Electrosynthesis of 4-chloropyrazolecarboxylic acids

Article abstract of DOI:10.1007/s11172-010-0004-8

4-Chlorosubstituted pyrazolecarboxylic acids were synthesized via chlorination of the corresponding acids at the Pt anode in NaCl aqueous solutions under conditions of divided galvanostatic electrolysis. The efficiency of the process depends on the structures of the initial pyrazolecarboxylic acids, particularly, on the donor-acceptor properties of the substituents and on their position in the pyrazole ring. The yields of the 4-chlorosubstituted products of chlorination of pyrazole-3(5)-carboxylic acid, 1-methylpyrazole-5- carboxylic acid, 1-methyl-pyrazole-3-carboxylic acid, 1-ethylpyrazole-3- carboxylic acid, and 1-methyl-3-nitropyrazole- 5-carboxylic acid are 92, 93, 69, 80, and 4%, respectively.

Full text of DOI:10.1007/s11172-010-0004-8

Russian Chemical Bulletin, International Edition, Vol. 58, No. 2, pp. 291—296, February, 2009
291
Electrosynthesis of 4ꢀchloropyrazolecarboxylic acids*
B. V. Lyalin, V. A. Petrosyan, and B. I. Ugrak
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 5328, Eꢀmail: petros@ioc.ac.ru
4ꢀChlorosubstituted pyrazolecarboxylic acids were synthesized via chlorination of the
corresponding acids at the Pt anode in NaCl aqueous solutions under conditions of divided
galvanostatic electrolysis. The efficiency of the process depends on the structures of the initial
pyrazolecarboxylic acids, particularly, on the donorꢀacceptor properties of the substituents and
on their position in the pyrazole ring. The yields of the 4ꢀchlorosubstituted products of chloriꢀ
nation of pyrazoleꢀ3(5)ꢀcarboxylic acid, 1ꢀmethylpyrazoleꢀ5ꢀcarboxylic acid, 1ꢀmethylꢀ
pyrazoleꢀ3ꢀcarboxylic acid, 1ꢀethylpyrazoleꢀ3ꢀcarboxylic acid, and 1ꢀmethylꢀ3ꢀnitropyrazoleꢀ
5ꢀcarboxylic acid are 92, 93, 69, 80, and 4%, respectively.
Key words: electrosynthesis, pyrazoleꢀ3(5)ꢀcarboxylic acid, 1ꢀmethylpyrazoleꢀ5ꢀcarboxylic
acid, 1ꢀmethylpyrazoleꢀ3ꢀcarboxylic acid, 1ꢀethylpyrazoleꢀ3ꢀcarboxylic acid, 1ꢀmethylꢀ3ꢀnitroꢀ
pyrazoleꢀ5ꢀcarboxylic acid.
Scheme 1
The present work is aimed at the electrochemical
synthesis of 4ꢀchloropyrazolecarboxylic acids. Interest in
the development of convenient methods for synthesis of
such acids is due to the wide use of these compounds as
byꢀproducts of synthesis of drugs1 and herbicides.2 When
solving the stated problem, we took into account the
known data on chemical chlorination of pyrazoleꢀ
carboxylic acids,3 whose electrochlorination was carried
out under the conditions of galvanostatic divided elecꢀ
trolysis of aqueous solutions of NaCl.
Anode:
Solution:
Results and Discussion
than by 25%). The decrease in the concentration of 1
from 0.5 to 0.25 mol L–1 (see Table 1, cf. entries 1 and 4),
on the contrary, increases the yield of 2 (by 10%). The
still greater increase in the yield of 2 (by 47%) and a
simultaneous increase in the conversion of initial 1 (by
36%) occur with an increase in the NaCl concentration in
the electrolyte from 2 to 4 mol L–1 (see Table 1, cf. entries
6 and 4). However, electrochlorination in a NaClꢀsatuꢀ
rated solution of the electrolyte (see Table 1, cf. entries
4 and 5) is not already accompanied by the further inꢀ
crease in the yield of 2. The variation of the current denꢀ
sity (Ja = 0.05—0.1 A cm–2) exerted almost no effect on
the yield of 2 (see Table 1, cf. entries 4 and 7). Thus, an
increase in the NaCl concentration turned out to be the
only factor that substantially affects the yield of the target
product. It is most likely that with the NaCl concentraꢀ
tion increase the concentration of electrogenerated Cl2 in
the solution bulk also increases and, as a consequence,
the rate of the chlorination step increases (see Scheme 1).
Already the first experiments (Table 1, entry 1) on the
electrochlorination of pyrazoleꢀ3(5)ꢀcarboxylic acid (1)
under mild conditions at Т = 15 °С (compared to the
chemical chlorination3 at Т = 70 °С) allowed one to
synthesize 4ꢀchloropyrazoleꢀ3(5)ꢀcarboxylic acid (2)
in good yield (∼69% based on initial acid 1) with 84%
conversion of 1. The process of electrochlorination of 1
can formally be described by Scheme 1.
We studied the influence of several factors on the
electrochlorination with the purpose of its optimization.
For example, it turned out (see Table 1, cf. entries 1—3)
that the increase in the temperature of the process from
15 to 50 °С decreases sharply both the yield of acid 2
(more than by 45%) and the conversion of acid 1 (more
* On the occasion of the 75th anniversary of the foundation
of the N. D. Zelinsky Institute of Organic Chemistry of the
Russian Academy of Sciences.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 2, pp. 291—296, February, 2009.
1066ꢀ5285/09/5802ꢀ0291 © 2009 Springer Science+Business Media, Inc.

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Lyalin et al.
Table 1. Influence of the experimental conditions on the yield of 4ꢀchloropyrazolecarboxylic acid (2) during anodic chlorination of
pyrazoleꢀ3(5)ꢀcarboxylic acid (1) in an aqueous solution of NaCla
Entry
Concentration /mol L–1
Т/°С
ja/A cm–2
Q/Qtheor Conversion of 1 (%)
Yieldb of 2 (%)
1
NaCl
I
II
1
2
3
4
5
0.5
0.5
0.5
0.25
0.25
4.0
4.0
4.0
15
30
50
15
15
0.1
0.1
0.1
0.1
0.1
1.0
1.0
1.0
1.0
1.0
84.2
71.4
58.1
84.9
84.3
69
57
22
78
76
82
80
37
92
90
4.0
Saturated
solution
2.0
6
7
8с
9
0.25
0.25
0.25
0.25
15
15
15
15
0.1
0.05
0.1
1.0
1.0
1.0
1.5
48.4
84.8
86.8
91.9
31
78
69
92
65
92
79
100
4.0
4.0
4.0
0.1
a Pt anode, Cu cathode, Qtheor = 2 F per mole of initial acid 1.
1
b Calculated from the Н NMR spectroscopic data for the isolated mixture of the electrolysis products: I, based on initial acid 1;
II, based on reacted acid 1.
с Electrolysis of the salt of acid 1.
In addition, the yield of 2 could be increased due to
accumulation of HClО (unlike volatile Cl2) in solution,
thus increasing the chlorination rate (see Scheme 2). Howꢀ
ever, all these expectations were in vain, because the yield
of 2 even somewhat decreased even for the chlorination
of salt 1 (see Table 1, cf. entries 4 and 8). This is most
likely due to the side process leading to the partial decomꢀ
position of target 2 (see below). For this reason, we
returned again to the electrochlorination of acid 1 and
1.5ꢀfold increased the quantity of passed electricity to
compensate the decrease in the efficiency of electrochloꢀ
rination due to volatilization of Cl2. As a result (see Table 1,
entry 9), both the yield of acid 2 and conversion of acid 1
increased noticeably.
At the same time, it should be mentioned that the low
rate of direct interaction of 1 with electrogenerated Cl2
(Scheme 2) results in the partial loss of unreacted Cl2 due
to its evolution to atmosphere because of its comparaꢀ
tively low solubility in an aqueous solution of NaCl. To
avoid this, we carried out the electrochlorination approxiꢀ
mately under the same conditions, only replacing acid 1
by its salt (see Table 1, entry 8): it was assumed that the
efficiency of electrochlorination would be enhanced due
to binding of НСl capable of interacting with the NH
group of the pyrazole ring to form the pyrazolium salt
with resulting deactivation of the lone electron pair of the
nitrogen atom. Note that equilibrium a exists in an elecꢀ
trolyte solution (see Scheme 2) and is completely shifted
to the left in the absence of salt 1. However, in the presꢀ
ence of salt 1, the equilibrium shifts to the right rapidly
due to the fast ion reaction in step b. Owing to this reacꢀ
tion, HCl is efficiently bound (AzCOOH is weaker than
HCl). Thus, the amount of unreacted and capable of
volatilizing Cl2 decreases.
Summing up this part of the study, it should be noted
that the electrochlorination of 1 under the optimal conꢀ
ditions (aqueous solution of 0.25 М 1—4 М NaCl as
electrolyte, Т = 15 °С, Pt anode, Ja = 0.05—0.1 A cm–2
,
Q = 2—3 F per mole of 1) makes it possible to obtain 2
with 78—92% yields based on loaded 1. It should be indiꢀ
cated for comparison that the chemical3 method for synꢀ
thesis of 2 (solvent АсОН, Т = 70 °С) provides a substanꢀ
tially lower yield of 40%.
Scheme 2
In further studies we considered the influence of the
substituent nature in pyrazolecarboxylic acids on their
reactivity in electrochlorination. For this purpose, we
studied the electrochlorination of pyrazolecarboxylic acꢀ
ids with the electronꢀreleasing (1ꢀmethylpyrazoleꢀ5ꢀcarꢀ
boxylic acid (3), 1ꢀmethylpyrazoleꢀ3ꢀcarboxylic acid (4),
and 1ꢀethylpyrazoleꢀ3ꢀcarboxylic acid (5)) and electronꢀ
withdrawing (1ꢀmethylꢀ3ꢀnitropyrazoleꢀ5ꢀcarboxylic acid
(6)) substituents (Table 2) affording products 7—10.
It turned out that the replacement of H by Me at the
nitrogen atom of the pyrazole ring on going from 1 to

Electrosynthesis of 4ꢀchloropyrazolecarboxylic acids Russ.Chem.Bull., Int.Ed., Vol. 58, No. 2, February, 2009
293
Since published data on chemical chlorination of acid
5 are lacking, we specially studied this process. It turned
out that the chlorination of acid 5 in АсОН at Т = 70 °С,
i.e., under the conditions analogous to those of chlorinaꢀ
tion of acids 3 and 4,3 gives 4ꢀchloroꢀ1ꢀethylpyrazoleꢀ3ꢀ
carboxylic acid (7). However, this process does not cease
at the formation of the monochloro derivative (74% yield).
1
According to the Н NMR spectroscopic data, the reacꢀ
tion mixture also contained 4,5ꢀdichloroꢀ1ꢀethylpyrazoleꢀ
3ꢀcarboxylic acid (22% yield), which is the product of
further chlorination of acid 7 with an excessive (comꢀ
pared to stoichiometry) amount of chlorine.
Using the 1Н NMR data, we could show that the
chlorination of acid 5 proceeded following strictly sucꢀ
cessive mechanism. Passing of a precisely stoichiometric
amount of chlorine through the solution resulted in the
formation of product 7, and 4,5ꢀdichloroꢀ1ꢀthylpyrazole
carboxylic acid was formed only after the complete conꢀ
version of the starting acid 5 (Scheme 3).
Table 2. Influence of the experimental conditions on the yield of
4ꢀchloropyrazolecarboxylic acids during anodic chlorination
of Nꢀsubstituted pyrazolecarboxylic acids in an aqueous soluꢀ
tion of NaCla
Entry
Initial Q/Qtheor Conversion Product Yieldb (%)
Scheme 3
acid
of acid (%)
I
II
1
2
3
4
3
4
5
5
5
5
5
6
1.0
1.0
1.0
1.2
2.0
1.0
1.0
1.0
96.2
69.8
85.6
86.1
87.8
89.6
46.3
23.8
9
10
7
7
7
7
7
8
93
69
84
80
69
77
34
4
97
99
98
93
78
86
73
16
5
6с
7c,d
8e
Reagents and conditions: i. Cl , AcOH, Т = 70 °С.
2
We somewhat improved the described3 chemical chloꢀ
rination of pyrazolecarboxylic acids. As a result, this proꢀ
cess carried out in the presence of NaOAc allowed one to
perform exact dosage of the required amount of passed
Cl2. The process was monitored through measuring the
weight increase of the reaction mixture: the volatile reacꢀ
tion product HCl (see Scheme 1) reacted with NaOAc
and transformed into NaCl. The use of NaOAc also
made it possible to decrease the chlorination temperature
by 10 °С. As a result, acid 7 was obtained in 80% yield,
and the further chlorination of the reaction mixture
afforded 4,5ꢀdichloroꢀ1ꢀethylpyrazoleꢀ3ꢀcarboxylic acid
in 46% yield.
The same results were expected for the electrochloriꢀ
nation of acid 5 under the above presented optimal (for
electrochlorination of 1) conditions. However, the result
was unexpected. After the theoretical quantity of electricꢀ
ity was passed, acid 7 was obtained (see Table 2, entry 3)
in 84% with a conversion of acid 3 of ∼86%. An increase
in the quantity of passed electricity by 1.2 and 2 times (see
Table 2, cf. entries 3—5) resulted only in an insignificant
(by 1—2%) increase in the starting acid conversion but in
a noticeable (by ∼15%) decrease in the yield of product 7.
It should be emphasized that under these conditions, in
spite of electrogenerated Cl2 excess (in excess of passed
a Pt anode, Cu cathode, Qtheor = 2 F per mole of the initial acid,
acid concentration 0.25 mol L–1, СNaCl = 4 mol L–1, Т = 15 °С,
ja = 0.1 A cm–2
.
1
b Calculated from the Н NMR spectroscopic data for the isoꢀ
lated mixture of the electrolysis products: I, based on the initial
acid; II, based on the reacted acid.
c Electrolysis of the salt of acid 5.
d Electrolysis at 50 °С.
e The concentration of the acid is 0.125 mol L–1
.
acids 3 and 4 increases* the yield of 4ꢀchloropyrazoleꢀ
carboxylic acids by ∼20% (cf. Table 2, entries 1 and 2 and
Table 1, entry 4). Consequently, the introduction of an
electronꢀreleasing substituent into the pyrazole cycle faꢀ
cilitates electrochlorination. This conclusion agrees esꢀ
sentially (cf. Table 2, entry 3 and Table 1, entry 4) with
the data on electrochlorination of 1ꢀethylpyrazoleꢀ3ꢀcarꢀ
boxylic acid 5, although the regularities of this process
have some specific features.
* The lower (69.4%) yield of 4ꢀchloroꢀ1ꢀmethylpyrazoleꢀ3ꢀcarꢀ
boxylic acid is evidently due to its insufficient solubility in the
electrolyte. In addition, this acid is a surfactant, most likely,
which impedes electrochlorination by foaming of the solution
during electrolysis.

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Lyalin et al.
electricity), no 4,5ꢀdichloroꢀ1ꢀethylpyrazoleꢀ3ꢀcarboxyꢀ
lic acid is formed, unlike chemical chlorination. Using in
electrochlorination of the salt instead of acid 5 (hoping to
increase noticeably the conversion of acid 5 and yield of
acid 7) gave no desirable result (see Table 2, cf. entries 6
and 3), although the conversion of the starting acid someꢀ
what increased. Also, contrary to expectations, an inꢀ
crease in the temperature of the process from 15 to 50 °С
(see Table 2, cf. entries 7 and 3) decreased sharply both
the conversion of acid 5 (by 40%) and the yield of acid 7
(by 50% based on the starting acid or by 25% based on the
reacted acid).
An analysis suggests that upon the electrochlorination
of acid 5, along with the target process yielding product 7,
the side process of its pyrazole cycle destruction occurs.
The destruction proceeds with lower or higher efficiency
depending on the experimental conditions. Judging by
the examples described,4 the destruction of the pyrazole
cycle could occur due to oxidation. Moreover, it is known5
that Nꢀhalogenazoles (Nꢀchloropyrazoles) have rather
high oxidative ability. In our case, the corresponding Nꢀ
chloro derivative is intermediately formed upon the
electrochlorination of acid 5. However, taking into
account that in an aqueous medium the Nꢀchloro derivaꢀ
tive of acid 5 can easily be hydrolyzed to form HClO, this
is the latter compound that seems to be the most probable
oxidant.
The regularities of electrochlorination of acid 5 can be
explained assuming that 4,5ꢀdichloroꢀ1ꢀethylpyrazoleꢀ
3ꢀcarboxylic acid is formed along with product 7 via both
chemical and electrochemical chlorination. However,
under the electrochlorination conditions, the acid comꢀ
pletely decomposes with the destruction of the pyrazole
cycle under the action of HClO as an oxidant. It seems
that acid 7 also partially undergoes this process, dependꢀ
ing on the experimental conditions.
We wrote the assumed equation of decomposition of
4,5ꢀdichloroꢀ1ꢀethylpyrazoleꢀ3ꢀcarboxylic acid (Scheme 4)
by HClO and estimated the amount Cl2 required for this
process to occur and the equivalent quantity of electricity
(see Scheme 4) for the generation of the oxidant (HClO).
Then a mixture of 4,5ꢀdichloroꢀ1ꢀethylpyrazoleꢀ3ꢀcarꢀ
boxylic acid and acid 5 (83 and 17 mol.%, respectively)
was subjected to electrochlorination (under the condiꢀ
tions of electrochlorination of acid 5) with passing the
oneꢀfourth part of the quantity of electricity found from
Scheme 4. It turned out that 55% (based on the taken
mixture of acids) of 4,5ꢀdichloroꢀ1ꢀethylpyrazoleꢀ
3ꢀcaboxylic acid remained after electrolysis under these
conditions. Thus, the experimental results do not contraꢀ
dict the hypothesis explaining the regularities of electroꢀ
chlorination of acid 3 in an aqueous solution.
Thus, the electrochlorination of pyrazoleꢀ3ꢀ and
pyrazoleꢀ5ꢀcarboxylic acids with Nꢀcentered donor subꢀ
stituents occurs under considerably milder conditions
compared to their chemical chlorination. Therefore, it
seemed interesting to study the electrochlorination of
pyrazolecarboxylic acids containing an acceptor substituꢀ
ent, whose chemical chlorination is impossible.* For this
purpose, we studied the electrochlorination of 1ꢀmethylꢀ
3ꢀnitropyrazoleꢀ5ꢀcarboxylic acid 6. It turned out that
this process is principally possible and gives 4ꢀchloroꢀ
1ꢀmethylꢀ3ꢀnitropyrazoleꢀ5ꢀcarboxylic acid (8) (see
Table 2, entry 8) in 4% yield based on the starting acid 6.
Summing up the work performed, we can say that we
developed a convenient electrochemical method for
preparation of 4ꢀchloropyrazolecarboxylic acids. As comꢀ
pared to the chemical synthesis, this method provides
the formation of target products under milder conditions
(water as solvent, Т = 15 °С) and in higher yields.
Experimental
Electrolysis was carried out in the galvanostatic regime using
the Bꢀ5ꢀ8 dc source and a temperatureꢀcontrolled glass cell with
a porous glass membrane; Pt anode (S = 30 cm2), Cu cathode.
The coulometer designed at the Specialized Design Bureau
(Institute of Organic Chemistry, Russian Academy of Sciences)
was fitted in the electric circuit. A magnetic stirrer was used for
stirring solution during electrolysis.
The starting substances pyrazoleꢀ3(5)ꢀcarboxylic acid (1),
1ꢀmethylpyrazoleꢀ3ꢀcarboxylic acid (4), and 1ꢀmethylpyrazoleꢀ
5ꢀcarboxylic acid (3) were synthesized using known procedures3;
1ꢀmethylꢀ3ꢀnitropyrazoleꢀ5ꢀcarboxylic acid 6 was synthesized
according to a procedure described in Ref. 6, and 1ꢀethylꢀ
pyrazoleꢀ3ꢀcarboxylic acid (5) was synthesized using the proceꢀ
dure described below.
Scheme 4
The compounds synthesized by pyrazole electrochlorination
1
were identified by Н NMR spectroscopy using the spectra of
earlier synthesized reference samples for comparison (4ꢀchloroꢀ
1ꢀethylpyrazoleꢀ3ꢀcarboxylic (7) and 4,5ꢀdichloroꢀ1ꢀethylꢀ
pyrazoleꢀ3ꢀcarboxylic acids) or the spectra described3 for
compounds 10, 8, and 9. The spectra were recorded with a
Bruker ACꢀ300 instrument, using DMSOꢀd6. as a solvent, and
chemical shifts were measured in the δ scale.
* Our attempts of chemical chlorination of 1ꢀmethylꢀ3ꢀnitroꢀ
pyrazoleꢀ5ꢀcarboxylic acid with gaseous chlorine under the
literature conditions3 gave no corresponding chloro derivative.
Anode:
i. Q = 16 F mol–1
.

Electrosynthesis of 4ꢀchloropyrazolecarboxylic acids Russ.Chem.Bull., Int.Ed., Vol. 58, No. 2, February, 2009
295
Synthesis of 4ꢀchloropyrazoleꢀ3(5)ꢀcarboxylic acid (2) by
electrochlorination of pyrazoleꢀ3(5)ꢀcarboxylic acid (1) (Table 1,
entry 4). A 4 М aqueous solution of NaCl (100 mL), and
compound 1 (2.80 g, 0.025 mol) were placed in the anodic
compartment of the cell. Electrolysis was carried out with a
current of 3 A at 15 °С, and Cl2 slipped into the space above the
anolyte during electrolysis (detected qualitatively by darkening
of the paper impregnated with an aqueous solution of KI). After
2 F electricity per mole of the starting substance (Q = 4824 C)
passed, the electrolysis was stopped, the reaction mixture was
stored with stirring for 1 h, and the precipitate was filtered off,
washed with water (2Ѕ20 mL), and dried at 100 °С. A white
powder (2.49 g) obtained was a 2—1 (5 : 1) mixture according to
the data (integral intensities of signals) of 1Н NMR spectroscopy:
δ 7.9 (s, 1 Н, Н5(3)) and 6.7 (s, 1 Н, Н(4)), respectively. After
the 2—1 mixture was separated, water was distilled off from the
mother liquor, and the precipitate formed was extracted with
Ме2СО (4×20 mL) and EtOH (4×20 mL). The product repreꢀ
senting (according to the 1Н NMR data) a 2—1 (5.95 : 1.0)
mixture was isolated additionally (0.8 g). The yield of acid 2 was
78% at the 84.9% conversion of 1.
Electrochlorination of 1ꢀmethylpyrazoleꢀ5ꢀcarboxylic acid (3)
(Table 2, entry 1). A 4 М aqueous solution of NaCl (100 mL)
and compound 3 (3.15 g, 0.025 mol) were placed in the anodic
compartment of the cell. The electrolysis and isolation of
products were carried out as for the electrochlorination of
acid 1. A white powder (3.24 g) was obtained, representing a
mixture of acids 9—3 (25.3 : 1.0) according to the 1Н NMR
data: δ 7.65 (s, 1 Н, Н(5)) and 6.80 (s, 1 Н, Н(4)), respectively.
After the major product was separated, water was distilled off
from the mother liquor, extraction was carried out (see the
previous experiment), and the product, representing (1Н NMR
data) a 9—3 (20.4 : 1.0) mixture, was additionally isolated
(0.63 g). The yield of 4ꢀchloroꢀ1ꢀmethylpyrazoleꢀ5ꢀcarboxylic
acid (9) was 93% at the 96.2% conversion of acid 3.
Electrochlorination of 1ꢀmethylpyrazoleꢀ3ꢀcarboxylic acid (4)
(Table 2, entry 2). A 4 М aqueous solution of NaCl (100 mL)
and compound 4 (3.15 g, 0.025 mol) were placed in the anodic
compartment of the cell. The electrolysis and isolation of the
products were carried out as for the electrochlorination of acids
1 and 3. A finely dispersed white powder (2.47 g) was obtained.
The powder represented a mixture of compounds 10—4 (10.0 : 1.0)
according to the 1Н NMR data: δ 8.05 (s, 1 Н, Н(5)) and 6.70 (s,
1 Н, Н(4)), respectively. After the 10—4 mixture was isolated,
water was distilled off from the mother liquor. The extraction gave
additional 0.63 g of a mixture of compounds 10—4 (0.43 : 1.0)
(1Н NMR data). The yield of product 5 was 69%, and the
conversion of acid 4 was 69.3%.
Synthesis of 1ꢀethylpyrazoleꢀ3ꢀcarboxylic acid (5). Diethyl
sulfate (48.8 g, 0.32 mol) was added with stirring to a solution of
acid 1 (33.6 g, 0.3 mol) in a 20% aqueous solution of NaOH
(140 mL) for 1 h at 30—35 °С. The reaction mixture was heated
for 2 h at 80—85 °С and then cooled to room temperature and
acidified with concentrated HCl to pH 1. A precipitate formed
(1ꢀethylpyrazoleꢀ5ꢀcarboxylic acid) was filtered off, and the
filtrate was extracted with CHCl3 (4×100 mL). The organic
phase was dried over MgSO4, the solvent was distilled off under
reduced pressure, and compound 3 (18.5 g) was obtained with
an admixture of 1ꢀethylpyrazoleꢀ5ꢀcarboxylic acid. The product
was recrystallized from PriOH, and 1ꢀethylpyrazoleꢀ3ꢀcarboxylic
acid was obtained (9.8 g, 23%), m.p. 176—177 °С. Found (%):
C, 51.52; H, 5.65; N, 20.11. С6H8N2O2. Calculated (%):
C, 51.43; H, 5.71; N, 20.00. Н NMR, δ: 1.38 (t, 3 Н, СН3,
1
J = 7.0 Hz); 4.18 (q, 2 Н, СН2,, J = 7.2 Hz); 6.71 (d, 1 Н, Н(4),
J = 1.9 Hz); 7.81 (d, 1 Н, Н(5), J = 1.9 Hz). 13С NMR, δ: 15.35
(qt, СН3, J = 131.0 Hz, J = 4.0 Hz); 47.00 (tq, СН2, J = 141.0
Hz, J = 4.7 Hz); 143.10 (dd, С(3), J = 11.0 Hz, J = 3.0 Hz);
108,34 (dd, С(4), J = 180.0 Hz, J = 8.8 Hz); 130.92 (ddt, С(5),
J = 193.0 Hz, J = 9.0 Hz, J = 2.6 Hz) 163.32 (s, СООН).
Synthesis of 4ꢀchloroꢀ1ꢀethylpyrazoleꢀ3ꢀcarboxylic acid (7)
by chemical chlorination of 1ꢀethylpyrazoleꢀ3ꢀcarboxylic acid (5).
A (in the presence of NaOAc). Gaseous Cl2 was passed through a
solution of compound 5 (18.8 g, 0.134 mol) and NaOAc (12.1 g)
in АсОН (200 mL) at 60 °С with stirring until the weight was
increased to 9.5 g. Then the reaction mixture was cooled to
room temperature, and the precipitate formed was filtered off.
The filtrate was concentrated by evaporation under reduced
pressure to dryness, the residue was joined with the precipitate
from filtration, and NaCl was washed off with water (2×40 mL).
The product was dried at 100 °С. Compound 7 (18.6 g, 80%)
was obtained, m.p. 176—177 °С. Found (%): C, 41.35; H, 4.11;
Cl, 20.27; N, 16.09. C6H7ClN2O2. Calculated (%): C, 41.26;
1
H, 4.01; Cl, 20.34; N, 16.04. Н NMR, δ: 1.38 (t, 3 Н, СН3,,
J = 7.1 Hz); 4.18 (q, 2 Н, СН2, J = 7.5 Hz); 8.10 (s, 1 Н, Н(5).).
13С NMR, δ: 14.82 (qt, СН3, J = 125.0 Hz, J = 3.6 Hz); 47.79 (tq,
СН2, J = 142.0 Hz, J = 4.4 Hz); 139.29 (d, С(3), J = 6.9 Hz);
110.69 (d, С(4), J = 5.7 Hz); 129.99 (dt, С(5), J = 195.8 Hz,
J = 2.3 Hz); 161.80 (s, СООН).
B (in the absence of NaOAc). Gaseous Cl2 was passed for 2 h
through a solution of compound 5 (14.0 g, 0.1 mol) in АсОН
(150 mL) at 70 °С with stirring. The products were isolated as
indicated above (see item А). A white powder obtained (17.55 g)
was a mixture of compound 5 and 4,5ꢀdichloroꢀ1ꢀethylpyrazoleꢀ
3ꢀcarboxylic acid (1 : 0.3) according to the 1Н NMR data: δ 8.10
(s, 1 Н, Н(5)) and 4.20—4.15 (q, 2 Н, СН2) for the total signals
of 4ꢀchloroꢀ1ꢀethylpyrazoleꢀ3ꢀcarboxylic acid and 4,5ꢀdichloroꢀ
1ꢀethylpyrazoleꢀ3ꢀcarboxylic acids, respectively. The yield of
compound 7 was 74%, and that of 4,5ꢀdichloroꢀ1ꢀethylpyrazoleꢀ
3ꢀcarboxylic acid was 22.2%.
Synthesis of 4,5ꢀdichloroꢀ1ꢀethylpyrazoleꢀ3ꢀcarboxylic acid
by chemical chlorination of 4ꢀchloroꢀ1ꢀethylpyrazoleꢀ3ꢀcarboxylic
acid (7). Gaseous Cl2 was passed through a solution of compound
5 (1.74 g, 0.01 mol) and NaOAc (1.23 g) in AcOAc (20 mL) at
60—70 °С with stirring until the weight increase reached 0.71 g.
The reaction mixture was stirred for 0.5 h more and cooled, and
the solvent was distilled off under reduced pressure. The residue
was washed with water (2×3 mL) and dried. 4,5ꢀDichloroꢀ
1ꢀethylpyrazoleꢀ3ꢀcarboxylic acid was obtained (1.44 g) with a
minor admixture of 4ꢀchloroꢀ1ꢀethylpyrazoleꢀ3ꢀcarboxylic acid
(according to the 1Н NMR data). The product was recrystallized
from 36% aqueous PriOH. 4,5ꢀDichloroꢀ1ꢀethylpyrazoleꢀ
3ꢀcarboxylic acid was obtained (0.86 g). The yield was 69%,
m.p. 165—166 °С. Found (%): C, 34.37; Н, 2.91; Сl, 33,85;
N, 13.45. C6H6Cl2N2O2. Calculated (%): C, 34.45; Н, 2.86;
Cl, 33,97; N, 13.40. 1Н NMR, δ: 1.32 (t, 3 Н, СН3, J = 7.0 Hz);
4.20 (q, 2Н, СН2, J = 7.0 Hz). 13С NMR, δ: 14.08 (qt,
СН3, J = 125.0 Hz, J = 4.4 Hz); 45.96 (tq, СН2, J = 138.0 Hz,
J = 4.3 Hz); 138.36 (s, С(3)); 109.70 (s, С(4)); 125.78 (t, С(5),
3JC(5)—NCH = 2.7 Hz); 161.10 (s, СООН).
2
Synthesis of 4ꢀchloroꢀ1ꢀethylpyrazoleꢀ3ꢀcarboxylic acid (7)
by electrochlorination of 1ꢀethylpyrazoleꢀ3ꢀcarboxylic acid (5)
(using entry 4 in Table 2 as an example). A 4 М aqueous solution

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Russ.Chem.Bull., Int.Ed., Vol. 58, No. 2, February, 2009
Lyalin et al.
of NaСl (100 mL) and compound 5 (3.5 g, 0.025 mol) were
placed in the anodic compartment of the cell. The electrolysis
and isolation of the products were carried out as for the
electrochlorination of acids 1, 3, and 4. A white powder (3.53 g)
obtained was a mixture of compounds 7—5 (7.2 : 1.0) according
(relative to the sum of the starting 4,5ꢀdichloroꢀ1ꢀethylpyrazoleꢀ
3ꢀcarboxylic and 1ꢀethylpyrazoleꢀ3ꢀcarboxylic acids).
Electrochlorination of 1ꢀmethylꢀ3ꢀnitropyrazoleꢀ5ꢀcarboxylic
acid (6) (exemplified by entry 8 in Table 2). A 4 М aqueous
solution of NaСl (100 mL) and compound 6 (2.14 g, 0.0125 mol)
were placed in the anodic compartment of the cell. The
electrolysis and isolation of products were carried out as described
above, passing 2413 C of electricity (2 F per mole of the starting
substance). A white powder was obtained (1.08 g), representing
the starting acid 6 (1Н NMR data). After the product was
isolated, water was distilled off from the mother liquor, extraction
was carried out, and a mixture of compounds 6—8 (6.5 : 1.0) was
additionally isolated (0.65 g). The molar ratio of the acids in
the reaction mixture was determined from integral intensities
of the signals from acid 4: δΗ 7.30 (s, 1 Н, Н(4)) and total signals
of 6 and 8: δΗ 4.20 (s, 3 Н, СН ). The yield of acid 8 was 4%,
and the conversion of acid 6 wa3s 23.8%.
1
to the Н NMR data: δ 8.10 (s, 1 Н, Н(5)) and 6.71 (s, 1 Н,
Н(4)), respectively. After a 7—5 mixture was isolated from the
mother liquor, water was distilled off, extraction was carried
out, and the product was additionally isolated (0.64 g), which
represented (according to the 1Н NMR data) a 7—5 (2.56 : 1.0)
mixture. The yield of product 7 was 69% at the 87.8% conversion
of the starting acid 5.
Electrochlorination of a mixture of 4,5ꢀdichloroꢀ1ꢀethylꢀ
pyrazoleꢀ3ꢀcarboxylic acid (83 mol.%) and 1ꢀethylpyrazoleꢀ
3ꢀcarboxylic acid (5) (17 mol.%). A 4 М aqueous solution of
NaСl (100 mL), 4,5ꢀdichloroꢀ1ꢀethylpyrazoleꢀ3ꢀcarboxylic acid
(2.61 g, 0.0125 mol), acid 3 (0.35 g, 0.0025 mol), and Na2CO3
(0.8 g, 0.0075 mol) were placed in the anodic compartment
of the cell. Electrolysis was carried out as indicated above (see
previous experiment) at 50 °С, passing 4 F electricity per mole
of 4,5ꢀdichloroꢀ1ꢀethylpyrazoleꢀ3ꢀcarboxylic acid (Q = 4825 C).
After the end of electrolysis, the reaction mixture was stirred for
1 h, and the precipitate was filtered off, stirred for 1 h, washed
with water (2×20 mL), and dried in air. A powder was obtained
This work was financially supported by the Council on
Grants at the President of the Russian Federation (Program
for the State Support of Leading Scientific Schools of the Rusꢀ
sian Federation, Grant NSh 5022.2006.3) and the Presidium
of the Russian Academy of Sciences (Program Pꢀ8).
1
(0.46 g), which was (according to Н NMR data) 4,5ꢀdichloroꢀ
References
1ꢀethylpyrazoleꢀ3ꢀcarboxylic acid with an admixture (7—8%)
of unknown substances giving 1Н NMR signals at δ 4.0 and 1.3.
The substances were not identified but, most likely, these signals
belong to 1ꢀ(2ꢀchloroethyl)ꢀ4,5ꢀdichloropyrazoleꢀ3ꢀcarboxylic
acid (4.0 ppm (m, 1 Н, CHCl)) and 1ꢀ(2ꢀdichloroethyl)ꢀ
4,5ꢀdichloropyrazoleꢀ3ꢀcarboxylic acid (1.3 ppm (s, 3 Н, СН3)).
To exclude the influence of migration of substances on the escape
of the products to the cathodic space, after isolation and washing
of the precipitate, aqueous solutions were combined with a
solution of the catholyte and acidified with concentrated HCl
to pH 1, and water was distilled off under reduced pressure.
The residue was extracted with Me2CO (2×20 mL) and EtOH
(2×20 mL). 4,5ꢀDichloroꢀ1ꢀethylpyrazoleꢀ3ꢀcarboxylic acid
(1.51 g) was obtained (1Н NMR data) with an admixture of
1ꢀethylpyrazoleꢀ3ꢀcarboxylic acid (1%) and 1ꢀ(2ꢀchloroethyl)ꢀ
4,5ꢀdichloropyrazoleꢀ3ꢀcarboxylic and 1ꢀ(2ꢀdichloroethyl)ꢀ
4,5ꢀdichloropyrazoleꢀ3ꢀcarboxylic acids (totally ∼5%). Accordꢀ
ing to the estimation by these data, after electrolysis 55%
of 4,5ꢀdichloroꢀ1ꢀethylpyrazoleꢀ3ꢀcarboxylic acid remained
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Received May 6, 2008;
in revised form July 7, 2008