A green reagent for the iodination of phenols

Article abstract of DOI:10.1055/s-2008-1078598

A new reagent (I₂/NaNO₂) for the iodination of the aromatic ring of phenols has been discovered. The reaction proceeds at room temperature in 1.5-6 hours. In the presence of this reagent, iodinated compounds are regioselectively formed in significant yields from the corresponding substrates. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1078598

PAPER
2327
A Green Reagent for the Iodination of Phenols
I
odination of Phen
.
ols
w
ith I2/NB
a
NO . Kiran, Takeo Konakahara,* Norio Sakai
2
Department of Pure and Applied Chemistry, Faculty of Science and Technology, Tokyo University of Science (RIKADAI),
Noda, Chiba 278-8510, Japan
E-mail: konaka@rs.noda.tus.ac.jp
Received 8 February 2008; revised 30 April 2008
ylphenol by preparing its iodinated product 6a with I2/
CAN3i was unsuccessful. Preparation of its iodinated
product, however, was reported in good yields in the pres-
ence of benzyltrimethylammonium dichloroiodate/
Abstract: A new reagent (I2/NaNO2) for the iodination of the aro-
matic ring of phenols has been discovered. The reaction proceeds at
room temperature in 1.5–6 hours. In the presence of this reagent, io-
dinated compounds are regioselectively formed in significant yields
from the corresponding substrates.
8a
CaCO3 and benzyltriphenylphosphonium peroxymono-
sulfate/KI.8b During an attempt to develop this work with
inexpensive and eco-friendly reagents, we accidentally
observed that iodine and sodium nitrite together work as
an effective iodination reagent for the aromatic ring of
phenol (Scheme 1).
Key words: iodination, phenols, sodium nitrite, Lewis acid, eco-
friendly
Iodination of a functionalized aromatic species is an ex-
ample of an electrophilic substitution. Many such aromat-
ic substitution reactions are the key routes to introduce
many other functional groups besides iodine in the aro-
matic ring. Direct iodination of aromatic compounds is
difficult due to the low electrophilicity of molecular io-
dine compared to the other halogens, and also due to the
reducing effect of the hydrogen iodide produced.1 Howev-
er, arenes have previously been successfully iodinated in
the presence of either a Lewis acid or an oxidizing
agent.1,2 Several iodination methods have been reported
using various reagents, such as tetramethylammonium
dichloroiodide,3a GeI2,3b I2/AgNO3,3c INO3,3d I2/Al2O3,3e I2/
Cu(OMe)2,3f I2/H2O2,3g NH4I/Oxone®,3h I2/CAN,3i ICl/
Lewis acid,3j I2/HgO,3k I2/Ag2SO4,3l n-BuLi/CF3CH2I,3m
I2/NaHCO3,3n and ICl/ZnO.3o Although these procedures
provide some improvement relative to other methods,
most of them still suffer from long reaction times, the ne-
cessity of drastic reaction conditions, and tedious work-
ups. Some of them require an excess of reagents, and the
catalysts from them are toxic. Many of these reagents also
are expensive, which effectively limits their application.
OH
OH
I2, NaNO2, H2O–MeOH
r.t., 1.5–6 h
I
R
R
R = H, Br, Me, NO2, CHO, OH
Scheme 1
Sodium nitrite, a naturally occurring chemical, a meat pre-
servative, and an antidote for cyanide poisoning, has
many other medicinal applications.9 However, apart from
its use to convert amines into diazo compounds10 and
preparation of aryl halide in the presence of halotrimeth-
ylsilane,11 its full synthetic utility is yet to be exploited. Its
low price, nontoxicity and eco-friendly nature make it an
ideal reagent for the iodination of phenol and its deriva-
tives.
Although the hydroxyl group is an ortho/para director in
the aromatic electrophilic substitution of phenols, iodina-
tion of phenols with I2/NaNO2 in H2O–MeOH occurs pre-
dominantly in the ortho position and 2-iodophenol is the
major product (Table 1, entries 1 and 17). When a phenol
has an ortho substituent, the iodine substitution primarily
takes place at the para position (Table 1, entries 2, 3, 6,
and 14), but 4,6-diiodo-2-nitrophenol is formed in the
case of o-nitrophenol (Table 1, entry 7). In p-methylphenol
and p-nitrophenol, the corresponding ortho-monoiodinat-
ed products are formed exclusively (Table 1, entries 5 and
9). With an aldehyde function at the para position, only
the ortho/ortho¢-diiodinated phenol is obtained (Table 1,
entry 12). With a methyl, nitro, or formyl substituent at
the meta position of the phenol, however, ortho/ortho¢-
double iodination occurred (Table 1, entries 4, 8, and 11).
Surprisingly, 2-hydroxybenzaldehyde and 3-hydroxyphe-
nol did not undergo iodination even after 24 hours
(Table 1, entries 10 and 15). Interestingly 4-hydroxyphe-
nol readily oxidized almost quantitatively to the corre-
Despite the great importance of aromatic iodinated com-
pounds as precursors for organic transformation via ionic,
radical and metal-catalyzed intermediates,4 as well as for
the preparation of pharmaceutical and bioactive com-
pounds,5 there is still a great need for the discovery of a
simple, inexpensive and nontoxic reagent system for the
introduction of iodine into an aromatic ring. Today, the
preparation and regiospecific modification of polysubsti-
tuted aromatic molecules is a fundamental problem for
both synthetic and industrial chemists.6
In our work on the development of useful synthetic meth-
odologies for the synthesis of ellipticine,7 an approach for
the synthesis of carbazole derivatives from 2,5-dimeth-
SYNTHESIS 2008, No. 15, pp 2327–2332
x
x.
x
x
.
2
0
0
8
Advanced online publication: 17.07.2008
DOI: 10.1055/s-2008-1078598; Art ID: F03408SS
© Georg Thieme Verlag Stuttgart · New York

2328
Y. B. Kiran et al.
PAPER
sponding p-quinone (16a)12 instead of undergoing successful in iodinating both electron-activated and
iodination.13 Generally, phenols with an electron-donat- -deactivated phenols. In all the reactions, some unreacted
ing substituent easily underwent iodination in less time starting material was recovered, and 10–20% of undetec-
(Table 1, entries 3, 4, and 5), in comparison to those sub- ted by-products were formed. Reaction at room tempera-
stituted with an electron-deactivating group (Table 1, ture with equimolar amounts of phenols, I2, and NaNO2 is
entries 7, 8, 9, 11, 12, and 13). But I2/NaNO2 is quite recommended for optimal results.
Table 1 Iodination of Phenols
Entry
Substance
Product; yield (%)
Time (h)a
ortho
para
meta
others
OH
OH
I
OH
I
c
1
–
–
4
I
1a (78)b
1b (7)b
OH
OH
Br
Br
2
–
–
–
3.5
I
2a (67)d
OH
OH
3
4
5
–
–
–
–
–
–
4
3
4
I
3a (23)d
OH
OH
OH
I
I
–
4a (13)d
OH
I
–
5a (59)d
OH
OH
I
OH
6
–
–
6
I
I
6a (68)d
6b (8)d
OH
I
NO2
OH
OH
NO2
7
8
–
–
–
–
6
6
I
7a (78)b
OH
I
I
–
–
NO2
NO2
8a (63)d
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PAPER
Iodination of Phenols with I2/NaNO2
2329
Table 1 Iodination of Phenols (continued)
Entry
Substance
Product; yield (%)
Time (h)a
ortho
para
meta
others
–
OH
I
OH
9
–
–
6
NO2
NO2
OH
9a (66)d
CHO
10
11
–
–
–
–
–
–
–
24
OH
OH
I
I
4.5
CHO
CHO
11a (24)d
OH
OH
I
I
12
13
–
–
–
–
–
–
–
6
CHO
12a (23)d
CHO
OH
OH
I
6
CHO
13a (66)d
CHO
OH
OH
OH
OH
OH
14
15
16
–
–
–
–
–
1.5
I
14a (53)d
–
–
24
OH
O
OH
OH
–
–
–
0.5
O
16a (94)d
I
OH
OH
17
–
–
6
17a (52)d
a Reactions were conducted at r.t. and the reaction time was determined by TLC after the addition of the corresponding phenol.
b GPC yields.
c No such product.
d Isolated yields are reported (a single run).
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2330
Y. B. Kiran et al.
PAPER
organic product was extracted with CHCl3 (3 × 15 mL). The com-
bined organic extracts were washed with of 0.1 M aq Na2S2O3 (25
mL) to remove the unreacted I2, followed by extraction with CHCl3
(3 × 10 mL). The combined CHCl3 extracts were dried (MgSO4),
filtered, and concentrated under reduced pressure in a rotary evapo-
rator. The residue obtained was purified by silica gel chromatogra-
phy with CHCl3–MeOH to obtain the corresponding pure aryl
iodides (Table 1). For the iodination of phenol (Table 1, entry 1),
however, purification was accomplished using a Recycling Prepar-
ative HPLC equipped with a gel permeation chromatography col-
umn (with CHCl3 as the eluent).
An increase in temperature to the reflux point did not im-
prove the product yield. A change of the solvent from
methanol to ethanol had no discernible solvent effect. The
time sequence of the addition of the phenol was found to
be critical to the outcome of the reaction. By stirring the
mixture of phenols, I2, and NaNO2 led to the formation of
more by-products and less of the main iodinated product.
On the other hand, when phenol was added after stirring a
mixture of I2/NaNO2 in H2O–MeOH for 30 minutes, the
yield of the iodinated product increased to a satisfactory
level. No other specific reaction was observed when sim-
ple phenol was allowed to react with molecular I2 or
NaNO2 individually in H2O–MeOH for six hours. This
suggests that NaNO2 initially reacts with molecular iodine
and helps to generate the active I+ electrophile.
2-Iodophenol (1a)3o
Mp 39–41 °C (Lit.16a mp 43 °C).
1H NMR (500 MHz, CDCl3): d = 5.51 (s, 1 H, OH), 7.50 (t, J = 8.0
Hz, 1 H, ArH), 7.64 (d, J = 6.5 Hz, 1 H, ArH), 7.79 (t, J = 8.0 Hz, 1
H, ArH), 8.28 (d, J = 6.5 Hz, 1 H, ArH).
13C NMR (125 MHz, CDCl3): d = 87.4, 116.2, 123.4, 128.4, 139.3,
Although any mechanistic discussion is speculative at this
point, a pathway for this reaction may be proposed based
on the experimental results and available litera-
155.5.
2,4-Diiodophenol (1b)16b
–
ture.3e,j,o,14a,b The ionic nature of Na+NO2 appears to act as
Mp 72–74 °C (Lit.16b mp 73.5–74.0 °C).
an effective catalyst for electrophilic iodination. It can po-
larize and activate I2 for the generation of HOI,14a which
can subsequently function as a source of the I+ electro-
phile.3e The nitrosonium ion (NO+) produced from NaNO2
under acidic conditions14c acts as a Lewis acid.15a Gener-
ally, Lewis acids polarize I2 to a more effective I+ electro-
phile.3e,15b,c
1H NMR (500 MHz, CDCl3): d = 6.52 (d, J = 6 Hz, 1 H, ArH), 7.69
(dd, J = 6.5, 2.0 Hz, 1 H, ArH), 8.02 (d, J = 2.5 Hz, 1 H, ArH).
2-Bromo-4-iodophenol (2a)16c
Mp 49–51 °C (Lit.16d mp 51 °C).
1H NMR (300 MHz, CDCl3): d = 5.53 (s, 1 H, OH), 6.80 (d, J = 8.7
Hz, 1 H, ArH), 7.51 (d, J = 9.1 Hz, 1 H, ArH), 7.75 (s, 1 H, ArH).
In conclusion, a new eco-friendly methodology for the re-
giospecific iodination of phenols at room temperature us-
ing an inexpensive, nontoxic green reagent (I2/NaNO2) is
reported. Predominantly, mono ortho iodination occurs in
unsubstituted and para-substituted phenols, and para io-
dination results with ortho-substituted ones. With meta-
substituted substrates, ortho/ortho¢ double iodination
takes place. Further, this reagent works successfully for
the iodination of both electron-activated and -deactivated
phenols and also for nearly quantitative oxidation of 1,4-
dihydroxybenzene to the corresponding quinone. This re-
agent is also effective for the iodination of a phenol with
a formyl group without affecting its formyl functionality
in significant yields. Although the literature enumerates a
4-Iodo-2-methylphenol (3a)16b
Mp 65–66 °C (Lit.16b mp 68.5–69.0 °C).
1H NMR (500 MHz, CDCl3): d = 2.32 (s, 3 H, CH3), 6.52 (d, J = 9.5
Hz, 1 H, ArH), 6.87 (d, J = 9.5 Hz, 1 H, ArH), 7.56 (d, J = 2.5 Hz,
1 H, ArH).
2,6-Diiodo-3-methylphenol (4a)16e
Black oil.
1H NMR (500 MHz, CDCl3): d = 2.17 (s, 3 H, CH3), 7.04 (m, 1 H),
8.43 (d, J = 6.5 Hz, 1 H).
2-Iodo-4-methylphenol (5a)16f
Light-brown oil (Lit.16f mp 34.5–35.5 °C; Lit.16g light-brown oil).
1H NMR (500 MHz, CDCl3): d = 2.21 (s, 3 H), 5.42 (br s, 1 H, OH),
number of reagents for the iodination of phenols, the sim- 6.75 (d, J = 8.0 Hz, 1 H), 6.88 (dd, J = 8.5, 2.0 Hz, 1 H), 7.03 (d,
plicity, environmental acceptability and inexpensiveness
J = 2.5 Hz, 1 H).
of this reagent makes it more practical. Further investiga-
4-Iodo-2,5-dimethylphenol (6a)8a
tion is underway in our laboratory to explore the scope
Mp 99 °C (Lit.8a mp 95–96 °C).
and limitations of this procedure.
1H NMR (500 MHz, CDCl3): d = 2.04, (s, 3 H, CH3), 2.19 (s, 3 H,
CH3), 6.34 (s, 1 H, ArH), 7.60 (s, 1 H, ArH), 9.54 (br s, 1 H, OH).
The melting points were determined by Yanaco micro melting point
13C NMR (125 MHz, CDCl3): d = 16.0, 17.0, 99.9, 121.4, 129.0,
132.6, 139.8, 145.9.
1
apparatus and are uncorrected. H and 13C NMR spectra were re-
corded on a JNM ECP-500 (500 and 125 MHz), using CDCl3 as a
solvent with TMS as an internal standard. Mass spectra were re-
corded on a JMS GCmate II GC-mass spectrometer.
Mp 63–64 °C (Lit.16h mp 63 °C).
4,6-Diiodo-2,5-dimethylphenol (6b)16h
1H NMR (500 MHz, CDCl3): d = 2.12 (s, 3 H, CH3), 2.47 (s, 3 H,
Iodination of Aromatic Species; General Procedure
CH3), 7.58 (s, 1 H, ArH).
A mixture of NaNO2 (69 mg, 1 mmol) and I2 (254 mg, 1 mmol) in
a 1:1 mixture of H2O (5 mL) and MeOH (5 mL) was stirred for 0.5
h. To this stirred solution, the respective phenol (1 mmol) was add-
ed directly at 5–10 °C. The resultant mixture was stirred at r.t. for
1.5–6 h (Table 1) under atmospheric air. The progress of the reac-
tion was monitored using TLC. After completion of the reaction, the
4,6-Diiodo-2-nitrophenol (7a)3d
Mp 98 °C (Lit.8a mp 98 °C).
1H NMR (500 MHz, CDCl3): d = 8.33 (d, J = 1.5 Hz, 1 H, Ar-H),
8.40 (d, J = 1.5 Hz, 1 H, Ar-H), 11.26 (br s, 1 H, OH).
Synthesis 2008, No. 15, 2327–2332 © Thieme Stuttgart · New York

PAPER
Iodination of Phenols with I2/NaNO2
2331
2,6-Diiodo-3-nitrophenol (8a)16e
Mp 72–73 °C.
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This work was partially supported by a grant from the Japan Private
School Promotion Foundation, and a fund for the ‘High-Tech Re-
search Center’ Project for Private Universities: a matching fund
subsidy from MEXT, 2000–2004 and 2005–2007. The authors are
also grateful for the financial support of a postdoctoral fellowship
from the Tokyo University of Science.
Synthesis 2008, No. 15, 2327–2332 © Thieme Stuttgart · New York

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