Antiradical activity of benzazole-2-thiones

Article abstract of DOI:10.1134/S1070363217090055

Reaction of benzoxazole-2-thione with 3,5-di-tert-butyl-4-hydroxybenzylacetate in methanol affords S-(3,5-di-tert-butyl-4-hydroxybenzyl)-2-mercaptobenzoxazole as the major product. Antiradical activity of S- and N-3,5-di-tert-butyl-4-hydroxybenzyl derivatives of benzothiazole(oxazole, imidazole)-2-thione with respect to 2,2-diphenyl-1-picrylhydrazyl is varies widely. S-Benzyl derivatives exhibit higher reactivity at 30°C.

Full text of DOI:10.1134/S1070363217090055

ISSN 1070-3632, Russian Journal of General Chemistry, 2017, Vol. 87, No. 9, pp. 1919–1923. © Pleiades Publishing, Ltd., 2017.
Original Russian Text © D.R. Gataullina, D.R. Mogilevtseva, G.N. Nugumanova, S.V. Bukharov, R.G. Tagasheva, R.Ya. Deberdeev, 2017, published in
Zhurnal Obshchei Khimii, 2017, Vol. 87, No. 9, pp. 1435–1439.
Dedicated to V. F. Mironov on His 60th Anniversary
Antiradical Activity of Benzazole-2-thiones
D. R. Gataullina, D. R. Mogilevtseva, G. N. Nugumanova*, S. V. Bukharov,
R. G. Tagasheva, and R. Ya. Deberdeev
Kazan National Research Technological University, ul. K. Marksa 68, Kazan, Tatarstan, 420015 Russia
*e-mail: gulia_nn@yahoo.com
Received May 11, 2017
Abstract—Reaction of benzoxazole-2-thione with 3,5-di-tert-butyl-4-hydroxybenzylacetate in methanol
affords S-(3,5-di-tert-butyl-4-hydroxybenzyl)-2-mercaptobenzoxazole as the major product. Antiradical
activity of S- and N-3,5-di-tert-butyl-4-hydroxybenzyl derivatives of benzothiazole(oxazole, imidazole)-2-
thione with respect to 2,2-diphenyl-1-picrylhydrazyl is varies widely. S-Benzyl derivatives exhibit higher
reactivity at 30°С.
Keywords: sterically hindered phenol, benzazole-2-thiones, 2,2-diphenyl-1-picrylhydrazyl, antiradical activity
DOI: 10.1134/S1070363217090055
Derivatives of benzazole-2-thiones are used as ad-
ditives to polymers [1–4] and biologically active sub-
stances [5–9]. N-(3,5-Di-tert-butyl-4-hydroxybenzyl)-
benzothiazole-2-thione is known as an semi-indu-
strially produced antioxidant Agidol-70 [10].
Imidazoline-2-thiones with one or several sterically
hindered para-hydroxyphenyl substituents have been
used as antioxidants for mineral or vegetable oils, fats,
(un)vulcanized rubber, polyurethanes, and polyolefins.
Keeping of a methanol solution of equimolar
amounts of benzyl acetate 1 and benzoxazole-2-thione
at room temperature during 18 days gave a reaction
mixture containing (1H NMR data) 78% of compound
2 [δ(CH2S) 4.53 ppm], 9.5% of unreacted benzyl
acetate 1 [δ(CH2O) 5.04 ppm], 9% of 2,6-di-tert-butyl-
4-methoxymethylphenol 4 [δ(CH2O) 4.37 ppm], and
3.5% of N-(3,5-di-tert-butyl-4-hydroxybenzyl)benzoxa-
zole-2-thione 5 [δ(CH2N) 5.20 ppm] (Scheme 2). Pure
S-(3,5-di-tert-butyl-4-hydroxybenzyl)-2-thiobenzoxa-
zole 2 was obtained via recrystallization from ethanol.
We have earlier reported a method of synthesis of
N- and S- sterically hindered hydroxybenzyl deriva-
tives of benzothiazole(oxazole, imidazole)-2-thiones
via the reaction of these heterocycles with (3,5-di-tert-
butyl-4-hydroxybenzyl) acetate 1 [13]. It should be
noted that the conditions discussed in [13] do not allow
the preparation of S-(3,5-di-tert-butyl-4-hydroxybenzyl)-
2-thiobenzoxazole 2 because of its rapid isomerization
into the N-benzyl derivative. Here we report on the
synthesis of S-benzyl derivative of 2-thio-benzoxazole
2 and the study of antiradical activity of S- and
N-hydroxybenzyl derivatives of benzazole-2-thiones.
It should be noted that the reported method of S-ben-
zylation of benzoxazole-2-thione was not applicable to
benzothiazole(imidazole)-2-thiones. Keeping a metha-
nolic solution of benzyl acetate 1 and benzothiazole-2-
thione at room temperature for 20 days yielded a
mixture containing 7% of 2-(3,5-di-tert-butyl-4-hydroxy-
benzyl)sulfanylbenzothiazole 6 [δ(CH2S) 4.56 ppm],
3% of N-(3,5-di-tert-butyl-4-hydroxybenzyl)benzothia-
zole-2-thione 7 [δ(CH2N) 5.61 ppm], 20% of benzyl
acetate 1 and 70% of phenol 4 (Scheme 3).
In the case of benzimidazole-2-thione, other condi-
tions being the same, a mixture containing 68% of
1-(3,5-di-tert-butyl-4-hydroxybenzyl)benzimidazole-2-
thione 8 [δ(CH2N) 5.44 ppm], 17% of 1,3-bis-(3,5-di-
tert-butyl-4-hydroxybenzyl)-1,3-dihydrobenzimidazole-
2-thione 9 [δ(CH2N) 5.51 ppm], and 15% of phenol 4
It is known that slow dissociation of benzyl acetate
1 dissolved in simplest alcohols affords highly reactive
methylene quinone 3 prone to competitive interactions
with the alcohol and a nucleophile present in the
system (Scheme 1) [14, 15].
1919

1920
GATAULLINA et al.
Scheme 1.
OH
t-Bu
Bu-t
MeOH
O
OH
O
t-Bu
Bu-t
Bu-t
t-Bu
MeOH
CH3
4
NuH
OH
CH2
O
t-Bu
Bu-t
H3C
O
3
1
Nu
Scheme 2.
Bu-t
OH
Bu-t
OH
1
4
Bu-t
N
O
NH
O
N
2
3
MeOH
1
+
4
+
+
S
S
S
O
Bu-t
2
5
Scheme 3.
Bu-t
OH
Bu-t
OH
Bu-t
H
N
N
N
S
MeOH
1
4
+
S +
+
S
S
S
S
Bu-t
7
6
was obtained. When a 1 : 2 mixture of benzimidazole-
2-thione and benzyl acetate 1 was used for the
reaction, compound 9 precipitated (yield 54%). The
filtrate contained 12% of compound 9, 42% of
compound 8, and 46% of phenol 4 (Scheme 4). The 1Н
NMR spectrum of the filtrate after the solvent removal
did not contain signals of the S-benzyl derivative
2-(3,5-di-tert-butyl-4-hydroxybenzyl)sulfanyl-1Н-
benzimidazole 10 {δ(CH2S) 4.73 ppm [13]}).
Thus, the lower reactivity of benzothiazole-2-thione
resulted in the formation of a large amount of phenol 4
(the product of methanol addition to methylene
quinone 3). In the case of benzimidazole-2-thione,
N-benzyl derivatives 8 and 9 were exclusively formed,
apparently due to rapid isomerization of the S-benzyl
derivative 10. The isomerization of compounds 2 and
10 in the methanol solution into the corresponding
N-benzyl derivatives was demonstrated in a special
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ANTIRADICAL ACTIVITY OF BENZAZOLE-2-THIONES
1921
Scheme 4.
Bu-t
Bu-t
OH
OH
Bu-t
Bu-t
NH
NH
N
N
N
MeOH
1
4
+
S
+
+
S
S
NH
Bu-t
8
OH
Bu-t
9
Scheme 5.
Bu-t
OH
Bu-t
OH
Bu-t
t-Bu
t-Bu
Bu-t
N
N
O
MeOH
+
HO
S
S
O
O
CH3
2
5
4
experiment. The isomerization was accompanied by
3,5-di-tert-butyl-4-hydroxybenzyl group elimination
leading to the formation of phenol 4 (Scheme 5).
dical activity of antioxidants for polymers and
lubricating agents should be judged from the activation
energy or the rate constant determined at temperature
close to that of operation. For example, the S-benzyl
derivative 6 exhibited higher antiradical activity
compared to the N-benzyl derivative 7 (Agidol-70) at
Kinetics of the reactions of benzylated benzazole-2-
thiones with a stable radical 2,2-diphenyl-1-picryl-
hydrazyl (DPPH) was studied to determine their
antiradical activity (Scheme 6). It is known that the
reactivity of phenol antioxidants towards DPPH is in
good agreement with their antioxidant activity [16,
17]. The reactions were carried out under the pseudo
first-order conditions with respect to the radical in 1,4-
dioxane. That solvent was chosen since it allows the
reaction to proceed via the radical mechanism. In polar
solvents, ionic or ion-radical mechanisms contribute
significantly [18, 19]. Kinetic parameters of the
studied reactions are given in Tables 1 and 2.
Table 1. Kinetic parameters of the reactions of substituted
benzazole-2-thiones with 2,2-diphenyl-1-picrylhydrazyl in
1,4-dioxane
k2 at 30°С,
Еа,
kJ/mol
ΔS≠,
Compound
L mol–1 s–1
J K–1 mol–1
2
0.05625±0.00089
0.0158±0.00006
0.164±0.0014
0.0346±0.0005
0.0389±0.0002
0.032а
56.7±1.0
38.5±2.5
36.4±0.8
46.1±0.3
34.4±0.4
50.9±1.6
34.2±3.3
–90±3
–161±8
–150±3
–129±6
–167±4
–114±5
–162±11
5
6
7
The obtained data revealed that the series of the
compounds activity estimated from the rate constant at
30°С and the activation energy did not match. Hence,
the commonly determined values of the rate constants
at 20–30°С or half-life of 2,2-diphenyl-1-picrylhyd-
razyl give correct assessment of antioxidant activity of
bioantioxidants used at low temperatures. The antira-
9
10
Ionolb
0.071±0.0006
The value was calculated using the Arrhenius equation. b 2,6-Di-
a
tert-butyl-4-methylphenol.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 87 No. 9 2017

1922
GATAULLINA et al.
Table 2. Logarithms of rate constant of the reactions between compounds 6, 7 and 2,2-diphenyl-1-picrylhydrazyl at different
temperatures
a
ln k2
Compound
30°С
50°С
100°С
150°С
200°С
250°С
6
7
–1.808
–0.915
0.902
2.314
3.384
4.269
–3.364
–2.232
0.070
1.828
3.215
4.336
a The value was calculated using the Arrhenius equation.
30–200°С. The inverse trend was observed at tem-
perature above 250°С.
recrystallized from ethanol. Yield 0.19 g (39%), mp
107–109°С (ethanol). Н NMR spectrum (CDСl3), δ,
1
ppm: 1.46 s (18H, CMe3), 4.54 s (2Н, СН2S), 5.25 s
(1Н, ОН), 7.23–7.35 m (2Н, Н1, Н4), 7.30 s (2Н, ArH),
7.44–7.49 m (1Н, Н2), 7.62–7.68 m (1Н, Н3). Found,
%: С 71.27; H 7.39; N 3.76. C22H27NO2S. Calculated,
%: С 71.51; H 7.36; N 3.79.
As shown in Table 1, the compensation effect was
observed within the series of related compounds [S-
and N-benzylated derivatives of benzothiazole(oxa-
zole, imidazole)-2-thiones]: the activation energy and
the activation entropy were inversely related. In the
cases of compounds 9 and 10, the increase in the ΔS≠
value for the dibenzyl derivative 9 can be caused by
less pronounced free rotation (because of the steric
hindrance) of the species in the activated complex with
bisphenols as compared to monophenols [20].
1,3-Bis(3,5-di-tert-butyl-4-hydroxybenzyl)-1,3-di-
hydrobenzimidazole-2-thione (9). A mixture of 0.1 g
of benzimidazole-2-thione, 0.374 g of benzyl acetate 1,
and 5 mL of methanol was kept at room temperature
for 20 days. The precipitate was filtered off, washed
with methanol, and dried in air. Yield 0.21 g (54%),
mp 243–245°С (mp 244–245°С [13]). 1Н NMR
spectrum (CDСl3), δ, ppm: 1.42 s (36H, CMe3), 5.18 s
(2Н, ОН), 5.52 s (4H, CH2N), 7.12–7.25 m (4Н, ArH),
7.40 s (4H, ArH).
EXPERIMENTAL
The 1H NMR spectra were recorded using a Bruker
AVANCE-600 spectrometer at 600.13 MHz with
respect to residual proton signal of the deuterated
solvents. Elemental analysis was performed using a
EuropaEA-3000 instrument (Europa Vector, Italy).
Kinetics of reaction of benzazole-2-thiones with
2,2-diphenyl-1-picrylhydrazyl was investigated by
means of spectrophotometry using a Lambda 35
(Perkin Elmer) instrument equipped with a Peltier
(Perkin Elmer) heater by monitoring the absorbance of
2,2-diphenyl-1-picrylhydrazyl (λmax 517 nm) in the
course of the process. The starting concentrations of
2,2-diphenyl-1-picrylhydrazyl and benzazole-2-thione
were about 10–5 and 0.01–0.02 mol/L, respectively.
The reaction was carried out until 50% conversion of
2,2-diphenyl-1-picrylhydrazyl. The reference experi-
1,4-Dioxane was purified as described in [21].
2-(3,5-Di-tert-butyl-4-hydroxybenzyl)sulfanylbenz-
oxazole (2). A mixture of 0.2 g of benzoxazole-2-
thione, 0.37 g of benzyl acetate 1, and 10 mL of
methanol was kept at room temperature for 20 days.
The reaction mixture was added to an aqueous solution
of NaCl. The formed precipitate was filtered off,
washed with water and methanol, dried in air, and
Scheme 6.
O
O
O
O
OH
O
N
N
N
t-Bu
Bu-t
t-Bu
Bu-t
+
+
Ph
Ph
HN
N
N
X
X
Ph
Ph
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 87 No. 9 2017

ANTIRADICAL ACTIVITY OF BENZAZOLE-2-THIONES
1923
10.1007/s10593-014-1623-z
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irradiation of the optical cell for 1 h.
10. Zaikin, A.E, Kharitonov, E.A., Kokorev, G.I.,
Badrutdinov, Sh.Kh., Gabutdinov, M.S., Kraev, V.M.,
Ivanov, L.A., and Arkhireev, V.P., Author’s Certificate
1557148, 1990.
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This work was carried out within the framework of
the governmental task of the Ministry of Education and
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