The use of ultrasound in the synthesis of 2-carboxy substituted diphenylethers using water as solvent

Article abstract of DOI:10.1081/SCC-120016350

An improved synthesis of 2-carboxy substituted diphenylethers using water as solvent can be achieved by ultrasound irradiation. A number of diphenylethers was prepared in good yields in a very short reaction time.

Full text of DOI:10.1081/SCC-120016350

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The Use of Ultrasound in the Synthesis of 2-Carboxy
Substituted Diphenylethers Using Water as Solvent
Rolando F. Pellón Comdom a & Maite L. Docampo Palacios a
a Center of Pharmaceutical Chemistry, Havana, Cuba
Version of record first published: 17 Aug 2006.
To cite this article: Rolando F. Pellón Comdom & Maite L. Docampo Palacios (2003): The Use of Ultrasound in the Synthesis of
2-Carboxy Substituted Diphenylethers Using Water as Solvent, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 33:6, 921-926
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 6, pp. 921–926, 2003
The Use of Ultrasound in the Synthesis of
2-Carboxy Substituted Diphenylethers Using
Water as Solvent
*
Rolando F. Pellon Comdom and Maite L. Docampo Palacios
Center of Pharmaceutical Chemistry, Havana, Cuba
ABSTRACT
An improved synthesis of 2-carboxy substituted diphenylethers using
water as solvent can be achieved by ultrasound irradiation. A
number of diphenylethers was prepared in good yields in a very
short reaction time.
Key Words: Ultrasound; 2-Carboxy diphenylethers; Water as
solvent
*Correspondence: Rolando F. Pellon Comdom, Center of Pharmaceutical
Chemistry, P.O. Box 16042, Havana, Cuba; Fax : þ(537) 336471; E-mail:
pellonrf@cqf.co.cu.
921
DOI: 10.1081/SCC-120016350
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
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922
Pellon Comdom and Docampo Palacios
Numerous studies have been reported on the Ullmann reaction, in
which an aryl halide and a phenolate react to give the diaryl ethers. This
reaction is promoted by copper compound and a base, and requires high
temperature and a large excess of copper, particularly when less reactive
aryl halide is employed.[1]
Ultrasound can be used in chemistry to increase reaction rates and
yields of products. The synthesis of diaryl ethers was found to be
improved by the use of ultrasound.[2] The yields of the products were
significantly higher than the literature yields without sonication and the
reaction also proceeds faster and at lower temperatures.
The usual procedure for the synthesis of diphenylethers using the
Ullmann-Goldberg condensation is to reflux a mixture of the o-halogeno-
benzoic acid with a phenol in a solvent, often amyl alcohol, in the
presence of copper as catalyst and a base such as potassium carbonate
to remove the hydrogen halide liberated in the reaction.[3]
In the present work, we decided to examine the effect of ultrasound
on the Ullmann-Goldberg reaction in the synthesis of 2-carboxy-
diphenylethers from o-chlorobenzoic acid and phenol derivatives using
water as solvent.
RESULTS AND DISCUSSION
In a previous paper,[4] phenols were shown to react in 2 h with
o-chlorobenzoic acid in presence of copper and pyridine as catalysts to
obtain 2-carboxy substituted diphenylethers by Ullmann-Goldberg
reaction using water as solvent.
As a continuation of our previous studies about the Ullmann-
Goldberg reaction using water as solvent, we described recently the
2-carboxydiphenylether acid synthesis optimization.[5] The optimum
concentration conditions determinated for each reactant were: o-chloro-
benzoic acid:phenol:potassium carbonate:pyridine as 1:2.5:1.5:0.75 and
the reaction time 2.4 h. Several other 2-carboxydiphenylether acid
derivatives were prepared with these conditions. In all cases the yield
obtained was equal or superior to those reported in the literature
where a high boiling point alcohol (130–170ꢀC) is employed as solvent.

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2-Carboxy Substituted Diphenylethers
Table 1. Effect of the time reaction on the yield.
923
Reaction time (min.)
Yield (%)
Standard deviation (%)
30
25
20
15
84
83
84
55
1.5
1.0
1.7
1.0
In order to reduce the reaction time and improve the yields we
examined the effect of ultrasound on the Ullmann-Goldberg
condensation using the reaction of o-chlorobenzoic acid with phenol in
presence of copper, cuprous iodide and pyridine as catalysts in water as
solvent as a model, employing the optimized quantities of each reactant.
To establish the minimum time necessary for the reaction, we
scanned various reaction times from 15–30 min (Table 1). It is
noteworthy that with reaction times of more than 20 min ultrasonic
irradiation the yield of the acid remains constant. Under these
conditions the use of 2.5 moles of phenol and 0.75 mole of pyridine per
mole of o-chlorobenzoic acid are critical to obtain a good yield.
All experiments performed in this work were repeated five times. The
yields reported represent an average of the obtained values for each reaction.
Table 2 shows the results of the 2-carboxyphenylether acid
derivatives synthesized from o-chlorobenzoic acid and several phenol
derivatives in presence of water as solvent. The corresponding yields
obtained using refluxing water (2.4 h) and using ultrasonic irradiation
(20 min) are reported.
EXPERIMENTAL
Standard Procedure
A mixture of o-chlorobenzoic acid (0.04 mol), phenol (0.1 mol), anhy-
drous potassium carbonate (0.06 mol), copper powder, (0.1 g), cuprous
iodide (0.1 g), pyridine (0.03 mol) and water (25 mL) was irradiated for
20 min with a sonic horn at 20 kHz. The reaction mixture was cooled and
acidified with diluted HCl (1:1). The solid was filtered off, washed with
water and dissolved in aqueous sodium hydroxide solution (10%). The
basic solution was acidified by addition of AcOH:H2O (1:3). The 2-car-
boxydiphenylether is crystallized from EtOH/H2O (1:1) (1H NMR and
13C-NMR data in tables 3 and 4 respectively).

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924
Pellon Comdom and Docampo Palacios
Table 2. Results of the synthesis of 2-carboxydiphenylether acid derivatives,
experimental microanalysis and molecular ion in mass spectra.
Yield
(%)
Yield
(%)
M.p.
(uncorr.) lit.
R3 R4 R5 (2.4 h. reflux) (ultras. 20 min.)
(ꢀC) (ꢀC)
M.p.
No. R1 R2
1
2
3
4
5
6
7
8
9
H
Cl
H
Cl
H
Cl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CH3
H
H
H
H
H
61
58
60
58
61
59
62
63
70
58
84
82
80
82
83
81
83
76
83
85
110–12 1136,7,8
114–16 1159
Cl
Cl
Cl
Cl
CH3
H
114–15 1147,8
164–65 1638
H
Cl
Cl
H
H
CH3
H
166–67 166.57,8
169–70 1697,8
133–34 133.57,8
94–96
117–19 1186
156
15611
9510
H
H
10 H OCH3
Calculated (%)
Experimental (%)
No.
Formula
C13H10O3
C13H9O3Cl
C13H9O3Cl
C13H8O3Cl2
C13H8O3Cl2
C13H7O3Cl3
C14H12O3
C
H
C
H
m/z
1
2
3
4
5
6
7
8
9
10
72.89
62.77
62.77
55.12
55.12
49.13
73.68
73.68
73.68
68.85
4.67
3.62
3.62
2.82
2.82
2.20
5.26
5.26
5.26
4.92
72.76
62.91
62.87
54.70
55.42
48.49
73.46
73.41
73.86
68.75
4.83
3.85
3.77
2.91
3.26
2.32
5.60
5.73
5.40
4.31
214
248
248
282
282
316
228
228
228
244
C14H12O3
C14H12O3
C14H12O4
ultras. ultrasound; M.p. melting point; uncorr. uncorrected; lit. literature.
CONCLUSIONS
The use of ultrasound irradiation improved the synthesis of
2-carboxy substituted diphenylethers using water as solvent. A number

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2-Carboxy Substituted Diphenylethers
925
Table 3. 1H NMR Data of 2-carboxydiphenylether acid derivatives.
No.
H3
H4
H5
H6
H8
H9
H10
H11
H12
H(CH3)
1
2
7.85
7.81
7.98
7.87
7.89
7.81
7.91
7.99
7.93
7.59
7.25
6.96
7.41
7.02
7.23
7.05
7.40
7.41
7.47
—
7.59
—
7.40
7.49
7.65
7.63
7.39
7.27
7.37
7.38
7.58
7.62
7.10
7.20
—
7.71
7.75
7.90
7.80
7.79
7.76
7.68
—
6.99
7.12
7.19
7.17
—
7.71
7.75
7.86
7.71
7.70
7.56
7.68
7.67
7.62
7.75
7.10
7.20
6.92
6.85
6.59
6.52
7.26
6.99
7.12
7.11
—
—
3
7.53
—
—
—
4
—
—
5
7.58
—
—
—
6
—
—
—
7
7.57
7.62
7.64
7.26
7.11
6.89
—
2.23
2.32
2.27
3.77
8
7.01
7.12
7.11
9
10
7.62
7.75
7.08
Table 4. 13C-NMR Data of 2-carboxydiphenylether acid derivatives.
No.
C1
C2
C3
C4
C5
C6
1
2
157.3
156.5
156.8
155.6
153.9
156.1
157.7
157.6
156.4
149.6
120.7
118.9
120.3
119.8
120.5
119.7
120.4
120.3
120.1
120.6
133.2
132.9
133.3
133.3
131.8
133.5
133.4
133.1
131.3
118.2
123.5
123.8
123.6
123.7
124.2
124.2
122.8
125.5
120.1
153.8
134.6
137.3
134.6
137.6
133.8
138.7
134.7
134.6
136.7
122.8
118.9
118.1
117.8
119.0
119.4
119.5
119.8
118.7
112.5
121.1
3
4
5
6
7
8
9
10
No.
C7
C8
C9
C10
C11
C12
C(CH3)
1
2
155.8
156.0
151.4
151.6
152.3
151.1
152.8
155.5
154.1
155.4
119.6
120.2
121.3
122.1
123.9
120.6
120.5
117.3
120.4
120.1
130.1
130.0
128.2
128.8
128.4
128.2
127.6
129.8
129.9
130.1
124.6
123.8
125.7
124.0
127.2
129.3
125.6
123.4
131.8
123.2
130.1
130.0
131.0
130.7
129.8
130.2
130.3
130.4
129.9
130.1
119.6
120.2
125.7
125.3
124.7
125.8
131.9
118.7
120.4
120.1
—
—
3
—
—
4
5
—
—
6
7
18.0
18.7
20.3
55.7
8
9
10

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926
Pellon Comdom and Docampo Palacios
of 2-carboxydiphenylether derivatives was prepared in good yields in a
very short reaction time.
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Received in the USA April 3, 2002