A facile synthesis of 1,4-dialkoxy-2,5-diiodobenzenes: reaction of dialkoxybenzenes with iodine monochloride in alcoholic solvents

Article abstract of DOI:10.1021/op025566h

A facile synthesis of 1,4-dialkoxy-2,5-diiodobenzenes via diiodination of the corresponding dialkoxybenzenes with iodine monochloride has been developed. Employment of ah alcoholic solvent as a reaction medium is crucial for attaining a high yield; the reaction in a nonalcoholic solvent usually resulted in a poor yield. The diiodobenzene derivatives are useful intermediates in the synthesis of such advanced materiais as soluble phenylenevinylene polymers anal dialkoxy derivatives of 7,7,8,8-tetracyanoquinodimethane.

Full text of DOI:10.1021/op025566h

Organic Process Research & Development 2003, 7, 98−100
A Facile Synthesis of 1,4-Dialkoxy-2,5-diiodobenzenes: Reaction of
Dialkoxybenzenes with Iodine Monochloride in Alcoholic Solvents
Koji Wariishi, Sin-ichi Morishima, and Yoshio Inagaki*
Ashigara Research Laboratories, Fuji Photo Film Co., Ltd., 210 Nakanuma, Minami-ashigara,
Kanagawa 250-0193, Japan
Abstract:
Scheme 1
A facile synthesis of 1,4-dialkoxy-2,5-diiodobenzenes via diio-
dination of the corresponding dialkoxybenzenes with iodine
monochloride has been developed. Employment of an alcoholic
solvent as a reaction medium is crucial for attaining a high
yield; the reaction in a nonalcoholic solvent usually resulted in
a poor yield. The diiodobenzene derivatives are useful inter-
mediates in the synthesis of such advanced materials as soluble
phenylenevinylene polymers and dialkoxy derivatives of 7,7,8,8-
tetracyanoquinodimethane.
8
(
1a) in a 92% yield. The treatment of 2a with a mixture of
molecular iodine-iodic acid-carbon tetrachloride in an
acetic acid-sulfuric acid mixture afforded 1a in an 84.4%
yield. The iodination of 2a with mercury(II) oxide-iodine
9
in dichloromethane at room temperature for 36 h gave 1a in
1
0
an 85% yield. The reaction with iodine chloride in acetic
acid, which appears most straightforward, gave 1a only in a
Introduction
1
1
3
6% yield. From a practical point of view, however, the
Dialkoxy-substituted 1,4-diiodobenzenes (1) are key
intermediates in the syntheses of soluble phenylenevinylene
polymers (PPVs) and 7,7,8,8-tetracyanoquinodimethanes
hitherto reported syntheses are still unsatisfactory: the use
of mercury(II) chloride, strongly acidic solvents, or oxidative
reaction conditions implies disadvantages concerning waste
disposal problems. In this contribution, we report an im-
proved practical process for diiodination of 1,4-dialkoxy-
benzenes (2) using iodine chloride in alcoholic solvents12
(TCNQs). Extended π-electron systems of PPVs constitute
very useful components in advanced materials with elec-
troluminescent, conductive, or nonlinear optical properties.
TCNQs serve as strong electron acceptors, showing unusual
molecular electromagnetic properties as well as photochemi-
cal stabilizing effects. Palladium-catalyzed coupling reac-
tions of the 1,4-diiodobenzenes furnish the most straight-
forward syntheses of PPVs and TCNQs; reactions of 1,4-
diiodo-2,5-dialkoxybenzenes (1) with vinylbenzenes give
PPVs, while those with malononitrile followed by oxidation
1
-4
(Scheme 1).
5
6
Results and Discussion
Dialkoxybenzenes 2 are allowed to react with an excess
amount of iodine monochloride for 4 h in refluxing methanol
or in other solvents at 70 °C. Reaction conditions and isolated
yields of diiodinated products 1 are listed in Table 1.
When 1,4-dimethoxybenzene 2a was allowed to react with
2
,4
7
give TCNQs.
Dialkoxy-substituted 1,4-diiodobenzenes (1) have been
prepared by direct diiodination of the corresponding di-
alkoxybenzenes (2). For example, the reaction of 1,4-
dimethoxybenzene (2a) with benzyltrimethylammonium
dichloroiodate-zinc(II) dichloride in acetic acid at room
temperature for 15 h gave 1,4-diiodo-2,5-dimethoxybenzene
1
1
ICl in acetic acid according to Sargent et al., we observed
development of red color reminiscent of molecular iodine
in the reaction mixture. Actually, the reaction mixture showed
an absorption band with a peak at 464 nm, which is identical
with that of molecular iodine in acetic acid. The product
analysis revealed that 2-iodo-1,4-dimethoxybenzene 3a and
2
-chloro-1,4-dimethoxybenzene 4a in addition to the desired
*
To whom correspondence should be addressed. E-mail: yoshio_inagaki@
diiodinated product 1a (31%) was also formed. In acetic acid,
an extended reaction period failed to improve the yield of
fujifilm.co.jp. Fax: +81-465-73-7921.
(
1) Gruber, J.; Li, R. W. C.; Hummelgen, I. A. In Handbook of AdVanced
Electronic and Photonic Materials and DeVices; Nalwa, H. S., Ed.;
Academic Press: San Diego, CA, 2001; Vol. 8, p 163.
1a. The reaction apparently stopped in the early stages when
(
(
(
(
2) Bao, Z.; Chen, Y.; Cai, R.; Yu, L. Macromolecules 1993, 26, 5281.
3) Ohnishi, T. Mol. Electron. Bioelectron. 2001, 12, 14.
(8) Kajigaeshi, S.; Kakinami, T.; Moriwaki, M.; Watanabe, M.; Fujisaki, S.;
Okamoto, T. Chem. Lett. 1988, 795.
4) Weder, C.; Wrighton, M. S. Macromolecules 1996, 29, 5157.
5) (a) Melby, L. R.; Harder, R. J.; Heltler, W. R.; Mahler, W.; Benson, R. E.;
Mochel, W. E. J. Am. Chem. Soc. 1962, 84, 3374. (b) Proceedings of the
International Conference on Science and Technology of Synthetic Metals,
T u¨ bingen, 1990. Synth. Met. 1991, 41-43. (c) Miller, J. S.; Epstein, A. J.;
Rieff, W. M. Chem. ReV. 1998, 88, 201.
(9) Shvartsberg, M. S.; Moroz, A. A.; Kiseleva, O. B. IzV. Akad. Nauk SSSR,
Ser. Khim. 1981, 4, 827.
(10) Orito, K.; Hatakeyama, T.; Takeo, M.; Suginome, H. Synthesis 1995, 1273.
(11) Sargent, T., III; Shulgin, A. S.; Mathis, C. A. J. Med. Chem. 1984, 27,
1071.
(6) Morishima, S.; Wariishi, K.; Inagaki, Y.; Shibata, M.; Ishida, T. Kubo, H.
Jpn. J. Appl. Phys. 1999, 38, 1634.
(12) Iodine or ICl, which is prepared by direct reaction of I
recyclable: ICl-containing solution recovered from a reaction vessel has
been utilized as a resource for I at an iodine refinery in Japan, the second
largest iodine-producing nation.
2 2
and Cl , are
(7) Uno, M.; Seto, K.; Masuda, M.; Ueda, W.; Takahashi, S. Tetrahedron Lett.
2
1
985, 26, 1553.
9
8
•
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10.1021/op025566h CCC: $25.00 © 2003 American Chemical Society
Published on Web 12/07/2002

Table 1. Isolated yields of 1 and reaction conditions
temperature resulted in spattering of the reaction mixture.
By contrast, use of a solvent is effective in suppressing the
vigorous reaction: we did not observe a significant rise in
temperature when we added 0.5 g of 1,4-dimethoxybenzene
to 3.18 g of ICl in 30 mL of methanol at 39.5 °C.
Although mixing a halogen with an alcohol often causes
highly exothermic reactions, we observed only slight evolu-
tion of heat on mixing ICl with methanol or 2-propanol; the
heat evolution on mixing methanol with ICl was estimated
to be ca. 9.7 kcal/mol ICl, which was well within the capacity
of our reactor. We have actually repeated the reaction quite
safely even at a scale of 400 mol.
ICl/2a
product
R
1
R
2
solvent
yield (%)
1
1
1
1
1
1
1
1
a
a
a
a
b
c
CH
3
3
3
3
3
CH
3
3
3
3
4.3
4.3
4.3
4.1
4.8
4.3
4.3
methanol
2-propanol
acetic acid
acetonitrile
methanol
methanol
methanol
methanol
85.0
82.0
31.0
13.0b
80.1
89.9
82.0
86.0
CH
CH
CH
CH
CH
CH
CH
C
C
2
H
H
5
C
2
H
5
H
2
5
d
e
n-C
4
9
4 9
n-C H
C H OH 5.0
2 4
C
2
H
4
OH
a
Mole ratio. b Not isolated: the yield was estimated based on the H NMR
1
of a mixture with the major product, 5a.
As we have not yet completed safety assessment regarding
the effects of contaminants and impurities in chemicals used
in the present reaction, we recommend not reusing an ICl-
containing solution as recovered from a reaction vessel.
2
I formation became remarkable. These observations suggest
that the conversion of ICl into less reactive molecular iodine
was the cause of the low yield of the diiodo derivative 1a.
We therefore sought such conditions that would maintain
the electrophilic iodinating reactivity of ICl during the
reaction.
Experimental Section
Proton NMR spectroscopy was determined on a Bruker
ARX-300 (300 MHz) spectrometer, and the chemical shifts
are quoted in ppm downfield from SiMe . IR spectra were
4
Reaction of arenes with ICl was reported to give
chlorinated or iodinated products depending on the reaction
1
3
conditions. In view of the solvent and salt effects on the
competition between chlorination and iodination in aromatic
halogenation with iodine monochloride, Hubig et al. de-
scribed that such polar solvents as acetonitrile favor iodi-
nation over chlorination by suppressing the formation of less
reactive molecular iodine without mentioning the effect of
any alcoholic solvents.13
In our case, however, application of acetonitrile as a
reaction medium resulted in a low conversion to the diiodo
derivative 1a (13.0%); the main product was 1-chloro-4-iodo-
recorded on a JASCO IR-810 spectrometer. UV/vis spectra
were recorded on a Shimadzu UV-3100PC spectrophotom-
eter. FAB mass spectra were measured with a JEOL DX-
3
03 mass spectrometer, and m/z values obtained for the
isolated compounds were consistent with the corresponding
molecular formulae. HPLC was performed on a Shimadzu
system with UV detection at 254 nm through a TSK-gel
ODS-80 column (4.6 mm × 150 mm) eluted with aqueous
acetonitrile containing 0.2 vol % of acetic acid and triethy-
lamine.
Materials. Solvents were obtained from commercial
sources and used without further purification. 1,4-Dimethoxy-
benzene (2a), 1,4-diethoxybenzene (2c), 1,4-dibutoxybenzene
2
1
,5-dimetoxybenzene 5a (58.3%). Just after the addition of
,4-dimethoxybenzene to a solution of ICl in acetonitrile,
the reaction mixture turned deep red due to I
By contrast, a reaction in an alcoholic solvent did not show
the color of I . When we used a polar solvent, methanol,
2
formation.
(
2d), 1,4-bis(2-hydroxyethoxy)benzene (2e), and iodine
monochloride were commercially available reagents. 1-Ethoxy-
-methoxybenzene (2b) was prepared as described in the
2
development of red color due to molecular iodine ceased to
be observed, and at the same time, the isolated yield of the
diiodo derivative 1a remarkably improved to 85%. The
reaction completed within 4 h of refluxing. The workup was
simple: the crystalline product, which crystallized out of the
reaction mixture on cooling, was collected by filtration and
rinsed with methanol. The purity by HPLC assay, 99.4% by
area, was sufficient for the use in the subsequent reactions.
The present process was successfully applied also to diio-
dination of 1-ethoxy-4-methoxybenzene (2b) 1,4-diethoxy-
benzene (2c), 1,4-dibutoxybenzene (2d), and 1,4-bis(2-
hydroxyethoxy)benzene (2e), as shown in Table 1. Since
4
14
literature.
1
,4-Diiodo-2,5-dimethoxybenzene (1a). Reaction in
Methanol. Iodine monochloride (175 g, 1.08 mol) was added
dropwise to 300 mL of methanol below 15 °C. To the
mixture were added 35 g (0.25 mol) of 2a below 15 °C, and
then the reaction mixture was heated under reflux for 4 h.
After cooling the reaction mixture to room temperature,
resulting crystals were collected by filtration. The crystals
were rinsed with methanol (300 mL) and air-dried to give
8
4 g of 1a (85% yield). HPLC assay 99.4%. Mp 171-172
15
1
°
C (lit. 171 °C). H NMR (CDCl
2H, s).
Reaction in 2-Propanol. The procedure was repeated
3
) δ 3.82 ( 6H, s), 7.19
2-propanol in place of methanol also facilitated the diiodi-
(
nation reaction, the employment of alcohols as reaction media
is crucial for the improvement of the yield and provides a
means for avoiding acidic solvents. Although hydrogen
chloride is among the byproducts of this reaction, the
stoichiometric amount of the acid is far less than the amount
of an acid as a solvent. In the absence of a solvent,
dialkoxybenzenes and ICl react very violently: addition of
except for using 2-propanol in place of methanol, and the
reaction mixture was heated at 70 °C. The yield of 1a was
8
0 g (82% yield).
Reaction in Acetic Acid. Iodine monochloride (7.5 g) was
dissolved in 10 mL of acetic acid. To the solution was added
0.67 g of 1,4-dimethoxybenzene to 3.2 g of ICl at room
(
14) Li, Y.; Zhong, H.; Huang, S.; Long, Y.; Sun, W. Huaxue Shiji 1998, 20,
168.
(13) Hubig, S. M.; Jung, W.; Kochi, J. K. J. Org. Chem. 1994, 59, 6233.
(15) Jones B.; Richardson, E. N. J. Chem. Soc. 1953, 714.
Vol. 7, No. 1, 2003 / Organic Process Research & Development
•
99

1
4
.6 g of 2a. The resulting solution was heated at 70 °C for
h and then cooled to room temperature. Deposited crystals
1,4-Diethoxy-2,5-diiodobenzene (1c). According to the
procedure for 1a except for using 23.3 g of 2c in place of
35 g of 2a, we obtained 52.6 g (89.9% yield) of 1c. Mp
144.5-146.5 °C (recrystallized from ethanol). IR (KBr)
were collected by filtration and rinsed with 10 mL of
methanol to give 1.4 g (31% yield) of 1a. From the filtrate,
an oily mixture of 3a and 4a in a mol ratio of 1:0.35 based
on the H NMR was obtained. H NMR (CDCl
to 3a13 δ 3.37 (s, 3H), 3.82 (s, 3H), 6.38 (d, 1H), 6.85 (dd,
-
1
2980, 2860,1488, 1352, 1205, 1058, 928, 826, 775 cm .
1
1
1
3
) signals due
H NMR (CDCl ) δ (6H, t), 4.01 (4H, q), 7.19 (2H, s). Calcd
3
for C10
H
12
I
2
O
2
C, 28.73; H, 2.89; I, 60.72. Found C, 28.50;
H, 2.73; I, 60.20.
,4-Dibutoxy-2,5-diiodobenzene (1d). According to the
13
1H), 7.33 (d, 1H); signals due to 4a δ 3.76 (s, 3H), 3.84
(s, 3H), 6.74 (dd, 1H), 6.85(d, 1H), 6.94 (d, 1H). MS m/z
1
263 (3a).
procedure for 1a except for using 55 g of 2d in place of 35
Reaction in Acetonitrile. Iodine monochloride (18.1 g, 111
g of 2a, we obtained 98 g (82% yield) of 1d. Mp 83-85 °C
mmol) was dissolved in 30 mL of acetonitrile. To the solution
was added 3.7 g (26.8 mmol) of 2a. The resulting solution
was heated at 70 °C for 4 h and then cooled to room
temperature. Deposited crystals were collected by filtration
and rinsed with acetonitrile to give 1.72 g of colorless
crystals, the NMR of which showed two sets of signals due
to 5a and to 1a in a intensity ratio of 1.3:1, which
corresponds to 0.86 and 0.86 g, respectively. On treatment
of the filtrate with a sodium sulfite solution (12 g/200 mL)
were deposited colorless crystals, which were collected by
filtration to give 4.3 g of a mixture of 5a and 1a in a mol
ratio of 10:1, which corresponds to 3.8 and 0.5 g, respec-
tively. Recrystallization of the mixture from 2-propanol gave
16
(
lit. 83-85 °C).
1
,4-Bis(2-hydroxyethoxy)-2,5-diiodobenzene (1e). Io-
dine monochloride (57 g, 0.35 mol) was added dropwise to
8
1
0 mL of methanol below 15 °C. To the mixture was added
4 g (0.07 mol) of 2e below 15 °C, and then the reaction
mixture was heated under reflux for 4 h. After cooling the
reaction mixture to 5 °C, resulting crystals were collected
by filtration. The crystals were rinsed with methanol (40
mL) and air-dried to give 27 g of 1e (86% yield). HPLC
assay 99.5%. Mp 163.5-165.5 °C (recrystallized from
acetonitrile). IR (KBr) 3190 (broad), 2950, 1490, 1345, 1220,
-
1 1
1
4
066, 935, 780 cm . H NMR (DMSO-d
.00 (4H, t), 4.81 (2H, broad s), 7.38 (2H, s). Calcd for
C, 26.69; H, 2.69; I, 56.40. Found C, 26.40; H,
6
) δ 3.7 (4H, t),
11
5a as colorless needles, which melted at 115-116.5 °C (lit.
10 12 2 4
C H I O
1
1
15-116 °C). H NMR (CDCl ) δ 3.83 (3H, s), 3.85 (3H,
3
2
.58; I, 56.20%.
s), 6.95 (1H, s), 7.32 (1H, s). Total yields of 5a and 1a were
.66 g (58.3%) and 1.36 g (13.0%), respectively.
-Ethoxy-2,5-diiodo-4-methoxybenzene (1b). Iodine
monochloride (68.1 g, 0.419 mol) was added dropwise to
Heat Evolution on Mixing ICl with Methanol. One
4
milliliter (3.18 g) of ICl was added to 30 mL of methanol at
6 °C. The temperature of the solution rose to 39.5 °C.
Letting the density and the heat capacity of methanol be
1
2
8
1
8 mL of methanol below 15 °C. To the mixture was added
3.3 g (0.087 mol) of 2b below 15 °C, and then the reaction
-
1
-1
0
.787 and 0.6 cal deg g , respectively, the evolved heat
was estimated to be ca. 9.7 kcal/mol ICl. To the solution
was added 0.5 g of 1,4-dimethoxybenzene. The temperature
of the solution was 39 °C.
mixture was heated under reflux for 4 h. The reaction mixture
was cooled to 5 °C. The resulting crystals were collected by
filtration rinsed with methanol (40 mL) and air-dried to give
Registry Numbers: 2a, 150-78-7; 2b, 5076-72-2; 2c, 122-
28.2 g of 1b (80.1% yield). HPLC assay 99.4%. Mp 93 °C,
9
5-2; 2d, 104-36-9; 2e, 104-38-1; 1a, 51560-21-5; 1c,
recrystallization from ethanol raised the mp to 101-102 °C.
IR (KBr) 3120, 3000, 2852, 1500, 1360, 1222, 1070, 942,
225243-10-7; 1d, 145483-70-1; 1e, 299217-85-9; 3a, 25245-
35-6; 4a, 2100-42-7; 5a, 90064-46-3; ICl, 7790-99-0.
-
1 1
8
58, 780 cm . H NMR (CDCl
s) 4.04 (2H, q), 7.20 (2H, s). Calcd for C
H, 2.49; I, 62.83. Found C, 26.70; H, 2.37; I, 62.40.
3
) δ 1.47 (3H, t), 3.82 (3H,
9
10 2 2
H I O
C, 26.76;
Received for review July 15, 2002.
OP025566H
(16) Wariishi, K. Jpn. Pat. Appl. 236,991A, 1998.
100
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Vol. 7, No. 1, 2003 / Organic Process Research & Development