Solvent-free iodination of organic molecules using the I 2/urea-H2O2 reagent system

Article abstract of DOI:10.1039/b614819k

Introduction of iodine under solvent-free conditions into several aromatic compounds activated toward electrophilic functionalisation was found to proceed efficiently using elemental iodine in the presence of a solid oxidiser, the urea-H₂O₂ (UHP) adduct. Two types of iodo- functionalisation through an electrophilic process were observed: iodination of an aromatic ring, and side-chain iodo-functionalisation in the case of arylalkyl ketones. Two reaction routes were established based on the required substrate: iodine: oxidiser ratio for the most efficient iodo-transformation, and the role of UHP was elucidated in each route. The first, requiring a 1: 0.5: 0.6 stoichiometric ratio of substrate to iodine to UHP, followed the atom economy concept in regard to iodine and was valid in the case of aniline (1a), 4-t-Bu-phenol (3), 1,2-dimethoxy benzene (5a), 1,3-dimethoxy benzene (5b), 1,2,3-trimethoxy benzene (7a), 1,2,4-trimethoxy benzene (7b), 1,3,5-trimethoxy benzene (7c), 1-indanone (11a) and 1-tetralone (11b). The second reaction route, where a 1: 1: 1 stoichiometric ratio of substrate: I₂: UHP was needed for efficient iodination, was suitable for side-chain iodo-functionalisations of acetophenone (1c) and methoxy-substituted acetophenones. Moreover, addition of iodine to 1-octene (13a) and some phenylacetylenic derivatives (15a, 15b) was found to proceed efficiently without the presence of any oxidiser and solvent at room temperature. This journal is The Royal Society of Chemistry.

Full text of DOI:10.1039/b614819k

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Solvent-free iodination of organic molecules using the I /urea–H O
2
2
2
reagent system
Jasminka Pavlinac, Marko Zupan and Stojan Stavber*a
a
a,b
Received 11th October 2006, Accepted 18th December 2006
First published as an Advance Article on the web 15th January 2007
DOI: 10.1039/b614819k
Introduction of iodine under solvent-free conditions into several aromatic compounds activated toward
electrophilic functionalisation was found to proceed efficiently using elemental iodine in the presence of a
solid oxidiser, the urea–H
2
2
O (UHP) adduct. Two types of iodo-functionalisation through an electrophilic
process were observed: iodination of an aromatic ring, and side-chain iodo-functionalisation in the case of
arylalkyl ketones. Two reaction routes were established based on the required substrate : iodine : oxidiser
ratio for the most efficient iodo-transformation, and the role of UHP was elucidated in each route. The
first, requiring a 1 : 0.5 : 0.6 stoichiometric ratio of substrate to iodine to UHP, followed the atom economy
concept in regard to iodine and was valid in the case of aniline (1a), 4-t-Bu-phenol (3), 1,2-dimethoxy
benzene (5a), 1,3-dimethoxy benzene (5b), 1,2,3-trimethoxy benzene (7a), 1,2,4-trimethoxy benzene (7b),
1
,3,5-trimethoxy benzene (7c), 1-indanone (11a) and 1-tetralone (11b). The second reaction route, where
a 1 : 1 : 1 stoichiometric ratio of substrate : I : UHP was needed for efficient iodination, was suitable
2
for side-chain iodo-functionalisations of acetophenone (1c) and methoxy-substituted acetophenones.
Moreover, addition of iodine to 1-octene (13a) and some phenylacetylenic derivatives (15a, 15b)
was found to proceed efficiently without the presence of any oxidiser and solvent at room temperature.
7
Introduction
extensively studied. Hydrogen peroxide, widely accepted as a
green oxidant, was used to activate and/or regenerate elemental
iodine. Having several advantageous properties compared to
other oxidants, the most notable being the formation of water as
Due to the importance of iodo-substituted organic compounds
as synthons or valuable precursors in organic synthesis, in
1
addition to their use as radioactively-labelled markers in medical
a benign by-product of oxidation, resulted in its comprehensive
application in several oxidation systems. The solid urea–H
2
diagnosis, the introduction of iodine into organic molecules has
8
2
O
2
received significant attention among the scientific community.
Since molecular iodine itself is poorly reactive, substantial efforts
have been invested in the development of efficient, selective and
mild methods for direct introduction of iodine into organic
compounds. Numerous diverse procedures using iodonium
adduct (NH
2
CONH
2
–H
2
O
2
, UHP) and sodium percarbonate
(
Na CO –1.5H
2
3
2
O
2
, SPC) are regarded as ‘dry carriers’ and safer
alternatives to hazardous, unstable concentrated liquid hydrogen
9
peroxide. Moreover, their easy handling, stability at room
temperature and ability to release oxidative species in a controlled
manner make them desirable oxidisers. Both already proved to be
efficient for oxidative iodination of various organic compounds
3
donating agents have been devised over the years. Beside the
use of volatile organic solvents as reaction media, many of them
employ harsh conditions, such as the extensive use of strong acids
or the use of heavy metal salts or their oxides as activators of
in an EtOAc–AcOH mixture under highly acidic conditions and
10
in CHCl
3
under microwave irradiation. In our on-going efforts
4
iodine, which require special safety precautions in experimental
11
to achieve environmentally friendlier halogenation procedures,
we investigated iodination using iodine in the presence of
both the above mentioned solid forms of hydrogen peroxide
handling and pose serious concerns regarding environmental and
health issues. Contrary to traditional thinking on the necessity
of an appropriate organic solvent for performing a reaction, in
keeping with a green chemistry approach, which emerged a decade
ago as a response to continuously growing concerns for sustainable
(
UHP and SPC) without the use of a solvent for carrying out
iodo-transformation, and compared the results with previously
performed studies on iodination using iodine and a 30% aqueous
solution of H
5
development, the best solvent is regarded to be ‘no solvent at all’.
11h,11i
2
O
2
as oxidiser in water.
In response to ever-
Thus, solvent-free reactions are garnering increased attention in
increasing demands for ecologically more acceptable procedures,
our research was aimed at solvent-free reaction conditions for
iodine introduction. Methoxy-substituted aromatic derivatives
were chosen as plausible substrates for investigating the course
of transformation because of the known fact that the activated
aromatic ring in the substituted molecules of the chosen substrates
can readily undergo ion-radical formation with various oxidising
agents. Moreover, the acetophenone moiety attracted our
attention for studying the regioselectivity of the transformation.
In regard to the studied substrates, the iodination process was
6
recent years. Their advantages over conventional methods may,
in many cases, be attributed to enhanced efficiency and selectivity,
cleaner products, milder reaction conditions, lower reaction times,
simplified procedures and hence the reduction of pollution.
However, iodination under solventless conditions has not been
a
Laboratory for Organic and Bioorganic Chemistry, ‘Jo zˇ ef Stefan Institute’,
Jamova 39, 1000, Ljubljana, Slovenia. E-mail: stojan.stavber@ijs.si
b
Department of Chemistry at the Faculty for Chemistry and Chemical
Technology, University of Ljubljana, A sˇ ker cˇ eva 5, 1000, Ljubljana, Slovenia
This journal is © The Royal Society of Chemistry 2007
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expected to proceed potentially through 3 different intermediates,
while types of iodo-functionalisation were anticipated,
which, however, is considered a ‘greener’ substitute compared to
widely-used harmful chlorinated solvents.
2
namely aromatic ring iodo-functionalisation and side-chain
functionalisation in the case of arylalkyl ketones (Scheme 1). In
accordance with our previous experience, an ionic mechanism
with formation of a r-complex in the intermediate stage was
expected to be differentiated from a SET process with ion-radical
Aniline (1a) was chosen as a model substrate. In a blank
experiment without the presence of any oxidiser and solvent, 4-
iodo aniline (2a) was formed in 20% yield after 5 hours at room
temperature (Table 1, entry 1); a slightly higher yield was obtained
◦
at 45 C (entry 2). The presence of the urea–hydrogen peroxide
11h
formation on the basis of the amount of reagent used.
(UHP) adduct remarkably affected the outcome of the reaction,
promoting iodine introduction with high conversion and atom
economy. In a typical experiment 0.5 mmol of finely powdered
iodine was added to 1 mmol of substrate. The reaction mixture was
vigorously shaken in order to obtain a good distribution between
the reagent molecules, followed by the addition of 0.6 mmol
of finely powdered UHP. An experiment performed at room
temperature proceeded with 81% conversion to 4-iodo aniline (2a,
◦
entry 3), whereas maintaining the temperature at 45 C for 5 hours
resulted in a complete conversion to 4-iodo aniline (2a, entry 4).
Sodium percarbonate (SPC) proved to be a less efficient mediator
of iodination. After 5 hours of reaction between 1 mmol aniline,
0
.5 mmol iodine and 0.6 mmol SPC, 65% conversion to 4-iodo
aniline (2a) was found (entry 5); prolongation of the reaction time
did not significantly improve the yield (entry 6).
To continue with the substrate of an aromatic ring activated
toward electrophilic functionalisation, iodination of anisole (1b)
under solvent-free conditions was examined. A reaction carried
◦
out for 7 hours at 45 C using the ratio of substrate to iodine
to UHP corresponding to 1 : 0.5 : 0.6 didn’t provide any
transformation of the substrate (entry 7). Prolonging the reaction
time to 19 hours contributed to the introduction of iodine into
anisole (1b) only moderately (entry 8). Also, increasing the amount
of reagent just slightly improved the yield (entry 9).
Research was extended to monosubstituted aromatic com-
pounds with a deactivated aromatic ring. The role of the UHP
adduct in iodination of acetophenone (1c) was investigated.
Besides the aromatic ring, the alkyl position in acetophenone is
also a reactive site for electrophilic functionalisation, and thus
the effect of reaction conditions on the regioselectivity of the
transformation was of primary interest. Previously, it was reported
that regioselective iodination of various acetophenones can be
regulated by the solvent or generally by the polarity of the reaction
12
system. Our study showed that iodination of acetophenone
can be accomplished under solvent-free conditions using the I
2
–
Scheme 1 Potentially reactive sites with possibly formed intermediates
for electrophilic iodo-functionalisation of methoxy substituted benzene
derivatives using I in the presence of supported (Su) forms of H O .
2 2 2
UHP combination. Iodine is regioselectively introduced into the
alkyl position, indicating the polar character of the reaction
system. In a blank experiment, no reaction occurred between
acetophenone and iodine under solvent-free conditions after
Besides the convenience of a method for iodo-transformation
performed under solvent-free conditions, the relation between
the structure and aggregation state of the substrate and reaction
conditions was carefully analysed. Additionally, the roles of two
◦
6 hours at 45 C (Table 1, entry 10), while electron-exchange
took place in the presence of UHP, enabling the formation of
2-iodo-1-phenylethanone (2c). In order to elucidate the role of
UHP, experiments were performed with various ratios of substrate
to iodine to oxidiser (entries 10–19). Results showed that the
highest conversion to 2c was achieved using 1 mmol of iodine and
different H-bonded solid forms of H
iodine introduction were investigated.
2
2
O during the process of
1
1
mmol UHP with 1 mmol of acetophenone after 6 hours (entry
7), consequently without atom economy of iodine introduction
Results and discussion
The convenience of solvent-free iodination using elemental iodine
and a supported form of H was first tested on mono-substituted
aromatic compounds (Scheme 2). At this point we would like to
stress that the term ‘solvent-free’ refers merely to the reaction itself.
The workup process still involved the use of a solvent (t-BuOMe)
and indicating the role of UHP as an activator of the iodination
process. In a reaction using SPC as the oxidiser, acetophenone
remained unchanged after 7 hours at 45 C (entry 19). During
our investigations on the role of the reaction conditions and the
atom economy concept of iodine introduction to various ketones,
2
O
2
◦
7
00 | Org. Biomol. Chem., 2007, 5, 699–707
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Scheme 2 Effect of functional groups and supported (Su) forms of H
2
O
2
on the course of iodination with elemental iodine under solvent-free conditions.
Table 1
Reaction conditions
a
b
◦
c
Entry
Substrate
Y=NH
(1a)
Oxidiser
Molar ratio (substrate : I
2
: oxidiser)
T/ C
t/h
Yield (%)
1
2
3
4
5
6
2
—
—
UHP
UHP
SPC
SPC
1 : 0.5 : 0
1 : 0.5 : 0
1 : 0.5 : 0.6
1 : 0.5 : 0.6
1 : 0.5 : 0.6
1 : 0.5 : 0.6
25
45
25
45
45
45
5
5
5
5
5
50 (2a, 20)
50 (2a, 24)
81 (2a, 52)
100 (2a, 83)
65 (2a, 40)
74 (2a, 46)
18
d
7
8
9
Y=OCH
3
(1b)
UHP
UHP
UHP
1 : 0.5 : 0.6
1 : 0.5 : 0.6
1 : 1 : 1
45
45
45
7
19
19
0
30 (2b, 8)
50 (2b, 16)
d
1
1
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
8
9
Y=COCH
3
(1c)
—
1 : 1 : 0
45
45
45
45
45
45
45
45
45
45
6
6
3
6
17
6
6
6
3
7
0
UHP
UHP
UHP
UHP
UHP
UHP
UHP
UHP
SPC
1 : 0.3 : 0.3
1 : 0.5 : 0.6
1 : 0.6 : 0.6
1 : 0.6 : 0.6
1 : 1 : 0.3
1 : 1 : 0.6
1 : 1 : 1
36 (2c, 19, 22*)
55 (2c, 31, 42*)
62 (2c, 40)
69 (2c, 46)
56 (2c, 31, 39*)
71 (2c, 49)
89 (2c, 65)
1 : 1 : 1
1 : 0.5 : 0.6
72 (2c, 52, 53*)
d
0
d
2
0
Y=CHO (1d)
; SPC = 2Na
UHP
1 : 1 : 1
45
20
0
a
b
c
1
UHP = urea–H
2
O
2
2
CO
3
–3H
2
O
2
.
Molar ratio substrate : I
2
: H
2
O
2
.
The first number represents conversion determined from
NMR spectra of crude reaction mixture, the first percentage in brackets represents isolated yield, the asterisked number is yield determined using
H
d
1
,1-diphenylethene as internal standard. Unreacted starting material.
we have already reported that iodination readily takes place under
very moderate reaction conditions in aqueous medium using I
gregate state at room temperature is known to potentially undergo
2
–
electrophilic substitution at the ortho position to the phenolic
11b
14
30% aq. H
2
O
2
.
However, this paper was overlooked in a recently
group, ipso-substitution at position 4 and addition processes.
published unusual procedure based on an enormous iodine excess
Moreover, due to its high reactivity a tendency toward formation
of the diiodo product was expected. In a blank experiment, in
which no oxidiser was present, no reaction between the substrate
(
(
susbstrate : I
bp 85 C) heated at 90 C for 3 hours.
2
amounting to 1 : 4) performed in dimethoxyethane
◦
◦
13
◦
Benzaldehyde (1d) was chosen as another molecule bearing a
(3) and iodine under solvent-free conditions at 45 C after 5 hours
deactivated aromatic ring in addition to the fact that the aldehyde
took place (Table 2, entry 1), while progressive electron exchange
◦
functionality is prone to oxidation. Nevertheless, after 20 hours
occurred in the presence of UHP as oxidiser at 45 C. After 5 hours
◦
◦
at 45 C using I
2
–UHP in a solventless system, only the starting
at 45 C with a ratio of substrate to iodine to UHP corresponding
substrate was isolated from the reaction mixture (entry 20). From
those initial experiments, it is evident that the structure of the
to 1 : 0.5 : 0.6 under neat conditions, 50% of 2-iodo-4-t-Bu-phenol
(4a), 25% of 2,6-diiodo-4-t-Bu-phenol (4b) and 25% of unreacted
substrate were present in the reaction mixture (entry 4). Raising
the amount of reagent resulted in a complete conversion of
4-t-Bu-phenol (3), but regulation of selectivity to either the
monoiodinated or diiodinated product was not achieved (entry 5).
various forms of H
of iodine into organic molecules. Urea–H
2
O
2
plays a significant role in the introduction
(UHP) was found to
2
O
2
be substantially more effective than sodium percarbonate (SPC)
in all cases of iodination under solvent-free conditions.
Furthermore, we studied the effect of reaction conditions on the
iodination of 4-t-Bu-phenol (3, Table 2). A substrate in a solid ag-
Even with a significant excess of reagent (1.3 mmol I
UHP) at 45 C after 6 hours, 17% of monoiodinated product
2
, 1.3 mmol
◦
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Table 2 Effect of reaction conditions on mono- and di-iodination of 4-t-Bu-phenol (3) without the use of a solvent
Reaction conditions
a
b
◦
c
Entry
Oxidiser
Molar ratio (substrate : I
2
: oxidiser)
T/ C
t/h
Conversion (%)
Ratio 4a : 4b
1
2
3
4
5
6
7
8
9
—
1 : 1 : 0
1 : 0.5 : 0.6
1 : 1 : 1
1 : 0.5 : 0.6
1 : 1 : 1
1 : 1.3 : 1.3
1 : 0.5 : 0.6
1 : 1 : 1
45
25
25
45
45
45
45
45
45
5
5
6
5
6
6
6
6
6
0
10
25
—
1 : 0
1 : 0
2 : 1
1 : 2.3
1 : 4.9
1 : 1
1 : 1.1
1 : 1.5
UHP
UHP
UHP
UHP
UHP
SPC
SPC
SPC
75
100
100
14
23
35
1 : 1.3 : 1.3
a
b
c
1
UHP = urea–H
2
O
2
; SPC = 2Na
2
CO
3
–3H
2
O
2
.
Molar ratio substrate: I
2
: H
2
O
2
.
Conversion determined from H NMR spectra of crude reaction
mixture.
was still present in addition to 83% of diiodinated product in
the reaction mixture (entry 6). An attempt to obtain only the
monoiodinated product with an excess of reagent by lowering the
temperature to room temperature also failed, since only moderate
conversion to 2-iodo-4-t-Bu-phenol (4a) was achieved (entries
9). Our results showed that a molar ratio of substrate to iodine to
UHP of 1 : 0.5 : 0.6 was sufficient for the introduction of iodine
into 1,2-dimethoxy benzene (5a) and 1,3-dimethoxy benzene (5b)
◦
with relatively high conversion after 7 hours at 45 C without the
use of any solvent (entries 2, 6), while 1,4-dimethoxy benzene (5c)
◦
2
, 3). Despite the poorly controllable regioselectivity, the atom
remained unchanged even after 23 hours at 45 C with a ratio of
economy aspect of the transformation should be stressed. Both
iodine atoms of the elemental iodine molecule were consumed in
the presence of UHP as an oxidiser. UHP was found to be superior
to SPC as an oxidiser under solvent-free conditions in this case as
well, since conversions and selectivities of iodo-transformations
using SPC as a mediator of iodination were considerably lower
than in the case of UHP (entries 7–9).
substrate to iodine to UHP of 1 : 1 : 1 under solvent-free conditions
(entry 9). In the case of 1,2-dimethoxy benzene (5a), the yield was
further improved by employment of an equimolar amount of I
and UHP with respect to the substrate (entry 3).
2
High conversions to iodo-products were achieved in all cases
of trimethoxy benzenes (7a, 7b, 7c) by the use of only a 0.5
molar equivalent of I
2
and 0.6 molar equivalents of UHP at
◦
In our previous study we demonstrated the effect of differ-
45 C without the use of solvent (Table 4, entries 2, 3, 7, 8,
11), thus providing reactions of high atom economy in regard to
iodine and indicating an ionic route of transformation through
the formation of a d-complex. It is evident that UHP plays
a dual role in such cases, acting as an activator in the first
step and as an oxidant of iodide to iodine in the next step.
The results on the route of iodo-transformation with regard
to the structure of dimethoxy- and trimethoxy benzenes are in
accordance with conclusions on iodination using water as reaction
ent solvents and two oxidisers, namely F-TEDA-BF
4
and a
3
0% aqueous solution of H , on the iodo-functionalisation
2
O
2
11h
of dimethoxy benzenes. The differences in reactivity of the
methoxy-substituted compounds could be illustrated by the
values of the halfway potential, indicating the possibility of
the formation of their cation-radicals, the stability of which is
15
16
known to importantly direct further transformation. In the same
above-mentioned study, two distinct reaction routes, requiring
different ratios of substrate to iodine to oxidiser and leading
to iodo-products, were proposed. Dimethoxy benzenes (Table 3)
and trimethoxy benzenes (Table 4) were also chosen as model
substrates for the present study in order to obtain insight into
the reaction pathway of iodination under solvent-free conditions
medium and 30% aqueous solution of H
2
O
2
as an oxidiser for
11h,11i
5a, 5b, 6a, 6b, 6c.
A noticeable difference should be pointed
out for 5c, namely the possibility of ion-radical formation in
water, while under solventless conditions iodo-functionalisation
through the formation of ion-radicals does not seem feasible.
This observation lead us to conclude that the reaction system
using solid carriers of H
2
2
O as mediators of iodination. In
blank experiments, where no oxidiser was present, conversions
of substrates were either very low or formation of a polymeric
material was noticed. On the other hand, the presence of UHP
contributed considerably to the efficiency and high atom-economy
of iodo-transformation in all cases, except in the case of 1,4-
dimethoxy benzene (5c), where even after a longer reaction time
I –UHP–no solvent is not convenient for the formation of ion-
2
radicals, while an alternative explanation could be connected with
the solid aggregate state of 1,4-dimethoxy benzene (5c), which
might circumvent transformation in this particular case. However,
it is interesting to note that substrate 5c with the lowest one-
15
electron oxidation potential (E1/2 = 1.30 V) was not transformed,
while 5a and 5b, requiring higher energy (E1/2 for 5a and 5b were
◦
at 45 C the starting material remained unchanged (Table 3, entry
7
02 | Org. Biomol. Chem., 2007, 5, 699–707
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Table 3 Effect of the structure of dimethoxy benzenes, their aggregate state and reaction conditions on iodination under solvent-free conditions
Reaction conditions
a
b
c
◦
d
Entry
Substrate
Oxidiser
Molar ratio (substrate : I
2
: oxidiser)
T/ C
t/h
Product
Yield (%)
1
2
3
4
—
1 : 1 : 0
1 : 0.5 : 0.6
1 : 1 : 1
45
45
45
45
7
7
7
7
27 (9)
UHP
UHP
SPC
63 (40)
91 (75)
e
1 : 1 : 1
0
1
: 1 : 1
5
6
7
8
—
1 : 1 : 0
45
45
45
45
7
7
7
7
15 (7)
UHP
SPC
SPC
1 : 0.5 : 0.6
1 : 0.5 : 0.6
1 : 1 : 1
78 (67)
39 (21)
65 (39)
e
9
0
UHP
SPC
1 : 1 : 1
1 : 1 : 1
45
45
23
23
0
0
e
1
a
b
c
Aggregate state at room temperature in parentheses, (l) liquid; (s) solid. UHP = urea–H
2
O
2
; SPC = 2Na
2
CO
3
–3H
2
O
2
.
Molar ratio substrate : I
2
:
d
1
H
2 2
O .e The first number represents conversion determined from H NMR spectra of crude reaction mixture, the bracketed number represents isolated
yield. Unreacted starting material.
Table 4 Effect of the structure of trimethoxy benzenes, their aggregate state and reaction conditions on iodination without the use of a solvent
Reaction conditions
a
b
c
◦
d
Entry
Substrate
Oxidiser
Molar ratio (substrate : I
2
: oxidiser)
T/ C
t/h
Product
Yield (%)
e
1
2
3
4
5
—
1 : 1 : 0
45
45
45
45
45
5
5
18
5
PM
UHP
UHP
UHP
SPC
1 : 0.5 : 0.6
1 : 0.5 : 0.6
1 : 1 : 1
76 (61)
90 (58)
100 (82)
f
1 : 1 : 1
6
0
e
6
7
8
9
—
1 : 1 : 0
45
45
45
45
5
5
17
6
PM
UHP
UHP
SPC
1 : 0.5 : 0.6
1 : 0.5 : 0.6
1 : 1 : 1
70 (50)
81 (58)
41 (15)
1
1
1
0
1
2
—
UHP
SPC
1 : 1 : 0
1 : 0.5 : 0.6
1 : 0.5 : 0.6
45
45
45
5
55
5
25 (12)
100 (89)
71 (52)
a
b
c
Aggregate state at room temperature in parentheses, (l) liquid; (s) solid. Oxidiser: A = urea–H
2
O
2
; B = 2Na
2 3 2 2 2
CO –3H O . Molar ratio substrate : I :
d
1
H
2 2
O .e The first number represents conversion determined from H NMR spectra of crude reaction mixture, the bracketed number represents isolated
f
yield. Polymeric material. Unreacted starting material.
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15
established to be 1.44 V and 1.58 V, respectively) were successfully
iodinated. SPC again proved to be less convenient as a mediator of
iodination without the use of a solvent, since considerably lower
conversions to iodinated products were achieved (Table 3, entries
oxyphenyl)-2-iodoethanone,
ethanone and 2-iodo-1-(3-iodo-4,5-dimethoxyphenyl)ethanone
was formed. To clarify the role of UHP, reactions were performed
1-(3-iodo-4,5-dimethoxyphenyl)-
with different amounts of I and UHP in regard to substrates 9a,
2
8
, 10 and Table 4, entries 9, 12). Moreover, in the cases of 1,2-
9b, 9c, 9d and also the effect of reaction time on the efficiency
dimethoxy benzene (5a) and 1,2,3-trimethoxy benzene (7a) no
reaction occurred (Table 3, entry 4 and Table 4, entry 5).
of the transformation was verified (Table 5). Blank experiments,
where only the substrate and iodine were heated at 45 C for
◦
Methoxy substituted acetophenones offer a further possibility
for studying the regioselectivity of the transformation. The
methoxy substituted acetophenones investigated in the current
research (9a–d, Table 5) were regioselectively iodinated at the
6 hours without the presence of a solvent and UHP, showed
either low conversion (entry 9) or no conversion at all (entries
1, 17, 25). The results demonstrated that the presence of UHP
facilitated the introduction of iodine at the alkyl position of
methoxy substituted acetophenones. The highest conversion to
iodinated products for 9a, 9c and 9d was achieved with a molar
ratio of substrate to iodine to UHP of 1 : 1 : 1 (entries 8, 22,
alkyl position of the acetophenone-moiety using the I –UHP
2
combination under solvent-free conditions, except for 1-(2,4-
dimethoxyphenyl)ethanone, where a mixture of 1-(2,4-dimeth-
Table 5 Effect of the structure of methoxy-substituted acetophenones and reaction conditions on side-chain iodination under solvent-free conditions
Reaction conditions
a
b
Entry
Substrate
Molar ratio substrate : I
2
: oxidiser
T/h
Yield (%)
c
1
2
3
4
5
6
7
8
1 : 1 : 0
6
6
3
6
6
6
3
6
0
1 : 0.3 : 0.3
1 : 0.5 : 0.6
1 : 0.5 : 0.6
1 : 1 : 0.3
1 : 1 : 0.6
1 : 1 : 1
26 (15, 23*)
52 (35, 44*)
48 (28, 31*)
33 (16, 21*)
56 (32. 38*)
73 (54, 61*)
79 (54, 58*)
1 : 1 : 1
9
1 : 1 : 0
6
6
3
6
3
6
6
6
17 (7)
1
1
1
1
1
1
1
0
1
2
3
4
5
6
1 : 0.3 : 0.3
1 : 0.5 : 0.6
1 : 0.5 : 0.6
1 : 1 : 1
1 : 1 : 1
1 : 1 : 0.6
1 : 1 : 0.3
50 (28, 31*)
50 (23, 30*)
46 (25, 30*)
37 (16, 21*)
37 (18, 23*)
47 (28, 34*)
44 (26, 33*)
c
1
1
1
2
2
2
2
2
7
8
9
0
1
2
3
4
1 : 1 : 0
6
6
3
6
3
6
6
6
0
1 : 0.3 : 0.3
1 : 0.5 : 0.6
1 : 0.5 : 0.6
1 : 1 : 1
1 : 1 : 1
1 : 1 : 0.6
1 : 1 : 0.3
36 (21, 20*)
53 (35, 36*)
78 (55, 59*)
77 (51, 55*)
88 (58, 60*)
60 (37, 42*)
39 (24, 25*)
c
2
2
2
5
6
7
1 : 0.5 : 0.6
1 : 1 : 1
1 : 1 : 1
6
6
17
0
17 (9)
34 (22)
a
b
1
Molar ratio substrate : I
2
: H
2
O
2
.
The first number represents conversion determined from H NMR spectra of crude reaction mixture, the first
c
bracketed number represents isolated yield; the asterisked number is yield determined using 1,1-diphenylethene as internal standard. Unreacted starting
material.
7
04 | Org. Biomol. Chem., 2007, 5, 699–707
This journal is © The Royal Society of Chemistry 2007

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2
7), which highlights UHP in the role of an activator of the
iodinating system under solvent-free conditions for these methoxy
substituted acetophenones. The atom economy principle was not
followed in these cases. In this respect, results of iodination under
solvent-free conditions using the I
from observations of iodine introduction using I
solution of H as an oxidiser and water as reaction medium.
2
–UHP reagent system differ
2
, a 30% aqueous
11i
2
O
2
In the latter case, high conversions to side-chain iodinated
products were obtained with 0.5 molar equivalent of reagent. An
exception to the behaviour of 9a and 9c was observed in the case
of 1-(3,4-dimethoxyphenyl)ethanone (9b), where introduction of
iodine under solventless conditions was more efficient when the
ratio of substrate to iodine to UHP was 1 : 0.5 : 0.6 compared
to the 1 : 1 : 1 ratio, but the conversion was still only moderate
Scheme 4 Effect of reaction conditions on addition of iodine to alkenes
and phenyl acetylenes under solvent-free conditions.
1
As determined from H NMR spectra of the crude reaction
(
entries 11, 12).
mixture, phenyl acetylene (15a) was converted to trans-(1,2-
diiodovinyl)benzene (16a) and 1-phenyl-1-propyne (15b) to trans-
(1,2-diiodopropenyl)benzene (16b) with 94 and 98% conversion,
respectively, after 6 hours at room temperature without the use of
any oxidiser or solvent, yielding 52 and 72% of isolated products.
In order to study the effect of ketone structure, the investigation
was additionally extended to cyclic alkyl aromatic ketones. The
introduction of iodine under solvent-free conditions proved to be
very efficient in the case of 1-indanone (11a) and 1-tetralone (11b)
as depicted in Scheme 3. Reacting 1 mmol of 1-indanone (11a)
with 0.5 mmol of iodine and 0.6 mmol of UHP with no use of
solvent for 5 hours at room temperature resulted in 55% formation
of 2-iodo-1-indanone (12a), while 2-iodo-1-tetralone (12b) was
Conclusions
The introduction of iodine using elemental iodine in the presence
of the urea–hydrogen peroxide adduct (UHP) under solvent-free
conditions and without the need for any metal or acid catalyst
proved to be feasible for several organic compounds activated
toward electrophilic functionalisation, namely aniline (1a), p-t-
Bu-phenol (3), dimethoxy- and trimethoxy benzenes (5a, 5b, 7a,
7b, 7c), acetophenones (1b, 9a, 9b, 9c), 1-indanone (11a) and
1-tetralone (11b). Sodium percarbonate (SPC) as a mediator of
iodination showed inferiority compared to UHP, since signifi-
cantly lower conversions to iodinated products were obtained.
The site of iodo-functionalisation was found to be crucially
dependant on the structure of the substrate, while its efficiency
could be further regulated by the amount of reagent, reaction
time and temperature. Based on the required ratio of substrate to
iodine to oxidiser for the most efficient iodo-transformation, two
reaction routes were established and the roles of UHP elucidated
in each route. The one requiring a 1 : 0.5 : 0.6 molar ratio for
achieving the highest efficiency of iodine introduction follows
atom economy in regard to iodine and proceeds through an ionic
mechanism with r-complex formation in the intermediate stage
(Scheme 5). The iodide ion liberated after initial electrophilic
attack of iodine is oxidised by UHP in the second stage, thus
providing regenerated iodine for a second electrophilic attack
on the substrate. The dual role of UHP as an activator of the
iodinating system and regenerator of iodine is evident in these
cases, which were present in iodination of aniline (1a), p-t-Bu-
phenol (3), 1,2-dimethoxy benzene (5a), 1,3-dimethoxy benzene
(5b), 1,2,3-trimethoxy benzene (7a), 1,2,4-trimethoxy benzene
(7b), 1,3,5-trimethoxy benzene (7c), 1-indanone (11a) and 1-
tetralone (11b).
formed with 0.5 mmol of I and 0.6 mmol of UHP after 6 hours at
2
room temperature with 40% conversion. Raising the temperature
◦
to 45 C with the same ratio of substrate to iodine to UHP and the
same reaction time remarkably improved the conversion in both
substrates. Thus, 1-indanone (11a) was 80% converted to 2-iodo-
1
1
-indanone (12a) and 2-iodo-1-tetralone (12b) was formed from
-tetralone (11b) with 90% conversion.
Scheme 3 Introduction of iodine into the a-alkyl position of 1-indanone
and 1-tetralone with molecular iodine in the presence of UHP under
solvent-free conditions.
A further extension of the investigation focused on methoxy
substituted benzaldehydes (3,4-dimethoxybenzaldehyde, 2,3,4-
trimethoxybenzaldehyde and 3,4,5-trimethoxybenzaldehyde), but
no or a very low amount of iodinated product was found in the
◦
case of 3,4-dimethoxy-benzaldehyde even after 18 hours at 45 C
with the ratio of substrate : iodine : UHP of 1 : 1 : 1.
Finally, we discovered that addition of iodine to some alkenes
and phenyl acetylenic derivatives efficiently proceeds under
solvent-free conditions without the need for an oxidiser at room
temperature (Scheme 4). This significantly contributes to a ‘green’
addition protocol since the reaction is completely atom economic
and no additional reagent, solvent or energy requirements are
needed. 1-octene (13a) was 93% converted to 1,2-diiodo-octane
On the other hand, atom economy was not attained in the cases
of acetophenone (1c) and methoxy-substituted acetophenones (9a,
9b, 9c, 9d), where the highest conversion to side-chain iodinated
product was achieved with a ratio of substrate to iodine to UHP
corresponding to 1 : 1 : 1. In these cases, UHP is believed
to play only the role of an activator of the iodinating system
(Scheme 6). Moreover, addition of iodine to 1-octene (13a),
(
14a) with 1 molar equivalent of iodine after 5 hours at room
temperature under solvent-free conditions, yielding 65% of prod-
uct after isolation. The addition of iodine to phenyl-acetylenes
under solventless conditions was found to be trans-oriented.
This journal is © The Royal Society of Chemistry 2007
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Scheme 6 Suggested reaction route for iodination of methoxy-substituted
2
acetophenones with required ratio of substrate to I to UHP corresponding
to 1 : 1 : 1 under solvent-free conditions.
NMR spectra were recorded on a Varian INOVA 300 spectrometer
at 300 MHz. IR spectra were recorded on a Perkin-Elmer 1310
spectrometer. Standard KBr pellet procedures were used to obtain
IR spectra of solids, while a film of neat material was used to obtain
IR spectra of liquid products. MS were obtained on an AutospecQ
instrument under EI conditions at 70 eV.
Scheme 5 Suggested reaction route for efficient iodination of dimethoxy-
and trimethoxy benzenes with the required ratio of substrate to I
2
to UHP
corresponding to 1 : 0.5 : 0.6 under solvent-free conditions.
General procedure
phenylacetylene (15a) and 1-phenyl-1-propyne (15b) was found
to proceed efficiently without the need of any oxidiser and solvent
at room temperature.
Finely powdered iodine (127 mg, 0.5 mmol; 254 mg, 1 mmol;
76 mg, 0.3 mmol; 330 mg, 1.3 mmol, see Tables 1–5) was added to
Finally, we would like to stress the ‘green’ approach of the
method in addition to its simplicity and mildness. Avoidance of
solvent for performing reactions, the use of a non-toxic, relatively
cheap, safe and stable oxidiser, its benign by-product of oxidation
and atom economy achieved in most cases are valuable attributes.
Since the listed attributes are also desirable characteristics in a
wider scientific context and in industrial chemical processes, we
believe that the results of this research might find application
on a more extensive scale, with considerably lower financial
and environmental impact than using other previously reported
iodination methods.
the neat liquid substrate (1 mmol) or finely powdered substrate in
cases of solid compounds. After shaking the mixture vigorously to
obtain a good distribution between substrate and iodine molecules
in a 5-mL round-bottom flask, finely powdered oxidiser UHP
(56.4 mg, 0.6 mmol; 94 mg, 1 mmol; 28.2 mg, 0.3 mmol; 125 mg,
1
0
1
.3 mmol, see Tables 1–5) or SPC (63 mg, 0.4 mmol; 110 mg,
.7 mmol; 141 mg, 0.9 mmol containing 20.4 mg, 0.6 mmol; 34 mg,
mmol; 44 mg, 1.3 mmol of active oxidant H
2
2
O , respectively, see
Tables 1–4) was added. The reaction mixture was again vigorously
shaken to enable a good contact between reacting molecules.
Pulverization of solid compounds was made in a mortar prior
to their transfer to the 5-mL round-bottom flask. Reactions were
◦
carried out either at room temperature or at 45 C for various times
Experimental
(
3–23 h, see Tables 1–5), followed by extraction of products with t-
BuOMe (20 mL). The organic phase was washed with an aqueous
solution of Na (10%, 20 mL) to destroy unreacted iodine,
O (20 mL), dried over anhydrous Na SO and concentrated
Iodine, UHP, SPC and substrates were purchased from Sigma
Aldrich. Solid reagents and substrates were finely powdered in a
mortar before use, while liquid substrates were used as received.
2
S
2
O
3
H
2
2
4
t-BuOMe was purchased from Riedel-de-Ha e¨ n, other chemicals
in vacuo. The crude reaction mixtures were analysed by TLC,
H NMR and mass spectroscopy and products identified on
1
1
(
Na
2
SO
4
and Na
2
S
2
O
3
) from Merck and were used as received. H
7
06 | Org. Biomol. Chem., 2007, 5, 699–707
This journal is © The Royal Society of Chemistry 2007

View Article Online
the basis of comparison with their spectroscopic data with the
Soc. Jpn., 1966, 39, 128–131; (c) B. R. Patil, S. R. Bhusare, R. P. Pawar
and Y. Vibhute, Tetrahedron Lett., 2005, 46, 7179–7181; (d) G. A. Olah,
Q. Wang, G. Sandford and G. K. S. Prakash, J. Org. Chem., 1993,
4f ,11a,17,18
literature.
Conversions and yields of iodinated products
obtained are listed in Tables 1–5.
5
8, 3194–3195; (e) A. Bachki, F. Foubelo and M. Yus, Tetrahedron,
994, 50, 5139–5146; (f) K. Orito, T. Hatakeyama, M. Takeo and H.
1
Iodination of 1,3,5-trimethoxy benzene (7c). No solvent was
used during performance of the reaction and product isolation
in the case of iodination of 1,3,5-trimethoxy benzene (7c) using
UHP as mediator of oxidation. Prior to the reaction performance,
substrate 7c, iodine and UHP were separately finely triturated in a
mortar, after which each was transferred to a 5-mL round-bottom
flask, where the reaction was performed. To the finely powdered
substrate 7c (168 mg, 1 mmol), finely powdered iodine (127 mg,
Suginome, Synthesis, 1995, 1273–1277; (g) B. Krassowska-Swiebocka,
P. Luli n´ ski and L. Skulski, Synthesis, 1995, 926–928.
5 (a) Green Chemistry, Frontiers in Benign Chemical Syntheses and
Processes, ed. P. T. Anastas and T. C. Williamson, Oxford University
Press, New York, 1998; (b) P. T. Anastas and J. C. Warner, Green
Chemistry: Theory and Practice, Oxford University Press, New York,
1
998; (c) S. K. Ritter, Chem. Eng. News, 2001, 79(29), 27–34; (d) P. T.
Anastas and M. M. Kirchhoff, Acc. Chem. Res., 2002, 35, 686–694;
e) R. A. Sheldon, Green Chem., 2005, 7, 267–278.
(
6
7
(a) Solvent-free Organic Synthesis, ed. K. Tanaka, Wiley-VCH, Wein-
heim, 2003; (b) K. Tanaka and F. Toda, Chem. Rev., 2000, 100, 1025–
1074; (c) J. O. Metzger, Angew. Chem., Int. Ed., 1998, 37, 2975–2978.
(a) A. R. Hajipour and A. E. Ruoho, Org. Prep. Proced. Int., 2002, 34,
0
.5 mmol) was first added. Vigorous shaking was followed by the
addition of UHP (56.4 mg, 0.6 mmol), and more strong shaking
◦
of the reaction mixture ensued. After 5 hours reaction at 45 C,
6
47–651; (b) A. R. Hajipour, M. Arbabian and A. E. Ruoho, J. Org.
an aqueous solution of Na
2
S
2
3
O (10%, 30 mL) was poured into
Chem., 2002, 67, 8622–8624; (c) J. C. Lee and Y. H. Bae, SYNLETT,
the reaction mixture and the solution obtained was vigorously
stirred for an hour at room temperature. Following filtration
under reduced pressure, only 2-iodo-1,3,5-trimethoxy benzene (8c,
2
003, 507–508; (d) V. M. Alexander, A. C. Khandekar and S. D. Samant,
SYNLETT, 2003, 1895–1897.
8
9
(a) R. Noyori, M. Aoki and K. Sato, Chem. Commun., 2003, 1977–1986;
(
b) C. W. Jones, Applications of Hydrogen Peroxide and Derivatives,
2
63 mg, 0.89 mmol) was present in the isolated mixture.
Royal Society of Chemistry, Cambridge, 1999; (c) Peroxide Chemistry:
Mechanistic and Preparative Aspects of Oxygen Transfer, ed. W. Adams,
Wiley-VCH, Weinheim, 2000.
(a) C.-S. Lu, E. W. Hughes and P. A. Gigu e` re, J. Am. Chem. Soc.,
1941, 63, 1507–1513; (b) S. Taliansky, SYNLETT, 2005, 1962–1963;
Addition of iodine to 1-octene (13a), phenylacetylene (15a) and 1-
phenyl-1-propyne (15b). Iodine was finely powdered in a mortar,
after which 254 mg (1 mmol) was transferred to a 5-mL round-
bottom flask containing the liquid substrate (1 mmol). The mixture
was strongly shaken and left to react at room temperature. After
(
c) J. Muzart, Synthesis, 1995, 1325–1347; (d) A. McKillop and W. R.
Sanderson, Tetrahedron, 1995, 51, 6145–6166.
1
1
0 (a) P. Lulinski, A. Kryska, M. Sosnowski and L. Skulski, Synthesis,
2004, 441–445; (b) A. Zielinska and L. Skulski, Molecules, 2005, 10,
1307–1317; (c) M. Sosnowski and L. Skulski, Molecules, 2005, 7, 867–
5
–6 hours products were extracted with t-BuOMe (20 mL). The
organic phase was washed with an aqueous solution of Na
10%, 20 mL), H O (20 mL), dried over anhydrous Na SO and
2
S
2
O
3
8
70.
1 (a) J. Iskra, S. Stavber and M. Zupan, Synthesis, 2004, 1869–1873;
b) M. Jereb, M. Zupan and S. Stavber, Chem. Commun., 2004, 2614–
2615; (c) G. Stavber, M. Zupan, M. Jereb and S. Stavber, Org. Lett.,
004, 6, 4973–4976; (d) M. Jereb, J. Iskra, M. Zupan and S. Stavber,
(
2
2
4
concentrated in vacuo. The crude reaction mixtures were analysed
(
1
by TLC, H NMR and mass spectroscopy and products identified
2
on the basis of comparison of their spectroscopic data with
19,20
Lett. Org. Chem., 2005, 2, 465–468; (e) M. Jereb, M. Zupan and S.
Stavber, Green Chem., 2005, 7, 100–104; (f) A. Podgor sˇ ek, S. Stavber,
M. Zupan and J. Iskra, Tetrahedron Lett., 2006, 47, 1097–1099; (g) A.
Podgor sˇ ek, S. Stavber, M. Zupan and J. Iskra, Eur. J. Org. Chem., 2006,
the literature.
Yields of the iodinated products obtained are
depicted in Scheme 4.
4
7
2
83–488; (h) J. Pavlinac, M. Zupan and S. Stavber, J. Org. Chem., 2006,
1, 1027–1032; (i) J. Pavlinac, M. Zupan and S. Stavber, Synthesis,
006, 2603–2607; (j) A. Podgor sˇ ek, S. Stavber, M. Zupan and J. Iskra,
Acknowledgements
The authors are grateful to the staff of the Slovenian NMR Centre
at the National Institute of Chemistry in Ljubljana for assistance
in recording NMR specta, to Dr B. Kralj and Dr D. Zigon for
MS spectra and to the Slovenian Research Agency for financial
support.
Tetrahedron Lett., 2006, 47, 7245–7247; (k) I. Pravst, M. Zupan and S.
Stavber, Tetrahedron Lett., 2006, 47, 4707–4710; (l) I. Pravst, M. Zupan
and S. Stavber, Green Chem., 2006, 8, 1001–1005.
ˇ
1
1
2 S. Stavber, M. Jereb and M. Zupan, Chem. Commun., 2002, 488–489.
3 M. L. N. Rao and D. N. Jadhav, Tetrahedron Lett., 2006, 47, 6883–6886.
14 I. Pravst, M. Pape zˇ Iskra, M. Jereb, M. Zupan and S. Stavber,
Tetrahedron, 2006, 62, 4474–4481; and references cited therein.
1
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Jonsson, J. Lind, T. Reitberger and T. E. Eriksen, J. Phys. Chem., 1993,
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