Correlation between the rates of benzylidene condensation of R-tetrazol-1-ylphenylamines and their dissociation constants

Article abstract of DOI:10.1134/S1070427213040101

Benzylidene condensation of R-tetrazol-1-ylphenylamines with 4-fluorobenzaldehyde was studied. The correlation between the logarithm of the rate constant of the condensation of 4-fluorobenzaldehyde with R-tetrazol-1-ylphenylamines and their pK _BH

Full text of DOI:10.1134/S1070427213040101

ISSN 1070-4272, Russian Journal of Applied Chemistry, 2013, Vol. 86, No. 4, pp. 515−519. © Pleiades Publishing, Ltd., 2013.
Original Russian Text © A.V. Pavlov, E.A. Veretennikov, B.M. Laskin, A.G. Egorov, 2013, published in Zhurnal Prikladnoi Khimii, 2013, Vol. 86, No. 4,
pp. 552−557.
ORGANIC SYNTHESIS
AND INDUSTRIAL ORGANIC CHEMISTRY
Correlation between the Rates of Benzylidene Condensation
of R-Tetrazol-1-ylphenylamines
and Their Dissociation Constants
A. V. Pavlova, E. A. Veretennikovb, B. M. Laskina, and A. G. Egorovc
a Applied Chemistry Russian Research Center, St. Petersburg, Russia
e-mail: anton_pawlow@mail.ru
b Chemical-Pharmaceutical Technologies, Company Limited, St. Petersburg, Russia
c Research Institute of Synthetic Rubber, St. Petersburg, Russia
Received January 28, 2013
Abstract—Benzylidene condensation of R-tetrazol-1-ylphenylamines with 4-fluorobenzaldehyde was studied.
The correlation between the logarithm of the rate constant of the condensation of 4-fluorobenzaldehyde with R-
tetrazol-1-ylphenylamines and their рKВН+ values was found. The reaction constant ρ in the Hammett equation
was determined.
DOI: 10.1134/S1070427213040101
was studied in sufficient detail [3]; as applied to the
compounds under consideration, without introduction of
additional catalysts, it follows Scheme 2.
It was noted previously [1] that (4-fluorobenzyl)
(R-tetrazol-1-ylphenyl)amines (1) (R = H) (Scheme 1)
exhibit potential biological activity. It is known that
introduction of substituents with pharmacophore
properties (CH3, OCH3, Cl) enhances the biological
activity [2]:
In this study, continuing our previous work [1], we
examined the kinetics of the benzylidene condensation
and determined the correlation between the logarithm
of the rate constant of the condensation of R-tetrazol-1-
ylphenylamines 2–14 with 4-fluorobenzaldehyde 15 and
рKBH+ of R-tetrazol-1-ylphenylamines 2–14.
Scheme 1.
R
N
N
N
EXPERIMENTAL
N
H
N
R-Tetrazol-1-ylphenylamines 2–14 with which the
condensation was performed were no less than 99.9 mol %
pure, according to NMR data. 4-Fluorobenzaldehyde
(CAS 459-57-4, Acros Organics) was freshly distilled.
The benzene used for the study was of ultrapure grade.
F
1
where R = H, CH3, OCH3, Cl.
The intermediates for the synthesis of compounds 1,
(4-fluorobenzylidene)(tetrazol-1-ylphenyl)amines 16–28
(Scheme 2), were prepared by benzylidene condensation
of R-tetrazol-1-ylphenylamines 2–14 with 4-fluorobenz-
aldehyde 15. Compounds 4, 5, and 14 were prepared and
described previously [1].
1
The Н NMR spectra were recorded with a Bruker
WM-400 spectrometer (400 MHz) from solutions in
DMSO-d6, the elemental analysis was performed with
a Hewlett–Packard 185B analyzer, and the UV spectro-
photometric analysis was performed with a Shimadzu
The mechanism of the benzylidene condensation
515

516
PAVLOV et al.
Scheme 2.
O
R
R
O_
H
H
N
N
N
N
+
N
N
+
N
N
NH2
N
F
12_14
15
H
H
F
R
R
OH
H
H
N
N
+ OH_
N
N
+
N
N
N
N
N
H
N
H
F
F
R
N
+ H2O
N
N
N
N
F
16_28
R = 4-OCH3-3-tetr (2), 3-CH3-4-tetr (3), 4-tetr (4), 3-tetr (5), 3-OCH3-4-tetr (6), 4-Cl-3-tetr (7), 2-OCH3-4-tetr (8), 2-OCH3-
5-Tetr (9), 2-CH3-4-tetr (10), 2-CH3-5-tetr (11), 2-Cl-4-tetr (12), 2-Cl-5-tetr (13), 2-Tetr (14).
UV-1800 device (cell thickness 1 cm).
Because the time required for complete conversion of
R-tetrazol-1-ylphenylamines 8–13 under the conditions
The rate constants of the condensation of R-tetrazol-1-
ylphenylamines 2–14 with 4-fluorobenzaldehyde 15 were
determined in benzene at 75°С and equimolar reactant
ratio. The concentration of the starting amines was 1.55
× 10–2 M. Kinetic analysis was performed with a UV
spectrophotometer (analytical wavelength 277–330 nm
depending on the optical properties of the particular
compound) by taking samples of the reaction mixture.
The experimentally determined extinction coefficient
and analytical wavelength for each compound are given
in Table 1.
Table 1.Analytical wavelengths and extinction coefficients
for (4-fluorobenzylidene)(R-tetrazol-1-ylphenyl)amines
Compound
λanal, nm
ε × 10–4, L mol–1 cm–1
16
17
18
19
20
21
22
23
24
25
26
27
28
321
277
325
278
277
281
324
335
327
330
323
321
300
1.27
1.69
2.48
1.29
1.58
1.35
1.22
1.13
0.97
1.04
0.85
0.97
0.93
The kinetic curves were plotted with respect to ac-
cumulation of the reaction product. The concentrations
were calculated by the formula
Dτ
с = —– ,
(1)
εd
where Dτ is the optical density corresponding to accumu-
lation of (4-fluorobenzylidene)(R-tetrazol-1-ylphenyl)
amine, determined at definite intervals during the experi-
ment; ε is the extinction coefficient of (4-fluorobenzyli-
dene)(R-tetrazol-1-ylphenyl)amine (L mol–1 cm–1); and
d is the cell thickness (cm).
RUSSIAN JOURNAL OF APPLIED CHEMISTRY Vol. 86 No. 4 2013

CORRELATION BETWEEN THE RATES OF BENZYLIDENE CONDENSATION
517
N 23.49. С15H12FN5O. Calculated, %: C 60.60, H 4.07,
N 23.56.
of the kinetic experiment can be as long as 14 days, the
measurements were performed in the initial portion of the
kinetic curve, from 0 to 10% (inclusive) of the theoretical
yield of the reaction product.
(4-Fluorobenzylidene)(4-chloro-3-tetrazol-1-ylphe-
nyl)amine 21. Yield 97%. 1Н NMR spectrum (DMSO-
d6), δ, ppm, J, Hz: 6.79 m (2Н, Н-5, Н-6), 7.28–7.31 m
(1Н, Н-2); 7.36–7.40 (Н-3', H-5'); 7.98–8.02 m (2Н, Н-2',
H-6'); 9.74 s (1Н, N=CH); 9.98 s (1Н, СНtetr). Found, %:
С 55.79, Н 3.10, N 23.14. С14H9ClFN5. Calculated, %:
С 55.73, Н 3.01, N 23.21.
Because the condensation of R-tetrazol-1-ylphenyl-
amines with 4-fluorobenzaldehyde occurs as bimolecular
nucleophilic substitution [3], the observed reaction rate
constants k (L mol–1 s–1) were calculated by the second-
order equation
(4-Fluorobenzylidene)(2-methoxy-4-tetrazol-1-
ylphenyl)amine 22. Yield 97%. Н NMR spectrum
cτ
1
k = ——————— ,
τcfin(сfin – сτ)
(2)
(DMSO-d6), δ, ppm, J, Hz: 3.92 s (3Н, OCH3); 7.13 d
(1Н, J6,5 = 8.68); 7.31–7.35 m (2Н, H-3', H-5'); 7.77 d
(1Н, J3,5 = 2.70, Н-3); 7.91 dd (1Н, J5,3 = 2.70, J5,6 = 8.68,
Н-5); 7.98–8.02 m (2Н, H-2', H-6'); 8.54 s (1Н, N=CH);
9.76 s (1Н, СНtetr). Found, %: С 60.52, H 4.01, N 23.67.
С15H12FN5O. Calculated, %: C 60.60, H 4.07, N 23.56.
where τ is time (s); cfin, final concentration of (4-fluo-
robenzylidene)(R-tetrazol-1-ylphenyl)amine (M); and
cτ, running concentration of (4-fluorobenzylidene)(R-
tetrazol-1-ylphenyl)amine (M).
(4-Fluorobenzylidene)(2-methoxy-5-tetrazol-1-
ylphenyl)amine 23. Yield 96%. Н NMR spectrum
General procedure of the synthesis of (4-fluoroben-
zylidene)(R-tetrazol-1-ylphenyl)amines. Compounds
16–28 were prepared by condensation of equimolar
amounts of 4-fluorobenzaldehyde and appropriate R-
tetrazol-1-ylphenylamine in benzene, following the
previously described procedure [1]. The compounds
were identified by 1Н NMR spectroscopy and elemental
analysis.
1
(DMSO-d6), δ, ppm, J, Hz: 3.91 s (3Н, ОСН3); 7.28 d
(1Н, J3,4 = 8.80, Н-3); 7.32–7.36 m (2Н, Н-3', Н-5');
7.60 d (1Н, J6,4 = 2.76, Н-6); 7.71 dd (1Н, J4,3 = 8.80,
J4,6 = 2.76, Н-4); 7.98–8.04 m (2Н, H-2', H-6'); 8.61 s
(1Н, N=CH); 9.99 s (1Н, СНtetr). Found, %: С 60.69, H
3.99, N 23.61. С15H12FN5O. Calculated, %: C 60.60, H
4.07, N 23.56.
(4-Fluorobenzylidene)(4-methoxy-3-tetrazol-1-
1
(4-Fluorobenzylidene)(2-methyl-4-tetrazol-1-
ylphenyl)amine 16. Yield 98%. Н NMR spectrum
1
ylphenyl)amine 24. Yield 98%. Н NMR spectrum
(DMSO-d6), δ, ppm, J, Hz: 3.92 s (3Н, ОСН3); 7.26–7.30
m (2Н, H-3’, H-5’); 7.38 d (1Н, J5,6 = 8.44, H-5); 7.52
(DMSO-d6), δ, ppm, J, Hz: 2.43 (3Н, s, СН3); 7.28 d (1Н,
J6,5 = 8.28, Н-6); 7.33–7.37 m (2Н, Н-3', Н-5'); 7.77 dd
dd (1H, J6,2 = 2.44, J6,5 = 8.44, H-6); 7.68 d (1H, J2,6
=
(1Н, J5,3 = 2.48, J5,6 = 8.28, Н-5); 7.83 d (1Н, J3,5 = 2.48,
Н-3); 8.03–8.07 m (2Н, Н-2', Н-6'); 8.56 s (1Н, N=CH);
10.03 s (1Н, СНtetr). Found, %: С 63.97, H 4.39, N 25.01.
С15H12FN5. Calculated, %: C 64.05, H 4.30, N 24.90.
2.44, H-2); 7.97–8.00 m (2Н, H-2’, H-6’); 8.70 s (1Н,
N=CH); 9.73 s (1Н). Found, %: С 60.73, H 3.95, N 23.51.
С15H12FN5O. Calculated, %: C 60.60, H 4.07, N 23.56.
(4-Fluorobenzylidene)(3-methyl-4-tetrazol-1-
1
(4-Fluorobenzylidene)(2-methyl-5-tetrazol-1-
ylphenyl)amine 17. Yield 99%. Н NMR spectrum
1
ylphenyl)amine 25. Yield 97%. Н NMR spectrum
(DMSO-d6), δ, ppm, J, Hz: 2.19 s (3Н, СН3); 7.25–7.33
m (4Н, Н-2, Н-6, Н-3', Н-5'); 7.50 d (1Н, J5,6 = 8.36,
Н-5); 8.00–8.03 m (2Н, Н-2', H-6'); 8.64 s (1Н, N=CH);
9.74 s (1Н, СНtetr). Found, %: С 64.12, H 4.24, N 24.82.
С15H12FN5. Calculated, %: C 64.05, H 4.30, N 24.90.
(DMSO-d6), δ, ppm, J, Hz: 2.40 s (3Н, CH3); 7.34–7.38
m (2Н, H-3', H-5'); 7.44 (1Н, J4,3 = 8.08, J4,6 = 2.18, Н-4);
7.52–7.56 m (2Н, Н-3, Н-6); 8.05–8.09 m (2Н, H-2',
H-6'); 8.47 s (1Н, N=CH); 10.07 s (1Н, СНtetr). Found,
%: С 64.15, H 4.37, N 24.79. С15H12FN5. Calculated, %:
C 64.05, H 4.30, N 24.90.
(4-Fluorobenzylidene)(3-methoxy-4-tetrazol-1-
1
ylphenyl)amine 20. Yield 99%. Н NMR spectrum
(DMSO-d6), δ, ppm, J, Hz: 3.93 s (3Н, ОСН3); 7.00 dd
(1Н, J6,2 = 1.96, J6,5 = 8.36, Н-6); 7.17 d (1Н, J2,6 = 1.96,
(4-Fluorobenzylidene)(2-chloro-4-tetrazol-1-ylphe-
nyl)amine 26. Yield 97%. 1Н NMR spectrum (DMSO-
d6), δ, ppm, J, Hz: 6.95 d (1Н, J6,5 = 8.76, H-6); 7.32–7.36
m (2Н, H-3’, H-5’); 7.52 dd (1Н, J5,3 = 2.28, J5,6 = 8.76,
H-5); 7.75 d (1Н, J3,5 = 2.28, H-3); 8.06–8.09 m (2Н,
H-2); 7.30–7.34 m (2Н, Н-3', Н-5'); 7.68 d (1Н, J5,6
=
8.36, H-5); 8.00–8.04 m (2Н, Н-2', Н-6'); 8.68 s (1Н,
N=CH); 9.68 s (1Н, СНtetr). Found, %: С 60.49, H 4.19,
RUSSIAN JOURNAL OF APPLIED CHEMISTRY Vol. 86 No. 4 2013

518
PAVLOV et al.
H-2’, H-6’); 8.63 s (1Н, N=CH); 10.11 s (1Н, СНtetr).
Found, %: С 55.67, Н 2.95, N 23.16. С14H9ClFN5. Cal-
culated, %: С 55.73, Н 3.01, N 23.21.
2
(4-Fluorobenzylidene)(2-chloro-5-tetrazol-1-
1
ylphenyl)amine 27. Yield 98%. Н NMR spectrum
(DMSO-d6), δ, ppm, J, Hz: 7.32–7.40 m (3Н, Н-4,
Н-3', H-5'); 7.74 (1Н, J3,4 = 8.52, Н-3); 7.86 (1Н, J6,4
=
2.52, Н-6); 8.06–8.10 m (2Н, Н-2', H-6'); 8.68 s (1Н,
N=CH); 10.10 s (1Н, СНtetr). Found, %: С 55.80, Н 3.08,
N 23.27. С14H9ClFN5. Calculated, %: С 55.73, Н 3.01,
N 23.21.
Fig. 1. Correlation between the logarithm of the condensation
rate constant and pKBH+ of R-tetrazol-1-ylphenylamines 2–14.
The logarithms of the rate constants of the condensa-
tion in benzene and the рKBH+ values of the correspond-
ing R-tetrazol-1-ylphenylamines are given in Table 2.
logkI = 1.5637рKBH+ – 7.7711 (R2 = 0.9983),
logkII = 1.4676рKBH+ – 8.0673 (R2 = 0.9992).
(3)
(4)
Analysis of the plot of the logarithm of the condensa-
tion rate constant vs. рKBH+ of R-tetrazol-1-ylphenyl-
amines (Fig. 1) allows us to subdivide the compounds
studied into three groups.
Compounds 8 and 9, which are structurally similar
to compounds of the second group, are not described
by Eq. (4). This is probably due to the presence of the
methoxy group, which exhibits strong electron-donor ef-
fect leading to increased values of рKBH+. Furthermore,
the methoxy group in compounds 8 and 9 apparently
produces considerably stronger steric hindrance to the
reaction (Scheme 2), compared to the methyl group and
chlorine atom (compounds 10–13).
The first group includes compounds 2–7, i.e., R-
tetrazol-1-ylphenylamines containing no substituents in
the phenyl ring in the o-position to the amino group. The
second group includes compounds 10–13, i.e., R-tetrazol-
1-ylphenylamines containing the tetrazole ring in the
m- or p-position and the methyl group or Cl atom in the
o-position to the amino group. The third group includes
R-tetrazol-1-ylphenylamines 8, 9, and 14.
The presence of the tetrazole ring, which is a strong
electron acceptor, in the o-position to the amino group
in compound 14 leads to considerably lower value of its
рKBH+ compared to the other tetrazol-1-ylphenylamines
4 and 5.
For the first and second groups of compounds, the
correlation between the logarithm of the rate constant of
the benzylidene condensation and the рKBH+ values of the
corresponding R-tetrazol-1-ylphenylamines is described
by linear equations (3) and (4), respectively:
Table 2. рKBH+ values of R-tetrazol-1-ylphenylamines and logarithms of the rate constants of their condensation with
4-fluorobenzaldehyde
Compound
рKBH+ (water, 25°С)
logkII (benzene, 75°С)
4-Methoxy-3-tetrazol-1-ylphenylamine 2
3-Methyl-4-tetrazol-1-ylphenylamine 3
4-Tetrazol-1-ylphenylamine 4
3.49
3.18
3.13
3.10
2.96
2.76
3.44
3.24
2.87
2.81
2.71
2.60
2.49
–2.32
–2.77
–2.89
–2.93
–3.14
–3.46
–3.71
–3.89
–3.85
–3.95
–4.09
–4.25
–3.06
3-Tetrazol-1-ylphenylamine 5
3-Methoxy-4-tetrazol-1-ylphenylamine 6
4-Chloro-3-tetrazol-1-ylphenylamine 7
2-Methoxy-4-tetrazol-1-ylphenylamine 8
2-Methoxy-5-tetrazol-1-ylphenylamine 9
2-Methyl-4-tetrazol-1-ylphenylamine 10
2-Methyl-5-tetrazol-1-ylphenylamine 11
4-Chloro-4-tetrazol-1-ylphenylamine 12
2-Chloro-5-tetrazol-1-ylphenylamine 13
2-Tetrazol-1-ylphenylamine 14
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CORRELATION BETWEEN THE RATES OF BENZYLIDENE CONDENSATION
519
Table 3. Total values of the Hammett σ constants for
disubstituted R-tetrazol-1-ylphenylamines 3, 4, and 6
σ
Σσ
Compound
m-
p-
3-Methyl-4-tetrazol-1-
ylphenylamine 3
–0.069 0.52 0.451
0.52 0.52
0
4-Tetrazol-1-ylphenylamine 4
Fig. 2. Correlation between the logarithm of the condensation
+0.111 0.52 0.635
rate constant and Hammett σ constants for R-tetrazol-1-
ylphenylamines in which the tetrazole ring is in the p-position
relative to the amino group.
3-Methoxy-4-tetrazol-1-
ylphenylamine 6
1-ylphenylamines.
CONCLUSIONS
It is known [4] that the condensation of substituted
anilines with benzaldehyde is fairly highly sensitive to
the nature of substituent in the phenyl ring, as judged
from the reaction constant ρ, which is equal to –2.004 for
the reaction under consideration. Thus, it is important to
determine the effect of the tetrazolyl substituent in the
phenyl ring of aniline on ρ of this reaction.
(1) The logarithms of the rate constants of the con-
densation of 4-fluorobenzaldehyde with R-tetrazol-1-
ylphenylamines 2–7 linearly correlate with their рKBH
+
values. The correlation is described by Eq. (3). For o-
substituted R-tetrazol-1-ylphenylamines 8–14, there is
no common correlation.
(2) The quantitative ρ–σ correlation for R-tetrazol-1-
ylphenylamines 3, 4, and 6 was constructed. The reaction
constant ρ of the condensation of 4-fluorobenzaldehyde
with R-tetrazol-1-ylphenylamines was found to be equal
to –2.024.
It is known that the logarithms of the rate constants
of the condensation of substituted anilines with benzal-
dehyde correlate with the Hammett σ constants of the
corresponding substituents [4].Along with the σ constants
of the methyl and methoxy groups [5], the σ constants are
known for the tetrazole ring in the p-position to the reac-
tion center [6]. Because the effect of several substituents
in the benzene ring is additive [5] [Eq. (5)], it is possible
to determine quantitatively the effect of substituents on
the reaction center in compounds 3, 4, and 6 (Table 3):
REFERENCES
1. Pavlov, A.V., Veretennikov, E.A., and Laskin, B.M., Izv.
Sankt-Peterb. Gos. Tekhnol. Inst. (Tekh. Univ.), 2012, no. 17,
pp. 48–50.
log(k/k0) = ρΣσ.
(5)
The quantitative ρ–σ correlation shown in Fig. 2 is
linear. The reaction constant ρ quantitatively character-
izing the relative sensitivity of the reaction of R-tetrazol-
1-ylphenylamines 3, 4, and 6 with 4-fluorobenzaldehyde
to variation of the starting compound structure is –2.024.
This value is close to the value of ρ for monosubstituted
anilines in benzene [6], indicating that introduction of
the tetrazole ring into the p-position of aniline does
not appreciably affect the correlation of the reaction
constant with рKBH+ in going from anilines to tetrazol-
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pp. 4029–4031.
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RUSSIAN JOURNAL OF APPLIED CHEMISTRY Vol. 86 No. 4 2013