodination of β-diketones, and it clearly demonstrates
synthetic, ecological, and economic advantages of the
a Bruker Avante-300 spectrometer (300 MHz) using
HMDS as internal reference and CDCl3 as solvent. The
melting points were determined on a Boetius melting
point apparatus.
The products were identified by comparing their
analytical and physical parameters with those of
authentic samples (no depression of the melting points
was observed on mixing).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 41 No. 6 2005

KRASNOKUTSKAYA et al.
858
Iodine(I) chloride was prepared by the procedure
an agate mortar until a uniform material was obtained,
0.14 g (1 mmol) of acetanilide was added, and the
mixture was stirred for about 5 min. During this
procedure the mixture melted and then crystallized in
30 min. The mixture was treated with 25 ml of a 10%
solution of Na2SO3, and the precipitate was filtered off,
washed with water on a filter, and dried. Yield of
4-iodoacetanilide 0.24 g (93%), colorless crystals,
described in [14]; it was purified and analyzed accord-
ing to [15]. Iodine of ultrapure grade, sulfuric and
acetic acids of analytical grade, p-toluenesulfonic acid
monohydrate of pure grade, N-bromosuccinimide of
chemically pure grade, and Silicagel L (40/100 μm)
were used. N-Iodosuccinimide was prepared by the
procedure reported in [5].
1
mp 179–180°C [17]. H NMR spectrum, δ, ppm:
General procedure for reaction of arenes with
ICl. Iodination of durene (I) in the presence of silica
gel. Preliminarily frozen iodine(I) chloride, 0.5 g
(2.8 mmol), and silica gel, 2.5 g, were thoroughly
ground in an agate mortar until a uniform mixture was
obtained. Durene, 0.27 g (2 mmol), was then added,
and the mixture was ground for 45 min, left to stand
for 15 min, and dissolved in acetonitrile. Silica gel was
filtered off, the filtrate was poured into 10% aqueous
Na2SO3, and the precipitate was filtered off, dried in
air, and recrystallized from glacial acetic acid. Yield of
iododurene 0.45 g (88%), mp 77–78°C; published data
[16]: mp 76–78°C.
2.163 s (3H, COCH3), 7.28 d (2H, Harom, J = 9 Hz),
7.6 d (2H, Harom, J = 8.7 Hz). 13C NMR spectrum, δC,
ppm: 26.24, 87.15, 122.2, 136.52, 138.02, 169.3.
Iodination of naphthalene (VI) with N-iodosuc-
cinimide in the presence of p-toluenesulfonic acid.
A mixture of 0.5 g (2.2 mmol) of NIS and 0.42 g
(2.2 mmol) of p-toluenesulfonic acid was ground in
an agate mortar until a uniform material was obtained,
0.26 g (2 mmol) of naphthalene was added, and the
mixture was ground for 10 min. The mixture was kept
for 2 h, treated with 15 ml of a 10% solution of
Na2SO3, and extracted with methylene chloride. The
extract was dried over MgSO4 and evaporated under
reduced pressure to obtain 0.3 g of an oily substance
which was subjected to column chromatography using
hexane as eluent. Yield of VIa 0.25 g (50%), colorless
oily substance. 13C NMR spectrum, δC, ppm: 99.8,
126, 126.6, 126.9. 127.9, 128.1, 128.7, 129.6, 132.3,
137.6. The spectrum also contained weak signals at
δC 92.5, 126.65, 129.86, 135.02, and 136.92 ppm,
belonging to 2-iodonaphthalene (~5%).
General procedure for reaction of arenes with
N-iodosuccinimide. Iodination of biphenyl (II) with
NIS–H2SO4. Three drops of sulfuric acid were added
to 0.5 g (2.2 mmol) of NIS, the mixture was ground in
an agate mortar until a uniform material was obtained,
0.3 g (2 mmol) of biphenyl was added, and the mixture
was ground for 10 min and was left to stand for 1.5 h.
The mixture was treated with a 10% aqueous solution
of sodium sulfite, and the precipitate was filtered off,
dried in air, and recrystallized from ethanol. Yield
of 4-iodobiphenyl 0.36 g (65%), colorless crystals,
mp 112–113°C [5].
Iodination of dibenzoylmethane (VIII) with
N-iodosuccinimide. A mixture of 0.22 g (1 mmol) of
dibenzoylmethane and 0.27 g (1.2 mmol) of NIS was
ground in an agate mortar for 10 min. The mixture was
then dissolved in 4 ml of acetonitrile, the solution was
poured into water, and the precipitate was filtered off,
washed with water, and dried in a desiccator. Yield
0.34 g (97%) of dibenzoyl(iodo)methane, light yellow
crystals, mp 104–105.5°C; published data [12]:
mp 100°C. 13C NMR spectrum, δC, ppm: 34.4, 129.6,
129.7, 133.6, 134.6, 190.5. 1H NMR spectrum, δ, ppm:
6.89 s (1H, CH), 7.96 – 7.39 m (10H, Harom).
Iodination of phenol (III) with iodine in the pres-
ence of sodium hydroxide. A mixture of 0.09 g
(1 mmol) of phenol and 0.5 g (12.5 mmol) of NaOH
was ground in an agate mortar. Silica gel, 0.2 g, and
iodine, 0.91 g (3.6 mmol), were added to the resulting
colorless crystalline material, and the mixture was
ground for 30 min and treated with dilute hydrochloric
acid. The precipitate was filtered off and dried. The
organic products were dissolved in benzene, silica gel
was filtered off, and the filtrate was evaporated under
reduced pressure. The residue was subjected to column
chromatography using benzene as eluent to isolate
0.326 g (70%) of 2,4,6-triiodophenol with mp 156–
157°C [17].
This study was performed under financial support
by the Ministry of Science and Education of the Rus-
sian Federation (project no. E02-5.0-176).
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