Butylated hydroxy benzylidene ring: an important moiety for antioxidant synergism of semicarbazones

Article abstract of DOI:10.1007/s10973-020-10199-8

Abstract: The compounds having two or more antioxidant functions in their structure exhibit antioxidant synergism that generally increase the antioxidant activity of these compounds. In this study, two series of semicarbazone (7a–j and 7a′–j′) bearing butylated ortho and para hydroxy benzylidene ring were prepared for the investigation of antioxidant synergism. This study found that intramolecular hydrogen bond can form in semicarbazones due to the inappropriate position of hydroxyl group on benzylidene ring, which adversely affects the antioxidant synergism. As consequence, butylated para hydroxyl benzylidene phenyl semicarbazone (7a) (IC₅₀ 12.27?μM) showed ~ 4.3 times and ~ 2.7 times better antioxidant activity than compounds 7a′ (IC₅₀ 53.30?μM) and BHT (IC₅₀ 32.63?μM), respectively, in DPPH assay. In addition, based on the solubility in trimethylolpropane trioleate (TMPTO) as synthetic base oil and obtained IC₅₀ results, oxidation stability of synthesized compounds was also evaluated by two kinds of differential scanning calorimeter (DSC) test, namely temperature ramping DSC and programmed temperature DSC. Thermogravimetric analysis is also performed for the thermal stability assessment. TMPTO incorporated with 0.25 mass% of 7c and 7e were found better oxidative (around 2 times) and thermal resistance than BHT. This DSC results showed another important aspect of semicarbazones that proper modification of semicarbazones can be used in the synthetic lubricant oil as a potential antioxidant. Thus, the results of this study are promising which can be taken under consideration to design and prepare more efficient multipotent semicarbazones. Graphic abstract: [Figure not available: see fulltext.]

Full text of DOI:10.1007/s10973-020-10199-8

Journal of Thermal Analysis and Calorimetry
https://doi.org/10.1007/s10973-020-10199-8
Butylated hydroxy benzylidene ring: an important moiety
for antioxidant synergism of semicarbazones
Amit R. Nath1 · Wageeh A. Yehye1 · Mohd Rafe Bin Johan1
Received: 1 September 2019 / Accepted: 19 August 2020
© Akadémiai Kiadó, Budapest, Hungary 2020
Abstract
The compounds having two or more antioxidant functions in their structure exhibit antioxidant synergism that generally
increase the antioxidant activity of these compounds. In this study, two series of semicarbazone (7a–j and 7a′–j′) bear-
ing butylated ortho and para hydroxy benzylidene ring were prepared for the investigation of antioxidant synergism. This
study found that intramolecular hydrogen bond can form in semicarbazones due to the inappropriate position of hydroxyl
group on benzylidene ring, which adversely afects the antioxidant synergism. As consequence, butylated para hydroxyl
benzylidene phenyl semicarbazone (7a) (IC50 12.27 µM) showed ~4.3 times and ~2.7 times better antioxidant activity than
compounds 7a′ (IC50 53.30 µM) and BHT (IC50 32.63 µM), respectively, in DPPH assay. In addition, based on the solubility
in trimethylolpropane trioleate (TMPTO) as synthetic base oil and obtained IC50 results, oxidation stability of synthesized
compounds was also evaluated by two kinds of diferential scanning calorimeter (DSC) test, namely temperature ramping
DSC and programmed temperature DSC. Thermogravimetric analysis is also performed for the thermal stability assessment.
TMPTO incorporated with 0.25 mass% of 7c and 7e were found better oxidative (around 2 times) and thermal resistance
than BHT. This DSC results showed another important aspect of semicarbazones that proper modifcation of semicarbazones
can be used in the synthetic lubricant oil as a potential antioxidant. Thus, the results of this study are promising which can
be taken under consideration to design and prepare more efcient multipotent semicarbazones.
Graphic abstract
Ortho
Para
OH
Oxidative
problems
Oxidative
problems
OH
Strong shield
Weak shield
N
N
H
N
H
HN
HN
N
O
O
Z
Z
Keywords Antioxidant synergism · DSC · Lubricant oil · Oxidative stability · TGA · Semicarbazones
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s10973-020-10199-8) contains
supplementary material, which is available to authorized users.
Extended author information available on the last page of the article
Vol.:(0123456789)
1 3

A. R. Nath et al.
reported pharmacophore which also possesses excellent
antioxidant properties. Butylated hydroxytoluene (BHT) is
well-known synthetic primary antioxidant. It has been exten-
sively used in the food industry, pharmaceuticals, rubber,
and lubricant due to its excellent free radical scavenging
capacity [13]. It is identifed as safe for use in food at low
concentration as a food preservative. Thus, it has been uti-
lized in the food industry, food packaging, fsh products and
so on [14, 15]. BHT is also broadly utilized in combination
with other antioxidants such as butylated hydroxyanisole
(BHA), propyl gallate, and citric acid for the stabilization
of oils and high-fat foods [16, 17]. BHT also exhibited good
synergism results with other antioxidants in the application
of rubber and lubricant oil.
Introduction
Oxidative stress is one of the main causes of etiology and
expansion of major human deteriorating disease. The imbal-
ance of production of free radical (reactive oxygen species)
and the ability of the body to counteract the free radical
cause oxidative stress [1, 2]. So excessive free radicals exert
toxic efects throughout the body especially responsible for
cancer and other chronic diseases [3, 4]. Apart from the oxi-
dative stress in the human body, free radicals cause auto-oxi-
dation and premature oxidation in industrial products such as
oils, rubbers, food and foodstufs [5–7]. Premature oxidation
is one of the major obstacles to develop the oxidatively and
thermally stable synthetic lubricant where eco-friendly syn-
thetic lubricants become a necessity of the modern world.
So, development of eco-friendly synthetic lubricant
from sustainable resources has drawn a great interest for
the last few years to replace the mineral lubricants because
of the risen environmental concerns and preventive proto-
cols [8–10]. Moreover, reliance on fossil-based resources is
no longer pragmatic in perspective of feasible, eco-friendly
and fnancial purposes and in addition, the reserve of fos-
sil-based resources is notably diminishing with time. As a
result, synthetic lubricant oils or vegetable oils have gained
a great consideration because it derived from cheaper renew-
able resources and their better lubricant properties than the
mineral oils [11]. Unfortunately, due to the lower oxidative
and thermal stability it has failed to get wide acceptance.
This is because the production of free radical in lubricant oil
causes premature oxidative degradation that is responsible
for product damage, discoloration, and reduced lifetime.
The premature oxidation or auto-oxidation process and
excess free radical production in vivo or in vitro can be
stopped or delayed by introducing antioxidant into the sub-
strates. Antioxidants can inhibit the diferent stages of the
oxidation process in industrial products by their diferent
mood of actions or mechanisms such as scavenging free
radicals or decomposing peroxides radicals and deactivating
metal ions. Thus, these are divided into three main groups
based on their mode of action: free radical scavenger or pri-
mary antioxidant, the other peroxide decomposer or second-
ary antioxidant and metal chelator or deactivator [12]. For
past few years, researchers have been trying to develop ef-
cient multipotent or multifunctional antioxidant by assem-
bling two or more antioxidant functions in one structure,
because high efcient multifunctional antioxidants would
be an efective solution to get over the problems caused by
free radical such as oxidative stress in the human body and
low oxidative stability of industrial product, e.g., synthetic
lubricant oil [11].
Again, semicarbazones, which are versatile pharmacoph-
ore agents, have earned interest in medicinal and pharma-
ceutical felds due to broad-spectrum biological activities
such as anticonvulsant, antitumor, and anticancer properties
[18–21]. Semicarbazones are also known tridentate or neu-
tral ligand since they contain multiple donor atoms in their
structure. Their metal complexes also exhibit signifcant
activity against bacteria, fungi, and viruses which extends
the versatility of the applications [22]. Moreover, substituted
semicarbazones can be used as a platform chemical to pre-
pare benzotriazepin compounds which are also an important
class of drug due to their psychostimulant, antidepressant,
anorexigenic, and antihypertensive properties [23]. Some
researchers also revealed their antioxidant activity as they
have two secondary amino in its structure [24, 25]. Sabari
et al. reported some new semicarbazone derivative of cur-
cumin for its antioxidant and antimicrobial properties. It is
believed that favorable substitution of semicarbazones would
afect signifcantly its free radical scavenging ability [26].
Example like chalcone semicarbazones, a pharmacophore
model, was found to have good antioxidant activity [27].
Comparing mono-functional antioxidants such as hin-
dered phenol and aromatic amine, inhibiting action of mul-
tifunctional antioxidants is more complicated and efective
because their structures contain multiple antioxidant func-
tions which involved in the termination of free radical chain
reaction through diferent mechanisms [28, 29]. Multifunc-
tional or multipotent antioxidants have been used widely into
pharmaceuticals, rubber, and petroleum because of their ef-
cacy in terminating free radicals. This type of antioxidants
has drawn a tremendous attention for the treatment of sev-
eral diseases [30]. For example, thiazolidinone derivatives
incorporated with butylated hydroxyphenyl (BHP) exhibit
antioxidant activity along with Ca2+ overload inhibitor and
Ca2+ channel blocker [31].
Therefore, discovering efective multipotent antioxidants
is now paramount need to efectively counteract the free rad-
icals to reduce the risk of oxidative stress as well as to give
better oxidative stability to synthetic lubricant oil. Herein,
Butylated hydroxytoluene (BHT) is one of the widely
used antioxidants, and semicarbazones are extensively
1 3

Butylated hydroxy benzylidene ring: an important moiety for antioxidant synergism of…
we have envisioned to make multipotent semicarbazone
incorporated with two types of butylated hydroxyphenyl
(BHP) as an efcient antioxidant. The purpose of this study
is to develop a group of efcient multipotent semicarbazones
which can exhibit excellent antioxidant activity and to study
the role of the ortho and para hydroxyl group of BHP incor-
porated semicarbazones on the antioxidant activity. Antioxi-
dant properties of these synthesized compounds were inves-
tigated by DPPH assay, and efects of diferent substituents
on the antioxidant activity were also studied. Furthermore,
some synthesized compounds were chosen based on easy
solubility in trimethylolpropane trioleate as synthetic ester-
based lubricant for the evaluation of oxidative stability by
diferential scanning calorimeter (DSC) and thermal stability
by thermogravimetric analysis (TGA) compared with com-
mercial antioxidant BHT.
Gel 60 (particle size: 0.040–0.063 mm). IR spectra were
recorded using FTIR-ATR of the solid samples. Melt-
ing points were approximated. 600 MHz and 150 MHz
NMR spectrometers were used for 1H NMR and 13C NMR,
respectively, and tetramethylsilane was used as a reference.
Chemical shifts (δ) were measured in ppm with respect
to the residual solvent peak (CHCl3, δ = 7.26; DMSO-d6,
δ = 2.51 for proton spectra; 13CDCl3, δ = 77.0; DMSO-d6,
δ = 40 for carbon spectra). High-resolution mass spectra
were performed on a time-of-fight Q-TOF LCMS system.
Synthesis of 2‑((3,5‑di‑tert‑butyl‑4‑hydroxybenzyl) thio)
acetohydrazide (3) and substituted semicarbazides 5a–j
2-((3,5-di-tert-butyl-4-hydroxybenzyl)thio)acetohydrazide
was synthesized according to a previously described
method (Scheme 1) [32].
Experimental
Acid hydrazide (1 g, 3.12 mmol) was stirred in tolu-
ene (20 mL), then an equimolar amount of aryl isocyanate
was introduced, and the reaction was monitored by TLC
(Scheme 2). All the substituted semicarbazides formed
white precipitates during the reaction, which were fltered
and washed several times with toluene. Dichloromethane
(CH2Cl2) was used for compounds 5c, 5d and 5i since
2,4-dichlorophenyl isocyanate, 4-cyanophenyl isocyanate
and 4-acylphenyl isocyanate are not soluble in toluene.
Compound structures were confrmed by IR, 13C NMR,
1H NMR and HRMS analyses. Characterization data were
presented in the supporting fles. We have already reported
the following synthesized substituted semicarbazides
General remarks
All chemicals and reagents were of analytical grade and
supplied by Sigma-Aldrich and Merck, Malaysia, and
used without further purifcation. Double-distilled water
was used throughout the experiment. Pre-coated silica gel
plates (0.25 mm) were utilized for analytical thin-layer
chromatography to monitor the reaction and imagined by
UV light. Column chromatography was done on Silica
Scheme 1 Preparation of acid hydrazide (3)
Scheme 2 Preparation of substituted semicarbazides
1 3

A. R. Nath et al.
5a–5c, 5f, 5h, and 5j with characterization data in the lit-
erature [33]. Herein, compounds 5d, 5e and 5g have been
reported with characterization data (Supporting fle). All
the synthesized compounds were solid and stored at ambi-
ent temperature.
To determine the concentration required to achieve 50%
inhibition (IC50) of DPPH radical, the percentage of DPPH
inhibition for each compound will be plotted against extract
concentration.
Diferential scanning calorimetry (DSC)
General procedure for the synthesis
of semicarbazones (7a–j and 7a′–j′)
Temperature ramping DSC
0.65 mmol of substituted semicarbazides (5a–j) and an equi-
molar quantity of aldehyde were taken into round-bottle fask
with approximately 10 mL of ethanol. Then the mixture was
stirred at 90 °C for 4–5 h in the presence catalytic amount
of HCl (1.6 mmol) until the disappearance of the starting
materials spot in the thin-layer chromatography. Afterward,
the reaction mixture was allowed to warm to ambient tem-
perature, stirred for around half an hour. The expected semi-
carbazones started the formation of solid precipitate during
ambient temperature stirring in some of the reactions. The
precipitate was fltered and washed with hexane for several
times. Then the resultant products were dried and either
recrystallized from hexane or column chromatography. How-
ever, the reaction in which no precipitates were found, the
reaction mixture was concentrated and purifed by column
chromatography on silica gel with hexane/EtOAc mixture as
the eluent. All characterization data have been included into
supporting fles.
Diferential scanning calorimetry was conducted for the
evaluation of oxidation induction time and oxidation onset
temperature by utilizing TA DSC Q2000. For the assess-
ment of OIT, 5 mg of sample oil was placed in an open
aluminum pan under 2 bar pressures of nitrogen. Metal
indium was used for the temperature calibration at 20 °C
heating rate. The sample was heated in a nitrogen atmos-
phere until reached the isothermal temperature 150 °C and
then switched to oxygen gas at 20 mL min−1 rate.
Programmed temperature DSC
This experiment was also carried out by the same instru-
ment. 3 mg of oil sample was placed in an open aluminum
pan for the maximum interaction between oil and reactant
gas in order to avoid gas difusions limitations. Temperature
scanning rate of 20 °C min−1 was kept in the temperature
ramping experiments, and 99.99% pure oxygen fow was
maintained at 20 mL min−1.
1, 1‑diphenyl‑2‑picrylhydrazyl (DPPH) assay
Thermogravimetric analysis (TGA)
DPPH radical scavenging assay was carried out accord-
ing to the literature [34] with some modifications. To a
range of various concentrations 60, 40, 20, 10 μM mL−1
of samples, DPPH solution (50μL, 0.203 mM in MeOH)
was added. Around 1 mg of synthesized compounds was
dissolved in MeOH (5.0 mL, 100%) as a stock solution.
This stock solution was diluted to a range of final extrac-
tion concentrations 60, 40, 20, and 10 μM. A negative con-
trol with the same DPPH concentration in MeOH without
sample was used. Each assay was carried out in triplicates.
The mixture was then incubated in dark for 60 min at
room temperature. Absorbance at 517 nm for each sample
was measured. BHT was used as positive control. The
free radical scavenging activity of the compounds will be
calculated as a percentage of radical inhibition by using
the formula:
The thermal stability of TMPTO and TMPTO with
0.25 mass% of BHT, 7c and 7e in air was investigated by
examining the thermal decomposition temperature by the
way of thermogravimetric analysis (TGA) over a tempera-
ture limit from ambient to approximately 600 °C, at scanning
rate of 10 °C min−1 using a thermal analyzer.
Results and discussion
Synthesis of BHA incorporated semicarbazones
Recently, we disclosed a robust reaction protocol for the
synthesis of semicarbazones to skip the limitations of previ-
ously reported methods such as functional group incompat-
ibility and lower yields [33]. In brief, this reaction protocol
involved the synthesis of acid hydrazide that was reacted
with aryl isocyanate to obtain substituted semicarbazides;
[
]
Percentage of Inhibition (%) = (Ac − As)∕Ac × 100,
where As=Absorbance of the compounds/positive control,
and Ac=Absorbance of control (MeOH solution).
1 3

Butylated hydroxy benzylidene ring: an important moiety for antioxidant synergism of…
it was then treated with benzaldehyde to get expected
semicarbazones.
also went into reaction with all the synthesized substituted
semicarbazides (5a–j) and also provided the noticeable
yields. The results are shown in Table 3. All N1-(3,5-di-
tert-butyl-2-hydroxy benzylidene)-N4-(substituted phenyl)-
semicarbazones (7a′–j′) were obtained with around 90%
more products yields.
Accordingly, 10 substituted semicarbazides were pre-
pared by the reaction of a pre-prepared acid hydrazide and
10 diferent aryl isocyanate at room temperature using two
diferent solvents: toluene and dichloromethane based on the
solubility of the reactants. All the substituted semicarbazides
(4a–j) were obtained with notable yields but at diferent
reaction completion period. The results are summarized in
Table 1.
Antioxidant activity evaluation by DPPH assay
The free radical scavenging ability of series N1-(3,5-di-
tert-butyl-4-hydroxy benzylidene)-N4-(substituted phenyl)-
semicarbazones (7a–j) and N1-(3,5-di-tert-butyl-2-hydroxy
benzylidene)-N4-(substituted phenyl)-semicarbazones
(7a′–j′) were evaluated by a non-enzymatic method DPPH
assay. Reduction of DPPH by antioxidant causes the color
changes from purple to yellow and it is also observed by the
decreasing absorption at 517 nm in the spectrophotometer.
The free radical scavenging properties of the synthesized
semicarbazones were investigated by the interaction between
experimental compounds and 0.2 mM 1,1-diphenyl-2-picryl-
hydrazine (DPPH) for 30 min. The antioxidant activities of
the series 1 of N1-(3,5-di-tert-butyl-4-hydroxy benzylidene)-
N4-(substituted phenyl)-semicarbazones (7a–j) obtained
from DPPH assay are summarized in Fig. 1.
Then the synthesized substituted semicarbazides were
taken into the reaction with 3,5-di-tert-butyl-4-hydroxy ben-
zaldehyde in the presence of acidic ethanol at 90 °C. The
results are outlined in Table 2. N1-(3,5-di-tert-butyl-4-hy-
droxy benzylidene)-N4-(substituted phenyl)-semicarbazones
(7a–j) were obtained successfully with notable yields. Semi-
carbazones containing 4-fuoro phenyl 7b, 2,4-di-chloro phe-
nyl 7c, 4-cyano phenyl 7d, 3-methoxy phenyl 7e, m-tolyl 7f,
naphthalene 7j attached at N-4 were isolated with around
90% more product yields. Again, acetyl 7h, ethyl ester 7i
substituted phenyl semicarbazones provided more than 80%
yields.
After obtaining the substituted semicarbazones (7a–j)
containing 3,5-di-tert-butyl-4-hydroxyphenyl, we prepared
another series of same substituted semicarbazones attaching
with 3,5-di-tert-butyl-2-hydroxyphenyl to investigate antiox-
idant activity of both series. Thus, pre-prepared substituted
semicarbazides (5a–j) were reacted with 3,5-di-tert-butyl-
2-hydroxy benzaldehyde 6′ upon heating with acidic etha-
nol. Interestingly, 3,5-di-tert-butyl-2-hydroxy benzaldehyde
Although all the compounds (7a–j) possessed the rea-
sonable free radical scavenging properties, most of them
exhibited promising oxidation inhibition in comparison with
standard BHT. The compound 7a showed remarkable anti-
oxidant activity in comparison with BHT as it is shown in
Fig. 1 that IC50 value of 7a was found 12.27 µM, whereas
Table 1 Evaluation of the
Substituted
Substituted
reaction of substituted
semicarbazides formation
5a–ja–c
Yields %
90b
Ar
Ar
Yields %
99b
semicarbazide
semicarbazide
5a
5b
5f
98b
5g
90b
5c
5d
5e
98c
95c
95b
5h
5i
5j
95b
90c
90b
aReagents and conditions: 3 (3.12 mmol), 4a–j (3.12 mmol), room temperature
bToluene was used as a solvent
cDichloromethane was used as a solvent
1 3

A. R. Nath et al.
Table 2 Evaluation of N1-(3,5-di-tert-butyl-4-hydroxy benzylidene)-N4-(substituted phenyl)-semicarbazones (7a–j)a,b
6
5a–j
8
7a–j
7e, 95%
7a, 92%
7d, 90%
7c, 90%
7b, 94%
7f, 90%
7g, 87%
7i, 85%
7j, 92%
7h, 88%
aReagents and conditions: 5a–g (0.65 mmol), 6 (0.65 mmol), HCl (1.6 mmol), ethanol (10 mL), 90 °C
bIsolated yield
IC50 32.63 µM value was obtained for BHT. The lower value
of IC50 of compounds indicates the better antioxidant activ-
ity. Compounds (7a–e, 7g, 7h) showed the lower IC50 val-
ues than standard BHT. The increasing order of IC50 can be
made from results in Fig. 1 as 7a>7b>7h>7e>7c>7g>
7d>7i>BHT>7j>7f.
Generally, it is observed in DPPH assay results (Figs. 1,
2) that N1-(3,5-di-tert-butyl-4-hydroxy benzylidene)-N4-
(substituted phenyl)-semicarbazones (7a–j) ofer the better
antioxidant activity than N1-(3,5-di-tert-butyl-2-hydroxy
benzylidene)-N4-(substituted phenyl)-semicarbazones
(7a′–j′). This may primarily be attributed to the position
of hydroxyl radical (-OH) on the benzylidene ring at N-1
of semicarbazones and the substituents efects of the N-4
ring.
The series of N1-(3,5-di-tert-butyl-2-hydroxy
benzylidene)-N4-(substituted phenyl)-semicarbazones
(7a′–j′) were also conducted with DPPH assay, and results
are shown in Fig. 2. Free radical scavenging properties
of these compounds can be ordered from the obtained
results as follows: 7e′>7i′>7h′​>BHT>7b′>7g′>7c′>
7d′ > 7a′ > 7f′ > 7j′.
Higher stability of phenoxy radical and lower bond dis-
sociation enthalpies BDE values of O–H bonds are the pre-
requisite of a hindered phenol to be an antioxidant. It is well
known that antioxidant activity of hindered phenol such as
BHT varies with the values of BDE of O–H bond and stabil-
ity of phenoxy radical [35]. The BDE values of O–H in BHT
depend on the OH group position on the benzene ring and its
substituents [13]. The stability of phenoxy radical depends
on the steric hindrance. So, in butylated hydroxytoluene, the
In this series, 3-methoxyphenyl semicarbazones, 3-eth-
oxy carbonyl phenyl semicarbazone and 4- acetyl phenyl
semicarbazones showed better radical scavenging proper-
ties than standard BHT, though the rest of the compounds
exhibited reasonably antioxidant properties.
1 3

Butylated hydroxy benzylidene ring: an important moiety for antioxidant synergism of…
Table 3 Evaluation of N1-(3,5-di-tert-butyl-2-hydroxy benzylidene)-N4-(substituted phenyl)-semicarbazones (7a′–j′)a, b
8
6′
5a–j
7a′–7j′
7c′, 92%
7d′, 92%
7a′, 95%
7b′, 96%
7e′, 95%
7g′, 90%
7f′, 91%
7i′, 90%
7h′, 88%
7j′, 95%
aReagents and conditions: 5a–g (0.65 mmol), 6′ (0.65 mmol), HCl (1.6 mmol), ethanol (10 mL), 90 °C
bIsolated yield
Fig. 1 Antioxidant activity of
70.00
synthesized compounds (7a–j)
57.18
by DPPH assay
60.00
50.00
45.98
40.00
32.21
32.10
32.63
27.17
30.00
23.83
23.41
18.31
7h
20.00
10.00
0.00
14.36
7b
12.27
7a
7d
7f
7g
7i
7c
7e
7j
BHT
Semicarbazone dervatives (7a–j)
sterically hindered hydroxyl group is obtained by fanking
two bulky groups like tertiary butyl groups to attain more
stable phenoxy radical. Thus, the phenoxy radical, formed
by donating a proton to reduce free radical, is not afected
by any electrophiles readily.
1 3

A. R. Nath et al.
Fig. 2 Antioxidant activity of
synthesized semicarbazones
(7a′​–j′) by DPPH assay
70.00
60.00
50.00
40.00
30.00
20.00
10.00
0.00
58.31
56.36
53.30
53.49
45.29
34.40
32.75
32.30
26.49
22.37
18.47
7d′
7f′
7g′
7h′
7i′
7a′
7b′
7c′
7e′
7j′
BHT
Semicarbazone dervaties (7a′–j′)
Scheme 3 Amide-imidic acid form of semicarbazone
In case of semicarbazones, amide-imidic acid tautom-
erism might play an important role on their antioxidant
properties shown in Scheme 3. Hydroxyl group of imidic
acid form of semicarbazones and/or secondary aromatic
amine might involve in the H-atom transfer mechanism (or
single electron transfer) to reduce the free radicals.
be afected by the substituents. Consequently, phenyl semi-
carbazones bearing BHP 7a showed promising antioxidant
activity (IC5012.27 µM or 4.51 µg/L) in DPPH assay which
is around 2.7 time better than BHT (IC50 32.63 µM). The
oxidation inhibition of phenyl semicarbazone bearing ben-
zylidene ring (N1-benzylidene-N4-phenyl-semicarbazones)
was reported 33.29 µg/L (IC50 value) in 0.1 mM DPPH con-
centration by Jafri et al. [24]. While phenyl semicarbazones
incorporated with BHP (7a) showed signifcant antioxidant
activity (IC50 4.51 µg/L) in 0.2 mM DPPH concentration
in this study. This is may be due to the combination of two
In the structure of frst series 1 (7a–j), the para hydroxyl
group of butylated hydroxyphenyl (BHP) is fanked by two
tertiary butyl groups, so the antioxidant activity of butylated
hydroxyphenyl moiety in 7a–j may remain same as BHT
due to the favorable position (ortho) of O–H group but may
1 3

Butylated hydroxy benzylidene ring: an important moiety for antioxidant synergism of…
antioxidant functions in one structure that able to exhibit
the antioxidant synergistic efect. However, this antioxidant
activity varies with the presence of diferent substituents at
N-4 ring of semicarbazones. BHA incorporated semicarba-
zones containing 4-fuoro 7b, 4-acetyl 7h, 3-methoxy 7e,
4-chloro 7c, 4-Cyano 7d, 4-ester 7i and 4-sec-butyl 7g at N-4
benzene ring of semicarbazone exhibited lower IC50 values
than BHT, but 3-methyl 7f and naphthyl 7j substituted semi-
carbazones showed higher IC50 values.
antioxidant compounds than the semicarbazones incorpo-
rated with 3,5-di-tert-butyl-2-hydroxyphenyl.
Oxidation stability assessment
of trimethylolpropane trioleate (TMPTO)
After the careful evaluation of antioxidant properties of the
series 1 and series 2 compounds, we proceeded to inves-
tigate the oxidation stability of synthesized compounds in
TMPTO as ester-based lubricant oil based on the solubility
and obtained IC50 results. Compounds 7a, 7b, 7c, 7e, 7g and
7a′ were easily soluble in TMPTO and we carried out two
types of diferential scanning calorimeter (DSC) test, namely
temperature ramping DSC and programmed temperature
DSC. Generally, lower mass% of antioxidant is preferred to
be used in the industrial lubricant composition which could
be generally 0.1–2 mass% [36]. The use of 0.25 mass% of
our experimented samples showed signifcant diference in
oxidative stability evaluation in the DSC experiment. Thus,
0.25 mass% were chosen to be blended with TMPTO base
oil for the evaluation of oxidative stability. The samples were
blended in TMPTO with very less amount (0.25 mass%) and
conducted temperature ramping DSC with a constant scan-
ning rate of 20 °C min−1 to assess their oxidation decom-
position temperature. The obtained results from tempera-
ture ramping DSC analysis are outlined in Fig. 4. Base oil
TMPTO exhibited the oxidation onset temperature (OOT)
at 173.93 °C, OOT of TMPTO incorporated with 0.25% of
BHT, compounds 7a and 7a′ did not show any signifcant
diference. However, TMPTO incorporated with N1-(3,5-di-
tert-butyl-4-hydroxy benzylidene)-N4-(3-methoxyphenyl)-
semicarbazones (7e) showed higher OOT at 185.4 °C.
Afterward, all experimental samples were carried out for
programmed temperature DSC at 150 °C isothermal temper-
ature for the evaluation of oxidation induction time (OIT).
OIT of the experimental samples is outlined in Fig. 5.
OIT of TMPTO base oil was observed 1.07 min, though
incorporation of 0.25 mass% of 7a and 7a′ didn’t show any
signifcant increase in OIT, whereas BHT showed 5.48 min
OIT. But TMPTO blended with 0.25 mass% of 7e and 7c
In the structure of the second series, the hydroxyl group
of BHP is not fanked by two tertiary butyl groups in 3,5-di-
tert-butyl-2-hydroxy benzylidene ring. This may increase
the BDE value of O–H group, resulting in the lower antioxi-
dant activity of the compounds of this series 2 in compari-
son with series 1. BDE value of O–H group of this series
might be afected by the hydrogen bond which would occur
between the hydrogen of OH group and nitrogen of imine
group. Due to the formation of a hydrogen bond between H
and N, it becomes difcult to abstract the proton from –OH
group due to the high BDE values. It can be displayed in
Fig. 3 that describes the probable formation of hydrogen
bond in series 2 structure (7a′–j′).
This hydrogen bond might decrease the normal anti-
oxidant activity of butylated hydroxyphenyl which results
are the lower antioxidant activity of series 2 compounds.
This series may not be able to provide any synergistic
efect between BHP and semicarbazones functional group
because of the formation of intramolecular H-bond. This
may be attributed to the higher IC50 value of the compound
7a′ (53.30 µM), resulting in the lower antioxidant activity
which is around 4.3 times lower than the antioxidant activity
of 7a (IC5012.27 µM). Thus, the antioxidant activity of series
2 might be obtained only from semicarbazones functions
which have been described earlier. Interestingly, 3-meth-
oxyphenyl 7e′, 4-ethyl carbonyl phenyl 7i′ and 4-acetyl
phenyl 7h′ semicarbazones incorporated with 3,5-di-tert-
butyl-2-hydroxyphenyl showed better antioxidant activ-
ity than standard BHT in DPPH assay. However, it can be
concluded from the above discussion that semicarbazone
bearing 3,5-di-tert-butyl-4-hydroxyphenyl can be efective
Fig. 3 Probable structure for the
formation of hydrogen bond in
series 2
1 3

A. R. Nath et al.
Fig. 4 Temperature ramping
DSC analysis for the TMPTO
with 0.25 mass% antioxidants
Temperature ramping DSC
185.4
188
186
184
182
180
178
176
174
172
170
168
178.23
177.53
175.49
174.72
174.53
174.1
BHT
173.93
7a
7a′
7b
7c
7e
7g
TMPTO
Fig. 5 Oxidation induction time
of TMPTO incorporated with
0.25% experimental sample at
150 °C isothermal
OIT at 150 °C isothermal
10.02
12
10
8
8
6.5
6.57
5.48
6
3.48
7a
4
2
1.19
1.07
0
7a′
7b
7c
7e
7g
BHT
TMPTO
showed better OIT values (10.02 min and 8 min, respec-
tively) shown in Fig. 6. Again, TMPTO incorporated 4-fuo-
rophenyl semicarbazones (7b) and 4-sec-butyl-phenyl semi-
carbazones (7g) showed almost identical OIT values (6.5
and 6.57 min, respectively).
with 0.25 mass% of 7c, 7e and BHT in order to evaluate the
thermal stability.
It was seen from Fig. 8 that TMPTO with 0.25 mass% of
compound 7e and 7c started decomposition at 373.93 °C and
372.77 °C, respectively, whereas only TMPTO decomposed
at 341.07 °C. On the other hand, 341.86 °C decomposition
temperatures were found for the TMPTO with 0.25 mass%
of BHT which indicates that synthesized compounds 7c and
7e showed the higher thermal stability in contrast with the
base oil TMPTO and standard antioxidant BHT.
This experiment was again carried out at 125 °C iso-
thermal temperature with the same blended TMPTO oil to
observe the change of OIT. The obtained results are dis-
played in Table 4.
It was found that 0.25 mass% 7e and 7c inhibited oxida-
tion stability (OIT) of TMPTO 42.23 min and 41.52 min,
respectively, at 125 °C isothermal (Fig. 7), while Blank
TMPTO showed 2.25 min OIT.
It was found in the DSC and TGA results that oxidation
stability of TMPTO increased signifcantly in the combi-
nation of compounds 7e and 7c compared to BHT. It was
reported that the compounds having two or more antioxidant
functions in one structure can able to exert auto-synergism
in lubricant oil [11]. Due to the presence of two antioxi-
dant functions (BHA and semicarbazone function) in the
Afterward, for the further assessment of antioxidant
blended oil, we carried out the conventional thermogravi-
metric analysis (TGA) with TMPTO base oil and TMPTO
1 3

Butylated hydroxy benzylidene ring: an important moiety for antioxidant synergism of…
(a) 7c at Isothermal temp 150 °C
(b) 7e at Isothermal temp 150 °C
2.0
2.0
1.5
1.5
1.0
1.0
N2
O2
N2
O2
0.5
0.0
0.5
0.0
10.02 min OIT
8.00 min OIT
10
0
20
30
40
0
10
20
30
40
Time/min
Time/min
Fig. 6 OIT at isothermal temperature 150 °C measured by the heat fow vs time
Table 4 Oxidation induction time of TMPTO incorporated with 0.25% experimental sample at 125 °C isothermal
Compounds
no.
0.25 mass% 7a 0.25 mass% 7b 0.25 mass% 7c 0.25 mass% 7e 0.25 mass% 7g 0.25 mass% 7a′ 0.25 mass%
TMPTO
2.25
BHT
OIT min
8.26
–
41.52
42.23
–
7.42
15.2
‘–’ No OIT was observed for the 7c and 7g
0.7
(a) 7c at Isothermal temp 125 °C
1.6
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0.0
(b) 7e at Isothermal temp 125 °C
0.6
0.5
0.4
0.3
0.2
0.1
0.0
N2
O2
N2
O2
42.23 min OIT
41.52 min OIT
– 20
0
20
40
60
80
100
120
140
160
0
50
100
150
200
Time/min
Time/min
Fig. 7 OIT at isothermal temperature 125 °C measured by the heat fow versus time
1 3

A. R. Nath et al.
may be a probable reason for the lower oxidation stability of
the synthesized compounds in oil. Interestingly, OIT results
of compounds 7e, 7c, 7b, and 7g show the better oxidation
stability in comparison with BHT.
100
80
60
40
20
0
Generally, semicarbazones were reported as neutral tri-
dentate ligand due to the presence of azomethine N and
carbamoyl O, which can provide the stronger binding abil-
ity to metal ions. So several binding modes can be observed
if additional coordinating functional group is present in
the semicarbazone derivatives [38, 39]. Thus, the metal
ions can easily be deactivated by appropriate semicarba-
zones through the formation of several coordination bond
between donor atoms and metal ions. Deactivating metal
ions in the lubricant oil is prerequisite to accelerate the
oxidation stability since metal ions are very susceptible
to convert the acid and hydroperoxide into free radicals.
Therefore, metal deactivators or chelators are one of the
important antioxidant classes in lubricant additives [40].
Generally metal deactivators or chelators deactivated the
metal ions in lubricant oil which are responsible for accel-
erating oxidation reaction by the production of free radicals
[41]. Therefore, all chelating metal deactivators contain
multiple donor atoms which can able to deactivate the
metal ions by the formation of complex compounds. Thus,
semicarbazones can act as metal deactivator because of
having multiple donor atoms. Due to the presence of addi-
tional donor atoms as substituents at N-4 ring of semicar-
bazones, several binding modes of semicarbazones might
be observed and would be efective metal deactivator. Com-
pounds 7e and 7c was found better oxidative stability in
TMPTO in DSC experiment, and this may be due to the
presence of 3-methoxy (7e) and 2,4-di-chlorine (7c) sub-
stituents at N-4 ring of semicarbazones. Thus, methoxy and
chlorine groups might act as donor atom and their favorable
position at N-4 ring of semicarbazone structure enhanced
the metal deactivator properties by the increase in the metal
binding mode [42, 43] which can be shown in Fig. 9.
BHT
7c
7e
Lube oil
0
100
200
300
400
500
600
Temperature/°C
Fig. 8 Thermal decomposition temperature of TMPTO base oil and
TMPTO with 0.25 mass% antioxidants obtained by thermogravimet-
ric analysis
one structure, the synthesized semicarbazone may able to
exhibit auto-synergistic efect to protect the oil from pre-
mature oxidation. But the OIT of compounds 7a and 7a′
obtained by programmed temperature DSC didn’t show any
signifcant efect in the oxidation stability of lubricant oil.
So, no antioxidant synergism was observed in the oil oxida-
tion stability test for the compound 7a and 7a′, though it
showed the highest antioxidant activity in non-enzymatic
free radical scavenger test DPPH assay (Fig. 1). It was found
in the literature [37] that the combination of two primary
antioxidants (phenolic antioxidant and secondary aromatic
amino antioxidant) exhibits negative synergistic efect in
the oxidation of lubricant oil. Unfortunately, both butylated
hydroxyphenyl (hindered phenol) and semicarbazone func-
tion (probably aromatic secondary amine) in structure of
synthesized semicarbazones act as primary antioxidant. This
Fig. 9 Metal binding mode of
compound 7e and 7c
7c
7e
1 3

Butylated hydroxy benzylidene ring: an important moiety for antioxidant synergism of…
Therefore, incorporation of butylated hydroxyphenyl
into semicarbazones provided signifcant free radical scav-
enging properties shown in DPPH results. However, it was
not observed in diferential scanning calorimeter test (oxi-
dation stability) of lubricant oil. However, the presence of
electron withdrawing substituents or donor atom at N-4
ring of semicarbazones may increase the metal binding
mode which would help to efciently deactivate the metal
ions in the lubricant oil. Moreover, insertion of suitable
functional groups at the appropriate position of the N-4
ring of semicarbazones helps to obtain several metal bind-
ing modes which are very useful to prepare a variety of
metal complexes with important chemical properties.
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Publisher’s Note Springer Nature remains neutral with regard to
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Afliations
Amit R. Nath1 · Wageeh A. Yehye1 · Mohd Rafe Bin Johan1
* Wageeh A. Yehye
wdabdoub@um.edu.my
1
Nanotechnology and Catalysis Research Centre
(NANOCAT), Block 3A, Institute for Advanced Studies,
University of Malaya, 50603 Kuala Lumpur, Malaysia
1 3