Structure of cyanoacetylhydrazones of aldehydes and ketones

Article abstract of DOI:10.1023/A:1013126309514

1D ¹H and ¹³C, and 2D ¹H NOESY NMR were used to establish that cyanoacetylhydrazones of aliphatic and aromatic aldehydes and ketones in CDCl₃ and (CD₃)₂SO solutions have a linear structure,

Full text of DOI:10.1023/A:1013126309514

Russian Journal of General Chemistry, Vol. 71, No. 7, 2001, pp. 1116 1120. Translated from Zhurnal Obshchei Khimii, Vol. 71, No. 7, 2001,
pp. 1182 1186.
Original Russian Text Copyright
2001 by Zelenin, Oleinik, Alekseev, Potekhin.
Structure of Cyanoacetylhydrazones of Aldehydes and Ketones
K. N. Zelenin, S. V. Oleinik, V. V. Alekseev, and A. A. Potekhin
Military Medical Academy, St. Petersburg, Russia
Received March 21, 2000
1
13
1
Abstract 1D H and C, and 2D H NOESY NMR were used to establish that cyanoacetylhydrazones of
aliphatic and aromatic aldehydes and ketones in CDCl and (CD ) SO solutions have a linear structure, exist
3
3 2
as a mixture of geometric isomers by the C=N bond, and exhibit hindered amide rotation.
Cyanoacetylhydrazones exhibit a broad-spectrum
biological activity (antimicrobial [1], antihelmintal
same time, the available information is controversial.
In detail, cyanoacetylhydrazones of benzaldehyde and
[
2], antiviral [3], modification of activity of brain
anisaldehyde [7] (by IR data), as well as para-chloro-
1
mitochondrial monoaminoxidase [4], and inhibition
of cell prolipheration [5, 6], which is valuable for
therapy of cancer and atherosclerosis).
benzaldehyde [8] and acetophenone [9] (by H NMR
data) were proposed to exist exclusively in hydrazone
1
form A. Zommer [10], based on H NMR, UV, and
IR data, stated that cyanoacetylhydrazones of acetone
and para-hydroxybenzaldehyde are present as two
Reliable data on their structure are necessary for
correct interpretation of biological properties. At the tautomers due to the keto-enol equilibrium A
B.
1
2
1
R = CH (I), C H (II), C H (III), C H -i (IV), C H (V), C H OCH -p (VI), R = H (I VI); R = CH (VII), C H -t
3
2
2
5
3
7
3
7
6
5
1
6
4
3
3
4 9
1
2
2
(
VIII), R = CH (VII, VIII); R , R = (CH ) (IX); R = C H (X), C H OCH -p (XI), C H NO -p (XII), R = CH
3
2 4
6
5
6
4
3
6
4
2
3
1
2
(
X XII); R = R = C H (XIII).
6 5
1
Avetisyan et al. [11] reported the H NMR evi-
authors stated that cyanoacetylhydrazones of propio-
naldehyde and acetone [13], as well as of other ali-
phatic aldehydes and ketones [14] exhibit the ring-
dence showing that cyanoacetylhydrazones of acetone,
butan-2-one, 3-methylbutan-2-one, and pentan-3-one
undergo irreversible cycloisomerization to the cor-
responding pyrazolidin-3-one derivatives C under
reflux in triethylamine. Nevertheless, the authors did
chain tautomerism A
C in solutions. On the one
hand, this contradicts the above data on isomerization,
and on the other, is not substantiated by convincing
spectral evidence. In [14], the authors only conclude
1
not present complete H NMR data underlying their
structural assessments. In [11], Avetisyan et al. ob-
tained pyrazolidin-3-ones C isomeric to cyanoacetyl-
hydrazones A by reactions of cyanoacetylhydrazine
with acetaldehyde, propionaldehyde, butyraldehyde,
1
that H NMR spectra are not enough informative. At
1
the same time, the cited work contains complete H
NMR spectra of those cyanoacetylhydrazones (of
benzaldehyde, acetophenone, and some of their para
derivatives) which have a single hydrazone form A.
1
and isobutyraldehyde [12], but the H NMR data
presented in this work are doubtful. Later the same
1
070-3632/01/7107-1116$25.00 2001 MAIK Nauka/Interperiodica

STRUCTURE OF CYANOACETYLHYDRAZONES OF ALDEHYDES AND KETONES
1117
Table 1. Physicochemical characteristics of first prepared compounds
Found, %
H
Calculated, %
Comp.
no.
Rfa
mp,
C
Formula
C
N
C
H
N
27.43
23.19
25.44
18.17
22.75
15.96
IV
VIII
IX
XI
XII
XIII
110 111
102 104
159 161
185 187
233 234
178 180
0.74
0.71
0.63
0.86
0.76
0.82
54.96
59.43
57.96
62.48
53.74
72.76
7.18
8.51
6.86
5.47
3.85
4.79
27.59
23.24
25.33
18.31
22.89
16.10
C H N O
54.89
59.64
58.17
62.33
53.66
72.99
7.24
8.34
6.71
5.67
4.09
4.98
7
11 3
C H N O
9
15 3
C H N O
8
11 3
C H N O
12 13 3
2
3
C H N O
11 10 4
C H N O
1
6 13 3
a
Benzene acetonitrile, 1:1.
Table 2. 1H NMR spectra of compounds I XIII in CDCl3
,
ppm (J, Hz)
Comp.
Form, %
no.
R1
R2
CH , s NH, br.s
2
I
EE , 53
EZ , 30
ZE , 13
ZZ , 4
E, 87
ZE , 6
ZZ , 7
E, 84
ZE , 8
ZZ , 8
E, 92
ZE , 3
ZZ , 5
E, 100
E, 100
100
1.98 d (5.5)
1.98 d (5.5)
1.95 d (5.6)
2.06 d (5.6)
7.36 q (5.5)
7.36 q (5.5)
6.82 q (5.6)
7.63 q (5.6)
7.40 t (4.9)
6.63 t (5.3)
7.57 t (5.3)
7.36 t (5.2)
6.64 t (5.6)
7.54 t (5.6)
7.29 d (4.8)
6.44 d (7.9)
7.43 d (6.0)
7.88 s
3.82
3.82
3.84
3.52
3.82
3.83
3.54
3.80
3.83
3.55
3.79
3.81
3.51
3.95
3.90
3.82
3.79
3.79
3.97
3.93
3.92
3.99
10.33
10.26
9.86
9.77
II
1.10 m (CH ), 2.30 m (CH )
10.53
10.04
10.02
10.52
10.18
10.13
10.47
10.12
9.84
9.57
8.65
9.72
9.96
3
2
1.10 m (CH ), 2.30 m (CH )
3
2
1.10 m (CH ), 2.30 m (CH )
3
2
III
IV
0.95 m (CH ), 1.55 m (CH CH ), 2.23 m (CH CH=N)
3 2 3 2
0.95 m (CH ), 1.55 m (CH CH ), 2.23 m (CH CH=N)
3
2
3
2
0.95 m (CH ), 1.55 m (CH CH ), 2.23 m (CH CH=N)
3
2
3
2
1.08 d (6.8) (2CH ), 2.50 m [(CH ) CH]
3
3 2
1.08 d (6.8) (2CH ), 2.86 m [(CH ) CH]
3
3 2
1.08 d (6.8) (2CH ), 2.50 m [(CH ) CH]
3
3 2
V
VI
VII
VIII
IX
X
XI
XII
XIII
7.2 7.8 m (HAr)
3.88 s (CH O), 6.9 7.7 m (H )
7.73 s
3
Ar
1.95 br.s (CH ), 2.01 br.s (CH )
3
3
E, 100
100
E, 100
E, 100
E, 100
100
1.11 s
1.89 s
1.69 1.95 m (H ), 2.25 2.45 m (H )
7.3 7.9 m
9.69
10.12
9.20
8.85
8.57
2.38 s
2.28 s
2.34 s
3.87 s (CH O), 6.9 7.8 m (H )
3
Ar
7.9 8.3 m
7.2 7.8 m
Note that the A
B tautomerism is an extremely
ketones (compounds I XIII, see Table 1) and studied
their structure by means of H and C NMR spec-
1
13
rare case of ring chain tautomerism involving C H
bond. Therefore, it is not surprising that the above-
mentioned results [13, 14] were included in the review
on the modern state of the problem of ring chain
tautomerism [15].
troscopy in CDCl3 and (CD ) SO solutions (see
3 2
Tables 2 4).
To make sure that we deal with an established
equilibrium, we measured NMR spectra of the solu-
Hence, the question on the structure of cyanoacetyl- tions just after their preparation, after handling for two
hydrazones in solutions have still remained open. To weeks at room temperature, and, finally, after heating
fill this gap, we synthesized a series of cyanoacetyl- for a day at 70 C. With all the compounds under
hydrazones of typical representatives of aldehydes and study, the spectra showed no alterations with time.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 71 No. 7 2001

1
118
ZELENIN et al.
Table 3. 1H NMR spectra of compounds I XIII in (CD ) SO
3
2
,
ppm (J, Hz)
Comp.
no.
Form, %
R1
R2
CH , s NH, br.s
2
I
EE , 61
EZ , 28
ZE , 8
ZZ , 3
EE , 68
EZ , 28
ZE , 3
ZZ , 1
1.85 m
1.85 m
1.85 m
1.85 m
7.33 q (5.3)
7.47 q (5.3)
6.73 q (5.5)
6.92 q (5.5)
7.35 t (4.8)
7.48 t (4.8)
6.58 t (5.3)
6.76 t (5.3)
7.33 t (5.3)
7.46 t (5.3)
6.61 t (5.6)
6.77 t (5.6)
7.27 d (4.8)
7.40 d (5.2)
6.38 d (8.1)
6.55 d (8.1)
8.00 s
3.96
3.65
4.00
3.79
3.98
3.66
4.03
3.79
3.96
3.66
4.02
3.79
3.90
3.60
3.95
3.74
4.13
3.82
4.17
3.78
3.89
3.68
3.94
3.74
3.97
3.74
4.23
3.90
4.17
3.89
4.30
3.95
4.34
3.82
11.30
11.30
10.86
10.58
11.35
11.27
10.92
10.60
11.33
11.26
10.92
10.59
11.29
11.15
10.96
10.57
11.78
11.78
11.66
11.66
10.51
10.25
10.53
10.33
10.46
10.20
11.04
10.70
10.93
10.62
11.27
10.91
10.24
10.38
II
1.01 t (7.3) (CH ), 2.21 m (CH CH )
3 3 2
1.01 t (7.3) (CH ), 2.21 m (CH CH )
3
3
2
1.01 t (7.3) (CH ), 2.21 m (CH CH )
3
3
2
1.01 t (7.3) (CH ), 2.21 m (CH CH )
3
3
2
III
IV
EE , 66 0.89 t (7.5) (CH ), 1.48 m (CH CH ), 2.16 m (CCH CH=N)
EZ , 27 0.89 t (7.5) (CH ), 1.48 m (CH CH ), 2.16 m (CCH CH=N)
ZE , 5
ZZ , 2
EE , 74
EZ , 25
ZE , 0.7
ZZ , 0.3
EE , 80
EZ , 20
EE , 78
EZ , 22
E , 67
3 3 2 2
3
3
2
2
0.89 t (7.5) (CH ), 1.48 m (CH CH ), 2.16 m (CCH CH=N)
3 3 2 2
0.89 t (7.5) (CH ), 1.48 m (CH CH ), 2.16 m (CCH CH=N)
3 3 2 2
1.06 m [(CH ) C], 2.46 m [(CH ) CH]
3 2 3 2
1.06 m [(CH ) C], 2.46 m [(CH ) CH]
1.06 m [(CH ) C], 2.46 m [(CH ) CH]
1.06 m [(CH ) C], 2.46 m [(CH ) CH]
3
2
3 2
3
2
3 2
3
2
3 2
V
7.3 7.8 m
7.3 7.8 m
3.80 s (CH O), 6.9 7.7 m (H )
3.80 s (CH O), 6.9 7.7 m (H )
8.18 s
7.95 s
8.11 s
VI
3
Ar
3
Ar
VII
VIII
IX
1.86 s (CH ), 1.92 s (CH )
1.86 s (CH ), 1.95 s (CH )
3 3
Z , 33
3
3
EE , 80
EZ , 20
E , 67
1.06 s
1.06 s
1.81 s
1.83 s
1.59 1.83 m (H3 ), 2.18 2.38 m (H
1.59 1.83 m (H3 ), 2.18 2.38 m (H
7.3 7.9 m
,4
2,5
)
)
,4
2,5
Z , 33
X
EE , 78
EZ , 22
EE , 78
EZ , 22
EE , 80
EZ , 20
E , 67
2.26 s
2.28 s
2.21 s
2.23 s
2.31 s
2.33 s
7.3 7.9 m
3.77 s (CH O), 6.8 7.9 m (H )
3.77 s (CH O), 6.8 7.9 m (H )
XI
3
Ar
3
Ar
XII
XIII
7.9 8.4 m
7.9 8.4 m
7.2 7.7 m
7.2 7.7 m
Z , 33
The spectral data show that in solutions of com-
pounds I XIII no B and C forms are present. Form
B is expected to give the CH= proton signal near 6 7
E/Z isomerism and hindered amide rotation (E /Z
isomerism).
1
In structural assessments of stereoisomeric forms
we used previously established rules and criteria
ppm in H NMR spectrum and double-bond carbon
1
3
signals at 85 90 and 175 180 ppm in the C NMR
[17 22]. Compounds VII, IX, and XIII in which the
spectrum [16]. Cyclic tautomer B can be easily found
4
1
E /Z isomerism is impossible and compounds V, VI,
VIII, and X XII which are known to be present as a
knowing that the H proton signal in the H NMR
spectrum should be observed at 3.5 4.5 ppm and the
single E isomer all exist in CDCl solutions exclu-
3
13
3
C carbon signals atom in the C NMR, at 65
0 ppm [18]. In this case, the observation of multiple
up to four) sets of signals in the spectra of com-
pounds I XIII should be related to stereoisomerism:
sively in hydrazone form A. In (CD ) SO solutions
3
2
7
(
of these compounds an appreciable amount (from 20
to 33%) of another form appears. From a comparison
of the chemical shifts of this form with those of the
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 71 No. 7 2001

STRUCTURE OF CYANOACETYLHYDRAZONES OF ALDEHYDES AND KETONES
1119
C=O
Table 4. 13C NMR spectra of compounds I XIII in (CD ) SO
3
2
C, ppm
Comp.
no.
Form
R1
R2
CH2
C N
C=N
I
EE
EZ
ZE
ZZ
EE
EZ
EE
EZ
EE
EZ
EE
EZ
EE
EZ
E
19.0
19.0
15.0
15.2
24.9
25.4
25.5
24.4
26.0
26.1
24.9
25.4
24.7
25.4
25.2
25.8
25.1
25.6
25.0
25.2
25.3
25.4
25.2
25.4
25.8
25.8
25.7
25.7
25.8
25.8
25.8
25.7
116.8
116.8
116.6
116.6
116.8
116.6
116.7
116.5
116.4
116.2
116.8
116.5
116.9
116.6
116.4
116.4
116.7
116.7
116.8
116.7
117.1
116.8
117.1
116.9
116.9
116.7
116.9
116.7
146.5
149.7
145.2
148.6
150.9
154.2
149.9
153.2
154.1
157.5
145.4
148.8
145.2
148.6
152.9
157.5
160.8
159.6
165.4
168.9
150.0
154.0
149.8
153.9
147.9
151.5
152.4
155.3
166.4
159.2
164.7
162.6
164.9
159.2
164.8
159.2
164.7
159.1
165.6
159.9
165.3
161.9
165.3
159.3
166.1
165.3
165.3
159.5
166.7
160.2
166.4
160.0
167.1
160.7
166.1
160.6
IIa
11.0 (CH ), 24.9 (CH CH )
3 3 2
11.2 (CH ), 25.4 (CH CH )
3
3
2
IIIa
IVa
V
14.3 (CH ), 19.9 (CH CH CH ), 34.5 (CH CH CH )
3 3 2 2 3 2 2
14.3 (CH ), 20.1 (CH CH CH ), 34.5 (CH CH CH )
3
3
2
2
3
2
2
20.1 (CH ), 31.6 [(CH ) CH]
20.3 (CH ), 31.8 [(CH ) CH]
3
3 2
3
3 2
127 135
127 135
VI
56.1 (CH O), 127 130, 159 162 (C )
3 Ar
56.1 (CH O), 127 130, 159 162 (C )
3
Ar
VII
VIII
IX
18.1 (CH ), 25.9 (CH )
3 3
Z
18.4 (CH ), 25. 6 (CH )
3 3
28.1 [CH ) C], 39.2 [(CH ) C]
28.2 [CH ) C], 39.3 [(CH ) C]
25.3 (C ), 29.3 (anti-C ), 33.9 (syn-C )
EE
EZ
E
13.0
13.4
3
3
3 3
3
3
3 3
3
,4
2
5
3
,4
2
5
Z
25.1 (C ), 29.4 (anti-C ), 33.7 (syn-C )
X
EE
EZ
EE
EZ
EE
EZ
E
126 140
126 140
56.0 (CH O), 114 150 (C )
14.8
15.2
14.5
14.9
14.7
15.1
XI
3
Ar
56.0 (CH O), 114 150 (C )
3
Ar
XII
XIII
123 145 (CAr)
123 145 (CAr)
128 139 (CAr)
128 139 (CAr)
Z
a
The signals of the ZE and ZZ forms are very weak (Table 2).
major isomer (a single form in CDCl ) with regard to
the known solvent effect on the isomer ratio [18 22]
we can conclude that it is a Z isomer.
change between the E and Z forms. From the nega-
tive cross peaks caused by NOE we gained a qualita-
tive information on the distances between various
groups in the molecule. The combined data allow a
conclusion that the more intense sets of signals in the
3
For compounds I IV, derivatives of aliphatic al-
dehydes, which were expected to exist as E/Z mix-
tures with prevalence of the E isomers, already in
1
H NMR spectra belong to the E form in relation to
the C=N bond, while the minor pairs, to the Z isomer.
In these pairs, the more intense signal is assignable to
the E form in relation to the amide NH CO bond,
while the minor one, to the Z form.
CDCl solutions we observed up to 4 stereoisomeric
3
forms. At first glance the signals of these forms were
difficult to assign. But here we made use of 2D
NOESY spectroscopy [23] in (CD ) SO to reliably
3
2
assess the structure of acetaldehyde and acetone
cyanoacetylhydrazones (I, VII) whose 1D H NMR
spectrum contain four and two sets of signal groups,
respectively. Both for major and for minor pairs of
Basing on the signal assignment for separate stereo-
isomeric forms of acetaldehyde cyanoacetylhydrazone
(I), we made assignments for the other aliphatic
aldehyde derivatives in both solvents. Note that the
geminal coupling constant J of the methine proton
in aliphatic aldehydes is larger for the Z isomers as
compared to the E isomers.
1
3
NH, CH, and CH signals on the dimetric matrix of
2
1
H NMR signals both intense and minor pairs of
positive cross peaks were observed, implying ex-
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 71 No. 7 2001

1
120
ZELENIN et al.
10. Zommer, S., Acta Pol. Pharm., 1972, vol. 29, no. 5,
EXPERIMENTAL
pp. 533 535.
The H and 13C NMR spectra were registered at
00 K on a Bruker DPX-300 spectrometer [300.130
H) and 75.47 MHz ( C)]. The delay time in the
1
1
1
1. USSR Inventor’s Certificate 1209687, 1984;
3
(
Otkrytiya, Izobret., 1986, no. 5, p. 124.
1
13
2. USSR Inventor’s Certificate 1321723, 1985;
NOESY experiment was 2 s. The chemical shifts were
measured in , ppm, against TMS. The concentrations
of the solutions were 5 15%.
Otkrytiya, Izobret., 1987, no. 25, p. 71.
13. Avatisyan, A.A., Kagramanyan, A.A., Marka-
ryan, Sh.A., and Melikyan, G.S., Arm. Khim. Zh.,
Alkylidene derivatives of cyanoacetylhydrazine
were prepared by boiling 10 mmol of carbonyl
compound with 10 mmol of cyanoacetylhydrazine in
1
988, vol. 41, no. 6, p. 385.
1
4. Ovcharenko, V.V., Terent’ev, P.B., Avetisyan, A.A.,
and Kagramanyan, A.A., Khim. Geterotsikl. Soedin.,
1
0 ml of methanol for 30 min. The resulting needle-
1
995, no. 11, pp. 1525 1530.
like crystals were crystaliized from methanol.
1
1
5. Valters, R.E., Fulop, F., and Korbonits, D., Adv.
Heterocycl. Chem., 1996, vol. 66, pp. 53 54.
REFERENCES
6. Oleinik, S.V., Zelenin, K.N., Alekseev, V.V., and Po-
tekhin, A.A., Khim. Geterotsikl. Soedin., 1999, no. 6,
p. 837.
1
2
3
4
5
6
7
8
. Ti, Chi-Jun, Acta Pharm. Sin., 1965, vol. 12,
no. 8, pp. 507 512.
. Shevchenko, R.V., Sb. Naucnh. Tr. Sib. Vet. Inst.,
1
1
1
2
7. Kitaev, Yu.P. and Buzykin, B.I., Hydrazony (Hydra-
1
980, no. 38, pp. 116 121.
. US Patent 4027039, Chem. Abstr., 1977, vol. 87,
3694d.
zones), Nauka, Moscow, 1974, pp. 48 56.
8. Walter, W. and Reubke, K.-J., Chem. Ber., 1970,
3
vol. 103, no. 7, pp. 2197 2207.
. Calnin’ya, I., Vopr. Med. Khim., 1981, vol. 27, no. 6,
9. Stewart, W.E. and Siddal, T.H., Chem. Rev., 1970,
pp. 773 779.
vol. 70, no. 5, pp. 517 551.
. ES Patent 2039161, Chem. Abstr., 1994, vol. 120,
0. Bezhan, I.P., Khrustalev, V.A., Zelenin, K.N., and
Nikolaev, B.P., Zh. Org. Khim., 1978, vol. 14, no. 4,
pp. 754 759.
2
70366f.
. Fiszer-Maliszewska, L., Arch. Immunol. Ther. Exp.,
987, vol. 35, no. 2, pp. 225 235.
1
2
2
1. Zelenin, K.N., Bezhan, I.P., Drabkin, A.E., and Kro-
tova, E.N., Zh. Org. Khim., 1977, vol. 13, no. 8,
pp. 1585 1589.
. Geissler, G., Hippius, M., and Tomaschewski, G.,
J. Prakt. Chem., 1982, vol. 324, no. 6, pp. 910 914.
. Aziz, S.I., Kandeel, Z.E., Husein, M.M., Gohary, S.E.,
and Abou El Maged, E.I., Heteroat. Chem., 1995,
vol. 6, no. 4, pp. 319 323.
2. Bezhan, I.P., Zelenin, K.N., and Pinson, V.V., Zh.
Org. Khim., 1982, vol. 18, no. 3, pp. 493 498.
9
. Reinecke, M.G., Woodrow, T.A., and Brown, E.S.,
J. Org. Chem., 1992, vol. 57, no. 3, pp. 1018 1021.
23. Derome, A.F., Modern NMR Techniques for Chemist-
ry, New York: Pergamon, 1987.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 71 No. 7 2001