N-Iodosuccinimide (NIS) in Direct Aromatic Iodination

Article abstract of DOI:10.1002/ejoc.201700173

N-Iodosuccinimide (NIS) in pure trifluoroacetic acid (TFA) offers a time-efficient and general method for the iodination of a wide range of mono- and disubstituted benzenes at room temperature, as demonstrated in this paper. The starting materials were generally converted into mono-iodinated products in less than 16 hours at room temperature, without byproducts. A few deactivated substrates needed addition of sulfuric acid to increase the reaction rate. Another exception was methoxybenzenes that preferentially were iodinated by NIS in acetonitrile with only catalytic amounts of TFA.

Full text of DOI:10.1002/ejoc.201700173

A Journal of
Accepted Article
Title: N-Iodosuccinimide (NIS) in Direct Aromatic Iodination
Authors: Maria Bergström, Suresh Ganji, Veluru Ramesh Naidu, and
Rikard Unelius
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201700173
Link to VoR: http://dx.doi.org/10.1002/ejoc.201700173
Supported by

10.1002/ejoc.201700173
European Journal of Organic Chemistry
Maria Bergström, Ganji Suresh, Veluru Ramesh Naidu and C. Rikard Unelius*
Dept. of Chemistry and Biomedical Sciences, Linnaeus University, Kalmar, 39182 Sweden.
*Supporting Information
ABSTRACT: NIS in pure TFA is a time-efficient and general method for the iodination of a wide range of mono- and disubstituted
benzenes at room temperature as demonstrated in this paper. The starting materials were generally converted into mono-iodinated
products in less than 16 hours at room temperature, without by-products. A few deactivated substrates needed addition of sulphuric
acid to increase reaction rate. Another exception was methoxybenzenes that preferentially were iodinated by NIS in acetonitrile
with only catalytic amounts of TFA.
INTRODUCTION
or concentrated sulfuric acid are very benign/versatile sol-
vents. Furthermore, solubilities of aromatic substrates are
low in these systems and they are not compatible with all
substrates because of side reactions due to the harsh reac-
tion conditions.
Aromatic iodo compounds are important intermediates in
several reactions that have found a wide application, such
as the Ullman, Heck and Suzuki reactions. Efficient meth-
ods for regioselective iodination of aromatic compounds
are therefore of high interest. Several methods performing
direct iodination of aromatics have consequently been
published, using different conditions and sources of iodine.
1,2 Iodine is a rather poor electrophile and has to be activat-
ed with an oxidant to perform well in aromatic iodination.
Another option is to use an iodination agent where iodine
has a more electrophilic character, such as N-iodoamides or
N-iodoimides. These have been reported to be efficient
iodination agents in combination with strong protic ac-
ids/acidic ionic liquids.1,2 The iodination agent in the reac-
tion is believed to be the electrophilic iodine complex of
the acid, formed in situ, which is a more reactive electro-
phile compared to the N-iodoamide/imide.2,3 The efficiency
of NIS in electrophilic iodination is therefore closely relat-
ed to the acid that is used as activator.
We have concluded that NIS has a wide applicability in
electrophilic iodination of benzenes, as exemplified above,
but the reported reaction conditions vary so substantially
that guidelines for each substitution pattern are needed. In
this report the effect of substituents on the aromatic ring is
evaluated and guidelines of new mild reaction conditions
for iodination of mono- and disubstituted benzenes are
presented. Furthermore, new observations regarding the
reaction mechanism in direct aromatic iodination by NIS
have been recorded.
RESULTS AND DISCUSSION
The evaluation of suitable reaction conditions for io-
dination by NIS was initiated because we wanted to io-
dinate ethyl o-toluate to produce a cheap and non-chiral
N-iodosuccinimide (NIS), in combination with different
acidic catalysts, has been demonstrated to perform well in
in the iodination of a variety of aromatic compounds.3-7
Electron-rich (activated) aromatics can even be iodinated
by NIS in pure acetonitrile, without adding an acidic cata-
lyst.8,9 Acidic conditions do, however, improve regioselec-
tivity as well as reaction rate.4,5,10 Catalytic amounts of p-
toluenesulfonic acid, sulfuric acid or trifluoroacetic acid
(TFA) have been used in iodination of activated aromatic
compounds.3-5 Methods for iodination of electron deficient,
deactivated aromatics are less abundant, but interestingly
enough, NIS has shown to work also in these reactions by
choosing stronger and more concentrated acids as catalysts.
A very reactive system was created by combining NIS and
pure trifluoromethanesulfonic acid (triflic acid) that was
demonstrated to iodinate strongly deactivated compounds,
such as nitrobenzene.6 The very aggressive triflic acid can
be replaced by NIS/BF3-H2O7 or concentrated sulfuric
acid,3 but reaction time has to be increased from 2 h to
about 20 h. However, neither triflic acid, nor NIS/BF3-H2O
substance related to ceralure
B
(ethyl 5-iodo-2-
methylcyclohexane-1-carboxylate), which is a strong at-
tractant to the Mediterranean fruitfly (Ceratitis capitata),11
an insect pest. Several methods for mild and regioselective
iodination were tried without success, including NIS in
acetonitrile with catalytic amount of TFA.5 Methods aiming
at iodination of activated aromatics were apparently not
potent
enough,
as
the
substrate
(ethyl
2-
methylcyclohexane-1-carboxylate or ethyl o-toluate) com-
prises a weakly activating methyl group in combination
with an electron withdrawing (deactivating) carbonyl
group. Eventually, pure TFA in combination with 1.1 molar
eq. NIS was tried and found to perform well (Scheme 1).
Iodination by NIS in pure TFA has, to our knowledge, not
been reported before.
Scheme 1.
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10.1002/ejoc.201700173
European Journal of Organic Chemistry
NIS-TFA: Reaction time for the iodination of ethyl o-tolute
(Figure 1 and entry 1, Table 1) was about 3 h in room tem-
perature using the NIS-TFA method (i.e. 13% of starting
material left according to GC-MS analysis). Only mono-
iodinated products were formed and the isolated yield was
86% (83% para-, 17% ortho- according to GC-MS and
NMR).
tive methods for these exceptional compounds are de-
scribed below.
Table 1. Iodination of arenes
Lowering the TFA concentration by performing the reac-
tion in acetonitrile + TFA (1:1) decreased the reaction rate
substantially; only 50% ethyl o-toluate was iodinated in 16
h under these conditions (data not shown).
100
entry 1
80
entry 2
60
entry 3
40
20
0
0
1
2
3
4
5
Reactiontime(hours)
Figure 1. Reaction of benzoic acid derivatives using 1.0 mmol substrate
and 1.1 mmol NIS dissolved in 3 mL TFA at room temperature. Conver-
sion into iodinated products is shown as the decrease of substrate concen-
tration in reaction mixtures after 1, 3 and 5 hours (determined by GC-MS).
Structurally related substrates such as o-toluic acid and o-
toluamide (Figure 1 and entries 2-3, Table 1) reacted in
close similarity to ethyl o-tolute. The reaction rates of al-
kylated benzaldehydes (entries 4, 5 and 6, Table 1) were
however considerably slower than o-toluic acid and o-
toluamide; after 3 h 20 - 30% of the aromatic aldehydes
were still unreacted (Figure 2). The methyl ketone tested
(entry 7, Table 1) showed similar reactivity as the alde-
hydes (Figure 2) although some iodination apparently oc-
curred at the methyl group (in analogy with an earlier re-
port on iodinations of acetophenones).12 Even if the effi-
ciency of these reactions were lower the isolated yields of
the iodinated products (entries 4-7) were still acceptable
(64% - 78%). Benzenes containing a carbonyl group in
combination with an activating hydroxyl group reacted
very similar to ethyl o-tolute, and were completed in 3
hours; see entries 19–21, Table 1.
Iodination of benzenes without any deactivating group
were also studied. As expected, iodination of these sub-
strates by NIS in pure TFA occurred almost instantly; see
entries 11-14 and 18 (Table 1). Arenes, such as o-xylene
and o-chlorotoluene (entries 8 and 9, Table 1), were also
efficiently iodinated by the NIS-TFA method.
* Percentage of conversion in the reaction mixture was determined by GC-
MS.
The only compounds that did not perform well with the
NIS-TFA method were completely deactivated compounds
such as o-nitrotoluene, benzoic acid derivatives and very
activated componds such as dimethoxybenzenes. Alterna-
** The isolated yield is calculated from the weight of the mono-iodinated
fraction.
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10.1002/ejoc.201700173
European Journal of Organic Chemistry
NIS-acetonitrile + H2SO4: As discussed previously, it was
not possible to iodinate ethyl toluate with NIS in acetoni-
trile + TFA, and this was the reason why pure TFA was
tried. As sulfuric acid apparently is a more potent activator
than TFA, and also less costly, we wanted to evaluate if it
was possible to perform iodination with NIS in acetonitrile,
using a low concentration of sulfuric acid as activator in-
stead of TFA. Reactions were performed with 1 mmol ethyl
o-toluate, 1.1 mmol NIS dissolved in 4 mL acetonitrile and
different amounts of sulfuric acid. It was found that apply-
ing 10 molar equivalents of sulfuric acid as catalyst (0.55
mL sulfuric acid in 4 mL acetonitrile) were almost as effi-
cient as performing the reaction in pure TFA (Figure 4).
Reaction rate was proportional to the concentration of sul-
furic acid. A drawback using NIS-sulfuric acid in acetoni-
trile is a lower solubility, in comparison to TFA, and also
potential side reactions. For example, it was not possible to
iodinate benzaldehyde by NIS-sulfuric acid (10 eq. sulfuric
acid) in acetonitrile, since the substrate reacted with ace-
tonitrile under these conditions. The amount of sulfuric
acid has to be optimized in for each substrate, and the reac-
tion in 100% TFA is therefore more straight-forward. Sul-
furic acid in combination with NIS is however cost-
efficient and may, in some cases, be an alternative to the
NIS-TFA method presented in this paper (e.g. in large-scale
synthesis).
100
80
60
40
20
0
entry 4
entry 5
entry 6
entry 7
0
1
2
3
4
5
Reactiontime(hours)
Figure 2. Reaction of benzaldehydes using 1.0 mmol substrate and 1.1
mmol NIS dissolved in 3 mL TFA at room temperature. Conversion into
iodinated products is shown as the decrease of substrate concentration in
reaction mixtures after 1, 3 and 5 hours (determined by GC-MS).
100
entry 10
80
entry 16
60
100
entry 17
40
20
0
80
H2SO4 (1eq)
60
H2SO4 (10eq)
TFA (100%)
40
0
1
2
3
4
5
Reactiontime(hours)
20
0
Figure 3. Reaction of “difficult substrates” using 1.0 mmol substrate and
1.1 mmol NIS dissolved in 3 mL TFA with catalytic amounts of sulfuric
acid (1 mmol for o-nitrotoluene (entry 10) and benzoic acid (entry 16),
and 0.3 mmol for benzaldehyde (entry 17)). Conversion into iodinated
products is shown as the decrease of substrate concentration in reaction
mixtures by time (determined by GC-MS).
0
1
2
3
4
5
Reactiontime(hours)
NIS-TFA + H2SO4: Unsubstituted (deactivated) benzoic
derivatives were very resistant to iodination by the NIS-
TFA method; less than 3% iodinated product was achieved
in 16 h with substrates such as benzaldehyde, benzoic acid
and benzamide (data not shown). These compounds have
previously been reported to be iodinated by NIS in concen-
trated sulfuric acid.3 We found that a milder alternative to
the published method is to add a small amount of sulfuric
acid to the NIS-TFA reaction mixture to speed up the reac-
tion; see entries 10, 16 and 17 (Table 1). For example,
benzoic acid and o-nitrotoluene was iodinated by adding 1
molar eq. sulfuric acid into the NIS-TFA reaction mixture
(Figure 3). Using the same amount of sulfuric acid for the
analogous m-iodination of benzaldehyde did, however,
induce oxidation to m-iodobenzoic acid. By decreasing the
concentration of sulfuric acid to 0.3 molar eq. the oxidation
could be kept on an acceptable level (< 5%) (Table 1, entry
17).
Figure 4. Reaction of ethyl toluate (entry 1) using 1.0 mmol substrate and
1.1 mmol NIS dissolved in 4 mL acetonitrile with different amounts of
sulfuric acid (1 or 10 mmol). Reaction in 100% TFA from Fig. 1 is shown
for comparison. Conversion into iodinated products is shown as the de-
crease of substrate concentration in reaction mixtures by time (determined
by GC-MS).
NIS-acetonitrile + TFA: It has been reported by Castanet et
al. that catalytic amount of TFA in acetonitrile (0.3 molar
equivalents) is the optimal condition for iodination of acti-
vated compounds by NIS.5 We found that this method
worked well only with methoxybenzenes that was iodinated
in 36-48 h at room temperature, while less than 30% of
toluene and o-xylene were iodinated with this method dur-
ing the same time (data not shown). When TFA concentra-
tion in acetonitrile was changed from 0.3 to 1.0 molar eq.
the reaction rate of all substrates containing a methoxy
group decreased while the reaction rate of toluene and o-
xylene increased. In order to understand this effect of the
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10.1002/ejoc.201700173
European Journal of Organic Chemistry
TFA concentration on the NIS iodination reaction rate, the
amount of TFA in acetonitrile was varied between 0.1 to 10
molar equivalents in the iodination of anisole and o-xylene
(Figure 5). We found that the iodination rate of o-xylene
was directly related to the amount of TFA, which seems
reasonable if the active agent is the iodine complex of TFA.
Anisole (methoxybenzene), on the other hand, had a rela-
tively high reaction rate at 0.1 molar equivalent TFA, but a
lower reaction rate at 0.3 and 1.0 molar equivalents of TFA.
Using 10 molar eq. of TFA was, however, more efficient
for both substrates (Figure 5), and the iodination reactions
were completed in ca 20 h with this method.
crease the reaction rate. Highly activated substances such
as dimethoxybenzenes can be iodinated by NIS with cata-
lytic amounts of TFA in acetonitrile.
A
100
80
60
40
20
0
0.1
0.3
1.0
10
The explanation of the phenomenon with anisole is possi-
bly the protonation of the methoxy group and the formation
of TFA complexes under acidic conditions. These complex-
es dominate when 0.3-1 molar equivalent of TFA is used
and TFA-iodine is not available as reactant. The iodination
reaction is therefore faster when TFA is present in low
concentrations (0.1 molar eq.), due to a negligible protona-
tion of the methoxy group at lower acid concentration,
keeping inductive and resonance effects at large. Finally,
when a surplus of TFA is added (10 molar eq.), the reaction
will proceed rather efficiently due to the high TFA content,
even though most substrate molecules hypothetically are
protonated and the ring thereby deactivated. Here we must
note the NIS-TFA method is much more efficient for o-
xylene and anisole as the reaction was completed in less
than an hour (entries 8 and 12, Table 1) compared to about
20 h with 10 molar eq TFA in NIS-aceotonitrile (Figure 5).
0
5
10
15
20
25
30
Reactiontime(hours)
B
100
80
60
40
20
0
0.1
0.3
1.0
10
As stated above, the highly activated dimethoxybenzenes
were not compatible with the NIS-TFA method, as they
over-reacted and turned to black tars when iodinated by
NIS in 100% TFA, and NIS in acetonitrile with catalytic
amounts of TFA is to prefer (entries 22 and 23, Table 1).
0
5
10
15
20
25
30
Reactiontime(hours)
Regioselectivity and di-iodination: Initially, the regioselec-
tivity of the reactions were confirmed by NMR e.g. for
ethyl o-toluate, o-xylene and bromobenzene. As expected
from theory, methyl and bromo substituents were found to
direct the iodine substitution mainly to the para-
position. The ratio of iodination ortho/para to the methyl
group was about 15% for ethyl o-toluate, o-xylene, and
bromobenzene. As the para- and ortho-substituted products
show a consistent elution order from the GC column it was
possible to determine the product ratios by GC-MS. Small
amounts of di-iodinated products were present in some
cases, especially when activated substrates were iodinated
(see Table 1).
Figure 5. Reaction of two activated compounds; anisole (A) and o-xylene
(B) using 1.0 mmol substrate and 1.1 mmol NIS dissolved in 4 mL ace-
tonitrile with different amounts of TFA (0.1, 0.3, 1.0 or 10 mmol). Con-
version into iodinated products is shown as the decrease of substrate
concentration in reaction mixtures by time (determined by GC-MS).
EXPERIMENTAL SECTION
Starting materials and reactants were obtained from com-
mercial sources and used without further purification. Re-
action mixtures and products were analyzed by separation
on a GC-MS (6890 GC and 5973 mass detector, Hewlett
Packard, Palo Alto, CA, USA). Helium was used as carrier
gas and a nonpolar capillary column (HP5, 30 m x 0.25
mm, ID 0.25 µm, J&W Scientific, USA). The temperature
programme was 50 ⁰C (2 min hold) then 10 °C/min to 200
⁰C (15 min hold). Mass fragments are given in decreasing
order of intensity. NMR spectra were recorded at 400 MHz
(1H) and at 100 MHz (13C). Chemical shifts (δ) are reported
in ppm, using the residual solvent peak in CDCl3 (H = 7.26
and C = 77.0 ppm), Acetone-d6 (H = 2.05 and C = 29.84
CONCLUSION
In conclusion NIS in pure TFA is an improved and time-
efficient iodination method for a wide range of aromatic
substrates, see Table 1. The method works well without
optimization for most aromatic substrates with only few
exceptions. For completely deactivated substrates we sug-
gest that a small amount (1 molar equivalent or less) of
sulfuric acid is used in combination with NIS-TFA to in-
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10.1002/ejoc.201700173
European Journal of Organic Chemistry
ppm) or DMSO-d6 (H = 2.50 and C = 39.52 ppm) as inter-
nal standard, and coupling constants (J) are given in Hz.
MHz, CDCl3):  19.0, 90.6, 132.7, 135.0, 135.2, 137.7,
139.2, 169.3; GC-MS m/z 261 (M+, 100%), 244, 245, 89,
217, 90, 216, 63, 122.
Iodination procedure NIS-TFA: Iodinations were performed
with 1 mmol of the aromatic starting material, which was
dissolved in 3 mL pure TFA (Sigma-Aldrich, St Louis, MO,
USA). Then 1.1 mmol of NIS (Alfa Aesar, Karlsruhe, Ger-
many) was added in small portions. The reaction mixture
was stirred at ambient temperature while sampled at time
intervals by mixing two drops of the reaction mixture into 3
mL of cold water, followed by extraction with 0.5 mL of
dichloromethane (DCM). The extract was analyzed by GC-
MS. Sampling was repeated until all starting material was
iodinated, or when the reaction had stopped according to
GC-MS. The iodinated products were isolated by pouring
the reaction mixture into cold water and then extracting it
with DCM (3 x 2.5 ml). The combined organic extracts
were washed with 10% Na2S2O4 in water, and dried over
Na2SO4. The crude residue obtained was subjected to sili-
cagel column chromatography using cyclohexane / ethyl
acetate. The distribution of isomers and di-iodinated prod-
ucts were determined by GC-MS / NMR.
1
5-Iodo-2-methylbenzaldehyde (4): Yellow solid; H NMR
(400 MHz, CDCl3):  2.60 (s, 3H), 7.01 (d, J = 8.0 Hz,
1H), 7.76 (dd, J = 8.0, 2.0 Hz, 1H), 8.07 (d, J = 2.0 Hz,
1H), 10.16 (s, 1H); 13C NMR (100 MHz, CDCl3): 19.0,
90.7, 133.6, 135.6, 139.9, 140.2, 142.2, 191.0; GC-MS: m/z
246 (M+, 100%), 245, 217, 90, 91, 89, 63, 65, 127.
3-Iodo-4-methylbenzaldehyde (5): Yellow flakes; 1H
NMR (400 MHz, CDCl3): 2.50 (s, 3H), 7.38 (d, J = 7.8
Hz, 1H), 7.74 (dd, J = 7.8, 1.5 Hz, 1H), 8.28 (d, J = 1.5 Hz,
1H), 9.88 (s, 1H); 13C NMR (100 MHz, CDCl3):  28.6,
101.2, 129.2, 130.2, 135.7, 140.2, 148.6, 190.2; GC-MS:
m/z 246 (M+, 100%), 245, 91, 90, 89, 217, 127. Spectros-
copy data accords with the literature.15
1
4-Ethyl-3-iodobenzaldehyde (6): Yellow liquid; H NMR
(400 MHz, CDCl3):  1.22 (t, J = 7.6 Hz, 3H), 2.78 (q, J =
7.6 Hz, 2H), 7.34 (d, J = 7.8 Hz, 1H), 7.76 (dd, J = 7.8, 1.5
Hz, 1H), 8.27 (d, J = 1.6 Hz, 1H), 9.86 (s, 1H); 13C NMR
(100 MHz, CDCl3):  14.0, 34.4, 100.5, 128.4, 128.8,
135.7, 140.6, 153.4, 190.2; GC-MS: m/z 260 (M+, 100%),
259, 245, 217, 77, 103, 105, 104, 131, 231.
Iodination procedure NIS-TFA + H2SO4: Iodination of o-
nitrotoluene and benzoic acid (1 mmol) was performed by
dissolving the starting in 3 mL pure TFA. Thereafter 1.1
mmol of NIS was added in small portions. When NIS was
dissolved, 55 L concentrated H2SO4 (1.0 molar equiva-
lent) was added. All subsequent steps were identical to
procedure NIS-TFA. Iodination of benzaldehyde was per-
formed with 18 L H2SO4 (0.3 molar equivalents).
Iodination procedure NIS-acetonitrile + TFA: Iodinations
were performed with 1 mmol of the aromatic starting mate-
rial, which was dissolved in 4 ml of acetonitrile. Then 1.1
mmol of NIS was added in small portions. When NIS was
dissolved, 25 L TFA (0.3 molar equivalent) was added.
All subsequent steps were in analogy to procedure NIS-
TFA. In one set of experiments different amounts of TFA (8
L, 25 L, 76 L and 760 L) was tried in the iodination
of anisole and o-xylene, while keeping the total volume at 4
mL.
1-(3-Iodo-4-methylphenyl)ethan-1-one (7): Brown liquid;
1H NMR (400 MHz, CDCl3):  2.54 (s, 3H), 7.30 (d, J =
8.0 Hz, 1H), 7.86 (d, J = 8.0 Hz), 8.38 (s, 1H); 13C NMR
(100 MHz, CDCl3): 26.5, 28.3, 101.2, 128.3, 129.6,
136.3, 138.8, 146.9, 196.2; GC-MS: m/z 245 (100%), 260
(M+), 90, 217, 89, 63. Spectroscopy data accords with the
literature.16
4-Iodo-1,2-dimethylbenzene (8): Colorless liquid; 1H
NMR (400 MHz, CDCl3): 2.210 (s, 3H), 2.22 (s, 3H),
6.88 (d, J = 7.8 Hz, 1H), 7.41 (d, J = 7.8 Hz, 1H), 7.48 (s,
1H); 13C NMR (100 MHz, CDCl3): 19.3, 19.4, 90.6,
131.4, 134.7, 136.1, 138.1, 139.0; GC-MS: m/z 232 (M+,
100%), 105, 103, 79, 77, 127, 217. Spectroscopy data ac-
cords with the literature.17,18
2-Chloro-4-iodo-1-methylbenzene (9): Colorless liquid;
1H NMR (400 MHz, CDCl3):  2.32 (s, 3H), 7.05 (d, J =
8.3 Hz, 1H), 7.43 (dd, J = 8.3, 2.2 Hz, 1H), 7.56 (d, J = 2.0
Hz, 1H); 13C NMR (100 MHz, CDCl3):  19.7, 91.2, 130.7,
132.3, 136.0, 138.4, 139.5; GC-MS: m/z 252 (M+, 100%),
254, 125, 89, 217, 127, 63.
4-Iodo-1-methyl-2-nitrobenzene (10): Yellow solid; 1H
NMR (400 MHz, CDCl3):  2.54 (s, 3H), 7.07 (d, J = 8.1
Hz, 1H), 7.79 (dd, J = 8.1, 1.6 Hz, 1H), 8.26 (d, J = 1.6 Hz,
1H); 13C NMR (100 MHz, CDCl3): 20.1, 89.7, 127.9,
133.1, 134.2, 141.8, 143.1; GC-MS: m/z 246 (100%), 263
(M+), 90, 89, 119, 91, 218, 63. Spectroscopy data accords
with the literature.19-21
4-Iodophenol (11): Brown solid; 1H NMR (400 MHz,
CDCl3):  6.62 (d, J = 8.8 Hz, 2H), 7.51 (d, J = 8.8 Hz,
2H); 13C NMR (100 MHz, CDCl3):  82.6, 117.8, 138.4,
155.3; GC-MS: m/z 220 (M+, 100%), 93, 65, 127, 110, 191.
Spectroscopy data accords with the literature.22,23
1
Ethyl 5-iodo-2-methylbenzoate (1): H NMR (400 MHz,
CDCl3):  1.39 (t, J = 7.2 Hz, 3H), 2.53 (s, 3H), 4.35 (q, J =
7.2 Hz, 2H), 6.98 (d, J = 8.0 Hz, 1H), 7.68 (dd, J = 8.0, 2.0
Hz, 1H), 8.20 (d, J = 1.6 Hz, 1H); 13C NMR (100 MHz,
CDCl3):
; GC-MS: m/z 244 (100%), 290 (M+), 245,
261, 89, 90, 216, 217, 134, 63. Spectroscopy data accords
with the literature.13
1
5-iodo-2-methylbenzoic acid (2): White solid; H NMR
(400 MHz, Acetone-d6):  2.67 (s, 3H), 7.09 (d, J = 8.0 Hz,
1H), 7.75 (dd, J = 8.0, 1.8 Hz, 1H), 8.21 (d, J = 1.8 Hz,
1H), 10.27 (s, 1H); 13C NMR (100 MHz, Acetone-d6): 
21.3, 90.2, 133.6, 134.5, 139.9, 140.5, 141.2, 179.8; GC-
MS: m/z 264 (M+, 100%), 109, 244, 216, 83, 89, 137. Spec-
troscopy data accords with the literature.14
1
Iodo-2-methylbenzamide (3): White solid; H NMR (400
1-Iodo-4-methoxybenzene (12): White solid; 1H NMR
(400 MHz, CDCl3):  3.78 (s, 3H), 6.68 (dd, J = 7.2 Hz,
MHz, DMSO-d6):  2.29 (s, 3H), 7.04 (d, J = 8.0 Hz, 1H),
7.43 (s, 1H), 7.64 (s, 2H), 7.80 (s, 1H); 13C NMR (100
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700173
European Journal of Organic Chemistry
2H), 7.55 (d, J = 7.2 Hz, 2H); 13C NMR (100 MHz,
CDCl3): 55.3, 82.6, 116.3, 138.2, 159.4; GC-MS: m/z 234
(M+, 100%), 219, 191, 92, 77, 63, 64, 127. Spectroscopy
data accords with the literature.22,24,25
1-Iodo-4-methylbenzene (13): Brown liquid; 1H NMR
(400 MHz, CDCl3):  2.29 (s, 3H), 6.93 (d, J = 7.8 Hz,
2H), 7.55 (d, J = 7.8 Hz, 2H); 13C NMR (100 MHz,
CDCl3): 29.6, 90.1, 131.2, 137.2; GC-MS: m/z 218 (M+,
100%), 91, 65, 127. Spectroscopy data accords with the
literature.25
Iodobenzene (14): White solid; 1HNMR (400 MHz,
CDCl3): δ 7.41 (s, 5H), 13C NMR (100 MHz, CDCl3): δ
93.4, 129.2, 139.3, 139.5; GC-MS: m/z 204 (M+, 100%),
77, 51, 127, 102. Spectroscopy data accords with litera-
ture.25,26
J = 8.8, 2.3 Hz, 1H), 8.12 (d, J = 2.3 Hz, 1H), 10.79 (s,
1H); 13C NMR (100 MHz, CDCl3):  14.3, 62.8, 80.4,
115.7, 120.9, 138.9, 144.9, 162.1, 169.6; GC-MS: m/z 246
(100%), 292 (M+), 218, 63, 92, 190, 137, 119. Spectrosco-
py data accords with the literature.33
1
4-iodo-1,2-dimethoxybenzene (22): White solid; H NMR
(400 MHz, CDCl3):  3.77 (s, 3H), 3.82 (s, 3H), 6.84 (s,
2H), 7.34 (d, J = 2.9 Hz, 1H); 13C NMR (100 MHz,
CDCl3): 55.9, 56.9, 85.9, 111.5, 114.6, 124.8, 152.6,
153.7; GC-MS: m/z 264 (M+, 100%), 249, 94, 79, 221, 63.
Spectroscopy data accords with the literature.34-38
2-Iodo-1,4-dimethoxybenzene (23): White solid; 1H NMR
(400 MHz, CDCl3):  3.84 (s, 3H), 3.85 (s, 3H), 6.61 (d, J
= 8.4 Hz, 1H), 7.10 (s, 1H), 7.20−7.23 (m, 1H) ; 13C NMR
(100 MHz, CDCl3): 55.9, 56.0, 82.3, 113.1, 120.3, 129.7,
149.1, 149.8; GC-MS: m/z 264 (M+, 100%), 249, 94, 221,
79, 63. Spectroscopy data accords with the literature.36-38
1
1-Bromo-4-iodobenzene (15): White solid; H NMR (400
MHz, CDCl3): 7.22 (d, J = 7.8 Hz, 2H), 7.54 (d, J = 7.8
Hz, 2H); 13C NMR (100 MHz, CDCl3):  92.0, 122.2,
133.4, 139.0; GC-MS: m/z 281/283 (M+, 100%), 155/157,
75, 76, 74, 50, 141/143, 127.
3-Iodobenzoic acid (16): White solid; 1H NMR (400 MHz,
DMSO-d6):  7.30 (t, J = 7.8 Hz, 1H), 7.92−7.98 (m 2H),
8.22 (t, J = 1.6 Hz, 1H), 13.25 (s, 1H); 13C NMR (100
MHz, CDCl3):  94.6, 128.6, 130.8, 132.9, 137.6, 141.3,
165.9; GC-MS: m/z 248 (M+, 100%), 121, 231, 65, 203, 76,
50. Spectroscopy data accords with literature.27
ASSOCIATED CONTENT
*S Supporting Information
The Supporting Information is available on the Wiley Pub-
lications website.
1H and 13C NMR spectra of compounds not previously
reported in the literature.
3-Iodobenzaldehyde (17): Yellow solid; 1H NMR (400
MHz, CDCl3):  7.28 (t, J = 7.6 Hz, 1H) 7.83 (dt, J = 7.6 ,
1.3 Hz, 1H), 7.94 (dt, J = 7.6, 1.6 Hz, 1H), 8.19 (t, J = 1.6
Hz, 1H), 9.91 (s, 1H); 13C NMR (100 MHz, CDCl3): 94.6,
128.8, 130.7, 137.9, 138.4, 143.1, 190.6; GC-MS: m/z 232
(M+, 100%), 231, 203, 76, 77, 50, 127, 105. Spectroscopy
data accords with the literature.28,29
3-Iodo-4-methoxytoluene (18): Brown liquid; 1H NMR
(400 MHz, CDCl3):  2.26 (s, 3H), 3.85 (s, 3H), 6.71 (d, J
= 8.3 Hz, 1H), 7.10 (dd, J = 8.3, 2.0 Hz, 1H), 7.60 (d, J =
2.0 Hz, 1H); 13C NMR (100 MHz, CDCl3):  19.9, 56.4,
85.7, 110.7, 129.9, 132.0, 139.8, 156.0; GC-MS: m/z 248
(M+, 100%), 233, 106, 78, 91, 121. Spectroscopy data ac-
cords with the literature.24
AUTHOR INFORMATION
Corresponding Author
rikard.unelius@lnu.se
orcid.org/0000-0001-7158-6393
https://lnu.se/en/research/searchresearch/ecological-
chemistry-group/
Notes
The authors declare no competing financial interest.
Acknowledgements
This study was supported by Linnaeus University, Kalmar
Sweden and The Carl-Tryggers Foundation, Stockholm,
Sweden.
1-(4-hydroxy-3-iodophenyl)ethan-1-one (19): White
1
solid; H NMR (400 MHz, Acetone-d6):  2.51 (s, 3H),
7.02 (d, J = 8.5 Hz, 1H), 7.88 (dd, J = 8.5, 2.1 Hz, 1H),
8.34 (d, J = 2.1 Hz, 1H), 10.00 (s, 1H); 13C NMR (100
MHz, CDCl3): 26.3, 84.3, 115.3, 131.3, 132.2, 140.9,
161.5, 195.3; GC-MS: m/z 247 (100%), 262 (M+), 219, 92,
120, 63. Spectroscopy data accords with the literature.30,31
1
Methyl 4-Hydroxy-3-iodobenzoate (20): White solid; H
NMR (400 MHz, Acetone-d6):  3.83 (s, 3H), 7.03 (d, J =
8.5 Hz, 1H), 7.87 (dd, J = 8.5, 2.1 Hz, 1H), 8.33 (d, J = 2.1
Hz, 1H), 10.29 (s, 1H); 13C NMR (100 MHz, CDCl3):
52.2, 83.8, 115.2, 124.0, 132.0, 141.5, 161.5, 165.5; GC-
MS: m/z 247 (100%), 278 (M+), 219, 92, 63, 136, 120.
Spectroscopy data accords with the literature.32
Ethyl 2-hydroxy-5-iodobenzoate (21): White solid; 1H
NMR (400 MHz, Acetone-d6):  1.41 (t, J = 7.1 Hz, 3H),
4.44 (q, J = 7.1 Hz, 2H), 6.81 (d, J = 8.8 Hz, 1H), 7.80 (dd,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700173
European Journal of Organic Chemistry
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