Synthesis of salicylic acid derivatives from the corresponding 2-chlorobenzoic acid using water as solvent

Article abstract of DOI:10.1081/SCC-120004857

An improved synthesis of salicylic acid using water as solvent can be achieved using the Ullmann-Goldberg reaction conditions in presence of pyridine as cocatalyst. A number of salicylic acids were prepared in good yield.

Full text of DOI:10.1081/SCC-120004857

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SYNTHESIS OF SALICYLIC ACID DERIVATIVES FROM THE
CORRESPONDING 2-CHLOROBENZOIC ACID USING WATER
AS SOLVENT
Rolando F. Pellón Comdom a & Maite L. Docampo Palacios a
a Centro de Química Farmacéutica, Apartado 16042, Havana, Cuba
Published online: 16 Aug 2006.
To cite this article: Rolando F. Pellón Comdom & Maite L. Docampo Palacios (2002): SYNTHESIS OF SALICYLIC ACID
DERIVATIVES FROM THE CORRESPONDING 2-CHLOROBENZOIC ACID USING WATER AS SOLVENT, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 32:13, 2055-2059
To link to this article: http://dx.doi.org/10.1081/SCC-120004857
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SYNTHETIC COMMUNICATIONS, 32(13), 2055–2059 (2002)
SYNTHESIS OF SALICYLIC ACID
DERIVATIVES FROM THE
CORRESPONDING 2-CHLOROBENZOIC
ACID USING WATER AS SOLVENT
*
Rolando F. Pellon Comdom
and Maite L. Docampo Palacios
Centro de Quımica Farmaceutica Apartado 16042,
Havana, Cuba
ABSTRACT
An improved synthesis ofsalicylic acid using water as solvent
can be achieved using the Ullmann–Goldberg reaction condi-
tions in presence ofpyridine as cocatalyst. A number of
salicylic acids were prepared in good yield.
Use ofwater as solvent in the synthesis of N-phenylanthranilic acid by
the condensation of2-chlorobenzoic acid with aniline was described by us. [1]
We also reported the use ofpyridine as cocatalyst in this reaction using
water or amyl alcohol as solvent in order to reduce the reaction time.[2]
The modification ofthe Ullmann–Goldberg condensation using water as
*Corresponding author. Fax: (537) 336471; E-mail: pellonrf@cqf.co.cu
2055
Copyright & 2002 by Marcel Dekker, Inc.
www.dekker.com

2056
PELLON COMDOM AND DOCAMPO PALACIOS
solvent was adapted to the synthesis of2-carboxydiphenylethers by the
condensation of2-chlorobenzoic acid with phenol and was demonstrated
[3]
the necessity ofincluding pyridine in order to proceed the reaction.
Salicylic acid was obtained as a by product in all cases when pyridine is
present in the reaction and was isolated together with unreacted 2-chloro-
benzoic acid.
When we used these conditions for the condensation of 2-chloroben-
zoic acid with 2-aminopyridine the corresponding pyridilanthranilic acid
was obtained in a low yield and salicylic acid was obtained as a main prod-
[4]
uct ofthe reaction.
The aim ofthis report is to present a simple procedure for the synthesis
ofsalicylic acid derivatives rfom the corresponding o-chlorobenzoic acids
using water as solvent.
RESULTS AND DISCUSSION
The hydrolysis of2-bromobenzoic acid in presence ofcopper
acetate and aqueous piperidine was reported by Listsyn,[5] but we have
not found studies related to the hydrolysis of 2-chlorobenzoic acid, and
only in the case of2-chloro-3,5-dinitrobenzoic acid in which the halogen is
very activated, the hydrolysis in the reaction with several phenols was
reported in presence ofpyridine giving the arylsalicylic acid with a low
yield.[6]
It is well known that the substitution ofchlorine atom in a benzene
ring does not take place easily, but 2-halogencarboxylic acids in presence of
copper permit the formation of an intermediary copper complex which
facilitates the nucleophylic substitution. This copper complex is destroyed
[7]
in a basic media and it is not possible the obtention ofsalicylic acid. The
use ofpyridine as cocatalyst in the Ullmann–Goldberg reaction reduces the
reaction time, even more ifpyridine is present. There is a competition
between the nucleophylic agent and the hydroxide group. These
results suggest that pyridine stabilizes the intermediary copper complex of
the reaction.[8]
This knowledge makes us to adapt the conditions previously used in
the Ullmann–Goldberg condensation ofphenylanthranilic acid or
phenoxybenzoic acid using pyridine as cocatalyst in presence ofwater as
solvent to the synthesis ofsalicylic acid derivatives.
The hydrolysis of2-chlorobenzoic acid was perofrmed using 3
equivalents ofpotassium carbonate, 2 moles ofpyridine and 3% of
copper powder (by weight) per mole of o-chlorobenzoic acid using

SALICYLIC ACID DERIVATIVES
2057
water as solvent and 2 h reaction time obtaining the salicylic acid in 90%
yield (Scheme 1).
The concentration ofpotassium carbonate was studied, it was demon-
strated that the minimum quantity was 3 equivalents.[3] Concentration
superior to 3 equivalents do not affect the yield ofthe reaction which
remains constant. To establish the minimum ofpyridine necessary of r the
reaction, some experiments were performed using as model the hydrolysis of
2-chlorobenzoic acid in presence ofwater as solvent.
Table 1 shows the results from several experiments of the hydrolysis of
2-chlorobenzoic acid with different quantities ofpyridine using copper
powder (3% in weight) and 3 equivalents ofpotassium carbonate per
mole of2-chlorobenzoic acid, the reaction time in all cases was 2 h. In
these reaction conditions the best results were obtained using one equivalent
ofpyridine.
Ifthe reaction time was reduced to 1.5 h using the conditions
previously reported the yield was decreased to 50% ofsalicylic acid. In
conclusion better yields could be obtained with 3 equivalents ofpotassium
carbonate, 1 equivalent ofpyridine, 3% (by weight) ofcopper per mole of
2-chlorobenzoic acid in 2 h reaction time. These conditions were used for the
synthesis ofseveral salicylic acid derivatives.
Scheme 1.
Table 1. Effect ofPyridine on the Reaction Yield
Using Water as Solvent
Equivalents of
Pyridine
% Yield of
Salicylic Acid
Standard
Deviation (S)
2.0
1.5
1.0
0.75
0.50
90
91
90
83
61
1.0
2.0
1.5
1.0
1.5

2058
PELLON COMDOM AND DOCAMPO PALACIOS
EXPERIMENTAL PART
General Procedure
Synthesis ofSalicylic Acid Derivatives Using Water as Solvent
A Mixture of2-chlorobenzoic acid derivative, (0.04 mol), anhydrous
potassium carbonate (0.06 mol), pyridine (0.04 mol), copper powder (0.2 g)
was refluxed in water (25 mL) for 2 h. The reaction mixture was cooled,
poured into water and acidified with hydrochloric acid (1 : 1) to pH 3, the
solid was filtered and crystallized from ethanol/water (1 : 2). The Rf values
Table 2. Salicylic Acids Derivatives Obtained and Analytical Results
Yield
(%)
M.P. (ꢀC)
Uncorrected
M.P. (ꢀC)
Reported
No
R
Rf
1
2
3
4
5
6
7
8
R1¼R2¼R3¼H
R2¼Cl
90
88
90
84
95
93
87
85
158
211
226
170
233
170
140
186
158–60
210–12
226
171–72
233–35
169–72
141
0.79
0.80
0.83
0.81
0.84
0.83
0.78
0.82
R2¼NO2
R3¼Cl
R3¼NO2
R1¼R3¼NO2
R3¼CH3
R1¼Cl
186
Elemental Analysis
Calculated (%)
Experimental (%)
No
Formula
C
H
C
H
1
2
3
4
5
6
7
8
C7H6O3
60.87
48.70
45.90
48.70
45.90
36.84
63.16
48.70
4.35
2.90
2.73
2.90
2.73
1.75
5.26
2.90
61.05
48.96
46.18
48.95
45.71
37.01
63.37
48.80
4.04
2.68
2.48
2.51
2.61
1.52
5.01
2.78
C7H5ClO3
C7H5NO5
C7H5ClO3
C7H5NO5
C7H4N2O7
C8H8O3
C7H5ClO3

SALICYLIC ACID DERIVATIVES
2059
were obtained using a mixture ofethyl acetate : n-hexane : acetic acid
(8 : 6 : 0.5).
In Table 2 are shown salicylic acid derivatives synthesized from
the corresponding 2-chlorobenzoic acids derivatives, the melting points
(uncorrected), the Rfvalues and the yield obtained were compared with
alternative preparations reported in the literature. All experiments per-
formed in this work were repeated five times. The yields reported represent
a media ofthe obtained values for each reaction.
CONCLUSION
The use ofpyridine as cocatalyst permits the hydrolysis of
2-chlorobenzoic acid derivatives to the obtention ofsalicylic acid derivatives
without the use ofpressure.
REFERENCES
1. Pellon, R.F.; Carrasco, R.; Rodes, L. Synth. Comm. 1993, 23(10),
1447.
2. Pellon, R.; Carrasco, R.; Marquez, T.; Mamposo, T. Tetrahedron Lett.
1997, 38(29), 5107.
3. Pellon, R.; Carrasco, R.; Milian, V.; Rodes, L. Synth. Comm. 1995,
25(7), 1077.
4. Pellon, R.; Carrasco, R.; Rodes, L. Synth. Comm. 1996, 26(20), 3869.
5. Logosvskaya, E.K.; Lisetsyn, V.N. Tr. Mosk. Khim. Tekhnol. Inst.
1972, 70, 87.
6. Mothukrshnan, R.; Kannan, R. J. Chem. Soc. Perkin. 1973, 1, 2949.
7. Goldberg, A. J. Chem. Soc. 1952, 4368.
8. Bunnett, J.; Zahler, R. Chem. Revs. 1951, 49, 392.
9. Korner, B. Ber. 1982, 25, 2189.
10. Ullmann, F.; Kopetschni, R. Ber. 1911, 44, 428.
11. Hirwe, N.H. Proc. Indian Acad. Sci. 1938, 8A, 208.
12. Ullmann, F.; Wagner, C. Ann. 1907, 355, 359.
13. Hirsch, M. Ber. 1900, 33, 3239.
14. Ullmann, F.; Liebigs, A. Der. Chemie. 1909, 366, 85.
15. Ullmann, F.; Kipper, H. Ber. 1905, 32, 2120.
16. Varnholt, A. J. Practice 1945, 36(2), 22.
Received in the USA July 19, 2001