Semicarbazide and thiosemicarbazide containing butylated hydroxytoluene moiety: new potential antioxidant additives for synthetic lubricating oil

Article abstract of DOI:10.1039/d0ra10626g

New multipotent antioxidants (MPAOs), namely semicarbazides and thiosemicarbazides bearing thiolated butylated hydroxytoluene (BHT), were synthesized. The antioxidant activity of the synthesized compounds was evaluated usingin vitroDPPH assay. Compounds containing thiosemicarbazides (5a′-h′) were found more active in free radical scavenger than semicarbazides (5a-h). Among the other compounds, compound5f′(IC₅₀of 25.47 ± 0.42 μM) showed the best antioxidant activity against DPPH radicals compared to standard antioxidant butylated hydroxytoluene (BHT). Based on DPPH results, compound5f′and its corresponding semicarbazide5fwere blended into trimethylolpropane trioleate (TMPTO) and isothermal differential scanning calorimetry (DSC) was carried out for the investigation of oxidative stability. At 125 °C isothermal DSC, TMPTO with 0.25 wt% of5f′showed 1.5 times higher oxidation stability than its corresponding semicarbazide5fand was 2 times better than BHT. It was anticipated that due to the strong auto-synergistic effect, compound5f′showed promising oxidative stability to TMPTO by protecting from pre-mature oxidative degradation.

Full text of DOI:10.1039/d0ra10626g

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Semicarbazide and thiosemicarbazide containing
butylated hydroxytoluene moiety: new potential
antioxidant additives for synthetic lubricating oil†
Cite this: RSC Adv., 2021, 11, 7138
a
a
a
b
Syabilah Sazeli, Amit R. Nath, Mohd Hafiz Ahmad, N. W. M. Zulkifli,
a
a
a
Mohd Rafie Johan, Wageeh A. Yehye and Lee Hwei Voon
*
New multipotent antioxidants (MPAOs), namely semicarbazides and thiosemicarbazides bearing thiolated
butylated hydroxytoluene (BHT), were synthesized. The antioxidant activity of the synthesized
0
compounds was evaluated using in vitro DPPH assay. Compounds containing thiosemicarbazides (5a –
0
h ) were found more active in free radical scavenger than semicarbazides (5a–h). Among the other
0
compounds, compound 5f (IC50 of 25.47 ꢀ 0.42 mM) showed the best antioxidant activity against DPPH
radicals compared to standard antioxidant butylated hydroxytoluene (BHT). Based on DPPH results,
0
compound 5f and its corresponding semicarbazide 5f were blended into trimethylolpropane trioleate
(
TMPTO) and isothermal differential scanning calorimetry (DSC) was carried out for the investigation of
Received 18th December 2020
ꢁ
0
oxidative stability. At 125 C isothermal DSC, TMPTO with 0.25 wt% of 5f showed 1.5 times higher
oxidation stability than its corresponding semicarbazide 5f and was 2 times better than BHT. It was
Accepted 1st February 2021
DOI: 10.1039/d0ra10626g
rsc.li/rsc-advances
0
anticipated that due to the strong auto-synergistic effect, compound 5f showed promising oxidative
stability to TMPTO by protecting from pre-mature oxidative degradation.
be one of the reasons of searching for new potential antioxi-
dants. In the history of the development of antioxidants, many
Introduction
Premature oxidation is one of the major hindrances to develop scientists have proven semicarbazide and thiosemicarbazide
oxidative and thermally stable synthetic lubricants. For the last derivatives as a superior oxidation inhibitors. This type of
few years, growing ecological alarms and expanding preventive compound has rising interests in the research group because of
etiquettes also have encouraged the enhancement of its multi-donor ligands. They had a wide range of pharmaco-
environmental-friendly lubricants worldwide. Therefore, synthetic logical activities not only as antioxidant, but also as antifungal,
ester-based biodegradable lubricant oils are a class of compound antibacterial, antitumor, antimalarial, antiviral, antimicrobial,
that need extra attention. The most commonly used ester-based anti-tubecular agents, which made it biologically active and
4
–7
lubricant is trimetylolpropane trioleate (TMPTO), a petrochemical nontoxic compounds.
derivative with naturally derived oleic acid. It has outstanding
1–3
On the other hand, BHT is the most common primary
lubricity, low-temperature properties, high viscosity index, and synthetic antioxidant which has been used in a wide range of
improved oxidative resistance compared to vegetable oil thus application until today. Current research found that BHT could
promoting it to be a competitive green lubricant.
Though TMPTO provides superior lubricant properties to excellent oxidative stability for synthetic ester based lubri-
be combining with other secondary antioxidant to obtain an
8–10
mineral oil, its wide application was restricted due to its poor cant.
Antioxidant synergism is the subsequent impact of
oxidative stability towards oil from premature oxidation or auto- utilizing at least two different type of antioxidants together
1
oxidation. Therefore, the development of antioxidants with conveys more noteworthy oxidation soundness than that of any
11
better oxidative stability properties and less toxicity appeared to individual antioxidant functions. Synergistic antioxidants
frameworks compromise convincing answers for issues where
12
a single antioxidant is decient to offer satisfactory outcomes.
a
The mixture of various antioxidants in denite proportion could
Nanotechnology & Catalysis Research Centre (NANOCAT), Universiti Malaya, Block
3
A, Inst. for Advanced Studies, 50603 Kuala Lumpur, Malaysia. E-mail: perform in a decent synergistic impact where oxidation stability
syabilahsazeli@hotmail.com; amit_cu.chem@yahoo.com; haz99414@yahoo.com;
8,13
is superior to the exclusively utilized antioxidants.
wdabdoub@yahoo.com; leehweivoon@um.edu.my
Organosulfur compounds are frequently used in the lubri-
cant compositions with BHT to have better synergistic impact
since it is essential additives for antioxidant, antiwear and
extreme pressure properties. Though, the least amount of
b
Department of Mechanical Engineering, Universiti Malaya, 50603 Kuala Lumpur,
Malaysia. E-mail: nurinmz@um.edu.my
†
Electronic supplementary information (ESI) available. See DOI:
0.1039/d0ra10626g
1
7138 | RSC Adv., 2021, 11, 7138–7145
© 2021 The Author(s). Published by the Royal Society of Chemistry

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sulfur-containing additive should be applied in advanced
engine oil formulation according to the current environmental
and economic constraint. In fact, the use of several antioxidants
in lubricant formulation may raise the environmental issue and
increase the cost. Therefore, multi-functional antioxidant has
become more popular to cut down the number of several anti-
oxidants in lubricant composition. Since multifunctional anti-
oxidants can possess several antioxidant functional groups in
their structure, which can provide auto-synergistic antioxidant
system by exhibiting radical scavenging and peroxide decom-
12,14,15
posing properties.
So, we envisioned to assemble several antioxidant func- Scheme 1 Preparation of acid hydrazide, 3.
tions in one structure by incorporating BHT moiety into
semicarbazide and thiosemicarbazide compounds to obtain better
added isocyanate (1 mmol), and the reaction mixture was stir-
red at room temperature for 2 hours until the reaction
completed (monitored by thin-layer chromatography). The
white precipitate was collected by ltration, washed with water
and boiled hexane, and dried at 50 C. The same procedure is
applied to respective isothiocyanate group of reactants.
antioxidant auto-synergistic effect. This article deals with the prep-
aration and evaluation of new series of semicarbazide and its cor-
responding thiosemicarbazide derivatives bearing BHT moiety for
their antioxidant activities using DPPH assays and DSC. BHT moiety
has been incorporated into semicarbazide and thiosemicarbazide
through thioether bridge to obtain multifunctional antioxidant
which can offer better auto-synergistic antioxidant system. To our
acquaintance, this is the rst report discussing the comparative
antioxidant activity between semicarbazide and thiosemicarbazide
derivatives. Thus, this study would help researchers to have deep
understanding on potential between multifunctional semicarbazide
and thiosemicarbazide derivatives as antioxidant inhibitor for future
global lubricant oxidative stability industry perspective.
ꢁ
2-(2-(3,5-Di-tert-butyl-4-hydroxybenzylthio)acetyl)-N-phenyl hy
drazinecarboamide, 5a. Yield: 0.42 g (95%); white solid; mp
ꢁ
ꢂ1
1
1
51 C; FTIR (ATR): 3619, 3252, 2960, 1605 cm ; H NMR (600
MHz, DMSO-d
): d ¼ 9.83 (s, 1H), 8.72 (s, 1H), 8.13 (s, 1H), 7.46 (d, J
6 Hz, 2H), 7.26 (t, J ¼ 6 Hz, 2H), 7.08 (s, 2H), 6.96 (t, J ¼ 6 Hz, 1H),
6
¼
13
6
.89 (s, 1H), 3.79 (s, 2H), 3.13 (s, 2H), 1.38 (s, 18H); C NMR (150
MHz, DMSO-d ): d ¼ 169.49, 155.68, 153.32, 140.06, 139.63, 129.12,
6
1
28.92, 125.73, 122.38, 118.90, 36.56, 34.95, 32.92, 30.83; HRMS (Q-
+
+
TOF): m/z [M + Na] ¼ 466.2161, calcd for C H NaN O S 466.2135.
24
33
3 3
Experimental methods
General reagents and instruments
2-(2-(3,5-Di-tert-butyl-4-hydroxybenzylthio)acetyl)-N-(4-uoro
phenyl)hydrazinecarboamide, 5b. Yield: 0.44 g (96%); white solid;
ꢁ
mp 160–162 C; FTIR (ATR): 3634, 3292–3344, 2871–2955,
All materials and solvents were purchased in analytical grade from
commercial suppliers and used without further purication.
Toluene was dried over molecular sieves 4A (Sigma-Aldrich) prior to
use. BHT and DPPH were purchased from Sigma-Aldrich. Merck
TLC aluminium sheets (Silica gel 60 F254) were used for thin layer
chromatography. All synthesized target compounds were charac-
terized using FTIR, NMR, LCMS, and melting point instrument. An
ꢂ1
1
1656 cm ; H NMR (600 MHz, DMSO-d
6
): d ¼ 9.81 (s, 1H), 8.76 (s,
1H), 8.15 (s, 1H), 7.47 (m, 2H), 7.10 (m, 2H), 7.07 (s, 2H), 6.89 (s, 1H),
13
3.78 (s, 2H), 3.12 (s, 2H), 1.37 (s, 18H); C NMR (150 MHz, DMSO-
d ): d ¼ 169.49, 158.64, 157.06, 153.31, 139.64, 136.40, 128.92,
6
1
20.70, 115.66, 115.52, 36.55, 34.94, 32.93, 30.82; HRMS (Q-TOF): m/
+
+
z [M + H] ¼ 462.2225, calcd for C24
33 3 3
H N O SF 462.2221.
2-(2-(3,5-Di-tert-butyl-4-hydroxybenzylthio)acetyl)-N-4-(cyano
infrared spectrum was recorded on a PerkinElmer, FTIR-Spectrum
phenyl)hydrazinecarboamide, 5c. Yield: 0.42 g (91%); white solid;
ꢂ1
4
00 spectrometer at wave number from 4000–400 cm . 1D and
ꢁ
mp 141–148 C; FTIR (ATR): 3589–3649, 3337, 2956–3025, 2234,
2D analysis of nuclear magnetic resonance (NMR) spectra were
ꢂ1
1
1
1
1
601 cm ; H NMR (600 MHz, DMSO-d
6
): d ¼ 9.89 (s, 1H), 9.27 (b,
obtained on Bruker Advance III 600 MHz. Spectra are reported in
units of ppm on the scale, relative to chloroform and DMSO. The
coupling constants are given in Hz. HR-mass spectra (ESI†) were
obtained with 6550 i-Funnel Q-TOF LC-MS. Melting points were
determined with Mel-Temp II melting point apparatus.
H), 8.43 (s, 1H), 7.71 (d, J ¼ 6 Hz, 2H), 7.65 (d, J ¼ 6, 2H), 6.88 (s,
13
H), 3.78 (s, 2H), 3.14 (s, 2H), 1.38 (s, 18H); C NMR (150 MHz,
DMSO-d ): d ¼ 169.51, 155.24, 153.33, 144.66, 139.64, 133.64, 128.89,
6
1
25.73, 119.75, 118.74, 103.86, 36.53, 34.95, 32.87, 30.82; HRMS (Q-
+
+
TOF): m/z [M + H] ¼ 469.2265, calcd for C25
33 3 4
H O N S 469.2268.
2-(2-(3,5-Di-tert-butyl-4-hydroxybenzylthio)acetyl)-N-(3-meth
Preparation of acid hydrazide
oxyphenyl)hydrazinecarboamide, 5d. Yield: 0.44 g (93%); white
ꢁ
ꢂ1
solid; mp 134–136 C; FTIR (ATR): 3624, 3288, 2961, 1683 cm
;
The 2-((3,5-di-tert-butyl-4-hydroxybenzyl)thio) acetohydrazide
1
H NMR (600 MHz, DMSO-d ): d ¼ 9.82 (b, 1H), 8.72 (b, 1H), 8.12
was synthesized according to previously described method
6
16
(
b, 1H), 7.16 (m, 1H), 7.08 (s, 2H), 6.98 (d, J ¼ 6 Hz, 1H), 6.88 (s,
shown in Scheme 1.
1
(
H), 6.54 (dd, J ¼ 6 J ¼ 6 Hz, 1H), 3.79 (s, 2H), 3.71 (s, 3H), 3.13
1
3
s, 2H), 1.38 (s, 18H); C NMR (150 MHz, DMSO-d
6
): d ¼ 169.49,
Preparation of semicarbazides and thiosemicarbazides:
general synthesis procedure
1
3
4
58.64, 157.06, 153.31, 139.64, 136.40, 128.92, 120.70, 115.59,
+
6.55, 34.94, 32.93, 30.82; HRMS (Q-TOF): m/z [M + H]
75.2470, calcd for C25
¼
To a solution of S-(3,5-di-tert-butyl-4-hydroxybenzyl) thioglycolic
acid hydrazide (3; 0.3241 g, 1 mmol), dry toluene (5 mL) was
+
H
37
O
4
N
3
S 475.2442.
©
2021 The Author(s). Published by the Royal Society of Chemistry
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2
-(2-(3,5-Di-tert-butyl-4-hydroxybenzylthio)acetyl)-N-(2,4-di 1H), 8.11 (s, 1H), 7.39 (m, 2H), 7.12 (s, 2H), 7.11 (d, J ¼ 6 Hz, 2H),
13
chlorophenyl)hydrazinecarboamide, 5e. Yield: 0.46 g (90%); 5.24 (s, 1H), 3.85 (s, 2H), 3.27 (s, 2H), 1.44 (s, 18H); C NMR (150
ꢁ
white solid; mp 104–106 C; FTIR (ATR): 3644, 3184–3332, MHz, CDCl
): d ¼ 166.22, 162.09, 160.46, 153.29, 136.47, 132.47,
3
ꢂ1
1
2
1
7
2
862–2956, 1591 cm
;
H NMR (600 MHz, DMSO-d
6
): d ¼ 127.07, 126.92, 125.86, 116.64, 116.49, 37.75, 34.35, 33.76, 30.23;
+
0.00 (s, 1H), 8.91 (s, 1H), 8.33 (b, 1H), 8.11 (d, 3J ¼ 6 Hz 1H), HRMS (Q-TOF): m/z [M + Na] ¼ 500.1827, calcd for C24
32 2
H O -
+
.62 (d, 4J ¼ 0 Hz 1H), 7.37 (dd, 3J ¼ 6, 4J ¼ 0 Hz 1H), 7.07 (s, NaN
3
S
2
F 500.1812.
1
3
H), 6.89 (s, 1H), 3.78 (s, 2H), 3.13 (s, 2H), 1.37 (s, 18H);
C
2-(2-(3,5-Di-tert-butyl-4-hydroxybenzylthio)acetyl)-N-(4-cyanophen
0
NMR (150 MHz, DMSO-d ): d ¼ 169.40, 155.03, 153.33, 139.63, yl)hydrazinecarbothioamide, 5c . Yield: 0.43 g (90%); white solid; mp
6
ꢁ
1
3
5
35.50, 129.06, 128.84, 128.14, 126.80, 125.74, 123.28, 122.57, 152–154 C; FTIR (ATR): 3634, 3127–3205, 2956, 2229, 1600,
+
ꢂ1 1
6.52, 34.94, 32.65, 30.81; HRMS (Q-TOF): m/z [M + Na]
¼
1240 cm ; H NMR (600 MHz, CDCl
): d ¼ 9.81 (b, 2H), 8.93 (b, 1H),
3
+
10.1373, calcd for C22
31 3 3 2
H O NaN SCl 510.1336.
7.66 (d, J ¼ 6 Hz, 2H), 7.53 (d, J ¼ 6 Hz, 2H), 7.03 (s, 2H), 5.17 (s, 1H),
13
2
-(2-(3,5-Di-tert-butyl-4-hydroxybenzylthio)acetyl)-N-(1-naph
3.76 (s, 2H), 3.25 (s, 2H), 1.34 (s, 18H); C NMR (150 MHz, CDCl ):
3
thyl) hydrazinecarboamide, 5f. Yield: 0.44 g (89%); white solid; d ¼ 179.79, 167.41, 153.42, 142.01, 136.63, 133.03, 126.59, 125.78,
ꢁ
mp 121–123 C; FTIR (ATR): 3639, 3200–3302, 2873–2961, 122.55, 118.55, 107.53, 37.78, 34.36, 33.97, 30.22; HRMS (Q-TOF): m/z
ꢂ1
1
+
+
1
8
1
610 cm ; H NMR (600 MHz, DMSO-d ): d ¼ 9.96 (s, 1H), [M + H] ¼ 485.2043, calcd for C25
33 2 4 2
H O N S 485.2039.
6
.79 (s, 1H), 8.43 (s, 1H), 8.06 (d, 4J ¼ 12 Hz, 1H), 7.92 (m,
2-(2-(3,5-Di-tert-butyl-4-hydroxybenzylthio)acetyl)-N-(3-methoxy
0
H), 7.80 (b, 1H), 7.67 (d, 3J ¼ 6 Hz, 1H), 7.53 (m, 2H), 7.46 phenyl)hydrazinecarbothioamide, 5d . Yield: 0.46 g (94%); white
ꢁ
(
t, 3J ¼ 6, 3J ¼ 6 Hz, 1H), 7.08 (s, 2H), 6.90 (s, 1H), 3.80 (s, solid; mp 109–111 C; FTIR (ATR): 3634, 3283–3332, 2834–2956,
1
3
ꢂ1 1
2
d
1
1
H), 3.16 (s, 2H), 1.36 (s, 18H); C NMR (150 MHz, DMSO- 1674, 1162 cm ; H NMR (600 MHz, DMSO-d
): d ¼ 169.60, 156.42, 153.32, 139.69, 134.58, 134.19, 9.68 (s, 1H), 9.54 (b, 1H), 7.24 (t, 3J ¼ 6, 3J ¼ 6 Hz, 1H), 7.17 (s, 1H),
28.90, 128.74, 126.41, 126.21, 126.16, 125.74, 124.25, 7.08 (s, 2H), 7.04 (dd, 3J ¼ 6, 4J ¼ 6 Hz, 1H), 6.89 (s, 1H), 6.74 (d, 3J
): d ¼ 10.09 (b, 1H),
6
6
13
22.38, 119.42, 36.59, 34.92, 32.91, 30.81; HRMS (Q-TOF): m/ ¼ 6 Hz, 1H), 3.79 (s, 2H), 3.74 (s, 1H), 3.17 (s, 2H), 1.38 (s, 18H);
C
+
+
z [M + H] ¼ 494.2473, calcd for C28H36O N S 494.2472.
NMR (150 MHz, DMSO-d
6
): d ¼ 181.20, 169.37, 159.50, 153.34,
3
3
2
-(2-(3,5-Di-tert-butyl-4-hydroxybenzylthio)acetyl)-N-(allyl)hydrazi 140.67, 139.66, 129.37, 128.86, 125.71, 110.93, 55.57, 36.68, 34.95,
ꢁ
+
necarboamide, 5g. Yield: 0.37 g (90%); white solid; mp 127–129 C; 33.33, 30.83; HRMS (Q-TOF): m/z [M + H] ¼ 491.2245, calcd for
ꢂ1
1
+
FTIR (ATR): 3619, 3436.3–3515, 3139, 2867–2956, 1675 cm ; H
NMR (600 MHz, DMSO-d
): d ¼ 9.63 (s, 1H), 7.86 (s, 1H), 7.06 (s, 2H),
C H O N S 491.2293.
25 36 3 3 2
2-(2-(3,5-Di-tert-butyl-4-hydroxybenzylthio)acetyl)-N-(2,4-dichloro
6
0
6
.86 (s, 1H), 6.47 (t, 3J ¼ 6, 3J ¼ 6 Hz, 1H), 5.80 (m, 1H), 5.15 (dd, 3J phenyl)hydrazinecarbothioamide, 5e . Yield: 0.51 g (96%); white
ꢁ
¼
18, 2J ¼ 0 Hz, 1H), 5.03 (dd, 3J ¼ 12, 2J ¼ 0 Hz, 1H), 3.75 (s, 2H), solid; mp 131–136 C; FTIR (ATR): 3634, 3174–3278, 2965, 1651,
13
ꢂ1 1
3
.66 (t, 3J ¼ 6, 3J ¼ 6 Hz, 2H), 3.08 (s, 2H), 1.38 (s, 18H); C NMR 1275 cm ; H NMR (600 MHz, DMSO-d ): d ¼ 10.19 (b, 1H), 9.90 (b,
6
(
150 MHz, DMSO-d ): d ¼ 169.39, 158.27, 153.30, 139.62, 136.75, 1H), 9.48 (b, 1H), 7.67 (s, 1H), 7.43 (d, 3J ¼ 6 Hz, 2H), 7.07 (s, 2H),
13
6
1
28.96, 125.68, 114.94, 41.94, 36.62, 34.94, 32.99, 30.84; HRMS (Q- 6.89 (s, 1H), 3.78 (s, 2H), 3.16 (s, 2H), 1.37 (s, 18H); C NMR (150
+
+
TOF): m/z [M + Na] ¼ 430.2154, calcd for C21
H
33
O
3
NaN
3
S 430.2135. MHz, DMSO-d
6
): d ¼ 182.34, 169.41, 153.34, 139.66, 136.35, 132.86,
2
-(2-(3,5-Di-tert-butyl-4-hydroxybenzylthio)acetyl)-N-butyl hydrazi 132.49, 131.94, 129.28, 128.85, 127.78, 125.69, 36.69, 34.94, 33.24,
ꢁ
+
necarboamide, 5h. Yield: 0.37 g (87%); white solid; mp 82–84 C; 30.83; HRMS (Q-TOF): m/z [M + Na] ¼ 526.1147, calcd for C22
H -
31
ꢂ1
1
+
FTIR (ATR): 3375, 3132, 2849–2917, 1635 cm ; H NMR (600 MHz,
DMSO-d
): d ¼ 9.60 (s, 1H), 7.75 (s, 1H), 7.06 (s, 2H), 6.87 (s, 1H), 6.26
O NaN S Cl 526.1138.
2 3 2 2
2-(2-(3,5-Di-tert-butyl-4-hydroxybenzylthio)acetyl)-N-1-naphthyl hy
6
0
(
(
t, 3J ¼ 6, 3J ¼ 6 Hz, 1H), 3.75 (s, 2H), 3.07 (s, 2H), 3.01 (m, 2H), 1.37 drazine carbothioamide, 5f . Yield: 0.47 g (92%); white solid; mp 119–
13
ꢁ
ꢂ1 1
s, 18H), 1.26 (m, 2H), 0.87 (t, 3J ¼ 6, 3J ¼ 6 Hz, 3H); C NMR (150 121 C; FTIR (ATR): 3644, 3166–3258, 2956, 1698 cm ; H NMR (600
MHz, DMSO-d ): d ¼ 169.35, 158.41, 153.30, 139.61, 128.93, 125.69, MHz, CDCl ): d ¼ 9.79 (b, 1H), 9.04 (b, 1H), 8.54 (s, 1H), 7.92 (m, 1H),
9.30, 36.59, 34.93, 32.92, 32.42, 30.82, 19.88, 14.17; HRMS (Q-TOF): 7.82 (m, 1H), 7.76 (d, 3J ¼ 12 Hz, 1H), 7.58 (d, 3J ¼ 12 Hz, 1H), 7.46
6
3
3
+
+
m/z [M + H] ¼ 424.2637, calcd for C22
H
38
O
3
N
3
S 424.2628.
(m, 1H), 7.45 (s, 1H), 7.42 (m, 1H), 7.00 (s, 2H), 5.08 (s, 1H), 3.72 (s,
13
2
-(2-(3,5-Di-tert-butyl-4-hydroxybenzylthio)acetyl)-N-phenyl
2H), 3.07 (s, 2H), 1.31 (s, 18H); C NMR (150 MHz, CDCl
): d ¼
3
0
hydrazinecarbothioamide, 5a . Yield: 0.43 g (94%); white solid; 179.16, 165.29, 153.24, 136.29, 134.51, 132.15, 129.58, 128.57; 128.53,
mp 126–128 C; FTIR (ATR): 3634, 3144, 2956, 1670, 1225 cm
ꢁ
ꢂ1
;
127.27, 126.87, 126.83, 125.87, 125.63, 124.92, 122.10, 37.62, 34.31,
1
+
H NMR (600 MHz, DMSO-d ): d ¼ 10.10 (s, 1H), 9.67 (s, 1H), 33.69, 30.24; HRMS (Q-TOF): m/z [M + H] ¼ 510.2241, calcd for
6
+
9
.60 (b, 1H), 7.45 (s, 2H), 7.34 (t, 3J ¼ 6, 3J ¼ 6 Hz, 1H), 7.17 (t, 3J
C
28
H
36
O
2
N
3
S
2
510.2243.
¼
6, 3J ¼ 6 Hz, 1H), 7.08 (s, 2H), 6.90 (s, 1H), 3.79 (s, 2H), 3.17 (s,
2-(2-(3,5-Di-tert-butyl-4-hydroxybenzylthio)acetyl)-N-(allyl) hy
1
3
0
2
1
1
H), 1.38 (s, 18H); C NMR (150 MHz, DMSO-d
6
): d ¼ 181.39, drazine carbothioamide, 5g . Yield: 0.47 g (85%); white solid; mp
ꢁ
69.38, 153.34, 139.66, 139.55, 128.87, 128.59, 126.09, 125.70, 113–124 C; FTIR (ATR): 3619, 3439–3512, 3141, 2868–2956, 1674,
25.51, 36.67, 34.95, 33.35, 30.84; HRMS (Q-TOF): m/z [M + H]
460.2096, calcd for C24H O N S 460.2087.
34 3 3 2
+
ꢂ1
1
1230 cm ; H NMR (600 MHz, DMSO-d
): d ¼ 9.88 (s, 1H), 9.32
6
+
¼
(s, 1H), 8.05 (s, 1H), 7.07 (s, 2H), 6.88 (s, 1H), 5.82 (m, 1H), 5.13
2
-(2-(3,5-Di-tert-butyl-4-hydroxybenzylthio)acetyl)-N-(4-uoroph (dd, 3J ¼ 18, 2J ¼ 6 Hz, 1H), 5.04 (dd, 3J ¼ 12, 2J ¼ 0 Hz, 1H), 4.10
0
13
enyl)hydrazinecarbothioamide, 5b . Yield: 0.45 g (95%); white (s, 2H), 3.75 (s, 2H), 3.11 (s, 2H), 1.38 (s, 18H); C NMR (150 MHz,
ꢁ
solid; mp 109–111 C; FTIR (ATR): 3624, 3139–3283, 2956, 1670, DMSO-d
220 cm ; H NMR (600 MHz, CDCl ): d ¼ 9.47 (b, 1H), 8.54 (b, 125.68, 115.76, 46.31, 36.66, 34.94, 33.27, 30.84; HRMS (Q-TOF):
6
): d ¼ 182.35, 169.39, 153.33, 139.64, 135.31, 128.87,
ꢂ1
1
1
3
+
+
m/z [M + H] ¼ 424.2110, calcd for C21
34 2 3 2
H O N S 424.2117.
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-(2-(3,5-Di-tert-butyl-4-hydroxybenzylthio)acetyl)-N-(butyl) hy
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ꢁ
ꢂ1
2
Temperature programmed ¼ 10 C min
0
drazine carbothioamide, 5h . Yield: 0.41 g (93%); white solid; mp
ꢁ
ꢁ
Isothermal temperature ¼ 125 C
1
1
9
22–127 C; FTIR (ATR): 3619–3639, 3346, 3215–3273, 2868–2956,
ꢂ1
1
664, 1225 cm ; H NMR (600 MHz, DMSO-d
.20 (s, 1H), 7.82 (s, 1H), 7.06 (s, 2H), 6.89 (s, 1H), 3.75 (s, 2H), 3.42
6
): d ¼ 9.83 (s, 1H),
Antioxidant composition range ¼ 0.25 wt%
(
2
d, 3J ¼ 6 Hz, 2H), 3.10 (s, 2H), 1.46 (m, 2H), 1.38 (s, 18H), 1.25 (m,
1
3
H), 0.88 (t, 3J ¼ 6, 3J ¼ 6 Hz, 3H); C NMR (150 MHz, DMSO-d ):
6
The induction periods from the isothermal experiments
were obtained by extrapolation of the front edge of the
exothermic peak to the baseline.
d ¼ 192.18, 169.49, 158.64, 157.06, 153.31, 139.65, 128.86, 125.69,
3.80, 36.63, 34.94, 33.19, 31.32, 30.83, 19.88, 14.25; HRMS (Q-
4
+
+
TOF): m/z [M + H] ¼ 440.2424, calcd for C22
Antioxidant assay (DPPH scavenging assay)
DPPH radical scavenging assay had been carried out according
38 2 3 2
H O N S 440.2400.
Results and discussion
Chemistry
17
to protocol reported by Ahmad et al. with some modications.
The preparations of the starting material S-(3,5-di-tert-butyl-4-
hydroxybenzyl)thioglycolic acid hydrazide, 3, a prerequisite
Around 0.2 mM of DPPH solution in methanol was added to
various concentrations; 10, 20, 40 and 60 mM of antioxidant
samples. A negative control (no sample) is using same
concentration of DPPH solution. Each assay was carried out in
triplicates. Then, the mixtures were vortexed and 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 had
calculated as a percentage of radical inhibition by using the
formula:
18,19
precursor, are outlined in Scheme 1.
Reaction between acid
hydrazide and isocyanates is a straightforward reaction at room
18
temperature that has been reported by our research group.
Herein, we carried out this reaction between prepared acid
hydrazide 3 and isocyanates 4a–h at ambient temperature
utilizing dry toluene solvent to give corresponding semi-
carbazides. Interestingly, the reaction started to form visible
products almost instantly giving very good yield, (89–96%). TLC
was used as indicator upon reaction completion. The results of
the reaction are summarized in Scheme 2.
A
c
ꢂ A
s
Percentage of inhibition ð%Þ ¼
ꢃ 100
A
c
1
13
Synthesized compounds were conrmed by H NMR,
C
NMR, high-resolution Q-TOF mass analysis. Tetramethylsilane
was used as an internal reference. 600 MHz and 150 MHz NMR
spectrometer were used for H NMR and C NMR respectively.
A
s
¼ absorbance of the compounds/positive control, and A ¼
c
absorbance of control (DPPH solution and methanol).
1
13
Percentage of DPPH inhibition of each compounds were
plotted against extract concentration in order to determine the
concentration required to achieve 50% inhibition (IC ) of
The IR spectroscopy of semicarbazides clearly showed an O–H
ꢂ1
stretching sharp band at range 3619–3644 cm and the pres-
5
0
ꢂ1
ence of C]O stretching bands at 1703–1715 cm . A strong
DPPH radical.
ꢂ1
band at 3242–3344 cm was assigned to the N–H stretching
ꢂ1
whereas C–H aliphatic bands appeared at 2955–2961 cm . The
Differential scanning calorimetry
mass spectrometry analysis of the products also conrmed the
molecular weight of compounds 5a–h. HRMS (ESI†) of each
compound had stated in experimental section.
The H NMR and C NMR of compound 5a–h were quite
similar to each other. The differences between them in the
spectra were accorded to the peak and chemical shi of the
different substituents on the hydrazides. Basically, each semi-
carbazides will have a singlet peak at 1.36–1.38 ppm due to
The antioxidant effect of hindered phenols and their synergistic
effect with secondary antioxidant were demonstrated in
thermo-oxidative stability test by differential scanning calo-
rimetry according to ASTM D 3895 with some modication. Free
radical contents of the oxidized oils were determined to explain
the antioxidant synergistic effect of hindered phenols with
secondary antioxidant compounds.
The DSC experiment involves heating a thin lm of oil
sample on an aluminium pan in an oxygen atmosphere and
detecting the exotherm corresponding to the onset of rapid and
accelerating oxidation. This was carried out in isothermal
temperature programmed mode where the temperature was
held constant and the elapsed time to the onset of oxidation
1
13
eighteen protons of 2-C(CH
between 6.87–6.90 ppm attributed to free phenolic hydroxyl. H-
and H-8 of thioether in 5a–h exhibited two separate singlet
3 3
) . Singlet peak at the region
7
peaks in the region 3.75–3.80 ppm and 3.07–3.16 ppm respec-
tively. H-3 and H-5 of the compounds appeared as singlet at
7.06–7.08 ppm which were assigned to the two symmetrical
(oxidative induction time) was measured. A longer oxidative
aromatic ring protons. All compounds exhibited a broad signal
induction time indicate an improvement of oxidation stability.
DSC test conditions as below:
at 9.60–10.00 ppm, 7.75–8.76 ppm and 6.26–9.27 ppm referring
1
3
to NH-1, NH-2 and NH-3 respectively. C NMR spectra of 5a–h
conrmed the presence of carbonyl from semicarbazides
Sample weight ¼ 10 mg
Gas flow rate ¼ 20 mL minꢂ1
Gas pressure ¼ 2 bar
–
NH(C]O)NH at C-10 in the range of 155.03–158.41 ppm.
As seems in semicarbazides, thiosemicarbazides group were also
successfully formed with the same method. Acid hydrazide 3 was
0
0
exposed to suitable corresponding thiocyanates 4a –h in toluene at
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had deshielding effect from sulphur making the region appeared at
160.49–182.35 ppm. Thus, conrmed the presence of thiocarbonyl
from thiosemicarbazides –NH(C]S)NH group.
Antioxidant evaluation by DPPH
All the compounds were carried out for the antioxidant evalu-
ation test using in vitro method of 1,1-diphenyl-2-picryl-
hydrazine (DPPH) assay. DPPH assay has been one of the
most widely used for measurement of free radical scavenging
ability of antioxidants due to its rapid, simple and inexpensive
21
properties. Overall antioxidant capacity of the system can also
be estimated with accuracy by this method.
BHT was used as standard antioxidant. The delocalization of
the electron in DPPH solution gives a deep violet color at
517 nm absorption. However, the color turns into yellow when
antioxidant was added into the DPPH solution due to the
reduction of divalent nitrogen (N) of DPPH by antioxidant
22
Scheme 2 Preparation of substituted semicarbazides, 5a–h.
molecule. The radical scavenging activity was expressed by the
half maximal inhibitory concentration (IC50), the concentration
needed to inhibit 50% of DPPH solution. Thus, the compound which
has a lower IC50 value would shows better antioxidant properties. The
free radical scavenging properties of the synthesized semicarbazides
room temperature giving very good yield (90–96%) under addition
0
0
reaction. All the eight corresponding thiosemicarbazides, 5a –h
were synthesized and reported for the rst time. The results of the
reaction are summarized in Scheme 3. The spectroscopic features of
0 0
(5a–h) and thiosemicarbazides (5a –h ) were investigated by the
interaction between experimental compounds and 0.2 mM 1,1-
diphenyl-2-picryl-hydrazine (DPPH) for 30 min. The antioxidant
activity of synthesized semicarbazides (5a–h) obtained from DPPH
assay is summarized in Fig. 1. All synthesized thiolated BHT bearing
semicarbazides 5a–h showed better antioxidant activity in compar-
ison with BHT. The decreasing order of IC50 values can be made from
results in Fig. 1 as 5e > 5h > 5a > 5g > 5b > 5f > 5c > 5d > BHT.
The antioxidant activity of synthesized thiolated BHT
0
0
5
a –h were quite similar to the 5a–h corresponding compounds. In
ꢂ1
IR, a very strong band at the region around 1100–1200 cm was
assigned to the C]S stretching showing a conrmation that
2
0
belongs to thiosemicarbazides' group.
1
13
In H NMR and C NMR spectra, the major difference was only
the chemical shi from N–H group due to neighbouring group and
carbon at C]S group. H NMR spectra of 5a –h showed three
singlet peaks at 9.47–10.19, 8.11–9.68, and 7.82–9.90 ppm referring
to NH-1, NH-2, and NH-3 respectively. It is believed that the chem-
ical shi of NH-2 and NH-3 had deshielding effects due to the thio-
1
0
0
0
0
bearing thiosemicarbazides (5a –h ) is also depicted in Fig. 2.
The moderate antioxidant activity was observed for all
compounds. Interestingly, thiosemicarbazides bearing naph-
thyl, 4-cyano, 2,4-di-Cl substituents showed signicant free
radical scavenging activity. Free radical scavenging properties of
synthesized compounds can be ordered from the obtained
13
neighbouring group, C]S. In C spectra, it proved that C-10 also
0
0
0
0
0
0
0
0
results as follows: 5f > 5c > 5e > 5a > 5d > 5g > 5b > 5h > BHT.
0
0
The IC50 values of novel compounds 5a–h and 5a –h obvi-
ously indicated that all synthesized compounds have better
radical scavenging activity than BHT. In general, the reason for
Fig. 1 Antioxidant activity of synthesized compounds 5a–h by DPPH
assay.
0
0
Scheme 3 Preparation of substituted thiosemicarbazides, 5a –h .
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synthesized semicarbazides has higher antioxidant activity tautomerism of synthesized thiosemicarbazides. Unlikely semi-
than BHT is due to the combination of butylated hydroxy carbazides, thiosemicarbazides might reduce DPPH radical in thi-
phenyl (BHP) moiety and semicarbazide moiety in a single oimidic acidic form as shown in Scheme 4.
0
structure. Semicarbazide moieties exhibit free radical scavenging
Gratifyingly, the IC50 value of thiosemicarbazide 5d (33.52 ꢀ
properties due to the presence of an NH group, which can donate 0.99) support the thioimidic acid form of thiosemicarbazide is
a hydrogen atom to the DPPH radical. Aer donating a hydrogen lower than its corresponding semicarbazide 5d. However, thi-
atom, compounds 5a–h exist in a radical form, and the radical osemicarbazides with electron donating substituent such as
electron could delocalize to the benzene ring to produce the stable butyl group (5h ) exhibited higher IC50 value (39.19 ꢀ 0.75)
0
resonance hybrid. The electron conjugation in the structure was though its corresponding 5h showed lower value. It is obvious
stabilized the radical and was prevented it from participating in from DPPH result that thiosemicarbazides with thiolated BHT
a destructive chemical reaction.
were found better antioxidant properties in comparison with
Thus, due to the antioxidant synergism, the compound 5a–h semicarbazides. There may have two possible reasons to obtain
showed better free radical scavenging properties than standard better scavenging properties of thiosemicarbazides: thioamide–
antioxidant BHT. However, the synthesized substituted semi- thioimidic acid tautomerism and lower electronegativity of
carbazides 5e, 5h, 5a and 5g showed IC50 value in the range of 33.46– sulfur (2.58) than oxygen (3.44). Due to lower electronegativity of
3
7.70 mM. It is known that electron donating substituents enhance sulfur atom, thiol can easily release proton to DPPH radical in
7,16,22,26
free radical scavenging properties than the electron withdrawing comparison of hydroxyl group (Scheme 4).
substituents on the benzene ring. The reason of this enhanced
In addition, it was found that the degree of conjugation in
antioxidant properties might be attributed to the electron resonance thioamides is considerably higher than amides which made it
27
effect of substituted benzene ring in radical 5e, 5h, 5a and 5g as stronger p-electron attractor.
Nevertheless, thio-
making the radical more stable in the presence of electron-donating semicarbazides with thiolated BHT could convert into several
groups. In contrast, semicarbazides containing highly electron radical by donating the proton to reduce DPPH radical. The
withdrawing group –CN (5c), –F (5b) showed higher IC50 value 39.26 possible radical formation of synthesized thiosemicarbazides
mM and 42.97 mM respectively. Again, though methoxy (–OMe) is an can be drawn as Scheme 5. Thus, the multiple active site of
electron donating substituent but highest IC50 value was found for donating proton to counteract the free radical has made our
compound 5d. This may attribute to the fact that m-substituent synthesized thiosemicarbazides more efficient antioxidant.
19
showed only small resonance effect.
On the other hand, synthesized thiosemicarbazides 5a –h
In summary, DPPH results have claried the difference
between C]O and C]S groups as well as the effect of substi-
0
0
showed better free radical scavenging properties in comparison with tution of electron-donating and – withdrawing on the scav-
corresponding semicarbazides 5a–h. Thiosemicarbazides bearing enging of free radicals. With the exception of compound 5h and
0
0
naphthyl substituent 5f exhibited best antioxidant activity (25.47 ꢀ its corresponding 5h , the IC50 values of thiosemicarbazides
0
0
.42 mM) among the thiosemicarbazides, followed by thio- 5a –g’ were lower than semicarbazides 5a–g group. It's clearly
0
0
0
semicarbazides containing –CN group 5c (27.84 ꢀ 1.12 mM), 2,4-di- showed that most thiosemicarbazides groups, 5a –g had
0
0
Cl 5e (28.25 ꢀ 0.37 mM) and no substituents 5a (30.40 ꢀ 0.61 mM). a greater degree in antioxidant activity than their corresponding
Strong delocalization of electron in naphthyl ring and steric semicarbazides group of compounds, 5a–g. This study high-
hindrance might be attributed to the exhibition of enhanced the lighted a novel nding that thiocarbonyl C]S in thio-
0
antioxidant activity of 5f . Moreover, compounds with naphthalene semicarbazides (NH
2
–CS–NH–NH
2
)
did play
a
role in
ring were found in many earlier reports as potential free radical antioxidant activity better than carbonyl in semicarbazides
23–25
scavenger.
2 2
Interestingly, thiosemicarbazides with strong electron (NH –CO–NH–NH ). Hence, thioamides carry better antioxi-
withdrawing substituent such as cyano (–CN) showed lower IC50 dants than amides. Further investigation on structural behav-
value, whereas corresponding semicarbazides with electron with- iour is needed by computational and kinetic studies.
drawing substituents found higher IC50 value. The reason of this
phenomenon might be attributed to the thioamide–thioimidic acid
Oxidation stability assessment with TMPTO
0
0
Based on DPPH result, the thiosemicarbazide compounds 5f
was found as the best antioxidant properties. So, compound 5f
and its corresponding semicarbazide compound 5f were carried
0
0
Fig. 2 Antioxidant activity of synthesized compounds 5a –h by DPPH Scheme
4 Possible thioamide–thioimidic acid tautomerism of
assay. thiosemicarbazides.
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Scheme 5 Possible radical formation of thiosemicarbazides bearing Fig. 3 Oxidative induction time of TMPTO, TMPTO + BHT, TMPTO +
0
ꢁ
ꢁ
thiolated BHT.
5f, and TMPTO + 5f at 150 C and 125 C isothermal temperature.
out for oxidation stability evaluation of synthetic lubricant oil
using differential scanning calorimetry (DSC) test. BHT was
used as standard antioxiant since it is widely utilized in lubri-
cant as a potential antioxidant. Trimethylolpropane trioleate
(
TMPTO) was used as synthetic ester-based lubricant. The
0
compounds 5f , 5f and BHT were blended into TMPTO with
0
.25 wt%. Isothermal DSC was carried out with the blended
0
Fig. 4 Important antioxidant functions in 5f and 5f for potential
oxidative stability of lubricant oil.
experimental samples to obtain oxidative induction time (OIT).
The longer OIT refers to extended oxidative stabiltiy of oil.
This experiment was conducted at two different isothermal
temperature: 150 C and 125 C. At rst, blended oil was carried
out isothermal DSC at 150 C to evaluate OIT. Aerwards, same
28
ꢁ
ꢁ
ꢁ
reported that antioxidants containing functional groups that
can provide free radical scavenger activity and peroxide
Thus, due to the
auto-synergistic effect, compound 5f and 5f showed better
oxidative stability than BHT.
Organosulfurs are one of the important additives in the lubricant
compositions because of their antioxidant, antiwear and extreme
pressure properties. And these have been usually utilized with the
hindered phenol or aromatic amine to get better synergistic effect.
Therefore, presence of two sulfur atoms and one hindered phenol in
ꢁ
experiment was conducted at 125 C isothermal temperature.
Both OIT results are outlined in Fig. 3.
29,30
decomposer moiety exhibit autosynergy.
0
According to Fig. 3, the standard TMPTO was stable only for
ꢁ
0.4 min at 150 C isothermal. Meanwhile, the OIT value of
0
0
.25 wt% of 5f blended with TMPTO was extended to 16.39 min.
But, 0.25 wt% of BHT blended with TMPTO was observed at
5.8 min OIT value. Here, it is clear that the incorporation of
1
0
compound 5f with TMPTO extended its oxidation stability
around 3 times more than 0.25 wt% of BHT.
Nevertheless, the highest oxidation stability of TMTPO
blended with synthesized compound was observed for 0.25 wt%
of 5f and 5f at 125 C isothermal DSC. As seen in Fig. 3, the base
oil of TMPTO at 125 C isothermal DSC has the OIT value of
0
structure 5f may exhibit better auto-synergistic effect than the
compound 5f. Thus, thiosemicarbazide containing thiolated BHT
(5f ) is better oxidative stable than the commercial antioxidant BHT
0
0
ꢁ
ꢁ
and semicarbazide 5f.
0
0.4 min. However, the addition of compounds 5f and 5f
increased the OIT values to 78.91 and 95.79 min, respectively. Conclusions
So, both novel multipotent antioxidant compounds showed
better oxidative stability of blended TMPTO (around 50%) than
the commercial antioxidant BHT.
In conclusion, semicarbazides (5a–h) and thiosemicarbazides
0 0
(5a –h ) bearing thiolated BHT were synthesized with high
product yields as a potential multipotent antioxidant. All the
synthesized compounds were carried out for DPPH assay for the
evaluation of antioxidant properties. Better antioxidant prop-
erties were found for all the synthesized compounds than
commercial antioxidant BHT. It was observed that electron
donating substituents in semicarbazides enhanced the free
radical scavenging properties than electro withdrawing
substituents. Though, poor antioxidant property was obtained
for semicarbazides containing electro donating substituent
methoxy group (5d) due to formation of intramolecular
hydrogen bond. However, thiosemicarbazides showed better
free radical scavenging properties than semicarbazides series. It
was anticipated that better antioxidant properties of
These results illustrated that the novel MPAOs have a great
potential as antioxidant additives for synthetic lubricating oil.
Furthermore, it was observed that thiolated BHT containing
0
thiosemicarbazide 5f exhibited stronger oxidative stability than
semicarbazides with thiolated BHT 5f. This observation also
supports the DPPH assay result where thiocarbonyls group give
better antioxidant activity than carbonyls. This higher activity of
0
this reporting compound 5f can be attributed to the presence of
three different antioxidant functions in one structure: BHT as
primary antioxidant, thioether and thioamide as secondary
antioxidant or peroxide decomposer (Fig. 4). Whereas, semi-
carbazide 5f possesses two primary antioxidants: BHT and
amide, one secondary antioxidant functions thioether. It was
0
0
compounds (5a –h ) were found due to the thioamide–
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thioimidic acid tautomerism. In addition, thioamide of thio-
semicarbazides can easily donate proton to reduce DPPH
radical due to the lower electronegativity of sulfur (2.58) than
oxygen (3.44). Again, based on the DPPH result and solubility in
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TMPTO, compound 5f and 5f were carried out isothermal DSC
at two different isothermal temperatures for the evaluation of
oxidative stability in comparison commercial antioxidant BHT.
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Author contributions
1
Data curation, Syabilah Sazeli; formal analysis, Syabilah Sazeli;
funding acquisition, Wageeh A. Yehye and NWM Zulkii; 18 A. R. Nath and W. A. Yehye, Synthesis, 2018, 50, 4301–4312.
investigation, Syabilah Sazeli, Amit R. Nath and NWM Zulkii; 19 W. A. Yehye, N. A. Rahman, A. Ariffin, S. B. Abd Hamid,
methodology, Syabilah Sazeli and Wageeh A. Yehye; project
A. A. Alhadi, F. A. Kadir and M. Yaeghoobi, Eur. J. Med.
administration, Syabilah Sazeli; supervision, Wageeh A. Yehye
Chem., 2015, 101, 295–312.
and Lee Hwei Voon; writing – original dra, Syabilah Sazeli and 20 N. T. Akinchan, D. X. West, Y. H. Yang, M. M. Salberg and
Amit R. Nath; writing – review & editing, Wageeh A. Yehye,
T. L. Klein, Transition Met. Chem., 1995, 20, 481–484.
NWM Zulkii, Amit R. Nath and Mohd Haz Ahmad.
21 K. Pyrzynska and A. P ˛e kal, Anal. Methods, 2013, 5, 4288–
4295.
2
2
2
2
2 M. K. Abdulwahab, A. Ariffin, W. A. Yehye, A. Abdul-Aziz,
H. S. Kareem and N. Nordin, Bull. Korean Chem. Soc., 2015,
Conflicts of interest
There are no conicts to declare.
36, 2716–2724.
3 M. C. Foti, E. R. Johnson, M. R. Vinqvist, J. S. Wright,
L. R. C. Barclay and K. Ingold, J. Org. Chem., 2002, 67,
Acknowledgements
5190–5196.
The authors would like to thank Grand Challenge (GC001C-
4 T. Ozen, M. Macit and M. Toka, Jurnal Sains Kesihatan
Malaysia (Malaysian Journal of Health Sciences), 2018, 16,
1
4AET), PPP Grant PG272-2015B, and FP127-2019A provided by
the Universiti Malaya and Ministry of Higher Education, Malaysia
MOHE) for their cordial support in completing this work.
4
5–55.
5 K. W. Ho and A. Ariffin, Russ. J. Phys. Chem. A, 2016, 90,
590–2599.
(
2
Notes and references
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©
2021 The Author(s). Published by the Royal Society of Chemistry
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