Synthesis, properties, and application of 4-nitrosemicarbazones

Article abstract of DOI:10.1007/s11172-016-1336-9

The studies of the condensation of 4-nitrosemicarbazide (4-NSC) with various aldehydes and ketones resulted in the development of an approach to the synthesis of N-nitrosemicarbazones, promising high-energy and biologically active compounds. Subsequent treatment with amines and alkalis led to the synthesis of water-soluble salts of nitrosemicarbazones, as well as the corresponding semicarbazones. The reaction of N,N′-diisopropyl- or N,N′-di-tert-butyl-1,2-ethanediimine with 4-nitrosemicarbazide led to the synthesis of glyoxal bis(nitrosemicarbazone) derivatives. A computer-aided screening using the PASS software showed a probability of high biological activity for the compounds obtained, whereas antiarrhythmic properties of camphor nitrosemicarbazone potassium salt were confirmed in experiments in rats.

Full text of DOI:10.1007/s11172-016-1336-9

Russian Chemical Bulletin, International Edition, Vol. 65, No. 2, pp. 550—560, February, 2016
550
Synthesis, properties, and application of 4ꢀnitrosemicarbazones*
V. S. Glukhacheva,a S. G. Il´yasov,a G. V. Sakovich,a T. G. Tolstikova,b A. O. Bryzgalov,b and N. V. Pleshkovab
aInstitute for Problems of Chemical and Energetic Technologies,
Siberian Branch of the Russian Academy of Sciences,
1 ul. Sotsialisticheskaya, 659322 Biisk Altaiskogo Kraya, Russian Federation.
Fax: +7 (385 4) 30 3043. Eꢀmail: ipcet@mail.ru
bN. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry,
Siberian Branch of the Russian Academy of Sciences,
9 prosp. Akad. Lavrent´eva, 630090 Novosibirsk, Russian Federation.
Fax: +7 (383) 330 9752. Eꢀmail: benzol@nioch.nsc.ru
The studies of the condensation of 4ꢀnitrosemicarbazide (4ꢀNSC) with various aldehydes
and ketones resulted in the development of an approach to the synthesis of Nꢀnitrosemicarbꢀ
azones, promising highꢀenergy and biologically active compounds. Subsequent treatment with
amines and alkalis led to the synthesis of waterꢀsoluble salts of nitrosemicarbazones, as well as
the corresponding semicarbazones. The reaction of N,N´ꢀdiisopropylꢀ or N,N´ꢀdiꢀtertꢀbutylꢀ
1,2ꢀethanediimine with 4ꢀnitrosemicarbazide led to the synthesis of glyoxal
bis(nitrosemicarbazone) derivatives. A computerꢀaided screening using the PASS software
showed a probability of high biological activity for the compounds obtained, whereas antiarꢀ
rhythmic properties of camphor nitrosemicarbazone potassium salt were confirmed in experiꢀ
ments in rats.
Key words: nitrosemicarbazones, nitrosemicarbazide, condensation.
Earlier, we reported a new direction in the preparation
ing aromatic substituents, fiveꢀmembered heterocyclic
rings, and different functional groups (see Table 1).
The PubChem database contains analogs of comꢀ
pounds 2—8 (see Scheme 1) with the substituents R =
= R´ = NH2 (see Ref. 11) and R = Ph, R´ = Me (see Ref.
of nitramides and nitramines from dinitrourea,1 including
the synthesis of 4ꢀnitrosemicarbazide2 (1, 4ꢀNSC). A relꢀ
atively new compound 1 currently is being studied in difꢀ
ferent fields of chemistry and technique: mainly this is the
preparation of nanopowders by the explosion and burnꢀ
ing.3 In the last years, the scope of application of semicarꢀ
bazide 1 is considerably broadening, with the studies being
carried out in the direction of the synthesis of both highꢀ
energy explosives4 and organic compounds possessing biꢀ
ological activity.5 It is known that many semicarbazones
(analogs of 1) possess potential biological activity and
are widely used in clinical practice as antileukemic, tuberꢀ
culostatic, antitumor, bacteriostatic, and antiseptic
agents.6—10 In this connection, it is interesting to study
nitrosemicarbazones obtained by the condensation of comꢀ
pound 1 and its derivatives with aldehydes and ketones.
In the present work, we for the first time study the
condensation reaction of compound 1 with different
aldehydes and diacetyl, which leads to the formation
of 4ꢀnitrosemicarbazones (Scheme 1, Table 1). Reaction
conditions were optimized for the synthesis of new comꢀ
pounds 2—8 in a series of 4ꢀnitrosemicarbazones containꢀ
Scheme 1
Compound
R
3ꢀMeO(4ꢀHO)C6H3
2ꢀHOC6H4
HC=NNHC(O)NH(NO2)
2ꢀFuryl
5ꢀNitroꢀ2ꢀfuryl
MeC=NNHC(O)NH(NO2)
Bn
R´
H
H
H
H
H
Me
H
2
3
4
5
6
7
8
* Dedicated to Academician of the Russian Academy of Sciencꢀ
es N. S. Zefirov on the occasion of his 80th birthday.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 2, pp. 0550—0560, February, 2016.
1066ꢀ5285/16/6502ꢀ0550 © 2016 Springer Science+Business Media, Inc.

4ꢀNitrosemicarbazones
Russ.Chem.Bull., Int.Ed., Vol. 65, No. 2, February, 2016
551
Table 1. Optimal conditions for the synthesis of compounds 2—8
Carbonyl
compound
Solvent
t/h
T/°С
Product
Yield*
(%)
3ꢀMeО(4ꢀНО)С6Н3СНО
2ꢀHOC6H4СНО
ОНСCНO
Water
80% Aqueous ethanol
Water
1
2
8
2
2
4
4
20
40
60
20
20
20
40
2
3
4
5
6
7
8
50
82
68
92
43
79
40
Furfural
Water
Ethanol
Water
Water
5ꢀNitrofurfural
MeC(O)C(O)Me
BnСНО
* Yield of isolated product.
Yield (%)
12), however, there is no literature information on their
preparation.
80
60
40
20
The condensation of 4ꢀNSC 1 with aldehydes and keꢀ
tones has a number of specific features: theoretically, acid
catalysts should accelerate the reaction;13 however, in our
case an additional acidification decreased the yield of hyꢀ
drazone 4 to 40% (Fig. 1). Such a dependence can be
explained by the acidic properties of the starting 4ꢀNSC 1,
that is why an additional introduction of an acid leads to
the acid hydrolysis of the synthesized hydrazone in the
course of the reaction.
2
3
1
4
An increase in the temperature leads to the increase in
the reaction rate, but at a temperature above 60 °C 4ꢀniꢀ
trosemicarbazide 1 undergoes decomposition, which results
in the decrease in the condensation product yield (Fig. 2).
Despite of this, the obtained compound have proved to
be quite stable due to the presence of the nitroamine subꢀ
stituent, which, apparently, strongly hinders cyclization
to pyrazoline.
2
4
6
t/h
Fig. 2. Yield of glyoxal bis(nitrosemicarbazone) 4 versus reaction
time (t) at the reaction temperature of 20 (1), 40 (2), 60 (3), and
80 °C (4).
1630—1583 cm–1, which confirms the formation of the C=N
bond and agrees with the literature data.14—16 In the case of
furfural nitrosemicarbazone 5 and 5ꢀnitrofurfural nitrosemiꢀ
carbazone 6, a doublet of vibrations for the C=N bond is
The IR spectra of compounds 2—8 do not contain abꢀ
sorption bands characteristic of the stretching vibrations of
the NH2 bond of the starting 4ꢀNSC 1 at 3473—3371 cm–1
,
with the absorption band of the NH bond vibrations retainꢀ
ing in the region of 3308—3117 cm–1. The absorption band
of the C=O bond shifts from 1666 to 1750—1693 cm–1 and
the appearance of new absorption bands is observed at
observed in the ranges of 1631—1601 and 1626—1603 cm–1
,
respectively, the IR spectrum of compound 6 also exhibits
a doublet of vibrations for the C=O bond at 1740 and
1703 cm–1 that indicates the presence of the isomeric forms
of these compounds.
If the UV spectra of aliphatic aldehyde alkylhydrꢀ
azones exhibit an absorption band at 230—240 nm, the
absorption of semicarbazones of aromatic aldehydes and
dicarbonyl compounds is characterized by a bathochroꢀ
mic shift of the absorption band to 300—320 nm attributꢀ
ed to the π→π* transition.13,17 As it was expected, comꢀ
pounds 2—8 have a characteristic absorption in the range
302—332 nm. Simultaneously, the peak at 258 nm correꢀ
sponding to the nitroamide group retains; in the case of
compounds 2, 3, and 8 this peak overlaps with absorption
of the aromatic ring.
Yield (%)
3
2
80
60
40
20
1
1
The H NMR spectra of obtained compounds exhibit
2
4
6
t/h
signals characteristic of the methine protons of the double
bond at δ 7.73—8.65. The signals at δ 12.50—13.34 indicate
the presence of the proton of the nitroamide group, while the
Fig. 1. Yield of glyoxal bis(nitrosemicarbazone) 4 versus reaction
time (t) at pH = 2 (1), 4 (2), and 6 (3).

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Glukhacheva et al.
Scheme 2
absence of a singlet for the protons of the NH2 group at δ 6.42
agrees with the structure of semicarbazones.17
For hydrazones, there are known examples of both
spatial and structural isomerism and in some case a tautoꢀ
meric equilibrium of two or three forms. Geometric isoꢀ
merism of hydrazones is a particular case of isomerism in
the azomethine system due to the sp2ꢀhybridization of the
imine nitrogen atom with a 120° angle between the bonds.
By analogy with oximes, the isomer in which the substiꢀ
tuted amino group and the methine hydrogen atom are in
the cisꢀposition relative to the C=N bond is usually reꢀ
garded as a synꢀisomer (Zꢀisomer), whereas the isomer
with the transꢀarrangement of this functional fragments,
ing to the 1H NMR spectra (Figs 4 and 5) one of the
isomers was found to be a predominant (more than 95%).
It is possible that the stabilizing factor became the formaꢀ
tion of the hydrogen bond between the hydroxy group at
orthoꢀposition of the aromatic ring and the C=O group.
In the present work, we did not study the structure of
the isomers in detail. However, using the lowꢀtemperature
spectra we clearly identified the signals undergoing exꢀ
change at room temperature, thus confirming the strucꢀ
ture of the synthesized compounds.
Unfortunately, with ketones such as camphor the reacꢀ
tion proceeds with the formation of a mixture of unseparꢀ
able products, and it was impossible to isolate camphor
nitrosemicarbazone 9 (Scheme 3) in the pure form. Thereꢀ
fore, we attempted to select reaction conditions directed on
the formation of hydrazones. The molecule of compound 1
is a multidentate one, therefore, three nitrogen atoms of
compound 1 are regarded as potential centers for the attack
by an active aldehyde molecule: the amine, the amide, and
the nitroamine atoms. The probability of the formation of
chemical bond is equal for each of the nitrogen atoms. The
reactivity of the nitramine nitrogen atom can be blocked by
as an antiꢀisomer (Eꢀisomer).13
1
The identification of compounds based on H and 13
C
NMR spectra is complicated by broadening of signals, which
can be caused by the presence of the exchange processes
due to the existence of Zꢀ and Eꢀisomers (Scheme 2).
Because of instability of compounds 2 and 3 in DMSO,
it was impossible to accelerate exchange by increasing the
temperature and observe the exchangeꢀnarrowed lines.
Therefore, the NMR spectra were recorded at decreased
temperature in acetone. Thus, for compound 2 the exꢀ
1
change was "frozen" at –90 °C, and the H NMR specꢀ
trum exhibited a double set of signals with the ratio of
intensities 4 : 6 assigned to Zꢀ and Eꢀisomers (Fig. 3).
Attempted recording of the 13C NMR spectrum for comꢀ
pound 2 did not give an acceptable signalꢀtoꢀnoise ratio
because of its poor solubility in acetone.
1
The lowꢀtemperature H and 13C NMR spectra were
recorded for compound 3. In this case, the exchange was
"frozen" already at –70 °C. However, in this case accordꢀ
a
7.95
6.86
8.41
7.53
7.37
7.13
7.07
11.00
6.88
9.23
11.26
13.51
9.28
b
6.86
7.15
7.46
12.50
8.14
10.75
10.30
12.5
12.0
11.5
11.0
10.5
10.0
9.5
9.0
8.5
8.0
7.5
7.0
δ
Fig. 3. Fragments of the 1H NMR spectra of compound 2 recorded at –90 (a) and 20 °C (b).

4ꢀNitrosemicarbazones
Russ.Chem.Bull., Int.Ed., Vol. 65, No. 2, February, 2016
553
6.96
a
8.76
7.37
7.43
11.63
11.51
14.04
b
14.5 14.0 13.5 13.0 12.5 12.0 11.5 11.0 10.5 10.0 9.5 9.0 8.5 8.0
7.5 7.0
6.5 δ
Fig. 4. 1H NMR spectra of compound 3 recorded at –70 (a) and 20 °C (b).
116.74 116.65
119.51
a
b
131.99
131.38
158.21
117.59
151.81
146.75
160
155
150
145
140
135
130
135
120
105
δ
Fig. 5. 13C NMR spectra of compound 3 recorded at –70 (a) and 20 °C (b).
the conversion of 4ꢀNSC to the potassium salt. Its subseꢀ
quent condensation with camphor leads to camphor niꢀ
trosemicarbazone potassium salt [9]K+ (see Scheme 3).
The use of K and Na salts of compound 1 in the conꢀ
densation reactions with monofunctional aldehydes conꢀ
siderably increases the yield of hydrazones excluding the
side reactions (Scheme 4).
A similar reaction of salt [1]K+ with a bifunctional
compound such as glyoxal leads to the formation of glyoxal
bis(nitrosemicarbazone) dipotassium salt [4]K2+. The
acidification of the reaction mixture removes the potassiꢀ
um cation to give glyoxal bis(nitrosemicarbazone) 4 in
98% yield (Scheme 5).
readily form the corresponding onium salts upon treatment
with bases.
Earlier, we have reported the synthesis of alkylsemiꢀ
carbazides from 4ꢀnitrosemicarbazide by the nucleophilic
substitution reaction with amines.18 A similar reaction is
also characteristic of nitrosemicarbazones, which possess
acidic properties and can be involved in the reaction with
bases with the formation of both the salts and the alkylꢀ
substituted semicarbazone derivatives. Taking glyoxal
bis(nitrosemicarbazone) 4 as a model, we studied the reꢀ
action of nitrosemicarbazones with aqueous solutions of
ammonia and amines. Thus, the onium salts of glyoxal
bis(nitrosemicarbazone) 10—16 are formed upon cooling.
Compound 4 was also obtained by the condensation of
glyoxal with 4ꢀnitrosemicarbazide ammonium salt at room
To sum up, we found that nitrosemicarbazones retain the
saltꢀforming properties of starting nitrosemicarbazide2 and

554
Russ.Chem.Bull., Int.Ed., Vol. 65, No. 2, February, 2016
Glukhacheva et al.
Scheme 3
Scheme 4
Nꢀnitrohydrazones. Thus, nitrosemicarbazones 2 and 4—6
were treated with ammonia upon reflux to obtain known
semicarbazones of salicylaldehyde, glyoxal, furfural, and
nitrofurfural in quantitative yields.
The reaction with secondary amines is spatially hinꢀ
dered, therefore, more time is required for the reaction to
reach completion. A side reaction of alkaline hydrolysis
greatly decreases the yield of the target product. As it is
seen from the data given in Table 2, the yield of the target
products strongly depends on the amine basicity. Thus, in
the formation of the salt the higher the basicity of amine,
the higher is the yield of the target product. Apart from
that, the yield of the product is affected by the steric and
natural factors. In the nucleophilic substitution reaction,
a reverse dependence is observed because of more drastic
reaction conditions and acceleration in the proceeding of
alkaline hydrolysis of the target product.
The use of dimethylsemicarbazide 23 and diethylsemiꢀ
carbazide 24 in the condensation with glyoxal gives higher
yields than bissemicarbazones 19 and 20: 67 and 85%,
respectively (Scheme 7).
To increase the yield of spatially branched salts of priꢀ
mary amines 15 and 16, we suggested an alternative methꢀ
od consisting in transimination of N,N´ꢀdiisopropylꢀ19
(25) or N,N´ꢀdiꢀtertꢀbutylꢀ1,2ꢀethanediimines20 (26) with
M = K, Na
R = 2ꢀHOC6H4 (3), 2ꢀfuryl (5), 5ꢀnitroꢀ2ꢀfuryl (6)
temperature (Scheme 6). An excess of ammonia or amines
upon reflux of the solution decomposes compound 4 to
glyoxal bis(semicarbazone) and its alkylꢀsubstituted deꢀ
rivatives 17—22 (see Scheme 6). The process of decompoꢀ
sition can be monitored using UV spectroscopy tracking
the disappearance of the absorption maximum at 258 nm.
This property of the nitroamine group of nitrosemicarbꢀ
azones was used in the counter synthesis of known hydraꢀ
zones, which confirmed the structure of earlier unknown
Scheme 5

4ꢀNitrosemicarbazones
Russ.Chem.Bull., Int.Ed., Vol. 65, No. 2, February, 2016
555
Scheme 6
Compound
10, 17
11
12, 18
13, 19
R
H
H
H
Me
R´
H
NH2
Me
Me
Compound
14, 20
15, 21
R
Et
H
R´
Et
Pri
But
16, 22
H
Scheme 7
4ꢀnitrosemicarbazide 1 in aqueous acetonitrile. The yields
of compounds 15 and 16 were increased to 88 and 78%,
respectively (Scheme 8).
As it is seen from Tables 3 and 4 summarizing the data
on the explosive properties and the sensitivity to impact21
and friction22 of glyoxal bis(nitrosemicarbazone) 4 and its
salts 10 and 11, these compounds are of interest as new
high energy compounds.
The tests of detonation velocity (Table 4) were carried
out on the samples pressed in blocks prepared by a cold
pressing method. An increase in the pressure above
1800 kg cm–2 led to disintegration (repressing) of the samꢀ
ple. To avoid this, we used wet pressing with EtOH or
Table 2. Reaction conditions and yields of products
10—22a
R = Me (19, 23), Et (20, 24)
water. Compounds 10 and 11 possess properties allowing
their use in ammunition as a combustion catalysts: the
low sensitivity to mechanical action as compared to comꢀ
pound 4, with retention of explosive characteristics. Thereꢀ
fore, we studied the burning rate of these products (Table 5).
The flegmatization with urethane (5%) strongly decreases
the burning rate of the glyoxal bis(nitrosemicarbazone)
b
Amine
рКa
Product
Yield (%)
NH3
9.25
5.9
10
11
12
13
14
15
16
17
18
19
20
21
22
84
97
59
100
27
48
70
98
40
27
20
32
39
NH2NH2
NH2Me
NHMe2
NHEt2
NH2Pri
NH2But
NH3
NH2Me
NHMe2
NHEt2
NH2Pri
NH2But
10.66
10.73
10.93
10.53
10.6
salts from 3800 to 1400 mm s–1
.
Thus, the analysis of the results of burning the samples
in a manometric bomb indicates that this group of comꢀ
pounds can be classified as fast burning. Compounds 10
and 11 can be recommended for further studies for the
compiling of safe nonexplosive compositions, for examꢀ
ple, for prevention of explosion of methane in mines.
To assess the potential of these compounds as biologiꢀ
cally active agents, we carried out a virtual screening using
the PASS program.23 This program proceeding from the
structural formula of compounds and using a uniform deꢀ
9.25
10.66
10.73
10.93
10.53
10.6
a Reaction temperature 0—5 °C for salts 10—16 and
85—90 °C for semicarbazones 17—22.
b Water, 25 °C.

556
Russ.Chem.Bull., Int.Ed., Vol. 65, No. 2, February, 2016
Glukhacheva et al.
Scheme 8
rats, using a single intragastric administration by Kerber's
method. The studies showed that the half lethal dose (LD50)
for all the compounds is higher than 1000 mg kg–1, thereꢀ
fore, these substances belong to the 3 class of moderately
toxic compounds. The studies of antiarrhythmic activity were
carried out by intravenous administration of test compounds
in different doses. It was shown that compound [9]K+ exhibꢀ
ited high activity in the doses 4 and 0.4 mg kg–1 on the
calcium chloride arrhytmia and in the dose of 0.4 mg kg–1 on
a model of adrenalin arrhytmia it prevented development of
the arrhytmia in 80% of cases.
It is known that vanillin, being a source of a methoxyꢀ
phenol substituent and a methine fragment to the strucꢀ
ture of aminoketones, plays an exclusive role in the synꢀ
thesis of biologically active compounds, analogs of carꢀ
dioprotectors, analgesics, bactericides, etc.24 Vanyllal niꢀ
R = Pri (15, 25), But (16, 26)
scription of chemical structure and a universal mathematꢀ
ical algorithm of finding the "structure—activity" relationꢀ
ship makes it possible to predict the probability of differꢀ
ent kinds of pharmacological activity. Based on this preꢀ
diction, it was shown that with a high probability the niꢀ
trosemicarbazones should possess antacid, cytoprotective,
antiischemic, antiinfective, antiprotozoal, and antituberꢀ
culosis properties. In this connection, the compounds posꢀ
sessing high coefficients of probability of exhibiting antiꢀ
arrhythmic activity were studied in vivo.
Biological experiments were carried out in the Laboratoꢀ
ry of Pharmacological Studies of the N. N. Vorozhtsov Noꢀ
vosibirsk Institute of Organic Chemistry of the Siberian
Branch of the Russian Academy of Sciences. Acute toxicity
of nitroderivatives 2—6 and salt [9]K+ was determined in
Table 4. Determination of the rate of explosive conversion of
compounds 4, 10, and 11
Comꢀ
pound
Sample
Detonation
/m s–1
Mass Diameter Height Density
/g
/mm
/mm
/g cm–3
4a
33.0
32.5
20
20
20.5
25.3
25.3
25.2
25.2
20.1
49.5
48
38.3
39
1.33
1.35
1.05
1.03
1.41
8000
8130
4740
4640
6890
4a
10b
10b
11c
45.8
a Specific pressure of pressing 430 kg cm–1
b Specific pressure of pressing 1000 kg cm–1
c Specific pressure of pressing 1800 kg cm–1
.
.
.
Table 3. Sensitivity to mechanical impact and explosive properties of hydrazones 4, 10, and 11
Comꢀ
pound
Sensitivity
to impacta
explosion frequency (%)c
to frictionb
low level/mm
(load weight/kg)
low level
/kgf cm–2
explosion frequency (%)d
4
76
0
<50 (10)
200 (2)
>500 (10)
— (2)
>500 (10)
— (2)
2000
4000
8
e
10
11
—
16
>7000
—
Note. The low level of sensitivity to impact is the minimum height of the load drop at which at least in one out of 10
or 25 trials an explosion took place. The low level of sensitivity to friction is the maximum pressure of pressing of the
blasting explosive sample placed between steel planes at which none of the explosions out of 25 trials took place at an
impact shift of one plane relative to the other.
a The Kast brisance meter.21
b A Kꢀ44ꢀ111 instrument.22
c Explosion frequency at the dropped load weight P = 10 kg and the height from which the impact is produced
H = 250 mm.
d Explosion frequency at Pspec = 2200 kgf cm–2
e Not tested, since the compound possesses low sensitivity to friction.
.

4ꢀNitrosemicarbazones
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557
Table 5. Sample characteristics, parameters of combustion initiation, and combustion rate of the samples of compounds
10 and 11
Comꢀ
pound
Samplea,b
Igniter massc
/g
Combustion rate
/mm S–1
Mass/g
Height/mm
Density/g cm–3
Without flegmatization
10
11
9.7
10.7
32.5
31.5
0.94
1.10
3
2
1350
3100
Flegmatization with urethane
10d
11
10.0
10.2
12.0
17.2
32.5
29.0
37.8
48.5
0.97
1.10
1.00
1.12
2
2
3
5e
8
1450
1500
1400
a If not indicated otherwise, pressing force is 800 kg cm–2
b Diameter of samples 20.1 mm.
.
c If not indicated otherwise, igniter is trotyl.
d Pressing force is 1200 kg cm–2
e Igniter is ballistite.
.
(δH 2.04, δC 29.8 and 206), and D2O (δ 4.80). Chemical shifts
trosemicarbazone 2 has proved inactive on a model of
calcium chloride arrhytmia, but showed good activity in
the dose of 0.5 mg kg–1 on a model of adrenalin arrhytꢀ
mia. In the doses 5 and 0.05 mg kg–1 no recovery of elecꢀ
trocardiogram (ECG) occurred.
H
in 1H and 13C NMR spectra are given relative to the residual
signals of solvents (an internal standard). 15N NMR spectra were
recorded on a Bruker AVꢀ600 spectrometer (60.84 MHz); chemꢀ
ical shifts are given relative to ammonia (an external standard).
The starting nitrosemicarbazide 1 was synthesized from diniꢀ
trourea upon treatment with hydrazine hydrate in aqueous soluꢀ
tion at the temperature below 30 °C. Further treatment with
KOH or NaOH gave its potassium ([1]K+) and sodium ([1]Na+)
salts.25 Dinitrourea was obtained in 85% yield by nitration of
urea with a H2SO4—HNO3 mixture according to the published
procedure26 with subsequent washing with trifluoroacetic acid.
Synthesis of dinitrosemicarbazones 2—8 (general procedure).
An aldehyde (1.2 mmol) (2 mmol of the aldehyde were in the
case of bisꢀnitrosemicarbazones 4 and 7) was slowly added to a
solution of 4ꢀnitrosemicarbazide (1 mmol) in the corresponding
solvent with vigorous stirring. Reaction conditions are given in
Table 1. After cooling, a precipitate formed was collected by
filtration and recrystallized from water or ethanol.
During studies of antihypertensive properties, comꢀ
pound [9]K+ was found to decrease the pressure in rats
with normal arterial pressure by 10% in a dose of 4 mg kg–1
.
The decrease in the pressure was observed 5 min after the
injection of the test compound in femoral vein. An inꢀ
crease in the dose of test compound led to insignificant
(3%) decrease in the pressure.
In conclusion, in the present work we showed a possiꢀ
bility to synthesize 4ꢀnitrosemicarbazones of various aldeꢀ
hydes and ketones, selected the optimal conditions for the
synthesis of earlier unknown compounds 2—8, their sodiꢀ
um, potassium, and onium salts, as well as alkyl derivaꢀ
tives. The synthesized compounds possess a number of
interesting properties: glyoxal nitrosemicarbazone and its
salts can be used as explosives; nitrosemicarbazones of
other aldehydes are regarded as intermediants of pharmaꢀ
ceutical agents.
Vanillal nitrosemicarbazone (2). M.p. 184 °C. UV (H2O),
λ
max/nm: 328, 211. IR (KBr), ν/cm–1: 3466 (OH); 3308 (NH);
3042, 2947, 2787 (CHring); 1704 (C=O); 1602 (C=N); 1543 (N—
NO2); 1513, 1430, 1346, 1295, 1270 (N—NO2); 1194, 1120 (C—N);
1
1067 (N—N); 1018, 943. H NMR (500.13 MHz, acetoneꢀd6),
δ: 3.86 (s, 1 H, OCH3); 6.86 (d, 1 H, ArH, 3J = 8.0 Hz); 7.15 (d, 1 H,
3
ArH, J = 8.0 Hz); 7.46 (s, 1 H, ArH); 8.14 (br.s, 2 H, OH,
Experimental
CH=N); 10.74 and 10.27 (both br.s, 1 H each, NH); 12.50 (br.s,
1 H, NHNO2). 13C NMR (125.75 MHz, acetoneꢀd6), δ: 56.2,
110.0, 115.8, 123.4, 126.6, 145.9, 148.0; 148.7, 150.0, 150.6).
Found (%): C, 42.11; H, 4.23; N, 22.37. C9H10N4O5. Calculatꢀ
ed (%): C, 42.52; H, 3.93; N, 22.05.
Melting points were measured on a VEB Analytik Dresden
PHMK device. UV spectra were recorded on a Varian Cary 50
spectrophotometer in water. IR spectra of the samples in KBr
pellets were recorded on a FTꢀ801 Fourierꢀtransform spectromꢀ
eter in the region from 4000 to 500 cm–1. Elemental composition
was determined on FlashEATM 1112 elemental C,H,N,Oꢀ
analyzer. 1H and 13C NMR spectra of the samples were recorded
on Bruker DRXꢀ500 (500.13 and 125.75 MHz, respectively),
Bruker AVꢀ400 (400.13 and 100.62 MHz, respectively), and
Bruker AVꢀ600 spectrometers (600.30 and 150.95 MHz, respecꢀ
Salicylaldehyde nitrosemicarbazone (3). M.p. 172 °C. UV
(H2O), λmax/nm: 302, 284, 211. IR (KBr), ν/cm–1: 3236 (NH);
3050, 2970, 2785 (CHring); 1693 (C=O); 1603 (C=N); 1575
(δ(NH)); 1524 (N—NO2); 1489, 1390, 1335 1263 (N—NO2);
1187 (C—N); 1128 (C—N); 1109, 1067 (N—N); 970. 1H NMR
3
(500.13 MHz, acetoneꢀd6), δ: 6.93 (dd, 1 H, ArH, J = 8.5 Hz,
4J = 1.2 Hz); 6.93 (ddd, 1 H, ArH, 3J = 7.3 Hz, 3J = 7.3 Hz, 4J =
4
= 1.2 Hz); 7.33 (ddd, 1 H, ArH, 3J = 7.3 Hz, 3J = 8.6 Hz, J =
tively) in DMSOꢀd6 (δ 2.50,
δ
39.50), acetoneꢀd6
H
C

558
Russ.Chem.Bull., Int.Ed., Vol. 65, No. 2, February, 2016
Glukhacheva et al.
3
4
= 1.6 Hz); 7.40 (dd, 1 H, ArH, J = 7.3 Hz, J = 1.6 Hz); 8.65
(br.s, 1 H, CH=N); 11.08 (br.s, 2 H, NH, OH); 13.06 (br.s, 1 H,
NHNO2). 13C NMR (125.75 MHz, acetoneꢀd6), δ: 116.7, 117.8,
119.3, 131.0, 131.8, 146.6, 151.9, 158.3. Found (%): C, 43.23;
H, 3.21; N, 24.58. C8H8N4O4. Calculated (%): C, 42.86; H, 3.57;
N, 25.00.
salt was washed with diethyl ether (3×20 mL) from traces of
camphor. Then, the precipitate was dissolved in water (10 mL)
and reprecipitated with ethanol (30 mL), an impurity of niꢀ
trosemicarbazide potassium salt was filtered off, the filtrate was
concentrated dry to obtain a pure camphor nitrosemicarbazone
potassium salt. The yield was 0.76 g (30%), m.p. 118—120 °C. IR
(KBr), ν/cm–1: 3327, 3050, 1665, 1600, 1532, 1346, 1261, 1186;
1118, 1085, 1045, 957, 784, 684. Found (%): C, 45.52; H, 5.65;
N, 20.06. C11H17N4O3K. Calculated (%): C, 45.20; H, 5.82; N, 19.18.
Glyoxal bis(nitrosemicarbazone) dipotassium salt [4]+. A. A 40%
aqueous glyoxal (4.4 mL, 0.037 mol) was added to a solution
of nitrosemicarbazide potassium salt (11.85 g, 0.075 mol) in waꢀ
ter (200 mL) with stirring. The mixture was allowed to stand
for 8 h at room temperature. A precipitate formed was collected
by filtration and recrystallized from water. The yield was 11.6 g
(92%).
Glyoxal bis(nitrosemicarbazone) (4). M.p. 251 °C. UV (H2O),
λ
max/nm: 331.7, 258, 214. IR (KBr), ν/cm–1: 3297 (NH); 3182,
2940 (CH); 1750, 1740 (C=O); 1583 (C=N, NNO2, δ(NH));
1473, 1417, 1316 (NNO2); 1219, 1116 (C—N); 1043 (N—N);
967, 941. 1H NMR (400.13 MHz, DMSOꢀd6), δ: 7.82 (br.s, 1 H,
CH); 11.69 (s, 1 H, NH). 13C NMR (100.62 MHz, DMSOꢀd6),
δ: 147.98, 144.86. Found (%): C, 18.36; H, 2.41; N, 42.85.
C4H6N8O6. Calculated (%): C, 18.32; H, 2.29; N, 42.75.
Furfural nitrosemicarbazone (5). M.p. 135 °C. UV (H2O),
λ
max/nm: 315, 257, 204. IR (KBr), ν/cm–1: 3287 (NH); 3146,
3117, 3084 (CH); 2979—2801 (CHfur.ring); 1703 (C=O); 1630,
1601 (C=N); 1580 (δ(NH)); 1537 (N—NO2); 1476, 1410, 1335
(N—NO2); 1192, 1164 (C—N); 1111, 1060 (N—N); 1017, 942.
1H NMR (400.13 MHz, DMSOꢀd6), δ: 6.61 (dd, 1 H, ArH, 3J =
= 3.40 Hz, 3J = 1.78 Hz); 6.93 (d, 1 H, ArH, 4J = 3.40 Hz); 7.82
(d, 1 H, ArH, 3J = 1.78 Hz); 8.09 (br.s, 1 H, ArH); 11.47 (s, 1 H,
NH); 13.34 (br.s, 1 H, NHNO2). 13C NMR (100.62 MHz,
DMSOꢀd6), δ: 112.3, 114.2, 138.1, 145.4, 147.7, 149.9. Found (%):
C, 36.66; H, 2.61; N, 27.86. C6H6N4O4. Calculated (%): C, 36.36;
H, 3.03; N, 28.28.
B. A mixture of compound 4 (1.31 g, 0.005 mol) and KOH
(0.56 g, 0.01 mol) in distilled water (150 mL) was allowed to
stand for 30 min at room temperature. A yellow precipitate
formed was collected by filtration and recrystallized from water.
The yield was 1.2 g (71%). T.decomp. 235 °C. UV (H2O), λmax/nm:
334, 256, 203. IR (KBr), ν/cm–1: 3480, 3403 (NH); 3193, 3034
(CH); 1687 (C=O); 1660 (C=N); 1580 (δ(NH)); 1541, 1369,
1336 (N—NO2); 1231, 1144 (C—N); 1072 (N—N); 978. 1H NMR
(500.13 MHz, DMSOꢀd6), δ: 7.66 (s, 1 H, CH); 10.59 (s, 1 H,
NH). 13C NMR (100.62 MHz, DMSOꢀd6), δ: 140.86, 157.8.
Found (%): C, 12.98; H, 1.69; N, 29.58. C4H4N8O6K2. Calcuꢀ
lated (%): C, 12.83; H, 2.17; N, 29.94.
Synthesis of salts 10—14 (general procedure). An amine
(0.03 mol) was added in portions to a suspension of compound 4
(2.62 g, 0.01 mol) in distilled water (200 mL) with stirring and
cooling to 0—5 °C. The mixture was allowed to stand for 1 h.
A precipitate formed was collected by filtration and recrystalꢀ
lized from water. To isolate compound 12, the reaction mixture
was concentrated dry on a rotary evaporator, a precipitate was
recrystallized from 50% aqueous ethanol. The yields of salts 10—14
are given in Table 2.
Nitrofurfural nitrosemicarbazone (6). M.p. 226 °C. UV
(H2O), λmax/nm: 350, 284, 250. 201. IR (KBr), ν/cm–1: 3330
(NH); 3251, 3152, 3118, 3011 (CH); 2873 (CHfur.ring); 1741,
1703 (C=O); 1626, 1604 (C=N, δ(NH)); 1545 (N—NO2, NO2);
1476, 1395, 1347 (NO2); 1316, 1254 (N—NO2); 1221, 1167 (C—N);
1
1068 (N—N); 1017, 963. H NMR (500.13 MHz, acetoneꢀd6),
δ: 7.23 (d, 1 H, ArH, 3J = 3.8 Hz); 7.61 (d, 1 H, ArH, 3J = 3.8 Hz);
8.25 (br.s, 1 H, CH=N); 11.01 (br.s, 1 H, NH=N); 13.00 (br.s, 1 H,
NHNO2). 13C NMR (125.75 MHz, acetoneꢀd6), δ: 113.3, 114.0,
146.8, 151.1, 151.2, 152.1. Found (%): C, 29.56; H, 2.28; N, 28.80.
C6H5N5O6. Calculated (%): C, 29.63; H, 2.06; N, 28.81.
Diacetyl bis(nitrosemicarbazone) (7). M.p. 258 °C. UV (H2O),
Glyoxal bis(nitrosemicarbazone) diammonium salt (10).
T.decomp. 255 °C. UV (H2O), λmax/nm: 334; 258, 205. IR (KBr),
ν/cm–1: 3435, 3190, 3034, 1616, 1578, 1540, 1388, 1328, 1308,
1234, 1154, 1068, 914. Found (%): C, 16.3; H, 4.04; N, 47.14.
C4H12N10O6. Calculated (%): C, 16.22; H, 4.05; N, 47.30.
Glyoxal bis(nitrosemicarbazone) hydrazinium salt (11). M.p.
λ
max/nm: 324, 257, 208. IR (KBr), ν/cm–1: 3356, 3323 (NH);
3143, 3075, 2977, 2798 (CH3); 1709 (C=O); 1597 (C=N, N—NO2,
δ(NH)); 1524, 1343 (N—NO2); 1412, 1245, 1205 (C—N); 1143,
1049 (N—N); 981, 960. 1H NMR (400.13 MHz, DMSOꢀd6),
δ: 2.11 (s, 6 H, CH3); 10.57 (s, 2 H, NHN=); the signal for the
proton of the NHNO2 group was not found because of exchange
with water. 13C NMR (100.62 MHz, DMSOꢀd6), δ: 11.3, 147.9,
151.5. Found (%): C, 24.63; H, 3.34; N, 38.85. C6H10N8O6.
Calculated (%): C, 24.83; H, 3.45; N, 38.62.
Phenylacetaldehyde nitrosemicarbazone (8). M.p. 118 °C. UV
(H2O), λmax/nm: 273, 207. IR (KBr), ν/cm–1: 3256, 3128 (NH);
3060, 3027, 2973, 2802 (CHring); 1676 (C=O); 1639, 1612, 1538
(C=N, N—NO2, δ(NH)); 1493, 1375, 1333 (N—NO2); 1417,
1221 (C—N); 1088, 1056 (N—N); 987. Found (%): C, 48.63;
H, 4.34; N, 25.45. C9H10N4O3. Calculated (%): C, 48.87; H,
4.07; N, 25.34.
Camphor nitrosemicarbazone potassium salt [9]K+. Potassiꢀ
um hydroxide (0.56 g, 0.01 mol) was gradually added to a soluꢀ
tion of nitrosemicarbazide (1.2 g, 0.01 mol) in 50% aqueous
dioxane (160 mL). The reaction mixture was allowed to stand for
10 min at room temperature. Then, a solution of camphor (1.52 g,
0.01 mol) in dioxane (10 mL) was added with vigorous stirring,
keeping temperature below 25 °C. Then the reaction mixture
was allowed to stand for 17 h at 20 °C and concentrated dry. The
180 °C. UV (H2O), λmax/nm: 330, 258.4, 213. IR (KBr), ν/cm–1
:
3433, 3338, 3188, 3032, 1658, 1612, 1575, 1538, 1383, 1315,
1253, 1152, 1097, 1068, 929, 871, 780, 692. Found (%): C, 16.08;
H, 2.91; N, 47.46. C4H10N10O6. Calculated (%): C, 16.33; H, 3.40;
N, 47.62.
Glyoxal bis(nitrosemicarbazone) methydammonium salt (12).
M.p. 218—220 °C. UV (H2O), λmax/nm: 330, 258, 212. IR (KBr),
ν/cm–1: 3436, 3190, 3050, 1658, 1642, 1572, 1530, 1502, 1401,
1222, 1132, 1066, 967, 862, 760. 1H NMR (600.30 MHz, D2O),
δ: 2.56 (s, 6 H, CH3); 7.77 (s, 2 H, CH=N). 13C NMR
(150.95 MHz, D2O), δ: 24.01, 143.93, 158.86. Found (%): C, 21.89;
H, 4.67; N, 43.42. C6H16N10O6. Calculated (%): C, 22.22; H, 4.94;
N, 43.21.
Glyoxal bis(nitrosemicarbazone) dimethydammonium salt (13).
M.p. 92—96 °C. UV (H2O), λmax/nm: 334, 257, 214. IR (KBr),
ν/cm–1: 3467, 3204, 3022, 2964, 2850, 2779, 2438, 1650, 1581,
1539, 1429, 1302, 1237, 1146, 1017, 928, 871. Found (%):
C, 27.53; H, 5.94; N, 39.89. C8H20N10O6. Calculated (%): C, 27.27;
H, 5.68; N, 39.77.

4ꢀNitrosemicarbazones
Russ.Chem.Bull., Int.Ed., Vol. 65, No. 2, February, 2016
559
Glyoxal bis(nitrosemicarbazone) diethydammonium salt (14).
M.p. 224—225 °C. UV (H2O), λmax/nm: 334, 258, 213. IR (KBr),
ν/cm–1: 3466, 3198, 3032, 2974, 2936, 2800, 2738, 2677, 2490,
1649, 1581, 1539, 1475, 1430, 1398, 1330, 1304, 1226, 1146,
1067, 1035, 927, 780. Found (%): C, 35.09; H, 6.55; N, 34.65.
C12H28N10O6. Calculated (%): C, 35.29; H, 6.86; N, 34.31.
Synthesis of salts 15 and 16 (general procedure). Compound 1
(2.4 g, 0.02 mol) was dissolved in distilled water (100 mL) with
stirring, then diimine 25 or 26 (0.01 mol) was gradually added.
The mixture was allowed to stand for 1 h at room temperature.
A precipitate formed was collected by filtration and recrystalꢀ
lized from water.
3100, 2967, 2873, 1660, 1547, 1468, 1358, 1325, 1263, 1181,
1140, 1061, 929. 1H NMR (600.30 MHz, DMSOꢀd6), δ: 1.10
3
(d, 12 H, CH3, J = 6.6 Hz); 3.83 (d.septet, 2 H, CH(CH3)2
3J = 6.6 Hz, J = 8.3 Hz); 6.49 (d, 2 H, NHCH, J = 8.3 Hz);
7.51 (s, 2 H, CH=N); 10.50 (s, 2 H, NHN=). 13C NMR (150.95,
DMSOꢀd6), δ: 22.76, 40.94, 138.35, 154.25. 15N NMR (60.84,
DMSOꢀd6), δ: 100 (NHCH); 158 (NHN=); 330 (NHN=).
Found (%): C, 46.60; H, 7.9; N, 33.09. C10H20N6O2. Calculated
(%): C, 46.88; H, 7.81; N, 32.81.
3
3
Glyoxal bis(tertꢀbutylsemicarbazone) (22). M.p. 236—238 °C.
UV (H2O), λmax/nm: 297, 200. IR (KBr), ν/cm–1: 3415, 3197,
3090, 2970, 2950, 1670, 1525, 1460, 1394, 1365, 1322, 1285,
1228, 1209, 1144, 1057, 926. 1H NMR (600.30 MHz, DMSOꢀd6),
δ: 1.30 (s, 18 H, CH3); 6.05 (s, 2 H, NHCH); 7.48 (s, 2 H, CH=N);
10.38 (s, 2 H, NHN=). 13C NMR (150.95, DMSOꢀd6), δ: 28.96,
49.62, 138.05, 154.76. Found (%): C, 46.39; H, 9.41; N, 32.60.
C10H24N6O2. Calculated (%): C, 46.15; H, 9.23; N, 32.31.
Glyoxal bis(dimethylsemicarbazone) (19). Compound 1 (12.0 g,
0.1 mol) was added to a 33% aqueous dimethylamine (30.6 mL,
0.2 mol) with stirring. The mixture was heated for 4 h at 75—85 °C.
The solvent was evaporated in vacuo, the resulting dimethylsemiꢀ
carbazide 23 was dissolved in water (100 mL), followed by the
addition of a 40% aqueous solution of glyoxal (5.5 mL, 0.046 mol)
with stirring. The mixture was allowed to stand for 3 h at room
temperature. A precipitate of compound 19 was collected by
filtration and recrystallized from water. The yield was 7.0 g (67%).
Physicochemical characteristics of the samples of compound 19
obtained by alternative methods (see above) are similar.
Glyoxal bis(diethylsemicarbazone) (20). 4ꢀNitrosemicarbꢀ
azide 1 (12 g, 0.1 mol) was added to a solution of diethylamine
(31.2 mL, 0.3 mol) in water (15 mL) with stirring. The mixture
was heated for 4 h at 75—85 °C. The solvent was evaporated
in vacuo, diethylsemicarbazide 24 was dissolved in water (100 mL),
followed by the addition of a 40% aqueous solution of glyoxal
(5.4 mL, 0.045 mol) with stirring. The mixture was allowed to
stand for 3 h at room temperature. A precipitate of compound 20
was collected by filtration and recrystallized from water. The
yield was 10.9 g (85%). Physicochemical characteristics of the
samples of compound 20 obtained by alternative methods (see
above) are similar.
Glyoxal bis(nitrosemicarbazone) isopropydammonium salt (15).
The yield was 88%, m.p. 225—227 °C. UV (H2O), λmax/nm: 334,
256, 203. IR (KBr), ν/cm–1: 3478, 3094, 3032, 2985, 2544, 1649,
1
1582, 1511, 1408, 1307, 1226, 1125, 1061, 1034, 932. H NMR
3
(600.30 MHz, D2O), δ: 1.25 (d, 6 H, CH3, J = 6.5 Hz); 3.45
3
(septet, 1 H, CH(CH3)2, J = 6.5 Hz); 7.76 (s, 1 H, CH=N).
13C NMR (150.95 MHz, D2O), δ: 19.74, 43.96, 144.40, 159.37.
Found (%): C, 46.69; H, 7.53; N, 32.48. C10H24N10O6. Calcuꢀ
lated (%): C, 46.88; H, 7.81; N, 32.81.
Glyoxal bis(nitrosemicarbazone) tertꢀbutylammonium salt (16).
The yield was 78%, m.p. 266—268 °C. UV (H2O), λmax/nm: 335,
254, 210. IR (KBr), ν/cm–1: 3429, 3100, 3040, 2982, 2893, 2825,
2725, 2618, 2585, 1643, 1588, 1523, 1403, 1381, 1325, 1240,
1133, 1052, 967. 1H NMR (500.13 MHz, D2O), δ: 1.43 (s, 9 H,
CH3); 7.86 (s, 1 H, CH=N). 13C NMR (125.75 MHz, D2O),
δ: 23.3, 51.6, 144.0, 159.0. Found (%): C, 35.42; H, 6.67; N, 34.03.
C12H22N10O6. Calculated (%): C, 35.29; H, 6.86; N, 34.31. Comꢀ
pounds 15 and 16 were obtained in 48 and 70% yields by the
reaction of glyoxal bis(nitrosemicarbazone) 4 with the correꢀ
sponding amines (see Scheme 6 and Table 2).
Synthesis of glyoxal semicarbazones 17—22 (general proceꢀ
dure). An amine (0.04 mol) was gradually added to a suspension
of compound 4 (2.62 g, 0.01 mol) in distilled water (50 mL) with
stirring. The mixture was refluxed for 1—3 h. The reaction
progress was monitored by UV spectroscopy. After disappearꢀ
ance of absorption maximum at 258 nm, the reaction mixture
was cooled, a precipitate formed was collected by filtration and
recrystallized from water. The yields of compounds 17—22 are
given in Table 2.
Biological activity of synthesized compounds was studied in
the Laboratory of Pharmacological Studies of the N. N.
Vorozhtsov Novosibirsk Institute of Organic Chemistry of the
Siberian Branch of the Russian Academy of Sciences according
to the guidance on laboratory practice (GLP)27 and the correꢀ
sponding manuals.28,29 The studies were carried out on 190—
210ꢀg Vistar rats obtained from vivarium of the Institute of Cyꢀ
tology and Genetics of the Siberian Branch of the RAS. The
experimental animals were kept under constant access to food
and water: a full diet of the extruded briquetted food (Chara,
Russia, GOST (State Standard) for food R 50258ꢀ92) and drinkꢀ
ing water were used. Animals were kept in a vivarium in plastic
cages with stainless steel barred lids and with litter of wood shavꢀ
ings at 20—22 °C and 12ꢀhour light regime (12 h of light, 12 h of
darkness) with five—six rats in a cage. All the manipulations
were carried out according to the rules and principles of humane
treatment of animals. Experiments were carried out at the same
time, from 900 to 1200 h.
Glyoxal bis(methylsemicarbazone) (18). M.p. 255—256 °C.
UV (H2O), λmax/nm: 294, 200. IR (KBr), ν/cm–1: 3352, 3186,
3117, 2965, 1666, 1547, 1416, 1314, 1274, 1151, 1117, 928. 1H NMR
3
(400.13 MHz, DMSOꢀd6), δ: 2.64 (d, 6 H, CH3, J = 4.5 Hz);
6.81 (q, 2 H, NHCH, 3J = 4.5 Hz); 7.51 (s, 2 H, CH=N); 10.54
(s, 2 H, NHN=). 13C NMR (100.62, DMSOꢀd6), δ: 26.1, 138.2,
155.6. Found (%): C, 36.5; H, 5.9; N, 41.8. C6H12N6O2. Calcuꢀ
lated (%): C, 36.00; H, 6.00; N, 42.00.
Glyoxal bis(dimethylsemicarbazone) (19). M.p. 235—237 °C.
UV (H2O), λmax/nm: 298, 195. IR (KBr), ν/cm–1: 3247, 2870,
2810, 1728, 1659, 1544, 1491, 1409, 1304, 1217, 1164, 1093,
1017, 920, 888, 822, 731. Found (%): C, 42.52; H, 7.9; N, 36.80.
C8H16N6O2. Calculated (%): C, 42.11; H, 7.02; N, 36.84.
Glyoxal bis(diethylsemicarbazone) (20). M.p. 230—232 °C.
UV (H2O), λmax/nm: 300, 200. IR (KBr), ν/cm–1: 3237, 3060,
2970, 2932, 1651, 1537, 1488, 1457, 1408, 1374, 1314, 1266,
1178, 1078, 1099, 1083, 1043, 986, 936. Found (%): C, 50.51;
H, 8.9; N, 29.82. C12H24N6O2. Calculated (%): C, 50.70; H,
8.45; N, 29.58.
"Accute" toxicity was determined by the Kerber's method,30
using a single intragastric administration of compounds 2—6.
Standard models of calcium chloride and adrenalin arrhytꢀ
mia were used for the assessment of antiarrhythmic effect. The
Glyoxal bis(isopropylsemicarbazone) (21). M.p. 244—245 °C.
UV (H2O), λmax/nm: 296, 200. IR (KBr), ν/cm–1: 3372, 3192,

560
Russ.Chem.Bull., Int.Ed., Vol. 65, No. 2, February, 2016
Glukhacheva et al.
arrhytmia was caused by a single injection into the femoral vein of
a lethal dose of a 10% solution of CaCl2 in the dose 250 mg kg–1
(calcium chloride arrhytmia) or adrenalin hydrochloride (AH)
in the dose 0.2 mg kg–1 (adrenalin arrhytmia). These doses of
CaCl2 and AH are lethal for rats in 100% of cases. To carry out
the studies, the rats were separated into groups with eight aniꢀ
mals in each. Aqueous solutions of test compounds 2 and [9]K+
were administered to animals intravenously in the doses 5, 0.5,
and 0.05 mg kg–1. After 1 min, calcium chloride or AH were
injected and the extent of ECG recovery was assessed. A criteriꢀ
on of the antiarrhythmic effect was the recovery of the ECG
parameters after injection of compounds causing arrhytmia. Acꢀ
tivity parameters were recorded on a LabLink V polyfunctional
electrophysiological complex (USA). Electrocardiograms were
recorded during 10 min. Electrocardiograms were recorded in
the second standard lead on a LabLinK V model v75ꢀ11 instruꢀ
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method of variation statistics using Student's tꢀtest (see STATISTIꢀ
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experiment by introducing a cannula in the carotid artery. Figures
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Date of request 04.09.2015.
Received April 28, 2015;
in revised form September 9, 2015