A comparison of microwave-accelerated and conventionally heated iodination reactions of some arenes and heteroarenes, using ortho-periodic acid as the oxidant

Article abstract of DOI:10.3390/10020401

A fast and simple method for the oxidative iodination of some activated arenes and heteroarenes, either under microwave irradiation or by conventional heating, is reported, using diiodine and ortho-periodic acid as the oxidant. The reactions were carried out in hot 95% ethanol under a reflux condenser. For the microwave assisted reactions, the reaction times were always notably shortened, but the yields were nearly the same as those afforded by the conventional method.

Full text of DOI:10.3390/10020401

Molecules 2005, 10, 401-406
molecules
ISSN 1420-3049
http://www.mdpi.org
A Comparison of Microwave-Accelerated and Conventionally
Heated Iodination Reactions of Some Arenes and Heteroarenes,
Using ortho-Periodic Acid as the Oxidant†
Maciej Sosnowski and Lech Skulski *
Chair and Laboratory of Organic Chemistry, Faculty of Pharmacy, Medical University, 1 Banacha
Street, PL 02-097 Warsaw, Poland.
† This short paper was presented at the Eighth Electronic Conference on Synthetic Organic Chemistry
(ECSOC-8, http://www.mdpi.net/ecsoc-8), November 1-30, 2004 (paper E006).
* To whom correspondence should be addressed. E-mail: lechskulski@yahoo.com Tel./Fax: +(48) 22
5720643;
Received: 8 November 2004; in revised form: 18 November 2004 / Accepted: 18 November 2004 /
Published: 28 February 2005
Abstract: A fast and simple method for the oxidative iodination of some activated arenes
and heteroarenes, either under microwave irradiation or by conventional heating, is
reported, using diiodine and ortho-periodic acid as the oxidant. The reactions were carried
out in hot 95% ethanol under a reflux condenser. For the microwave assisted reactions, the
reaction times were always notably shortened, but the yields were nearly the same as those
afforded by the conventional method.
Keywords: Oxidation, ortho-periodic acid as oxidant, oxidative iodination of activated
arenes and heteroarenes, diiodine, microwave irradiation
Introduction
The use of microwave irradiation to simplify and improve classic organic reactions has become a
very popular technique, because it sometimes results in shorter reaction times, higher yields and
cleaner reactions [1-4]. A number of reflux systems have been developed in an effort to use solvents in
microwave assisted organic synthesis without the risk of explosion, since they work at atmospheric

Molecules 2005, 10
402
pressure and flammable organic vapors cannot be released into the microwave cavity [1-4] – precisely
with such a reflux system, with using also the focused monomode microwave irradiation, some
microwave enhanced oxidative iodination reactions of a number of arylamines (highly activated
arenes) have been carried out in our laboratory since 2003. In parallel, we have always carried out the
same, or nearly the same, conventionally heated oxidative iodination reactions of the same arylamines
in order to compare results, i.e. the reaction times and the yields of the purified iodinated products
afforded by the two different experimental techniques. Our earlier microwave-accelerated iodination
reactions were carried out under a reflux condenser using either boiling CHCl3 (b.p. 61 °C) as the
solvent of choice and a urea-hydrogen peroxide addition compound (UHP) as the oxidant [5], or
boiling CH2Cl2 (b.p. 42 °C) as the solvent of choice and ortho-periodic acid (H5IO6) as the oxidant [6].
In the both cases, the microwave assisted oxidative iodination reactions of several arylamines afforded
nearly the same yields of the purified iodinated products as those heated conventionally, but the
reactions were always notably accelerated by microwave irradiation; for more details see our former
papers [5, 6]. However, we could hardly iodinate effectively some less activated arenes under the
aforesaid experimental conditions. The aim of this work is thus the extension of the scope of our
former iodination methods to other substrates, i.e. to a number of activated arenes or heteroarenes
(Table 1), all less active than arylamines in their electrophilic substitution reactions.
It is necessary to strongly emphasize that our former paper [5], published in 2002, was the first one
in the literature to report that oxidative iodination of arenes (viz. highly activated arylamines) was
notably accelerated by microwave irradiation. In 2003 Italian chemists [7] reported the direct
microwave-assisted iodination of several pyrimidinones and pyrimidine nucleosides mixed with
N-iodosuccinimide and DMF to give the corresponding 5-iodo derivatives in high yields; the samples
were irradiated for 3 minutes in a microwave oven at 200 W, whereas the same yields were obtained
under thermal conditions for 360 minutes at 70 °C. Application of this microwave-assisted reaction to
polymer-bound pyrimidinones was also investigated there. In 2004 Bogdal and co-workers [8]
reported the effective application of microwave irradiation to the oxidative chlorination, bromination,
and iodination of carbazole and several aromatic compounds, in the presence of hydrogen peroxide -
hydrohalic acids (water solutions of HCl, HBr or HI) system.
Results and Discussion
It is known from the literature [9, 10] that the oxidative iodination reactions of aromatics are very
often notably accelerated by acid catalysts (e.g. concd H2SO4 or aq. HCl). ortho-Periodic acid, H5IO6,
exhibits some definite acidic properties in aqueous solutions [11], hence we changed the previously
o
used toxic chlorinated solvents [5, 6] for a commercial 95% ethanol (bp 78 C) in which H5IO6 alone
-
would satisfactorily be dissociated to H3O+ + H4IO6 to facilitate the oxidation of diiodine by H5IO6,
and to form some I+ species, capable of effectively iodinating a number of activated arenes or
heteroarenes, ArH, shown in Table 1:
7 I+ (a preliminary stoichiometry)
3 I2 + I(VII)
7 ArH + 7 I+
7 ArI + 7 H+
EtOH/H+
7 ArH + 3 I2 + H5IO6
7 ArI + 6 H2O

Molecules 2005, 10
403
Thus, H5IO6 and finely powdered diiodine were suspended, with stirring, in a suitable volume of
95% ethanol. Next, a chosen arene or heteroarene, ArH, was added, and such composite reaction
mixtures were further reacted in two different ways as follows:
a) by conventional heating: the vigorously stirred reaction mixtures were heated under a reflux
condenser at 60 °C for 30-60 minutes (Table 1);
b) by focused monomode microwave irradiation under an externally attached reflux condenser
and with stirring: the reaction mixtures were placed into the microwave cavity and were then
irradiated for 1-10 minutes (Table 1); an appropriate power output was used to secure mild,
uninterrupted reflux of the solvent.
After completing the reactions (which were monitored by TLC), the cooled reaction mixtures were
poured into a vigorously stirred excess of aq. Na2SO3 solution (a reductant used to destroy any
unreacted diiodine and all possible oxidized species). The liquid suspensions were extracted with
CHCl3, the organic layers were dried over anhydrous MgSO4, filtered, the solvent was distilled off and
the oily residues were fractionated under vacuum to obtain the purified liquid products. The
precipitated crude solid products were collected by filtration, washed well with cold water, air-dried in
the dark, and recrystallized from appropriate organic solvents to give the purified solid products. The
purities and homogeneities of the purified products were first checked by TLC, then their 1H- and 13C-
NMR spectra (not shown here) were compared with those of authentic specimens [12]. Fairly sharp
melting points (uncorrected) were very close to those reported in the literature [13], as well as correct
microanalyses (I ± 0.4%) which further confirmed the chemical structures of the purified iodinated
products.
Only the purified 4-iodotoluene obtained from toluene, the 4-iodo-1,2-dimethylbenzene obtained
from o-xylene, and the 2-iodoimidazole obtained from imidazole were admixed with ca. 5-8% of their
isomeric monoiodinated side products, as revealed by TLC and the NMR spectra; these byproducts
could not be removed by simple repeated recrystallizations or by repeated fractionations under
vacuum. Such isomeric mixtures can be resolved only by chromatographic techniques or by tedious
fractional crystallizations from appropriate solvents [14].
From Table 1 it is seen that the microwave assisted iodination reactions afforded 44-91% yields,
whereas conventionally heated ones also gave 41-92% yields, but the former ones were always notably
accelerated as compared with the “classical” ones (Table 1), hence it is worthwhile to apply
microwaves for the enhancement of some oxidative aromatic iodination reactions. However, we have
established that for the iodination reactions carried out in very strongly polar and acidic media, e.g. in
anhydrous AcOH/Ac2O/concd H2SO4 solutions [10] or in 90% (v/v) sulfuric acid [15], the strict
temperature control during the irradiation by microwaves is hardly possible, due to the easy
overheating of such reaction mixtures, which very often ends up in overboiling.
Experimental
General
The melting points for the freshly recrystallized and microanalyzed (%I) iodinated products are
uncorrected (Table 1). All reagents were commercial (Aldrich), only 95% ethanol was produced in

Molecules 2005, 10
404
Poland. Elemental microanalyses (%I) were performed at the Institute of Organic Chemistry, Polish
1
Academy of Sciences in Warsaw, while H- and 13C-NMR spectra (not given here) were recorded at
r.t. with a Brucker AVANCE DMX 400 MHz spectrometr, and next they were compared with the
same spectra of authentic specimens [12]. Our microwave experiments were performed with a
microwave oven (at 2450 MHz) purchased from “Plazmatronika” (Wroclaw, Poland), described in
detail in our former papers [5, 6]; Our present iodination experiments were carried out with a focused
monomode MW irradiation.
Table 1. Pure iodinated products prepared. The literature m.p. or b.p. are taken from Ref. 13.
Conventional method
Microwave irradiation
Product
Time
(min)
30
Yield
(%)
89
M.p./Lit. M.p.
Time
(min)
Yield
(%)
86
M.p./Lit. M.p.
(°C)
(°C)
4-iodoanisole
50-51/51-52
5
7
50-51/51-52
4-iodophenetole
30
72
29-30/29-30
71
30-31/29-30
Iodomesitylene
30
89
30-31/30-31
7
85
30-31/30-31
4-iodoacetanilide
30
86
183-184/182-184
44-45/44-45
5
82
182-184/182-184
43-44/44-45
4-iodo-3-methylanisole
4-iodo-1-methoxynaphthalene
1-iodo-2-methoxynaphthalene
4-iodo-1,3-dimethoxynaphthalene
4-iodotoluenea
30
72
5
71
30
84
53-55/54-56
5
83
53-55/54-56
30
91
87-88/88-89
5
91
89-90/88-89
30
92
40-41/40-41
1
91
40-41/40-41
45
43
bp 101-103(15)/
bp 210-211(760)
bp 139-141(15)/
bp 229-230(760)
bp 134-135(15)/
bp 230-231(760)
bp 139-142(15)/
bp 228-232(760)
bp 127-130(15)/
bp 242-243(760)
277-278/276-277
262-264/263-265
112-113/112-113
191-192/192-194
bp 180-182(760)/
bp 180-182(760)
40-41/40-41
10
44
bp 103-104(15)/
bp 210-211(760)
bp 139-142(15)/
bp 229-230(760)
bp 134-136(15)/
bp 230-231(760)
bp 140-143(15)/
bp 228-232(760)
bp 129-131(15)/
bp 242-243(760)
278-279/276-277
262-264/263-265
112-113/112-113
191-192/192-194
bp 179-181(760)/
bp 180-182(760)
40-41/40-41
4-iodo-1,2-dimethylbenzenea
4-iodo-1,3-dimethylbenzene
3-iodo-1,4-dimethylbenzene
4-iodo-1,2-ethylenedioxybenzene
45
45
45
45
48
75
41
73
10
10
10
7
46
75
42
70
5-iodouracil
45
45
30
45
30
82
80
75
72
69
10
10
7
81
80
77
72
68
5-iodo-6-methylouracil
4-iodopyrazole
2-iodoimidazolea
10
5
2-iodothiophene
2,5-diiodothiophene
60
62
10
64
a The recrystallized compounds were admixed by ca. 5-8% of isomeric monoiodinated side products (TLC, NMR).

Molecules 2005, 10
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Conventionally Heated Iodination Reactions
H5IO6 (1.43 g, 6.25 mmol; 25% excess), finely powdered I2 (3.81 g, 15.0 mmol; 0% excess), and
then an appropriate arene (35.0 mmol; 0% excess) [for the diiodination of thiophene 17.5 mmol, 0%
excess] were suspended in 95% ethanol (15 mL). The reaction mixtures were stirred and heated under
a reflux condenser at ca. 60 °C for 30-60 min (Table 1). The cooled reaction mixtures were quenched
by pouring them into stirred ice-water (100 g) containing prior dissolved Na2SO3 (5 g). The oily crude
iodinated products were extracted with CHCl3 (3 x 20 mL), the collected extracts were dried over anh.
MgSO4, filtered, the solvent was distilled off, and the oily residues were fractionated under vacuum to
give the purified liquid products (Table 1). The solid crude products were collected by filtration,
washed well with cold water, dried preliminarily by the suction, and next air-dried in the dark. They
were recrystallized from appropriate organic solvents to give the purified solid products (Table 1).
Microwave-Accelerated Iodination Reactions
The same as above amounts of H5IO6, I2, and the appropriate arene were suspended in 95% ethanol
(25 mL). The reaction mixtures were put into the microwave cavity, and the magnetic stirrer was
switched on. An appropriate power output was applied (50%, 500 W) to secure a slight, uninterrupted
boil of the solvent under a reflux condenser attached outside. After a definite time (1-10 min, see the
Table 1), the reaction mixtures were cooled to r.t., and then they were poured, as above, into stirred
ice-water (100 g) containing Na2SO3 (5 g). The following workups and purification of the oily or solid
crude products were quite the same as above. For the final results thus obtained see the Table 1.
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Electronic
Conference
on
Synthetic
Organic
Chemistry
(ECSOC-6,
http://www.mdpi.net/ecsoc-6), September 1-30, 2002 (paper E006).

Molecules 2005, 10
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