Inhibiting effect of 6-methyluracil derivatives on the free-radical oxidation of 1,4-dioxane

Article abstract of DOI:10.1007/s11172-010-0138-8

The antioxidation activity of 5-substituted 6-methyluracils was quantitatively estimated in the model system of initiated radical-chain oxidation of 1,4-dioxane. The rate constants of the reactions of 1,4-dioxane peroxide radicals with 6-methyluracil (1), 6-methyl-5-piperidino- uracil (2), 6-methyl-5-morpholinomethyluracil (3), 6-methyl-5-morpholinouracil (4), 6-me- thyl-5-methylaminouracil (5), 5-ethylamino-6-methyluracil (6), and 5-hydroxy-6-methyluracil (7) were measured. Among compounds 1-7, derivative 7 is most efficient with an inhibition rate constant of (5.2±0.1)·104 L mol-1 s-1 (60 °C).

Full text of DOI:10.1007/s11172-010-0138-8

Russian Chemical Bulletin, International Edition, Vol. 59, No. 3, pp. 517—521, March, 2010
517
Inhibiting effect of 6ꢀmethyluracil derivatives
on the freeꢀradical oxidation of 1,4ꢀdioxane
L. R. Yakupova, A. V. Ivanova, R. L. Safiullin, A. R. Gimadieva,
Yu. N. Chernyshenko, A. G. Mustafin, and I. B. Abdrakhmanov
Institute of Organic Chemistry, Ufa Research Center of the Russian Academy of Sciences,
71 prosp. Oktyabrya, 450054 Ufa, Russian Federation.
Fax: +7 (347) 235 6066. Eꢀmail: jkupova@anrb.ru
The antioxidation activity of 5ꢀsubstituted 6ꢀmethyluracils was quantitatively estimated in
the model system of initiated radicalꢀchain oxidation of 1,4ꢀdioxane. The rate constants of the
reactions of 1,4ꢀdioxane peroxide radicals with 6ꢀmethyluracil (1), 6ꢀmethylꢀ5ꢀpiperidinoꢀ
uracil (2), 6ꢀmethylꢀ5ꢀmorpholinomethyluracil (3), 6ꢀmethylꢀ5ꢀmorpholinouracil (4), 6ꢀmeꢀ
thylꢀ5ꢀmethylaminouracil (5), 5ꢀethylaminoꢀ6ꢀmethyluracil (6), and 5ꢀhydroxyꢀ6ꢀmethyluracil
(7) were measured. Among compounds 1—7, derivative 7 is most efficient with an inhibition
rate constant of (5.2 0.1)•104 L mol–1 s–1 (60 °C).
Key words: radical chain oxidation, inhibition rate constant, 5ꢀhydroxyꢀ6ꢀmethyluracil.
duced pressure and by the precipitation of the product with ethaꢀ
nol. 6ꢀMethylꢀ5ꢀmethylaminouracil (5) and 5ꢀethylaminoꢀ6ꢀ
methyluracil (6) were synthesized by heating of a mixture of
5ꢀbromoꢀ6ꢀmethyluracil (0.05 mol) and the corresponding amine
hydrochloride in an aqueous solution of potassium hydroxide in
an autoclave for 7 h at 160 °C followed by cooling of the reaction
mixture and separation of the precipitate formed. 6ꢀMethylꢀ5ꢀ
morpholinomethyluracil (3) was synthesized by the reflux of
a mixture of 6ꢀmethyluracil (0.05 mol), morpholine (0.05 mol),
and 31% formalin (6.7 mL) in ethanol (150 mL) for 6 h with the
separation of the precipitate formed from the cooled reaction
mixture. The yields of compounds 2—6 after recrystallization
from ethanol were 75, 86, 54, 69, and 64%, respectively.
1H and 13C NMR spectra of compounds 2—6 were recorded
on a Bruker AMꢀ300 instrument in DMSOꢀd6 using Me4Si as an
internal standard. IR spectra of suspensions of the substances in
Nujol were obtained on a Specord URꢀ20 spectrometer (Carl
Zeiss Jena) equipped with NaCl and LiF prisms. The UV spectra
of 0.00001% solutions were recorded on a Specord Mꢀ400 inꢀ
strument in the range of 200—350 nm in a 10ꢀmm optical cell.
Melting points were determined on a Boetius heating stage. The
physicochemical and spectral characteristics of compounds
2—6 are given in Table 1.
Uracil derivatives are used in medicines as drugs with
a wide range of pharmacological activity associated, in
particular, with the antiradical properties of these comꢀ
pounds. The inhibiting effect of 6ꢀmethyluracil (1) and its
5ꢀsubstituted derivatives 2—7 on the oxidation process
was quantitatively estimated in the present work. The initiꢀ
ated radicalꢀchain oxidation of 1,4ꢀdioxane was chosen as
a model system to solve this problem.1 The inhibition rate
constants were measured. The influence of substituents in
position 5 of the 6ꢀmethyluracil cycle on the antioxidation
activity was analyzed.
Experimental
The initiator was AIBN. The initiation rate was calculated
by the equation
1,4ꢀDioxane was purified by multiple fractional distillation
over potassium hydroxide. Azobis(isobutyronitrile) (AIBN) was
twice recrystallized from freshly distilled ethanol and then dried
in vacuo.
wi = 2ekd[AIBN]
6ꢀMethyluracil (1) (JointꢀStock Company "Farmakon") was
used as received. 5ꢀHydroxyꢀ6ꢀmethyluracil (7) was synthesized
and purified according to the known procedure.2
6ꢀMethylꢀ5ꢀpiperidinouracil (2) and 6ꢀmethylꢀ5ꢀmorpholiꢀ
nouracil (4) were synthesized by the reflux of 5ꢀbromoꢀ6ꢀmethꢀ
yluracil (0.01 mol) in morpholine or piperidine excess (0.5 mol),
respectively, followed by the removal of the solvent under reꢀ
using the rate constant for AIBN decomposition (kd) in cycloꢀ
hexanol (logkd = 17.70 – 35/(4.575T•10–3), e = 0.5). The choꢀ
sen kd value is satisfactorily consistent with the rate constants for
AIBN decomposition in 1,4ꢀdioxane measured from the rate of
nitrogen evolution.3
1,4ꢀDioxane was oxidized with air oxygen at 60 °C in a glass
reactor. The reactor was loaded with a solution of the initiator in
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 507—511, March, 2010.
1066ꢀ5285/10/5903ꢀ0517 © 2010 Springer Science+Business Media, Inc.

518
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 3, March, 2010
Yakupova et al.
Table 1. Physicochemical and spectral characteristics of compounds 2—6
Comꢀ M.p.
pound /°C
Found
Calculated
Empirical
formula
UV*,
IR,
ν/cm–1
NMR, δ
(%)
N
λ
λ
/
min max
1H
13C
/nm
C
H
2
3
4
215— 57.78 7.95 20.42 C10H15N3O2 234/262 1116—1263 (=N—), 1.65 (t, 2 H, C(11)H2,
—217 57.40 7.23 20.08 1377 (СН3), 1456 J = 5.8); 1.82 (q, 4 H,
(СН2), 1647 (С=С), C(8)H2, C(10)H2,
14.78 (C(6)CH3);
24.62 (C(9));
27.62 (C(8), C(10));
51.80 (C(7), C(11));
1662, 1762 (С=О),
2852, 2920 (СН),
3109, 3159 (NH),
3213 (=N—)
J = 5.8); 2.20 (s, 3 H,
С(6)CH3); 3.20 (t, 4 H, 123.02 (C(5));
C(7)H2, C(11)H2,
J = 5.5); 10.10 (br.s,
2 H, N(1)H, N(3)H)
150.40 (C(6));
151.33 (C(2)=O);
163.40 (C(4)=O)
—
269— 53.83 6.95 18.58 C10H15N3O3 234/266 1002—1244 (=N—), 2.26 (s, 3 H, С(6)CH3);
—271 53.32 6.71 18.66
1377 (СH3), 1113
(С—О—С), 1448,
1460 (СH2), 1645
(С=С), 1660, 1726
(С=О), 2852, 2920
(СH), 3136, 3199
2.36 (t, 4 H, C(8)H2,
C(10)H2, J = 4.4); 3.22
(s, 2 H, C(7)H2); 3.55
(t, 4 H, C(9)H2,
C(11)H2, J = 5.6);
10.90 (br.s, 2 H,
(NH), 3267 (=N—) N(1)H, N(3)H)
205— 51.78 5.95 20.02 C9H13N3O3 246/267 1093—1228 (=N—), 2.10 (s, 3 H, С(6)CH3); 16.54 (C(6)CH3);
—207 51.18 6.20 19.89
1111 (С—О—С),
1379 (СH3), 1455
(СH2), 1651 (С=С), (t, 4 H, C(7)H2,
3.07 (t, 4 H, C(9)H2,
C(10)H2, J = 4.7); 3.75
53.91 (C(7), C(8));
67.32 (C(9), C(10));
105.97 (C(5));
1664, 1732 (С=О),
2852, 2921 (СH),
3109, 3157 (NH),
3209 (=N—)
C(8)H2, J = 4.7);
10.80 (br.s, 2 H,
N(1)H, N(3)H)
151.61 (C(6));
151.59 (C(2)=O);
160.18 (C(4)=O)
5
6
175— 46.83 5.95 27.42 C6H9N3O2
—177 46.45 5.85 27.08
253/284 1037—1247 (=N—), 2.05 (s, 3 H, С(6)CH3);
1377 (СH3), 1458 2.45 (s, 3 H, CH3);
(СH3), 1649 (С=С), 3.40 (br.s, 1 H,
—
1670, 1735 (С=О),
2852, 2924 (СH),
3034, 3196 (NH),
3321, 3344 (NH)
NHC(5)); 10.40
(br.s, 1 H, N(1)H);
11.00 (br.s, 1 H,
N(3)H)
219— 49.83 6.95 24.42 C7H11N3O2 253/285 1012—1234 (=N—), 1.00 (t, 3 H, CH3NH,
—
—221 49.70 6.55 24.84
1377 (СH3), 1446,
1460 (СH2, СH3),
1631 (С=С), 1654,
1734 (С=О), 2852,
2922 (СH), 3070
(NH), 3213, 3323
(NH)
J = 7.1); 2.00 (s, 3 H,
С(6)CH3); 2.70 (q,
2 H, C(7)H, J = 7.1);
3.10 (br.s, 1 H, NH);
10.40 (br.s, 1 H,
N(1)H); 11.00 (br.s,
1 H, N(3)H)
* In EtOH.
1,4ꢀdioxane, and the temperature was maintained constant for
several minutes. Then the inhibitor in a 1,4ꢀdioxane solution
was added, and the oxygen absorption in the gas phase was monꢀ
itored using a universal manometric differential setup. The meaꢀ
surement part of the setup was a highly sensitive differential
pressure gauge based on a silicon membrane cell. Two reactors
were attached to the pressure gauge; one of them was the workꢀ
ing reactor. The reactors were disconnected during measureꢀ
ments, the change in the gas pressure in the working reactor was
detected using a microprocessor device, and the results were
transmitted to a computer for processing. Oxygen absorption
rate in the liquid phase was calculated as described earlier.4 The
rate of 1,4ꢀdioxane oxidation (w) was determined from initial
part of the kinetic curve for oxygen absorption.
Results and Discussion
The liquidꢀphase oxidation of 1,4ꢀdioxane (RH)
under our experimental conditions (60 °C, wi
=
= 5.3•10–8 mol L–1 s–1) proceeds via the radicalꢀchain
mechanism with square chain termination.1
AIBN
r•
R•
R• + O2
RO2
•
RO2• + RH
RO2• + RO2
ROOH + R•
•
Molecular products

Inhibition effect of methyluracil derivatives
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 3, March, 2010
519
w•10–7/mol L–1 s–1
F
The introduction of 6ꢀmethyluracils (InH) into the
oxidized substrate decreases the oxygen absorption rate
due to the appearance of an additional channel of conꢀ
sumption of peroxide radicals
10
8
6
RO2• + InH
ROOH + In•,
•
In• + RO2
Inactive products.
4
2
6
As can be seen from the experimental data, in the presꢀ
ence of 6ꢀmethyluracils in a medium of oxidized 1,4ꢀdiꢀ
oxane, the chain length is at least five units and, hence,
the chain regime is retained. In this case, the following
equation is appropriate for the quantitative estimation of
the inhibition efficiency5:
4
2
0.0002 0.0004 0.0006 0.0008
[7]/mol L–1
Fig. 1. Oxygen absorption rate (w) during 1,4ꢀdioxane oxidation
and inhibiting effect parameter (F) vs 5ꢀhydroxyꢀ6ꢀmethyluracil
(7) concentration (r = 0.98, 60 °C, wi = 5.3•10–8 mol L–1 s–1).
F = w0w–1 – w(w0)–1 = fk7[InH]0(2k6wi)–0.5
,
(1)
where w0 and w are the initial rates of oxygen absorption in
the absence and in the presence of 6ꢀmethyluracils, reꢀ
spectively, mol L–1 s–1; [InH]0 is the initial concentration
of 6ꢀmethyluracils, mol L–1; 2k6 and fk7 are the rate conꢀ
stants for oxidation chain termination in the reaction of
recombination of 1,4ꢀdioxane peroxide radicals and on
inhibitor molecules, respectively, mol L–1 s–1; f is the
stoichiometric inhibition factor.
The typical dependence of the initial rate for 1,4ꢀdiꢀ
oxane oxidation on the 6ꢀmethyluracil concentration
and the results of experimental data processing by Eq. (1)
are shown in Fig. 1. The observed satisfactory linear
dependence of the F parameter on the concentration
of compound 7 makes it possible to quantitatively estimate
the efficiency of 6ꢀmethyluracil as an inhibitor of
1,4ꢀdioxane oxidation. The rate constants (fk7) obꢀ
tained for compounds 1—7 studied as inhibitors are listed
in Table 2 (it was accepted in the calculation that 2k6 =
= 109 mol L–1 s–1).1
inhibitor molecules and radicals. Then the inhibitor is conꢀ
sumed with a constant rate
wInH = f –1wi.
In this case, at wi = const the inhibition time (induction
period τ) is as follows:
τ = f[InH]0(wi)–1
.
(2)
In the case of long chains, the following equation is
valid for the reaction rate:
w = –d[O2](dt)–1 = wik2[RH](fk7[InH])–1
.
(3)
For a given time t, Eq. (2) can be written as
t = f([InH]0 – [InH])(wi)–1
.
(4)
If the inhibited oxidation rate w is much lower than w0,
it can be assumed that almost all chains terminate on the
After substituting [InH] from Eq. (4) to Eq. (3)
and integrating, the following equation can be obꢀ
Table 2. Rate constants for the reactions of the peroxide radicals of 1,4ꢀdioxane with 6ꢀmethyꢀ
luracil (1) and its 5ꢀsubstituted derivatives 2—7 (InH) (60 °C, wi = 5.3•10–8 mol L–1 s–1
)
а
b
c
InH
[InH]
/mol L–1
fk7
fk7
k7
L mol–1 s–1
1
2
3
4
5
6
7
(0.065—7.0)•10–3
(0.065—2.9)•10–3
(0.1—7.6)•10–4
(0.19—8.5)•10–3
(3.0 15.0)•10–3
(1.7 7.0)•10–3
(4.4 0.6)•102
(5.3 0.3)•103
(2.5 0.2)•103
(2.4 0.2)•103
(3.8 0.4)•103
(4.6 0.1)•103
(5.2 0.1)•104
—
—
4.7•103
1.9•103
—
—
(3.7 0.5)•103
(3.8 0.4)•103
(6.0 0.4)•103
(6.3 0.2)•104
(1.8 0.2)•103
(1.5 0.1)•103
(2.8 0.2)•103
(3.4 0.3)•104
(0.0068—10.3)•10–4
a Calculated by Eq. (1).
b Calculated by Eq. (3).
c Calculated by Eq. (5).

520
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 3, March, 2010
Yakupova et al.
tained for low hydrocarbon conversions ([RH] ≈
≈ [RH]0)5:aa
reaction of ethylbenzene peroxide radicals with compound
7 measured by the chemiluminescence method (k7 =
= 2.6•104 mol L–1 s–1 at 50 °C)7 agrees satisfactorily with
our results under assumption that f equals 2 (Table 3).
Most likely, the difference in the fk7 values for compound
7 in 1,4ꢀdioxane and in isopropyl alcohol (see Table 3) is
due to the fact that the 1,4ꢀdioxane peroxide radicals are
less reactive in the reaction of hydrogen elimination than
the hydroperoxide radicals, which lead the oxidation
chains of isopropyl alcohol oxidation at the initial moꢀ
ments of the reaction.8
The quantum chemical analysis of 5ꢀsubstituted 6ꢀmeꢀ
thyluracils has been performed earlier,9 and the dissociaꢀ
tion energies of the N—H bonds were calculated by the
method of isodesmic reactions and by the G3MP2B3 proꢀ
cedure. It was established that the antioxidation activity of
6ꢀmethyluracils is determined by the N(1)—H bond
strength (DN(1)—H), because the N(3)—H bond is stronger
by 40—90 kJ mol–1. A comparison of the inhibition rate
constants fk7 and the N(1)—H bond strength in the
6ꢀmethyluracils studied shows (see Table 3) that the corꢀ
relation between logfk7 and DN(1)—H is observed only for
compounds 1, 3, and 7. For 6ꢀmethyluracil unsubstituted
in position 5, the N(1)—H bond strength is 422.5 kJ mol–1
and the inhibition rate constant is (4.4 0.6)•102 mol L–1 s–1.
This value is by an order of magnitude lower than those for
other 6ꢀmethyluracils in which the N(1)—H bond strength
is lower than 400 kJ mol–1. However, not all studied comꢀ
pounds can be described by this correlation. In particular,
although the N(1)—H bond strength in compound 7 is by
20 kJ mol–1 higher than those in compounds 5 and 6, the
rate constant fk7 for the latter is by an order of magnitude
lower. This possibly indicates that in compound 7 the
N(1)—H bond is not the single site of attack by the perꢀ
oxide radical.
Δ[O2] = –k2(k7)–1[RH]ln(1 – t/τ),
(5)
where Δ[O2] is the change in the oxygen concentration
during the reaction.
The length of the induction period for the initiated
oxidation of 1,4ꢀdioxane in the presence of 6ꢀmethyluracils
was calculated by Eq. (2). At rather high concentrations of
the inhibitor, the initial part of the kinetic curves of oxyꢀ
gen consumption are satisfactorily linearized in the coorꢀ
dinates of Eq. (5). The typical semilogarithmic transforꢀ
mation of the kinetic curve of oxygen absorption during
1,4ꢀdioxane oxidation inhibited by compound 7 is shown
in Fig. 2. The satisfactory linear dependence makes it posꢀ
sible to determine the k2(k7)–1 ratio. To calculate k7, the
k2 constant was accepted equal to 9.48 mol L–1 s–1. This
value was calculated from the oxidizability parameter
k2(2k6)–0.5 = (3.0 0.5)•10–4 L0.5 mol–0.5 s–0.5 assuming
that 2k6 = 109 mol L–1 s–1. The rate constants obtained
for the inhibition of 1,4ꢀdioxane oxidation by 6ꢀmethylꢀ
uracils studied are listed in Table 2. As can be seen, the
rate constants fk7 calculated by Eqs (1) and (3) agree satꢀ
isfactorily with the k7 value found from Eq. (5) assuming
that f equals 2. To evaluate parameter f for all compounds
used in this work further studies are necessary.
The introduction of substituents into position 5 of the
uracil cycle increases the inhibition activity of 6ꢀmethylꢀ
uracils (see Table 2). The inhibition rate constant obꢀ
tained for compound 7 is by two orders of magnitude higher
than the fk7 constant measured for unsubstituted 6ꢀmethꢀ
yluracil and by an order of magnitude higher than this
constant for other substituted uracils. Analogous results
were obtained for 5ꢀsubstituted 6ꢀmethyluracils in isoproꢀ
pyl alcohol6 and ethylbenzene.7 The rate constant for the
Thus, 6ꢀmethyluracils are inhibitors of the radicalꢀ
chain oxidation of 1,4ꢀdioxane. Among compounds 1—7,
Δ[O2]•10–4/mol L–1
Table 3. Bond strengths DN(1)—H and the rate constants
fk7 for 6ꢀmethyluracil (1) and its 5ꢀsubstituted derivaꢀ
tives 2—7
16
14
12
10
8
8
Comꢀ
pound
DN(1)—H
f k7
/kJ mol–1
/L mol–1 s–1
1
2
3
4
5
6
7
7
7
422.5
—
400.4
—
349.9
350.1
371.5
371.5
371.5
(4.4 0.6)•102
(5.3 0.3)•103
(2.5 0.2)•103
(2.40 0.15)•103
(3.8 0.4)•103
(4.6 0.1)•103
(5.2 0.1)•104
1.5•105 *
6
4
2
0.2
0.4
0.6 –ln(1 – t/τ)
5.2•104 **
Fig. 2. Semilogarithmic transformation of the oxygen absorpꢀ
tion kinetic curve (ΔO2) during 1,4ꢀdioxane oxidation (60 °C,
wi = 5.3•10–8 mol L–1 s–1, [7] = 1.4•10–4 mol L–1).
* In isopropyl alcohol (see Ref. 6).
** In ethylbenzene (see Ref. 7).

Inhibition effect of methyluracil derivatives
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 3, March, 2010
521
3. A. F. Moroni, Makromol. Chem., 1967, 105, 43.
5ꢀhydroxyꢀ6ꢀmethyluracil (7) has the highest efficiency and
its inhibition constant fk7 is (5.2 0.11)•104 mol L–1 s–1
at 60 °C, which is twice as large as the constant measured
for ionol in this model system.1
4. R. N. Zaripov, R. L. Safiullin, Sh. R. Rameev, I. R. Akhunov,
V. D. Komissarov, Kinet. Katal., 1990, 31, 1086 [Kinet. Catal.
(Engl. Transl.), 1990, 31].
5. E. T. Denisov, V. V. Azatyan, Ingibirovanie tsepnykh reaktsii
[Inhibition of Chain Reactions], Chernogolovka, 1997, 266 pp.
(in Russian).
6. A. Ya. Gerchikov, G. G. Garifullina, I. V. Safarova, I. B.
Abdrakhmanov, A. G. Mustafin, V. P. Krivonogov, Dokl.
Akad. Nauk, 2004, 394, 215 [Dokl. Chem. (Engl. Transl.), 2004].
7. V. A. Myshkin, A. B. Bakirov, Oksimetiluratsil (Ocherki
eksperimental´noi farmakologii) [Hydroxymethyluracil (Experiꢀ
mental Pharmacology Assays)], Ufa, 2001, 218 pp. (in Russian).
8. E. T. Denisov, T. G. Denisova, Neftekhimiya, 2006, 46, 333
[Petroleum Chem. (Engl. Transl.), 2006, 46].
This work was financially supported by the Ministry of
Education and Science of the Russian Federation (Anaꢀ
lytical Departmental Target Program "Development of the
Scientific Potential of Higher School (2006—2008)," RNP
Project No. 2.2.1.1.6332) and the Russian Foundation
for Basic Research (Project Nos 06ꢀ03ꢀ32667ꢀa and
08ꢀ03ꢀ99011).
References
9. I. F. Dautova, S. L. Khursan, Vestn. Bashkirskogo unꢀta [Bashꢀ
kir University Bulletin], 2009, 14, No. 1, 57 (in Russian).
1. L. R. Yakupova, V. R. Khairullina, R. L. Safiullin, A. Ya.
Gerchikov, G. R. Baimuratova, Kinet. Katal., 2008, 49, 387
[Kinet. Catal. (Engl. Transl.), 2008, 49].
2. Author´s Certificate 2 000 298 RF; Byul. Izobr. [Invention Bulꢀ
letin], 1993, 33 (in Russian).
Received June 11, 2009;
in revised form November 5, 2009