An aromatic iodination method, with iodic acid used as the only iodinating reagent

Article abstract of DOI:10.3390/10020394

Benzene, halobenzenes, and a number of more or less deactivated arenes, including nitrobenzene, readily reacted in anhydrous HIO₃/AcOH/ Ac₂O/conc. H₂SO₄ mixtures to probably give ArIO₂ intermediates or other hypervalent species (not isolated). The final reaction mixtures were poured into excess aq. Na₂SO₃ solution (a reductant) to give the purified iodinated products in 39-83% yields.

Full text of DOI:10.3390/10020394

Molecules 2005, 10, 394-400
molecules
ISSN 1420-3049
http://www.mdpi.org
An Aromatic Iodination Method, with Iodic Acid Used as the
Only Iodinating Reagent†
Barbara Krassowska-Swiebocka, Grazyna Prokopienko and Lech Skulski*
Chair and Laboratory of Organic Chemistry, Faculty of Pharmacy, Medical University, Banacha 1, 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 A023).
* To whom the correspondence should be addressed; E-mail: lechskulski@yahoo.com; Tel./Fax: +(48)
22-5720643
Received: 8 November 2004; in revised form: 28 January 2005 / Accepted: 29 January 2005 /
Published: 28 February 2005
Abstract: Benzene, halobenzenes, and a number of more or less deactivated arenes,
including nitrobenzene, readily reacted in anhydrous HIO3/AcOH/Ac2O/conc. H2SO4
mixtures to probably give ArIO2 intermediates or other hypervalent species (not
isolated). The final reaction mixtures were poured into excess aq. Na2SO3 solution (a
reductant) to give the purified iodinated products in 39-83% yields.
Keywords: Arenes, iodoarenes, aromatic iodination, iodic acid as reactant and
iodinating agent
Introduction
In 1892 Meyer and Wachter [1], in describing iodosylbenzoic acid, the first iodosylarene, included
there the following passage: “Ferner ist zu prüfen, ob man durch Behandlung von aromatischen
Substanzen mir Schwefelsäure und Jodsaüre, - JO2OH, entsprechend der Reaction der Salpetersäure,
NO2OH, - Verbindungen mit der Gruppe -JO2 erhalten kann. Wir können vorläufig nur mittheilen,
dass Benzol beim Zusammenbringen mit Jodsäure und Schwefelsäure äusserst heftig reagirt und auf
Zusatz von Wasser einen festen Körper abscheidet, welchen wir not näher untersuchen werden“. It

Molecules 2005, 10
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means [1] that they had suggested the following reaction to occur, but this idea was not exploited by
them further on:
concd. H2SO4
H2O
PhH + HIO3
PhIO2 * H2SO4 (in solution)
PhIO2
(1)
- H2SO4
- H2O
Iodylbenzene sulfate [2]
In 1935 Masson and co-workers [2] had however established that benzene derivatives and HIO3 in
sulfuric acid readily formed diaryliodonium salts in high yield; later on, their initial discovery was
extended considerably [3]:
I+3 + 2 ArH
2 H+ + Ar2I+ or alternatively IO+ + 2 ArH
H2O + Ar2I+
(2)
Some experimental evidence was given that a primary deoxidation of the iodic acid to the iodous
stage by a fraction (ca. 15%) of the aromatic reagent, ArH (which is thereby converted into an open-
chain unsaturated substance), was followed by the direct interaction of the iodous acid and the
aromatic reagent to give the diaryliodonium salts; aryl iodides were also formed there as side products,
and the production of CO2 was observed. Hence, the above reactions had a very complex mechanism,
the details of which are still not clear.
Beringer and co-workers [4a, 5] coupled some reactive aromatic compounds (benzene, toluene,
mesitylene, t-butylbenzene, n-dodecylbenzene, cyclohexylbenzene, anisole, acetanilide, and
succinanil) with KIO3 in AcOH/Ac2O/H2SO4 mixtures to obtain the respective symmetrical
diaryliodonium bisulfates:
-
Ar2I+ + 2 HSO4 + 4 AcOH + [O]
(3)
-
2 ArH + IO3 + 2 H2SO4 + 2 Ac2O
If the temperature of reaction mixtures was not kept below 15 oC during the addition of the sulfuric
acid and for some hours thereafter, a vigorous, exothermic reaction was observed. They suggested that
in such instances the iodate was effecting a deep-seated oxidation of the aromatic compounds. By
anion metatheses of the diaryliodonium bisulfates, they isolated the corresponding chlorides, bromides,
iodides, and one nitrate in 9-88% yields. Diaryliodonium salts are fairly resistant towards the action of
cold aq. Na2SO3 solutions; only their prolonged treatment with excess sodium sulfite in boiling water
can effectively split them up as follows [4]: Ar2I+X- + Na2SO3 → ArI + ArSO3Na + NaX.
In 1969 Ciustea and Panescu [6] briefly reported that the treatment of halobenzenes, benzoic acid,
nitrobenzene or benzamide, dissolved in H2SO4, H3PO4, (CH3CO)2O, CH3COOH, H2O or in sulfuric
acid with an amount of water added, with HIO3, possibly resulted in the formation of the respective
iodylarenes, ArIO2, or 3,5-diiodylbenzamide; these compounds can next be reduced to the
corresponding aryl iodides or 3,5-diiodobenzamide. This short communication, with no experimental
details, analytical data or physico-chemical support, was never followed up either then or after 1969 in
a more detailed experimental paper [7, p. 1355].
reduction
ArI
(4)
ArH + HIO3 + H2SO4 (H2O)
ArIO2
Taking into account all the aforementioned literature information, in fact all very controversial and
potentially misleading, in 2003 we endeavored in our laboratory to carry out some preliminary
experiments on the possibility of preparing iodylarenes, ArIO2, from the corresponding arenes. Rudzki
[8] on reacting chlorobenzene with HIO3 in anhydrous Ac2O/concd H2SO4 mixtures, under widely
varied reaction conditions, obtained in the best possible manner 4-chloroiodylbenzene, 4-ClC6H4IO2,

Molecules 2005, 10
396
albeit in only 18% crude yield. In contrast, when he reacted chlorobenzene for 10 hours with HIO3 in
hot (80oC) 75% (v/v) H2SO4, he isolated bis(4-chlorophenyl)iodonium sulfate in 63% yield; 1-chloro-
4-iodobenzene (30%) was isolated there as a side product. Simultaneously, we have established [9]
that benzene, halobenzenes and some deactivated arenes (excluding however nitrobenzene) readily
reacted in anhydrous NaIO4/AcOH/Ac2O/concd H2SO4 mixtures. Next, the final reaction mixtures
were poured into excess aq. Na2SO3 solution (a reductant) to give the purified iodinated products in
27-88% yields. This is a quite novel approach to aromatic iodination:
aq. Na2SO
reduction3
AcOH/Ac2O/concd. H2SO
4
[ArIO3] (not isolated)
ArI
(5)
ArH + NaIO4
- NaHSO4
where [ArIO3] are hypothetical transient periodylarenes, not isolable in spite of many attempts.
So, we have decided to carry out the iodinating reactions as follows:
AcOH/Ac2O/concd. H2SO4
ArH + HIO3 + Ac2O
2 AcOH + [ArIO2 * H2SO4] (not isolated)
(6)
reduction
39-83%
[ArIO2 * H2SO4] or other hypervalent iodine species + excess aq. Na2SO3
ArI (7)
Our final results presented in the Table 1 do confirm that this approach to aromatic iodination is
quite successful and promising.
Table 1. Iodinated pure products obtained from some arenes, their yields, elemental
analyses, and melting or boiling points (uncorrected).
Yield, Analysis, % I
Lit, mp (oC)
[10]
129
129
92
Substrate
Product
1,4-I2C6H4
1,4-I2C6H4
4-BrC6H4I
4-ClC6H4I
3-IC6H4NO2
3-IC6H4COOH
3-IC6H4COOMe
3-IC6H4COOEt
3-I-4-MeC6H3COOH
3-I-4-MeC6H3NO2
3-I-4-MeOC6H3NO2
4-I-2-O2NC6H3NHCOCH3
Mp (oC)/Sa)
(%)
60
58
71
39
82
67
59
51
78
40
83
52
calcd (found)
76.95 (76.5)
76.95 (77.2)
44.86 (44.8)
53.22 (52.7)
50.96 (50.4)
51.17 (51.2)
48.43 (48.5)
45.97 (45.8)
48.43 (48.2)
48.25 (47.9)
45.51 (45.1)
41.50 (41.5)
C6H6
PhI
PhBr
PhCl
PhNO2
127-128/E
127.5-129/E
95-97/E
54-56/E
35-37/P
189-190/C
55-56/EW
bp 170-172/29
211-212/C
52-54/E
57
35-36
188-189
54-55
bp 150/15
210-212
54-56
97
PhCOOH
PhCOOMe
PhCOOEt
4-MeC6H4COOH
4-MeC6H4NO2
4-MeOC6H4NO2
2-O2NC6H4NHCOCH3
94-96/E
110-112/EW
112
a) Solvents used for crystallization: C – CCl4; E – EtOH; P – petroleum ether; EW – EtOH/H2O
Results and Discussion
For benzene (which was only diiodinated), three halobenzenes and eight deactivated arenes,
including nitrobenzene (Table 1), we carried out the iodinating reactions according to the
stoichiometry shown in Eq. 6, where: [ArIO2 * H2SO4] are the assumed iodine(V) intermediates,

Molecules 2005, 10
397
possibly strongly admixed with ArI(OSO3H)2; it is known that amphoteric iodylarenes freely form
o
salts with strong mineral acids, and the hygroscopic sulfate PhIO2·H2SO4 (mp 127 C) was analyzed
and examined [2].
Thus, iodic acid and chosen arenes, ArH, were suspended in cooled (5 °C) anhydrous AcOH/Ac2O
mixtures, and then a large excess of concd. (95%) sulfuric acid was slowly added dropwise, with
o
vigorous stirring, to the reaction mixtures, while keeping the temperature below 10 C. The strongly
acidified reaction mixtures were then stirred for one hour in an ice-water bath, next for one hour at
o
room temperature and then for 2 hours at 45-50 C. We have established that somewhat better yields
are achieved when the reaction mixtures were finally left overnight at room temperature. The final
reaction mixtures were quenched by pouring into stirred ice-water containing a previously dissolved
excess of Na2SO3 (a reductant), Eq. 7. The oily or solid crude products that precipitated out were
typically isolated and purified (see the Experimental) to give the purified monoiodinated products in
39-83% yields, except in the case of 1,4-diiodobenzene, which was obtained in 60% yield (Table 1).
The chemical structures of the purified products were next confirmed by their melting or boiling
points, all close to those reported in the literature [10], elemental analyses (%I), and comparison of the
1H and 13C NMR spectra (not reported here) with the corresponding spectra of authentic samples.
Their homogeneities were checked by TLC.
We have also tried to isolate the purported iodine(V) intermediates, i.e. ArIO2, by pouring the final
reaction mixtures into ice-water (ArIO2·H2SO4 is readily hydrolyzable [2]). However, the crude yields
of ArIO2 thus obtained were usually lower than 20%, and the crude ArIO2 had to be recrystallized
from boiling water at least once – which lowered the yields further. The best result was obtained with
bromobenzene that afforded 1-bromo-4-iodylbenzene in 40% crude yield (see the Experimental).
Hence, these attempts were deemed unworthy of further study. It should be pointed out that we
previously devised in our laboratory two easy and effective methods of preparing ArIO2 from ArI
using NaIO4 as the oxidant, acting either in boiling water [11] or in boiling 30% (v/v) aq. acetic acid
[12]. The crude yields of ArIO2 thus obtained were good to excellent, while the snow-white crude
products had a 98-99% purity, established iodometrically.
We present in this paper an easy and effective approach to the aromatic iodination, which allows
one to obtain iodoarenes, in good yields, from halobenzenes and several deactivated arenes, including
nitrobenzene; cf. Ref. [9]. The transient protonated iodic acid, O3I+H2, was the sole iodinating agent
present, capable of forming the stable C-I bond in the starting arenes, which is preserved after the
reduction with excess aq. Na2SO3 solution to afford the final mono- or diiodinated arenes (Table 1).
However, activated arenes, e.g. anisole, acetanilide, N, N – dimethylaniline, etc., were easily oxidized
under the given reaction conditions to form some tarry products, which could not be purified in spite of
our numerous attempts.
Note added in proof. For comparison, also NaBrO3 is a powerful brominating agent for deactivated
aromatics. Addition of a strong acid into a stirred aq. solution, or slurry, of the substrate and NaBrO3 at
o
40-100 C, leads to the decomposition of the bromate ions and production of the active brominating
species. Substrates such as nitrobenzene, benzoic acid, and benzaldehyde were specifically brominated
in 85-98% yields. The reaction is especially useful for the bromination of disubstituted benzenes, such
as 4-FC6H4NO2 or 4-FC6H4COOH. Dinitrobenzenes and nitrobenzoic acids did not undergo
bromination at all. See Ref. 13.

Molecules 2005, 10
398
Experimental
General
All the reagents and solvents were commercial (Aldrich) and were used without further
purification. The melting or boiling points of pure iodinated products (Table 1) are uncorrected.
Elemental microanalyses (%I) were performed at the Institute of Organic Chemistry, the Polish
1
13
Academy of Sciences in Warsaw. H- and C-NMR spectra (not shown here) were recorded at room
temperature, in CDCl3 solutions, with a Bruker Avance DMX 400 MHz spectrometer; sometimes, in
1
order to get better assignments, also H-13C correlation spectra were recorded. The spectra confirmed
the chemical structures of the purified iodinated products (Table 1).
Optimized Preparations of Iodoarenes from Arenes
Iodic acid (3.25 g, 20 mmol) was suspended in a mixture made of glacial AcOH (20 mL) and
acetic anhydride (10 mL), then an appropriate arene (20 mmol) was added with stirring. The stirred
o
mixture was cooled to ca. 5 C, and concd. (95%) sulfuric acid (10 mL, ca. 0.2 mol) was very slowly
added dropwise while keeping the temperature below 10 oC. The reaction mixtures were stirred for 1 h
o
in an ice-water bath, then for 1 h at r.t. and next for 2 h at 45-50 C. The stirring was continued
overnight at r.t. The final reaction mixtures were poured into ice-water (100 g) containing previously
dissolved Na2SO3 (a reductant, 5 g). After a few hours, the precipitated crude solid products were
collected by filtration, washed well with cold water until the filtrates were neutral, dried preliminarily
by suction, and next air-dried in the dark. They were recrystallized from appropriate organic solvents
(Table 1) to give the purified solid iodinated products. If the crude iodinated products were oily or
semisolid, they were extracted with CHCl3 (3 x 20 mL), the combined extracts were dried over anh.
MgSO4, filtered, the solvent was distilled off, and the residues were fractionated under vacuum to give
the purified liquid iodinated products (Table 1). The purified iodoarenes should be preserved in the
o
dark, preferably at 0-5 C. Note: When benzene was diiodinated as above to give pure 1,4-diiodo-
benzene, only half of its amount, i.e. 10 mmol, was added to the reaction mixture.
Possibly Optimized Preparation of 1-Bromo-4-iodylbenzene from Bromobenzene
Iodic acid (5.28 g, 30 mmol) was suspended in a mixture made of glacial AcOH (10 mL) and Ac2O
(5 mL), then bromobenzene (4.71 g, 30 mmol) was added with stirring. Concd. (95%) H2SO4 (2 mL)
o
was very slowly added dropwise with vigorous stirring, keeping the temperature below 50 C. Next,
the stirring was prolonged within 2 h at ambient temperature. The final reaction mixture was poured
into ice-water, and the precipitated oily product slowly solidified. The precipitate was collected by
filtration, washed with a little ice water, then with acetone. The colorless final product, obtained in
40% crude yield, decomposed at 235 oC with detonation, lit. [12] mp 236 oC with detonation.

Molecules 2005, 10
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References and Notes
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The German passage in the text can be translated as follows: “Next, it has to be checked out
whether the reaction of aromatic compounds with sulfuric acid and iodic acid, IO2OH,
corresponding to the reaction with nitric acid, NO2OH, can afford the respective compounds
substitued by the –IO2 group. We can only preliminarily report that benzene reacts violently with
iodic acid and sulfuric acid, and after addition of water, a solid compound precipitates out, which
was not closer investigated”. Mason and Race (Ref. 3, footnote in p. 1723) commented the first
German attempt to prepare PhIO2 from benzene as follows: “It does not appear that the experiment
was followed up either then or after 1894, when the iodoxy- and the iodonium group were
discovered”.
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1679.
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