Antioxidant activity of hydrazones with sterically hindered phenol fragments

Article abstract of DOI:10.1134/S0036024412120205

Kinetic parameters of the antiradical activity of derivatives of hydrazones of 4-hydroxy-3,5-di-tert-butyl-benzaldehyde are determined photocolorimetrically in their reactions with a stable diphenylpicrylhydrazyl radical, and by chemiluminescence from the capture of peroxide radicals upon the initiated oxidation of ethylbenzene. It is found that during inhibited oxidation, the reactive centers (N-H and O-H) in hetaryl-and acylhydrazone molecules operate in parallel. Regularities of the compounds' inhibiting effect are studied in heterogeneous systems upon the initiated oxidation of ethylbenzene in emulsion, and in a waterlipid model of the oxidation of phosphatidylcholine dispersion. It is established that hydrazone derivatives are antioxidants of combined action in heterophase processes of the oxidation of unsaturated substrates, displaying properties of hydroperoxide deactivators in addition to their antiradical activity. Pleiades Publishing, Ltd., 2012.

Full text of DOI:10.1134/S0036024412120205

ISSN 0036ꢀ0244, Russian Journal of Physical Chemistry A, 2012, Vol. 86, No. 12, pp. 1816–1820. © Pleiades Publishing, Ltd., 2012.
Original Russian Text © A.N. Nikolaevskii, O.P. Kniga, E.I. Khizhan, G.A. Tikhonova, V.V. Vinogradov, A.I. Khizhan, 2012, published in Zhurnal Fizicheskoi Khimii, 2012,
Vol. 86, No. 12, pp. 1953–1957.
PHYSICAL CHEMISTRY
OF SOLUTIONS
Antioxidant Activity of Hydrazones
with Sterically Hindered Phenol Fragments
A. N. Nikolaevskiia, O. P. Knigaa, E. I. Khizhana, G. A. Tikhonovaa,
V. V. Vinogradova, and A. I. Khizhanb
a Donetsk National University, Donetsk, 83001 Ukraine
b Litvinenko Institute of Physicoorganic Chemistry and Coal Chemistry, National Academy of Sciences of Ukraine,
Donetsk, 340114 Ukraine
eꢀmail: antioxidant104@yandex.ua
Received September 29, 2011
Abstract—Kinetic parameters of the antiradical activity of derivatives of hydrazones of 4ꢀhydroxyꢀ3,5ꢀdiꢀ
tertꢀbutylꢀbenzaldehyde are determined photocolorimetrically in their reactions with a stable diphenylpicrylꢀ
hydrazyl radical, and by chemiluminescence from the capture of peroxide radicals upon the initiated oxidaꢀ
tion of ethylbenzene. It is found that during inhibited oxidation, the reactive centers (NꢀH and OꢀH) in
hetarylꢀ and acylhydrazone molecules operate in parallel. Regularities of the compounds’ inhibiting effect are
studied in heterogeneous systems upon the initiated oxidation of ethylbenzene in emulsion, and in a water–
lipid model of the oxidation of phosphatidylcholine dispersion. It is established that hydrazone derivatives are
antioxidants of combined action in heterophase processes of the oxidation of unsaturated substrates, displayꢀ
ing properties of hydroperoxide deactivators in addition to their antiradical activity.
Keywords: hetarylhydrazone, antioxidant, rate constant, stoichiometric inhibition coefficient, oxidation in
emulsion.
DOI: 10.1134/S0036024412120205
INTRODUCTION
hydrazone part of the molecules to increase their resisꢀ
tance with respect to molecular oxidizers.
Despite the wide variety of inhibitors, the problem
of excluding undesirable oxidation processes in
organic materials with the participation of atmoꢀ
spheric oxygen remains of interest. An analysis of
investigations in this field shows that combining a
functionally substituted fragment and a sterically hinꢀ
dered phenol group in one molecule can produce new
compounds that have a number of useful properties
and display biological activity [1–3]. Highly efficient
antiꢀinflammatory agents as well as preparations able
to suppress the development of neoplastic processes
and radiation damage have been found among the
derivatives of hydrazones, including those of 4ꢀ
hydroxyꢀ3,5ꢀdiꢀtertꢀbutylꢀbenzaldehyde [4]. One of
the most important characteristics of drugs’ biological
activity is their effectiveness as antioxidants.
The aim of this work was to study the antiradical
and antioxidant activities (ARAs and AROs) of hydraꢀ
zone derivatives of aromatic aldehydes containing
sterically hindered phenol fragments in their reactions
with a stable radical, diphenylpicrylhydrazyl (DPPH),
and upon a liquidꢀphase oxidation of ethylbenzene
(ETB) and model aqueous–organic media.
EXPERIMENTAL
The investigated substances were synthesized and
identified in the Department of Chemistry of Biologꢀ
ically Active Compounds, Litvinenko Institute of
Physicoorganic Chemistry and Coal Chemistry,
National Academy of Sciences of Ukraine. Their
structural formulas are presented in the table.
Arylhydrazone compounds are interesting from
this point of view. The presence of an aminoꢀgroup
similar in its properties to aromatic amines but having
a more labile bond and lower toxicity makes them
promising antioxidants (InH) with very high constant
rate values for their interactions with peroxyradicals
The efficiency of antioxidants upon the liquidꢀ
phase oxidation of ethylbenzene initiated by thermal
decomposition of azobisꢀisobutyronitrile (AIBN) was
investigated using a chemiluminescent setup with a
FEUꢀ38 photoelectronic multiplier in the presence of
a glowing activator, 9,10ꢀdibromoanthracene. Hydraꢀ
zones are poorly soluble in nonpolar solvents, so they
were initially dissolved in a small amount of dimethylꢀ
(
~106 L/(mol s)) [5]. At the same time, however, these
compounds are easily oxidized by atmospheric oxyꢀ
gen. Heterocyclic substituents are introduced into the sulfoxide. Ethylbenzene was then added to obtain the
1816

ANTIOXIDANT ACTIVITY OF HYDRAZONES
1817
Chemical formulas of the investigated compounds and their ARA parameters
InH
Formula
W, mol/(L s)
f
k7, L/(mol s)
C(CH )
3 3
N
S
1
(1.1 0.1)
(3.6 0.2)
(6.0 0.2)
(1.3 0.1)
×
×
×
×
10–6
10–6
10–6
10–7
1.7
(1.5 0.1)
×
×
×
×
105
104
104
104
NH N CH
OH
C(CH )
3 3
C(CH )
3 3
N
NH
2
3
4
0.5
0.5
2.0
(3.9 0.4)
(2.0 0.1)
(3.1 0.3)
H C
C NH N CH
OH
C(CH )
3
O
H C
3
3 3
C(CH )
3 3
N
S
S CH C NH N CH
OH
C(CH )
2
O
3 3
(H C) C
3
3
HO
CH
3
(H C) C
3
3
required concentration, and an aliquot of this solution radicals of the substrate subjected to oxidation. The
was introduced into the reaction mixture.
A direct ethylbenzene : water emulsion (1 : 3) and chains terminated by one inhibitor molecule) along
stoichiometric inhibition coefficient f (the number of
an aqueous dispersion of phosphatidylcholine (PC)
stabilized with sodium dodecylsulfate (SDS) were
used as model systems. The PC was the drug Lecithin
(Pharmetics Inc., Canada), an extract of soybeans.
The dispersion was prepared ultrasonically, ensuring
the micellar solubilization of AIBN. The emulsions
were oxidized with atmospheric oxygen in a glass bubꢀ
bling reactor with the kinetics process being controlled
iodometrically (through the accumulation of peroxide
compounds).
with the ratio of the induction periods of peroxide
accumulation in the presence ( ) and the absence (τ0
of additives were used as AOA parameters.
τ
)
RESULTS AND DISCUSSION
We investigated recently synthesized hydrazones
with the same aldehyde part (a sterically hindered
phenol fragment) and different substituents in the
hydrazone part of the molecule: hetarylꢀ or acylꢀ (see
table). The compounds’ efficiency of inhibition was
ETB was preliminarily purified by distillation, folꢀ
lowing standard procedures. AIBN was recrystallized
from methanol and dried in vacuum.
compared to that of a standard inhibitor, 3,5ꢀdiꢀtert
ꢀ
The ARA of hydrazones in their reaction with the
stable colored radical DPPH was studied by photocolꢀ
orimetry on a KFKꢀ3 photometer. The ethanol soluꢀ
tion of DPPH had a maximum absorption in the visiꢀ
ble spectral range at λmax = 520 nm. Solutions of
hydrazones and DPPH were mixed at an equimolar
ratio of the components in the range of reactant conꢀ
centrations 10–3–10–5 mol/L, and the changes in optiꢀ
cal density over time were recorded.
butylꢀ4ꢀmethylphenol (ionol).
The rates of reaction between the investigated subꢀ
stances and DPPH, determined from the initial parts
of kinetic curves for the consumption of this radical,
are presented in the table. According to our data, the
compounds displayed a high level of activity with
respect to DPPH radicals. The derivatives of hydraꢀ
zones used in this work have two active sites of interacꢀ
tion with DPPH, the NH group of the hydrazone
molecular fragment (1) and the OH group in the aldeꢀ
hyde part (2):
ARA was characterized quantitatively by the rate of
reaction between the hydrazones and diphenylpicrylꢀ
hydrazyl (
W
) and by the rate constant (k7) for interacꢀ
ROi2
tion between the investigated compounds and
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1818
NIKOLAEVSKII et al.
NO2
C(CH3)3
OH
N
S
(1)
.
+
+
O2N
N N(Ph)2
H
N N C
H
C(CH )
NO
3 3
2
NO2
C(CH3)3
N
S
.
+
N N C
OH O N
N N(Ph)
2
2
H
H
NO
C(CH )
2
3 3
C(CH )
NO
2
N
S
3 3
(2)
.
O N
2
N N(Ph)
2
H
N N C
O
H
H
NO
C(CH )
2
3 3
As can be seen from the table, the values of
W
for
The stoichiometric inhibition coefficient was
hydrazones exceed the rate of their interaction with determined by the formula:
DPPH by one order of magnitude (compound 4); i.e.,
τWi
of the two parallel processes, reaction (1) is the limitꢀ
ing stage.
,
]
f =
InH
[
The antiradical activity of hydrazones was also
determined by chemiluminescence from their capture
of peroxide radicals in the model reaction of ethylbenꢀ
zene oxidation. Chemiluminescence (CL) is based on
the luminescence (I0) generated upon the recombinaꢀ
tion of peroxyradicals during the oxidation of organic
substances:
where is the induction period of oxidation on the CL
τ
curves, and Wi is the rate of process initiation due to
the thermal decomposition of AIBN. Our results are
presented in the table.
As compared to the data for phenylhydrazones
obtained earlier [7], it should be noted that changing
the phenyl radical in part of the hydrazone molecule to
a heterocyclic one (compound 1) lowers the k7 value
by an order of magnitude due to the strengthening of
the N–H bond from inserting acceptor heteroatoms
into the ring.
i
i
k7
RO2 + RO2 ⎯⎯⎯→ [ROOOR]
→ R=O* → R=O + hν.
The inhibitor interacts with peroxyradicals (at rate
constant k7), leading to a sharp drop in chemiluminesꢀ
A comparison of the obtained k7 values (the table)
allows us to assume that the rate of reaction between
the compounds and ETB peroxyradical is determined
by the interaction of the N–H group in the hydrazone
part of the molecule only in the case of hetarylhydraꢀ
zone (compound 1). In the case of acylhydrazones, the
reaction between the ETB peroxyradical and the sterꢀ
ically hindered phenol fragment in the aldehyde part
of the inhibitor molecules is probably the limiting
reaction, as the k7 values for ionol and compounds 2
and 3 are very close.
cence (І). This effect can be enhanced by raising the
concentration of inhibitor (Fig. 1).
i
i
k7
.
RO2 + InH ⎯⎯⎯→ ROOH + In
The rate constants for reactions of hydrazones with
ETB peroxyradicals were calculated from the concenꢀ
tration dependences of the parameter I/I0 [6]:
∂(I /I )
k7
⎡
⎤
0
= 0.22
Wi .
⎢
⎥
⎦
⎣
∂t
k6
max
The differences in the hydrazone derivatives’ effiꢀ
ciency of inhibition are related to the stability of the
radicals formed from them due to their electronic
structure.
I/I0
The geometric structures of the molecules and Nꢀ
centered radicals of the investigated compounds were
optimized using the semiempirical quantumꢀchemical
0.8
0.4
1
2
3
t
PM3 approach. The torsion angle
zone molecules is 28°, while the most stable radical
structures are coplanar ( CNNC = 0°); i.e. the priꢀ
∠
CNNC in hydraꢀ
∠
mary structural elements (the ring in the aldehyde part
and the C=N–N bonds) lie in the same plane. The
forming hydrazonyl radicals are thus additionally staꢀ
0
50
100
bilized by the delocalization of unpaired ꢀelectrons
π
t, s
on nitrogen atoms over the conjugation system of the
azomethine bonds and aromatic ring bonds in both the
aldehyde and hydrazone parts of the molecules. In the
case of Nꢀacyl substituent, the conjugation chain is
shorter and the radical stability is therefore lower. As a
result, radicals of compounds 2 and 3 participate
Fig. 1. Kinetic curves of the change in relative CL intensity
upon ETB oxidation in the presence of hetarylhydrazone 1.
–2
Т
= 343 K; [AIBN] = 1.0
6
×
10 mol/L; [InH] ×
10 mol/L. (1) 3.7, (
2) 6.8, and (
3) 20.0.
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ANTIOXIDANT ACTIVITY OF HYDRAZONES
1819
103, mol/L
PP, %
0.5
[ROOH]
1.6
×
1
1
2
2
3
4
1.2
0.8
0.4
0.3
3
4
5
5
0.1
0
200
400
t, min
0
100
200
300
, min
t
Fig. 3. Kinetic curves for the accumulation of peroxide
Fig. 2. Kinetic curves for the accumulation of hydroperoxꢀ
compounds upon the initiated oxidation of 2% aqueous
ides upon the oxidation of an ETB : water (1 : 3) emulsion
PC dispersion (
1
) in the absence and in the presence of
) 2, ( ) 1, and ( ) 3. = 333 K;
10 mol/L; [AIBN] = 2.0
–4
compounds ( ) 4, (
2
3
4
5
T
(
1
) in the absence and in the presence of 1.0
of hydrazones: ( ) 3, ( ) 2, ( ) 4, and ( ) 1.
[AIBN] = 1.0 10 mol/L; [SDS] = 0.5 mol/L. Comꢀ
× 10 mol/L
–4
–2
2
3
4
5
T
= 343 K;
[InH] = 5.0
×
×
10 mol/L;
–2
–2
×
[SDS] = 5.0
×
10 mol/L. Compound numbers correꢀ
pound numbers correspond to the table.
spond to the table.
readily in chain propagation reactions and other side
processes, leading to low f values (the table).
Different regularities were observed for oxidation
inhibition by hydrazone derivatives in a waterꢀlipid
system, i.e., PC : water dispersion. The liposoluble iniꢀ
tiator AIBN was used to minimize the effect of iron
ions, which are known [14] to catalyze the peroxide
oxidation of lipids. It was established that the hydraꢀ
zones investigated in this work inhibit oxidation of this
system almost independently of their structure (Fig. 3)
and with twice the efficiency of ionol.
The stoichiometric inhibition coefficient depends
on the mechanism of chain termination by the inhibiꢀ
tor [8, 9]. It was found earlier that for arylhydrazones,
f
= 1 during ETB oxidation in the absence of phenyl
group in the aldehyde part of the molecule [7]; i.e., the
disproportionation of hydrazonyl radicals is favored
over their interaction with peroxide radicals. The high
f
value for compound 1 (see table) points to an addiꢀ
tional contribution from the interaction of ETB perꢀ
oxyradicals with the sterically hindered phenol fragꢀ
ment in the aldehyde part and with the corresponding
phenoxyꢀradical.
[ROOH]
30
×
103, mol/L
2
1
Hetarylhydrazone with the sterically hindered pheꢀ
nol fragment is thus a highly efficient antioxidant of
liquidꢀphase oxidation processes, while acylhydraꢀ
zone behaves as a weak inhibitor under these condiꢀ
tions.
20
10
To clarify the mechanism of the effect in heterogeꢀ
neous biological systems, the antioxidant activity of
hydrazone derivatives was studied in SDSꢀstabilized
model ETB : water emulsions, their oxidation being
initiated by AIBN. In a heterogeneous system, the
efficiency of the inhibitor depends to a large extent not
only on its antiradical activity but also on a number of
physical and chemical factors governing the dispersion
structures and reactant localizations [10–13]. Our
results agree with this concept (Fig. 2). Acylhydraꢀ
zones exhibited very low efficiency, and the induction
periods observed in their presence are practically half
those measured for ionol at the very close ARA of
these compounds with respect to ETB peroxyradicals.
3
4
5
0
100
200
300
, min
t
Fig. 4. Decomposition of cumene hydroperoxide in 30%
aqueous solution of isopropanol ( ) without an inhibitor
and in the presence of compounds ( ) 4, ( ) 1, ( ) 2, and
= 343 K. Compound
1
2
3
4
–2
(5) 3. [InH] = 2.0 × 10 mol/L; T
numbers correspond to the table.
RUSSIAN JOURNAL OF PHYSICAL CHEMISTRY A
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1820
NIKOLAEVSKII et al.
These data indicate an additional contribution to aqueous organic systems is thus considerably lower
the mechanism of the inhibiting effect of hydrazones than in the case of homogeneous processes.
that is not related to their ARA. Since it is known [15]
that autooxidation contributes a great deal to the initiꢀ
ated oxidation of unsaturated compounds due to the
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