Relationship between the structure of newly synthesized derivatives of 1,3,4-oxadiazole containing 2-methylphenol and their antioxidant and antibacterial activities

Article abstract of DOI:10.13005/ojc/330423

1,3,4-oxadiazole-5-thion ring(2) successfully formed at position six of 2-methylphenol and five of their thioalkyl(3a-e). Furthermore 6-(5-(Aryl)-1,3,4-oxadiazol-2-yl)-2-methylphenol (5a-i) were formed at position six by two method. The first method was f

Full text of DOI:10.13005/ojc/330423

ISSN: 0970-020 X
CODEN: OJCHEG
2017, Vol. 33, No. (4):
Pg.1781-1798
ORIENTAL JOURNAL OF CHEMISTRY
An International Open Free Access, Peer Reviewed Research Journal
www.orientjchem.org
Relationship Between the structure of Newly Synthesized
derivatives of 1,3,4-oxadiazole Containing 2-Methylphenol and
their Antioxidant and Antibacterial Activities
SHAIMAA ABEd SAOUd1, KHALId FAHAd ALI*1 and RAIEd MUSTAFA SHAKIR*1
1Department of Chemistry, Ibn Al-haitham, University of Baghdad, Baghdad 61023, Iraq.
*Corresponding author E-mail address: shaimaachem@hotmail.com
http://dx.doi.org/10.13005/ojc/330423
(Received: June 03, 2017; Accepted: June 14, 2017)
ABSTRACT
1,3,4-oxadiazole-5-thion ring(2) successfully formed at position six of 2-methylphenol
and five of their thioalkyl(3a-e). Furthermore 6-(5-(Aryl)-1,3,4-oxadiazol-2-yl)-2-methylphenol
(5a-i) were formed at position six by two method. The first method was from cyclization their
correspondinghydrazones(4a-e) of 2-hydroxy-3-methylbenzohydrazide (1)using bromine in glacial
acetic acid.The second method was from cyclization the hydrazide with aryl carboxylic acid in the
presence of phosphorusoxy chloride. The newly synthesized compounds were characterized from
their IR, NMR and mass spectra. The antioxidant properties of these compounds were screened
by 2,2-Diphenyl-1-picrylhydrazide (DPPH) and ferric reducing antioxidant power (FRAP) assays.
Compound (4d) and (5h) exhibited significant antioxidant properties in both assays, compared to
ascorbic acid, while compound (4e) exhibited slightly less antioxidant properties than ascorbic acid.
Antibacterial activity was tested for the twenty one compounds against eight microorganisms (gram
negative and gram positive). Compound (4d)and (5d) exhibited significant antibacterial activities
compared to Amoxicillin and Kanamycin as antibiotic standards.
Keywords: 2-methylphenol, hindered phenol, 1,3,4-oxadiazole, antioxidant, antibacterial
INTROdUCTION
damages by prevent formation free radicals or
elimination of its damages. Antioxidant compounds
are effective in the treatment and prevention of
several diseases such anti-inflammatory6 and
anticancer7. Furthermore, the digestive, anti-
inflammatory, anti-necrotic, neuroprotective, and
hepatoprotective medicines possess an antioxidant
The effects of free radicals and reactive
oxygen species (ROS) embroiled in causes
severe damages for biomolecules cells1. These
damages grounds of several diseases such as
cancers2inflammatory3, chronic diseases4besides
to degenerative diseases5.Antioxidants among the
significant defense agents against free radicals
8
capability . However, the antioxidants have been
exhibited some potential adverse health effects.9

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SAOUD et al., Orient. J. Chem., Vol. 33(4), 1781-1798 (2017)
The free radical scavenger donates a was recorded using Shima dzu GCMS-QP2010Ultra
proton to the reactive radical and terminated it or (Al-Mustansiriyah University, College of Science,
breaks the chain reaction. After donating a proton Department of Chemistry), UV spectroscopy Power
were converted to a stable radical; this stability Wave X340,BIO-TEK instrument INC was used to
enhances the property of the antioxidant10. Large recorded the FRAP Assay and DPPH assay.
number of literature reviews emphasized strongly
at the relationship between the structure and the Synthesis of 2-hydroxy-3-methyl benzo
antioxidant efficiency. Extent of delocalization, hydrazide
multiple phenolic hydroxyl groups, and steric
Ethyl 2-hydroxy-3-methylbenzoate (9 g,
hindrance of phenol besides the type and positions of 50 mmol) was dissolved in 50 mL of ethanol and
the substituted group could play an important role to stirred with heating to 600C for 15 minutes; excess
enhance the antioxidant ability10-15.This shedlight on of hydrazine hydrate was added with small portions.
the close relationship between the chemical structure After complete the addition the mixture left under
and antioxidant ability.
reflux for 18 h. On cooling a precipitate was filtered,
washed with cold water and recrystallized from
Recently, 1,3,4-oxadiazoles derivatives aqueous ethanol to afford white precipitate 7.1 g,
exhibited broad spectrum of biological activates 86% yield, m.p.(191-193) °C. IR (KBr, υmax/ cm-1)
likewise antitumor16,antiproliferative17, a-glucosidase 3323, 3267, 3136 (NH2, NH and OHphenol), 3049,
inhibitors18,anti-inflammatory19-21,antibacterial22, 3014 (CHaromatic) 2972-2765 (CHaliphatic), 1650 (C=O),
antifungals23,24 as well the antioxidant ability25-27
.
1583- 1433 (C=C). 1H NMR (400 MHz, DMSO-d6)
Many researchers have reported that the substituent d, ppm;2.22 (s, 3H, CH3), 4.69 (bs, 2H, NH2), 6.95 (t,
group at ortho of phenols possess directly control 1H, J 7.4, H4), 7.36 (d,1H, J 7.34, H5), 7.44 (d, 1H,
to improve or disprove the antioxidant capacity28-32
This work presented that formation 1,3,4-oxadiazole
ring at position six cause increase both the steric 6-(5-thio-1,3,4-oxadiazol-2-yl)-2-methylphenol
hindrance and the resonance effect. The 1,3,4- To a solution of hydrazide (1.66 g, 10 mmol)
.
J 7.82, H3), 9.41 (bs, 1H, NH).
oxadiazoles-5-thione were synthesized in addition and excess of carbon disulfide (2.5-3 mL) in absolute
to a series of their alkyl as well the series of 1,3,4- ethanol, potassium hydroxide (0.62 g, 11 mmol) was
oxadiazole-5-Aryl have been investigated for their added in one portion at ambient temperatures. The
antioxidant capacity.
ExpERIMENTAL
General Chemistry
mixture was stirred and refluxed for 5h. The solvent
was removed under vacuum. Distilled water (25 mL)
was added to the residue and stirred for another 15
minutes. It was filtered and the filtrate acidified with
5% hydrochloric acid and finally re-filtered.The white
The chemicals used for synthesis were precipitate was washed with water, recrystallized
purchased from Sigma-Aldrich, Fisher and and from ethanol to affords white crystal, yield 1.83 g,
Merck. Melting point was determined by open (88 %); m.p. (212-213) RC; IR (KBr, υmax/ cm-1) 3365
capillary tube method using OMEGA MPS10 (NH) 3066 (OHphenol), 2931, 2765 (CHaliphatic), 1606
1
apparatus and is uncorrected.Purities of compounds (C=N), 1579-1469 (C=C), 1122 (C=S); H NMR
were checked with a thin layer chromatography (400 MHz, DMSO-d6) d, ppm; 2.21 (s, 3H, CH3),
(Silica gel TLC) plate’s brand Merck, and the spot 6.92 (t, 1H, J 7.2, H4), 7.34 (d,1H, J 7.3, H3), 7.45
located with UV lights and iodine vapors. The IR (d, 1H, J 7.8, H5), 9.16 (bs, 1H, NH); 13C APT (100
spectrums were obtained with Perkin Elmer 400 MHz, DMSO-d6) ä, ppm; 16.51 (1C, CH3), 109.65
FourierTransform Infrared (FTIR) Spectrometer (the ( 1C,C6), 120.51 (1C, C4), 126.35 (1C,C5), 127.04
central service laboratory, College of education for (1C,C2(, 135.11 (1C, C3), 154.30 (1C, C1(, 160.59
pure science-Ibn Al-haitham). NMR spectra were (1C, C7,(C=N)), 177.24 (1C, C8,(C=S)).
recorded on Bruker AVN 400 (University of Malaya,
Malaysia) and 300 MHz (AL- Bayt University, Jordan), General method of Alkylation 6-(5-thio-1,3,4-
DMSO-d6 used as a solvent with TMS as internal oxadiazol-2-yl)-2-methylphenol (3a-e)
standard, measurements were The mass spectrum
Alkyl halide (1 mmol) was added in small

SAOUD et al., Orient. J. Chem., Vol. 33(4), 1781-1798 (2017)
1783
1
portions to a stirred suspension of 1,3,4-oxadiazole
(0.21 g, 1 mmol) in dry acetone and anhydrous
potassium carbonate( 0.13g, 1 mmol). The mixture
was left to stand overnight with stirring at ambient
temperature. The solvent was evaporated and the
residue extracted with 25 mL chloroform. It was
dried under anhydrous magnesium sulfate and
recrystallized from suitable solvent.
1678 (C=O), 1614 (C=N), 1591-1477 (C=C); H
NMR (400 MHz, DMSO-d6) d, ppm; 2.25 (s, 3H,
CH3), 5.16 (s, 2H, CH2), 6.95 (t, 1H, J 7.3, H4), 7.39
(d, 1H, J 7.0, H3), 7.55 (d, 1H, J 7.3, H5), 7.81 (d,
2H, J 8.1, H13), 8.02 (d, J 8.3, 2H, H12), 9.81 (s, 1H,
OH); 13C APT (100 MHz, DMSO-d6) d, ppm; 16.19
(1C, CH3), 40.83 ( 1C, CH2), 108.13 (1C, C6), 120
(1C, C4), 125.33 (1C, C5), 126.55 (1C, C2), 128.73
(1C, C14), 130.94 (2C, C12), 132.50 (2C, C13), 134.44
(1C, C11), 135.16 (1C, C3), 154.73 (1C, C1), 163.20
(1C, C8,(C=N)), 165.38 (1C, C7,(C=N)), 192.44 (1C,
C10,(C=O)).
6-(5-(ethylthio)-1,3,4-oxadiazol-2-yl)-2-
methylphenol(3a)
The crude product was recrystallized from
ethanol to give white crystal. Yeild 0.197 g, (83%);
m.p. (74-76 RC); IR (KBr,υmax/ cm-1) 3172 (OHphenol),
3030(CHaromatic), 2964-2864 (CHaliphatic), 1610 (C=N),
1556-1425 (C=C);1H NMR (400 MHz, DMSO-d6), d,
ppm; 1.44 (t, 3H, J 7.3, CH2CH3), 2.25 (s, 3H,CH3),
3.34 (s, 2H, CH2), 6.96 ( d, 1H, J 7.2, H3), 7.45 (m,
2H, H4, H5), 9.89 (s, 1H, OH) ; 13C APT (100 MHz,
DMSO-d6) d , ppm; 15.30 (1C, CH2CH3), 16.20 (1C,
CH3), 27.25 (1C, CH2), 108.25 (1C, C6), 120.34 (1C,
C4), 125.21 (1C, C5), 126.44 (1C, C2), 134.95 (1C,
C3), 154.78 (1C, C1), 163.73 (1C, C8), 165.28 (1C,
C7).
6-(5-((ethoxyformyl)methylthio)-1,3,4-oxadiazol-
2-yl)-2-methylphenol
Recrystallization of the crude product from
chloroform to give pale yellow precipitate.Yield 0.22
g, 74% m.p.(71-73) C, IR (KBr, υmax/ cm-1) 3207
(OHphenol), 3037 (CHaromatic), 2983-2931 (CHaliphatic),
1728 (C=O), 1606 (C=N), 1556-1481 (C=C);1H NMR
(300 MHz, DMSO-d6) d, ppm;1.20 (t, 3H,J 6.96, H12),
2.26 (s, 3H, CH3), 4.16 (q, 2H, J 7.16, H11), 4.32
(s, 2H, SCH2, H9), 6.99 (t, 1H, J 7.72, H4), 7.41 (d,
1H, J 7.35, H3), 7.59 (d, 1H, J 7.2, H5), 9.82 (s, 1H,
OH); 13C NMR (75 MHz, DMSO-d6) d , ppm; 13.93
(1C, C12), 15.74 (1C, CH3), 33.87 (1C,C9), 61.63 ( 1C,
C11), 107.72 (1C, C6), 119.95 (1C, C4), 124.87 (1C,
C5), 126.08 (1C, C2), 134.65 (1C, C3), 154.28 (1C,
C1), 162.44 (1C, C8,(C=N)), 164.94 (1C, C7,(C=N)),
167.62 (1C,C10,(C=O)).
6-(5-(((benzoimidazol-2-yl)methyl)thio)-1,3,4-
oxadiazol-2-yl)-2-methylphenol
The solid crude was recrystallized from
(1:1) ethyl acetate: methanol to give light brownish
crystal. Yeild0.26 g, (77%); m.p.(173-175)C ; IR
(KBr, υmax/ cm-1) 3174 (NH), 3080 (OH phenol), 3024
(CHaromatic), 2989-2924 (CHaliphatic), 1618(C=N),
6-(5-(benzylthio)-1,3,4-oxadiazol-2-yl)-2-
methylphenol
1
1556-1439 (C=C); H NMR (400 MHz, DMSO-d6)
d, ppm; 2.23 (s, 3H, CH3), 4.80 (s,2H,CH2), 6.93
(t, 1H, J 7.46, H4), 7.18 (m, 2H, H13), 7.37 (d, 1H,
J 7.1, H3), 7.52 (m, 3H, H5, H12), 9.85 (s, 1H, OH),
12.67 (bs, 1H, NH); 13C APT (100 MHz, DMSO-d6)
d , ppm;16.17 (1C, CH3), 30.16 (1C, CH2), 108.11
(1C, C6), 120.42 (1C, C4), 122.61 (2C, C12, C13),
125.37 (1C, C5), 126.54 (1C, C2), 135.16 (1C, C3),
149.85 (2C, C10, C11), 154.74 (1C, C1), 162.69 (1C,
C8), 165.67 (1C, C7)
The desired product (3e) was purified by
flash column chromatography using hexane: ethyl
acetate (6:1) as eluent to give white precipitate.Yield
0.2g, 67%, m.p.(100-103) C, IR (KBr, υmax/ cm-1) 3153
(OHphenol), 3041 (CHaromatic), 2924-2860 (CHaliphatic),
1606 (C=N), 1556-1414 (C=C); 1H NMR (300 MHz,
DMSO-d6) d, ppm; 2.26 (s, 3H, CH3), 4.60 (s, 2H,
SCH2), 6.97 (td, 1H, J 7.6, 3.2, H13), 7.29-7.51 (m,
6H, H3, H4, H11, H12), 7.58 (d, 1H, J 7.9, H5), 9.85 (s,
1H, OH);13C NMR (75 MHz, DMSO-d6) d, ppm;15.71
(1C, CH3), 35.92 (1C, C9), 107.68 (1C, C6), 119.91
(1C, C4), 124.81 (1C, C5), 125.99 (1C, C2), 127.79
(1C, C13), 128.57 (2C, C11), 129.03 (2C, C12),134.57
(1C, C3), 156.42 (1C, C10), 154.31 (1C, C1), 162.74
(1C, C8,(C=N)), 164.96 (1C, C7,(C=N)).
6-(5-((4-bromobenzoyl)methylthio)-1,3,4-
oxadiazol-2-yl)-2-methylphenol
The crude product was recrystallized from
acetonitrile to give white precipitate. Yield 0.35 g,
86% m.p.(164-166) C, IR (KBr, υmax/ cm-1) 3192
(OHphenol), 3033 (CHaromatic), 2960-2924 (CHaliphatic),

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GeneralsynthesisofN’(substitutedbenzylidene)2- N’(4-hydroxy-3-methoxybenzylidene)2-hydroxy-
hydroxy-3-methylbenzohydrazide
( hydrazone) (4a-e)
3-methylbenzohydrazide
Recrystallization of the crude product
To a warm stirred solution of arylaldehyde(3 (4c)from methanole to give pale yellow precipitate.
mmol) in 20 mL absolute ethanol, 2-hydroxy-3- Yield 0.72 g, 83%, m.p.(203-206) C, IR (KBr, υmax
/
methylbenzohydrazide (0.48 g, 3 mmol) was added cm-1) 3311 NH, 3194 (OHphenol), 3060 (CHaromatic),
in small portions, and refluxed for 7h, upon cooling; 2962-2856 (CHaliphatic), 1633 (C=O), 1603 (C=N),
the mixture was stored overnight in a refrigerator at 1550-1431 (C=C);1H NMR (400 MHz, DMSO-d6)
5°C. The precipitate was washed with cold ethanol d, ppm;2.23 (s, 3H, CH3),3.88 (s, 3H, O-CH3), 6.89
and recrystallized from suitable solvent.
(m, 2H , H4,H13), 7.16 (dd, 1H, J 8 , H14), 7.39 (m,
2H, H10, H3), 7.83 (d, 1H,J 7.9, H5), 8.44 (s, 1H,
N’(4-methylbenzylidene)2-hydroxy-3- H8), 9.66 (s, 1H, OHVanillin), 11.90 (s, 1H, NH), 12.80
methylbenzohydrazide
(s, 1H, OHphenol); 13C APT (100 MHz, DMSO-d6)
Thecrudeprecipitate(4a)wasrecrystallized d, ppm; 15.96 (1C, CH3), 56.03 (1C,O-CH3), 109.47
from ethanol to give white crystals. Yield 0.52 g, (1C, C10), 113.31 (1C, C6), 115.94 (1C, C13), 118.39
67%, m.p.(173-174)C, IR (KBr, υmax/ cm-1) 3240 (NH (1C, C14), 123.11 (1C, C4), 125.12 (1C, C5), 125.81
and OHphenol), 3087-3028 (CHaromatic), 2954-2910 (1C,C9), 126.66 (1C,C2), 135.38 (1C, C3), 148.57 (1C,
(CHaliphatic), 1603 (C=Oamide) and (C=N), 1572-1446 C11), 149.86 (1C, C12), 150.45 (1C, C8), 159.96 (1C,
(C=C); 1H NMR (300 MHz, DMSO-d6) d, ppm; 2.19 C1), 166.89 (1C, C7,(C=O)).
(s, 3H, C2-CH3), 2.36 (s, 3H, C12-CH3), 6.87(t, 1H, J
7.6, H4), 7.3 (d, 2H, J 7.9, H11), 7.37 (d, 1H, J 7.3, N’(4-hydroxy-3,5-dimethoxybenzylidene)2-
H3), 7.65(d,2H, J 7.9, H10), 7.81 (d, 1H, J 7.9, H5), hydroxy-3-methylbenzohydrazide
8.48 (s, 1H, H8, (CH=N)), 11.99 (s, 1H, NH), 12.67
Recrystallization of the crude product (4d)
(s, 1H, OH); 13C NMR (75 MHz, DMSO-d6) d, ppm; from methanol to give pale brown precipitate. Yield
15.46 (1C, C2-CH3), 21.02 (1C, C12-CH3), 112.73 (1C, 0.77 g, 81%,m.p.(210-213) C, IR (KBr, υmax/ cm-1)
C6), 117.96 (1C, C4), 124.69 (1C, C5), 126.17 (1C, 3317 (NH and OHphenol), 3086-3022 (CHaromatic), 2951-
C2), 127.27 (2C, C10), 129.48 (2C, C11), 131.21 (1C, 2844 (CHaliphatic), 1630 (C=O) and (C=N), 1587-1425
1
C9), 135.01 (1C, C3), 140.33 (1C, C12), 149.44 (1C, (C=C); H NMR (300 MHz, DMSO-d6) d, ppm;2.2
C8), 159.43 (1C, C1), 166.61 (1C, C7).
(s, 3H, CH3), 3.83 (s, 6H, 2×OCH3), 6.87 (t, 1H, J
7.6, H4), 7.02 (s, 2H, H10), 7.37 (d, 1H, J 7.3, H3), 7.8
N’(4-hydroxybenzylidene)2- hydroxy-3- (s, 1H, J 7.9, H5), 8.39 (s, 1H, H8(CH=N)), 9.01 (s, 1H,
methylbenzohydrazide
C12-OH), 11.93 (s, 1H, NH), 12.74 (s, 1H, C1-OH);13C
Recrystallization of the crude product(4b) NMR (75 MHz, DMSO-d6) d, ppm; 15.48 (1C, CH3),
from methanole to give white precipitate. Yield 0.6 56.02 (2C, 2×OCH3), 104.83 (2C, C10), 112.82 (1C,
g, 78%,m.p.(240-242) C, IR (KBr, υmax/ cm-1) 3278 C6), 117.92 (1C, C4), 124.11 (1C, C9), 124.67 (1C,C5),
NH, 3205 (OHphenol), 3080-3020 (CHaromatic), 2985- 126.16 (1C,C2), 134.91 (1C, C3), 138.29 (1C, C12),
2912 (CHaliphatic), 1603 (C=O) and (C=N), 1554-1435 148.12 (1C, C8,(C=N)), 150.02 (2C, C11), 159.42 (1C,
(C=C); 1H NMR (300 MHz, DMSO-d6) d, ppm; 2.19 C1), 166.39 (1C, C7,(C=O)).
(s, 3H, CH3), 6.86 (m, 3H, H4, 2×H11), 7.36 (d,1H,
J 6, H3), 7.6 (d, 2H, J 8.3, H10), 7.8 (d,1H, J2.24, H5), N’(2-hydroxy-3,5-di-tertbutylbenzylidene)2-
8.41(s,1H, H8,(CH=N)), 10.02 (bs, 1H,C12-OH), 11.86 hydroxy-3-methylbenzohydrazide
(bs, 1H, NH), 12.80 (bs, 1H,C1-OH); 13C APT (75
Recrystallization of the crude product
MHz, DMSO-d6) d, ppm;15.47 (1C, CH3), 112.76 (1C, (4e) of from ethanol and water to give white
C6), 115.75 (2C, C11), 117.89 (1C, C4), 124.54 (1C, precipitate. Yield 0.85 g, 77%, m.p.(205-208) C, IR
C5), 124.88 (1C, C2), 126.15 (1C,C9), 129.12 (2C,C10), (KBr, υmax/ cm-1);3217 NH, 3174 (OHphenol), 3049
134.87 (1C, C3), 149.73 (1C, C8,(C=N)), 159.46 (1C, (CHaromatic), 2962-2864 (CHaliphatic), 1633 (C=O) and
1
C1), 159.73 (1C, C12), 166.38 (1C, C7,( C=O)).
(C=N), 1587-1435 (C=C); H NMR (300 MHz,

SAOUD et al., Orient. J. Chem., Vol. 33(4), 1781-1798 (2017)
1785
DMSO-d6) d, ppm;1.30-1.42 (s, 18H, CH3), 2.21 (s,
3H, CH3), 6.91 (m, 1H, H4), 7.26 (d, 1H, J 2.3, H12),
7.34 (d,1H, J 2.1, H14), 7.41 (d,1H , J 6.8, H3), 7.8
(d, 1H, J 7.9, H5), 8.65 (s, 1H, H8,(C=N)), 12.23 (bs,
1H, NH), 12.43 (bs, 2H, 2OH); 13C NMR (75 MHz,
DMSO-d6) d, ppm; 15.57(1C, CH3), 29.25 (3C, C16,
C(CH3)3), 31.25 (3C, C18, C(CH3)3), 33.84 (1C, C17,
C(CH3)3), 34.62 (1C, C15, C(CH3)3), 116.99 (1C, C6),
117.74 (1C, C9), 119.12 (1C, C4), 120.30 (1C, C14),
124.97 (1C, C12), 125.65 (1C,C5), 125.81 (1C,C2),
126.19 (1C, C3), 135.64 (1C, C11), 140.38 (1C, C13),
152.11 (1C, C8,(C=N)), 154.83 (1C, C10), 159.62 (1C,
C1), 166.48 (1C, C7,(C=O)).
6-(5-(4-hydroxylphenyl)-1,3,4-oxadiazol-2-yl)-2-
methylphenol
The crude product (5b) was recrystallized
from methanole to give pale beige precipitate.Yield
0.2 g, 75%, m.p.(224-227) C, IR (KBr, υmax/ cm-1)
3464 (OH), 3150 (OHphenol), 3078 (CHaromatic), 2978-
2924 (CHaliphatic), 1622 (C=N), 1599-1402 (C=C);1H
NMR (300 MHz, DMSO-d6) d, ppm; 2.18 (s, 3H,
CH3), 6.85 (m, 3H, H4,2×H11), 7.35 (d, 1H, J 6, H3),
7.59 (d,2H, J 8.3, H10), 7.79 (d,1H , J 6.6, H5), 11.85
(s, 1H, C12-OH), 12.79 (s, 1H, C1-OH); 13C NMR (75
MHz, DMSO-d6) d, ppm;15.50(1C, CH3), 112.80 (1C,
C6), 115.78 (2C, C10), 117.92 (2C, C11), 124.63 (1C,
C4), 124.91 (1C, C5), 126.18 (1C,C2), 129.15 (1C,C9),
134.91 (1C, C3), 159.50 (1C, C1), 159.78 (1C, C12),
164.34 (1C, C7), 165.07 (1C,C8).
General synthesis of 6-(5-(Aryl)-1,3,4-oxadiazol-
2-yl)-2-methylphenol (5a-i)
Method A
To a suspension of N’(substituted
benzylidene)2- hydroxy-3-methylbenzohydrazide
(1 mmol) in 5 mL glacial acetic acid and (2 mmol)
of anhydrous sodium acetate, bromine solution (1
mmol) in 3 mL glacial acetic acid was added dropwise
at ambient temperatures. The mixture was refluxed
for 4 h. After cooling the mixture was poured into
100 mL ice water and stirred for another 30 minutes.
The precipitate was collected, washed with water
and dried. The crude product was purified either by
flash column chromatography using suitable eluent
or by recrystallization from suitable solvent.
6-(5-(4-hydroxy-3-methoxyphenyl)-1,3,4-
oxadiazol-2-yl)-2-methylphenol
The product (5c) was purified by flash
column chromatography using hexane-ethyl acetate
(4:1) as eluent to afford pale yellow precipitate.
Yield0.23 g, 78%, m.p.(110-115) C, IR (KBr, υmax
/
cm-1)3282 (OHvanillin), 3120 (OHphenol), 3012 (CHaromatic),
2931-2850 (CHaliphatic), 1674 (C=N), 1591-
1425(C=C);1H NMR (400 MHz, DMSO-d6) d, ppm;
2.07 (s, 3H, CH3), 3.72 (s, 3H, O-CH3), 6.73 (m,
2H, H4,H10), 7 (d, J 8.07, 1H,H3), 7.23 (over lap,
2H, H5,H13), 7.67 (d, J 8.07, 1H,H14), 11.74 (s,1H,
C12-OH), 12.64 (s, 1H, C1-OH); 13C APT (100 MHz,
DMSO-d6) d, ppm; 15.96 (1C, CH3), 56.03 (1C,O-
CH3), 109.47 (1C, C10), 113.31 (1C, C6), 115.93 (1C,
C13), 118.40 (1C, C14), 123.09 (1C, C4), 125.12 (1C,
C5), 125.80 (1C,C9), 126.66 (1C,C2), 135.38 (1C, C3),
148.57 (1C, C11), 149.85 (1C, C12), 159.95 (1C, C1),
161.68 (1C, C7), 166.77 (1C, C8).
6-(5-(4-methylphenyl)-1,3,4-oxadiazol-2-yl)-2-
methylphenol
The product (5a) was purified by flash
column chromatography using hexane-ethyl acetate
(3:1) as eluentto give off-white precipitate.Yield 0.18
g, 73%, m.p.(158-160) C, IR (KBr, υmax/ cm-1) 3128
(OHphenol), 3026 (CHaromatic), 2962-2848 (CHaliphatic),
1610 (C=N), 1543-1417 (C=C); 1H NMR (300 MHz,
DMSO-d6) d, ppm; 2.03 (s, 3H, C2-CH3), 2.2 (s, 3H,
C12-CH3), 6.7(t, 1H, J 7.6,H4), 7.13 (d, 2H, J 7.9,
H11), 7.21(d,1H, J 7.3, H3 ), 7.49 (d, 2H, J 7.9, H10),
7.64(d,1H, J 7.9, H5),11.83 (s, 1H, OH);13C NMR (75
MHz, DMSO-d6) d, ppm; 15.26(1C, C2-CH3), 20.83
(1C,C12-CH3), 112.53 (1C, C6), 117.76 (1C, C4),
124.50 (1C, C5), 125.96 (1C, C2), 127.06 (2C, C11),
, 129.28 (2C,C10), 131.00 (1C, C12), 134.81(1C, C3),
140.13 (1C,C9), 159.23 (1C, C1), 163.59 (1C, C7),
165.39 (1C,C8).
6-(5-(4-hydroxy-3,5-dimethoxyphenyl)-1,3,4-
oxadiazol-2-yl)-2-methylphenol
Recrystallization of the crude (5d)product
from methanole to give light beige precipitate.Yield
0.27 g, 84%, m.p.(122-125) C, IR (KBr, υmax/ cm-1)
3510 (OH), 3242 (OHphenol), 3091-3008 (CHaromatic),
2970-2864 (CHaliphatic), 1630 (C=N), 1591-1423
(C=C);1H NMR (300 MHz, DMSO-d6) d, ppm;2.05
(s, 3H, CH3), 3.69 (s, 6H, 2×OCH3), 6.72 (t, 1H, J
7.63, H4), 6.87 (s, 2H, H10), 7.22 (d, 1H, J 7.35, H3),
7.65 (d, 1H, J 7.91, H5), 11.78 (s, 1H, C12-OH), 12.60

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SAOUD et al., Orient. J. Chem., Vol. 33(4), 1781-1798 (2017)
(s, 1H, C1-OH);13C NMR (75 MHz, DMSO-d6) d, ppm; 2972-2852 (CHaliphatic), 1610 (C=N), 1539-1406
1
15.52 (1C, CH3), 56.06 (2C, 2×OCH3), 104.87 (2C, (C=C); H NMR (300 MHz, DMSO-d6) d, ppm; 2.2
C10), 112.86 (1C, C6), 117.96 (1C, C4), 124.15 (1C, (s, 3H, CH3), 6.93 (t, J 8.77, 1H, H4), 7.11 (d, J 9.01,
C9), 124.71 (1C,C5), 126.20 (1C,C2), 134.95 (1C, C3), 2H, H11), 7.33 (d, J 8.78, 1H, H3), 7.73 (d, J 8.56, 1H,
138.33 (1C, C12), 150.06 (2C, C11), 159.46 (1C, C1), H5), 8.00 (d, J 9.1, 2H, H10), 10.1 (s, 1H, OH); 13C
163.30 (1C, C7), 165.65 (1C,C8).
NMR (75 MHz, DMSO-d6) d, ppm; 15.72(1C, CH3),
107.77 (1C, C6), 119.91 (1C, C4), 121.84 (1C, C9),
6-(5-(2-hydroxy-3,5-di-tertbutylphenyl)-1,3,4- 125.13 (1C, C5), 126.00 (1C, C2), 128.59 (2C,C10),
oxadiazol-2-yl)-2-methylphenol 129.62 (2C,C11), 134.72 (1C, C3), 137.00 (1C, C12),
The product (5e) was purified by flash 154.71 (1C, C1), 162.16 (1C, C8,(C=N)), 164.11 (1C,
column chromatography using hexane-ethyl acetate C7,(C=N)).
(8:1) as eluent to afford white precipitate.Yield 0.27 g,
72%, m.p.(225-227) C, IR (KBr, υmax/ cm-1) 3192 (OH) 2-(5-(4-methoxyphenyl)-1,3,4-oxadiazol-2-yl)-6-
& (OHphenol), 3020 (CHaromatic), 2956-2871 (CHaliphatic), methylphenol
1610 (C=N), 1543-1433(C=C);1H NMR (300 MHz,
Recrystallization of the crude product (5g)
DMSO-d6) d, ppm; 1.26-1.38 (s, 18H, CH3), 2.17 (s, from ethanol and water to give pale pink precipitate.
3H, CH3), 6.86 (t, J6.9, 1H, H4), 7.29 (m, 3H, H3, H12, Yield 0.29 g, 71%, m.p.(161-164) C, IR (KBr, υmax
/
H14), 7.75 (d,1H, J 7.9, H5), 12.18 (s, 1H, C10-OH), cm-1); 3421 (OHphenol), 3097 (CHaromatic), 2987-2852
12.38 (s, 1H, C1-OH); 13C NMR (75 MHz, DMSO-d6) (CHaliphatic), 1610 (C=N), 1543-1429 (C=C), 1173
d, ppm; 15.45(1C, CH3), 29.12 (3C, C16, CH3), 31.13 or 1142 (C-O-CH3); 1H NMR (300 MHz, DMSO-d6)
(3C, C18, CH3), 33.72 (1C, C17), 34.50 (1C, C15), d, ppm; 2.28 (s, 3H, CH3), 3.87 (s, 3H, O-CH3), 7.02
116.88 (1C, C6), 117.61 (1C, C9), 119.00 (1C, C4), (t, J 7.6, 1H, H4), 7.19 (d, J 9, 2H,H10), 7.42 (d, 1H,
120.17 (1C, C14), 124.84 (1C, C12), 125.53 (1C,C5), H3), 7.82 (d, J 7.9, 1H,H5), 8.09 (d, J 8.9, 2H, H11),
125.69 (1C,C2), 126.07 (1C, C3), 135.64 (1C, C11), 10.18 (s, 1H, OH); 13C NMR (75 MHz, DMSO-d6)
140.26 (1C, C13), 154.71 (1C, C10), 159.49 (1C, C1), d, ppm; 15.70(1C, CH3), 55.56 (1C,O-CH3), 107.82
162.55 (1C, C7), 165.63 (1C, C8).
(1C, C6), 114.92 (2C, C11), 115.16 (2C, C10), 119.85
(1C, C4), 124.87 (1C, C5), 125.88 (1C,C2), 128.71
(1C,C9), 134.47 (1C, C3), 154.63 (1C, C1), 162.31
Method B
Excess of phosphorusoxy chloride (5 mL) (1C, C7,(C=N)), 162.82 (1C, C8,(C=N)), 163.54
was added dropwise, at room temperature into (1C,C12).
a mixture of 2-hydroxy-3-methylbenzohydrazide
(0.24 g, 1.4 mmol) and substituted carboxylic acid 2,6-di-tert-butyl-4-(5-(2-hydroxy-3-methylphenyl)-
(1.4 mmol) in a 250 mL round bottom flask. The 1,3,4-oxadiazol-2-yl)phenol
mixture was heated up to 80-90 °C and stirred for
The desired product (5h) was purified by
5 h. Upon cooling, 100 mL crushed ice was poured flash column chromatography using hexane-ethyl
into the mixture and stirred for 15 minutes. The acetate (10:1) as eluent to give orangish yellow
PH of the mixture was adjusted to 7-8 by adding a precipitate. Yield 0.4 g, 73%,m.p.(165-168) C, IR
solution of sodium bicarbonate.The precipitate was (KBr, υmax/ cm-1); 3610 (OHdi-tert-butyl), 3176 (OHphenol),
filtered, washed with distilled water and dried. The 3097 (CHaromatic), 2962-2871 strong (CHaliphatic), 1610
desired product was purified by recrystallization (C=N), 1550-1417 (C=C);1H NMR (300 MHz, DMSO-
from appropriate solvent or by flash column d6) d, ppm; 1,45 (s, 18H, CH3), 2.27 (s, 3H, CH3),
chromatography
5.56 (s, 1H, OH), 7.01 (t, 1H, J 7.6, H4), 7.4 (d, 1H,
J 7.2, H3), 7.78 (d, 1H, J 7.7, H5), 7.87 (s,2H, H10),
2-(5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl)-6- 10.24 (s, 1H, OH); 13C-NMR (75 MHz, DMSO-d6)
methylphenol
d, ppm; 15.69(1C, CH3), 29.92 (1C,C14,CH3), 34.59
The desired product (5f) was purified (1C,C13), 107.78 (1C, C6), 114.09 (1C, C9), 119.85
by flash column chromatography using hexane- (1C, C4), 123.60 (1C, C5), 124.77 (2C, C10), 125.80
ethyl acetate (4:0.5) as eluent to give white (1C,C2), 134.37 (1C,C3), 139.65 (1C, C11), 154.59
precipitate. Yield 0.33 g, 79%, m.p.(171-173) C, IR (1C, C1), 157.79 (1C, C12), 163.41 (1C, C7,(C=N)),
(KBr, max/ cm-1);3207 (OHphenol), 3086-3033 (CHaromatic), 163.55 (1C,C8,(C=N)).

SAOUD et al., Orient. J. Chem., Vol. 33(4), 1781-1798 (2017)
1787
6,6'-(1,3,4-oxadiazole-2,5-diyl)bis(2-methyl
phenol)
were Bacillus subtilis ATCC 6051, Enterococcus
faecalis, ATCC 29212 Streptococcus pyogenesATCC
19615, Staphylococcus aureus ATCC 29213.
The antibacterial activities were assayed in terms
of minimal inhibitory concentrations (MICs) by
employing the dilution assays according to the CLSI
guidelines 35.The dimethyl sulfoxide (DMSO) which
was used as solvent was included as (negative
control) with concentrations between 0.05 to 0.5
mg/mL of synthesized compounds. Amoxicillin and
kanamycin in DMSO (commercial antibiotics).In the
same concentrations range were taken as a positive
control. Bacterial stock cultures were supplied on
nutrient agar plates. A loopful of bacterial cultures
from the nutrient agar plates were diluted with
100 mL nutrient broth in 250 mL a side arm
Erlenmeyer flask and aerobically incubated at
37 °C for overnight with continuous shaking. After
incubation, cultures were diluted with fresh media
to give an O.D of 600 nm of 0.1volum. Fifty mL of
standardized 18 h incubated bacterial culture was
introduced into test tubes of 5 mL media (Muelen
Hintan broth) followed by the addition of various
concentration of the studied compounds. The MIC
was estimated as the lowest concentration that
inhibits the growth of the bacterial strains.All assays
were performed in triplicate and MIC’s values were
noted in mg/mL.
Recrystallization of the crude product
(5i)from ethanol and water to give pale yellow
precipitate.Yield 0.24 g, 61%, m.p.(280 dec.) C, IR
(KBr, υmax/ cm-1); 3475 & 3222 (OHphenol), 3022
(CHaromatic), 2962-2848 (CHaliphatic), 1614 (C=N), 1547-
1481 (C=C); 1H NMR (400 MHz, DMSO-d6) d, ppm;
2.24 (s, 6H, 2×CH3), 6.95 (t, 2H, J 7.62, H4), 7.37
(d, 2H, J 7.22, H3), 7.47 (d, 2H, J 7.72, H5), 9.85(s,
2H, 2OH); 13CAPT (100 MHz, DMSO-d6) d, ppm;
15.54(2C, 2×CH3), 108.67 (2C, C6), 119.54 (2C, C4),
125.38 (2C, C5), 126.06 (2C, C2),134.14 (2C,C3),
153.33 (2C, C1), 159.62 (2C, 2×C7).
Antioxidant
dppH assay
The assay was performed as reported by
Gerhauser et al. 33. Five microliters of the sample
(dissolved in ethanol) was added into 195 mL of
100 mM DPPH reagent in ethanol (96%) and mixed
in a 96-well plate. The intensity of the colour was
measured for 3 h at an interval of 20 min at 515 nm.
Ascorbic acid and BHT were used as references
FRAp assay
The FRAP assay was performed according
to the Benzie and Strain method34. The FRAP
reagent was prepared by combining 300 mM acetate
buffer and 10 mM 2,4,6-tripyridyl-s-triazine (TPTZ)
solution in 40 mMHCl and 20 mM FeCl3·6H2O, in a
ratio of 10:1:1. The FRAP reagent was incubated
at 37 °C prior to use. Ten microliters of the sample
was reconstituted in the carrier (solventor ultrapure
water) and mixed with 300 mL of FRAP reagent.
The mixture was incubated at 37 °C for 4 min in a
microplate reader. The absorbance of the complex
was performed at 593 nm.
RESULT ANd dISCUSSION
6-(5-thio-1,3,4-oxadiazol-2-yl)-2-
methylphenol(2) successfully synthesized from
2-hydroxy-3-methylbenzohydrazide following the
procedure depicted in Scheme 1. The structure
of compound (2) was conrmed by spectroscopic
analysis.The IR spectrum was displayed no signals
of carbonyl of the hydrazide at 1650 cm-1and NH2
at 3323-3267 cm-1. A new signal band of C=N
appeared at 1606 cm-1 and for C=S at 1122 cm-1.
The 1H NMR showed disappearing the broad signal
of amine(NH2) at 4.69 ppm moreover, the protons
of 2-methylgroup, NH and phenol were appeared
at their expected area.The13CAttached-Proton-
Test (APT) Spectrum exhibited five negative peaks
(pointing downwards) belonged to five quaternary
carbons C1, C2, C6, C7(C=N), C8(C=S) at (154.30,
127.04,109.65, 160.59, 177.24) ppm respectively.
In addition to that, the CH3 and CH were located as
positive peak for CH3, C3, C4, C5 at (16.51, 135.11,
determination of the antibacterial activity
The antibacterial activities of the following
synthesized compounds (2), (3a-e), (4a-e)and(5a-i)
were tested against standard typed strains of eight
bacteria.They were obtained from the Central service
laboratory-college education for pure science-Ibn Al-
haitham . These microorganism’s strains consist of
Gram negative bacteria:Acinetobactercalcoaceticus
ATCC 23055, Escherichia coli ATCC10538,
Pseudomonas aeruginosaATCC15442 , Salmonella
typhimurium ATCC14028.TheGrampositivebacteria

1788
SAOUD et al., Orient. J. Chem., Vol. 33(4), 1781-1798 (2017)
120.51, 126.35) ppm respectively. The electron and 3174 cm-1 respectively for the compound (3b).
ionization mass (EIMs) spectrum showed the value The 1H NMR spectra showed singlets at d 3.34-5.16
of the molecular ion M•+= 208 as well it is the same ppm which were assigned to the SCH2, moreover the
value of base peak (100%) .
rest protons of alkyl group and the 2-methyl phenol
were appeared at their expected area. Furthermore,
Alkylation of 6-(5-thio-1,3,4-oxadiazol-2-yl)- the 13C NMR and 13C APT of the 6-(5-(alkylthio)-
2-methylphenol achieved successfully by alkylation 1,3,4-oxadiazol-2-yl)-2-methylphenol (3a-e) showed
reaction in DMF. Five alkyl halides were used in characteristic peak in the d 162.44-163.73 ppm,
the presence of potassium carbonate at ambient which was assigned to new C=N besides the peaks of
temperature. The newly synthesized compounds thioalkyl group.13C APT spectrum of compound (3a)
(3a-e) were characterized from their IR, 1D NMR displayed the CH3 of ethyl group located as positive
and EIMs spectra. The IR spectra displayed the peak at 15.3 ppm, while the CH2 located as negative
disappearing of signal forthione, besides the peak at 27.25 ppm.The APT spectrum of compound
appearing of the new function group of alkyl such (3b) showed new peak of 2-methylbenzimidazole.
as C=O of ester at 1728 cm-1 for compound (3d), The CH2besides C1, C2, C6, C7, C8, C10 and C11
C=O of ketone at 1678 cm-1 for compound (3c) as were appeared at the negative position, while CH3,
well the C=N and NH for benzimidazol at 1618 cm-1 C3, C4, C5, C12 and C13 were exhibited as positive
Scheme 1. Synthetic route of compound (1-5i)
Table 1: Alkyl group and some selected properties of compounds (2-3e)
NO.
R
Yield %
m.p. ˚C
M.F
EIMs Calc.
M
EIMs Found
M
2
3a
-
88
83
212-213
74-76
C9H8N2O2S
C11H12N2O2S
208.03
236.06
208
236
H2C
CH3
N
CH2
3b
3c
3d
3e
77
173-175
164-166
71-73
C17H14N4O2S
C17H13BrN2O3S
C13H14N2O4S
C16H14N2O2S
338.08
403.98
294.07
298.08
338
403
294
298
N
H
O
86
H2C
Br
O
72.5
67
H2C
H2C
O
100-103

SAOUD et al., Orient. J. Chem., Vol. 33(4), 1781-1798 (2017)
1789
Table 2: Aryl group and some selected properties of compounds (4a-5i)
No.
Ar
Yield %
m.p. ˚C
M.F
EIMs Calc.
M
EIMs Found
M
CH3
OH
4a
4b
67
78
173-174
240-242
C16H16N2O2
C15H14N2O3
268.12
270.1
268
270
O
4c
4d
83
81
203-206
210-213
C16H16N2O4
C17H18N2O5
300.11
330.12
300
330
OH
O
OH
O
OH
4e
77
205-208
C23H30N2O3
382.23
382
CH3
5a
5b
73
75
158-160
224-227
C16H14N2O2
C15H12N2O3
266.11
268.08
266
268
OH
O
5c
5d
78
84
110-115
122-125
C16H14N2O4
C17H16N2O5
298.1
298
328
OH
O
328.11
OH
O
OH
5e
72
225-227
C23H28N2O3
380.21
379
5f
79
71
171-173
161-164
C15H11ClN2O2
C16H14N2O3
286.05
282.1
286
282
Cl
5g
OMe
5h
5i
73
61
165-168
280 dec.
C23H28N2O3
C16H14N2O3
380.21
282.1
379
282
OH
OH

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SAOUD et al., Orient. J. Chem., Vol. 33(4), 1781-1798 (2017)
peaks. The 13C NMR of compound (3c) and (3d) the HMBC was used with compound (4c). The aryl
showed the SCH2 group at 40.83 ppm and 35.92 group and some selective physical properties were
ppm respectively as well the ketone carbonyl group tabulated at Table 2.The IR spectra exhibited new
of (3c) located at 192.44 ppm and the carbonyl of signal of the imine group(C=N) at (1633-1603) cm-1.
ester of (3d) located at 167.62 ppm.The alkyl group The Carbonyl group of hydrazone displayed at (1735-
and some physical properties were tabulated in 1630) cm-1.
Table 1.
The 1H-NMR of these compounds showed
The Mass spectra showed the molecular disappearance of the NH2peak at 4.69 ppm.
ions (M•+) of the synthesized compounds (3a-e). Moreover, new peaks appeared such as C=N at
The base peak was showed the same value of the (8.39-8.65) ppm.The protons peaks of the aromatic
molecular ion as in compounds (3a, 3d) and (3e). aldehyde were appeared at their expected area and
The base beak of compound (3b) was appeared the OH signal appeared at range (12.43-12.80) ppm,
as 2-methyl benzimidazole carbocation [BIMCH2+], as well the NH signal appeared at (11.86-12.23) ppm.
while it appeared for compound (3c) as 6-(5-thio- The NMR spectra exhibited the substituted group
1,3,4-oxadiazol-2-yl)-2-methylphenol carbocation.
of aldehyde. The three protons of methyl group for
compound (4a) appeared at 2.36 ppm. The para
The N’(substituted benzylidene)2- hydroxy- hydroxyl group of compound (4b) appeared as broad
3-methylbenzohydrazide (4a-e) (hydrazones) were singlet signal at 10.02 ppm, the methoxy group for
synthesized as an intermediate compounds in the compounds (4c) and (4d) appeared at 3.42 ppm
formation of the 1,3,4-oxadiazole ring (5a-e). the and 3.83 ppm integrating for three and six protons
reactionofhydrazide(1)withsubstitutedbenzaldehyde respectively. The di-tert-butyl group for compound
to produce the corresponding hydrazones with (4e) appeared as two singlets with nine protons
significant yield. The hydrazones(4a-e) were integrating for each peak.
characterized by IR, 1D-NMR and EIMs.Furthermore,
Fig. 1: HMBC spectrum ,expansion aria of compound (4c)

SAOUD et al., Orient. J. Chem., Vol. 33(4), 1781-1798 (2017)
1791
The 13CNMR, 13C APT spectra showed
new carbons of aromatic substituted aldehyde
besides the interesting peak were assigned to
CH=N at 148.12-152.11 ppm.Moreover, the 13CNMR
assigned the substituted group at the aromatic
aldehyde. The methyl group of compound (4a)
appeared at 21.02 ppm. The carbon attached with
para hydroxyl group of compound (4b) appeared at
159.73 ppm, the methoxy group of compound (4c)
and (4d) appeared at 56.03 ppm and 35.00 ppm
respectively. The carbons of two di-tert- butyl group
of compound (4e) appeared at 29.25 ppm and 31.25
ppm.
The HMBC was used with compound (4c)
to solve any confusing with 1H and 13C NMR. HMBC
spectrum disclosed the correlation for long distance
coupling J3 and weak for J2. The HMBC spectrum
exhibited three correlations at 12.77-113.44 ppm,
12.77-127.19 ppm and 12.77-159.89 ppm as
displayed in Figure 1.
These correlations disclosed the relations
between the OH of 2-methylphenol with C6 and
C2 as J3, while the correlation with C1 exhibited as
J2.Although, the protons at 11.92 ppm and 9.62
ppm displayed just two correlations, However the
Table 3: Antioxidant properties of compound (2) and their alkyl (3a-e)
Compound
No.
Alkyl Group
dppH Inhibition % Sd a
100μg/mL
IC50 SEM b
(100μg/mL)
2
3a
3b
-
Et
68.21 0.0243
34.16 0.0513
66.72 0.0129
43.101 0.0451
100 >
49.03 0.0335
3c
3d
45.07 0.037
38.63 0.0662
89.90 0.0172
100 >
3e
48.66 0.0212
20.15 0.0189
84.08 0.0568
2-Me phenol
100 >
BHT
Ascorbic acid
66.03 0.022
90.65 0.025
79.835 0.015
22.71 0.020
a Standard deviation (SD) value in FRAP was between 0.01–0.16; bSEM standard mean error and IC50:
50%effective concentration

1792
SAOUD et al., Orient. J. Chem., Vol. 33(4), 1781-1798 (2017)
The newly synthesized compounds of 6-(5-
HMBC allowed to distinguished between the NH
of hydrazone and the OH of 3-methoxyphenol. The (aryl)-1,3,4-oxadiazol-2-yl)-2-methylphenol (5a-i)
peak at 11.92 ppm showed correlation with C8(C=N) were successfully synthesized by two methods.
at 11.92-151.48 ppm as J3.However, the correlation The first method was from cyclization of the
with C7(C=O) appeared as J2. These correlations hydrazones(4a-e)in the presence of bromine in
indicated that the proton at 9.62 ppm belongs glacial acetic acid.The second method, from reacting
to Hydroxyl group of 3-methoxyphnol. The two the hydrazide(1) with substituted benzoic acid in
characteristic correlations at 9.62-115.54 ppm and the presence of phosphorusoxy chloride. The new
9.62-147.97 ppm indicated the correlation between compounds were characterized by IR, NMR and
the proton of OH group and C13 as well with C11.The mass spectroscopy. The IR spectra showed the
most important correlation depicted in Figure 2.
OH group at 3471-3120 cm-1, (CHaliphatic) at 2987-
2746 cm-1, (CHaromatic)at 3097-3008 cm-1 and C=N
1
Furthermore, the HMBC spectrum allowed at 1622-1606 cm-1. The H NMR spectra exhibited
distinguishing between C1 and C12.The C1at 159.89 that the CH=N peak and the NH were disappeared
ppm showed correlations with OH of 2-methylphenol after cyclization the hydrazones. The NMR spectra
as mentioned earlier besides the correlation with of compounds which synthesized from cyclization
H3 at 7.39-159.89 ppm and correlation with H5 at the hydrazide with the carboxylic acid exhibited
7.8-159.89 ppm as J3. The C12 exhibited correlation disappearing of the NH, NH2 and OH of carboxylic
with H10 at 7.36-150.33 ppm and with H14 at 7.12- acid.Furthermore, the protons of the 2-methylphenol
150.33 ppm as J3. As demonstrated in HMBC key group appeared at their expected area.The 1H NMR
correlations. Furthermore, the structures of these spectra displayed the methyl group at 2.03-2.28 ppm,
compounds were characterized from their mass integrating for three protons, while in compound (5i)
spectra. The mass spectra confirmed the molecular appeared at 2.24 ppm integrating for six protons. As
weight of these compounds from their molecular ion, well the protons of 5-ary group of the 1,3,4-oxadiazoe
base peak and their fragmentations.
appeared in their expectedr egion. The 4-methyl
group of compound (5a) appeared at 2.2 ppm as
singlet peak. The para hydroxyl of compound (5b)
appeared at 12.79 ppm, 1H NMR of compound (5c)
showed singlet at 3.72 ppm, integrating for three
protons disclosed to 3-methoxyl. The multiples at
6.73 ppm, integrating for two protons disclosed the H4
and H10. The H13 and H14 appeared at 7.23 ppm and
7.67 ppm respectively.The compound (5d) exhibited
singlet peak at 3.69 ppm for two methoxy groups.
compound (5h) showed singlet at 1.45 ppm for two
Fig. 2: Selected HMBC correlations of
compound (4c)
Fig. 3: FRAp value of compound (2) and their alkyl (3a-e)

SAOUD et al., Orient. J. Chem., Vol. 33(4), 1781-1798 (2017)
1793
Table 4: dppH inhibition % and IC50 of compound (4a-e) and (5a-i)
No.
Ar
dppH Inhibition % Sd a
100μg/mL
IC50 ESM b
(100μg/mL)
CH3
OH
4a
4b
4c
65.72 0.0183
69.83 0.0311
74.65 0.0615
100 >
78.32 0.027
60.04 0.0198
O
OH
O
4d
4e
91.14 0.0187
87.31 0.030
38.09 0.061
43.15 0.0306
OH
O
OH
5a
5b
62.66 0.029
62.18 0.021
100 >
CH3
OH
81.96 0.022
O
5c
5d
68.9 0.027
80.11 0.014
49.04 0.018
OH
O
82.14 0.023
OH
O
OH
5e
78.33 0.034
53,08 0.012
5f
41.70 0.052
60.72 0.041
100>
Cl
5g
82.39 0.027
OMe
5h
93.09 0.0.33
74.31 0.062
20.15 0.0189
31.5 0.0189
57.83 0.0171
100 >
OH
OH
5i
OH
2-Me phenol
H3C
BHT
Ascorbic acid
66.03 0.022
90.65 0.025
79.835 0.015
22.71 0.020

1794
SAOUD et al., Orient. J. Chem., Vol. 33(4), 1781-1798 (2017)
tert-butyl groups, while the two tert-butyl groups for Antioxidant properties
compound (5e) exhibited at two singlet 1.26 ppm and
1.38 ppm.
The antioxidant activities of the newly
synthesized compounds (2, 3a-e, 4a-e and 5a-i)
were screened by DPPH assay which undergoes
The 13C NMR spectra displayed two a hydrogen atom transfer mechanism (HAT )36also
characteristic peaks at 161.68-164.34 ppm and they screened by FRAP assay which is prefer single
162.28-165.65ppm belonged to C7 and C8 of the electron transfer (SET)37. The radical scavenging
oxadiazole ring. The methyl of the 2-methylphenol power in both assays was compared with three
of compound (5a) appeared at 15.26 ppm while standard antioxidants, 2-methylphenol, BHT and
the 4-methyl appeared at 20.83 ppm. The Carbon ascorbic acid. Compound (2) exhibited highest
bearing the para hydroxyl group of compound (5b) inhibition percentage in DPPH assay than their alkyls
was appeared at 159.78 ppm. The spectrum of (3a-e). This diminution of antioxidant properties of
compound (5c) showed the methoxy group at 56.03 alkyl derivative in compound (2) could be attributed
ppm and 56.06 ppm for two methoxy groups of to disappearing the thioamide group which were
compound (5d). The six methyl of 3,5-di-tert-butyl reported as free radical scavengers.38 Moreover,
group of compound (5h) appeared as single peak at the NHCS group is considered as a part of thiourea
29.92 ppm whereas the six methyl of 2,4-di-tert-butyl system which is known as effective antioxidant.39The
of compound (5e) appeared as two single peaks at alkyls derivatives of compound (2)showed inhibition
29.12 ppm and 31.13 ppm. The values molecular percentage higher than 2-methylphenol (2Me
ion, base peak and their fragmentation confirmed Phenol). Compounds (2) and (3b) exhibited DPPH
the structures of the newly synthesized oxadiazole inhibitions slightly higher than BHT, whereas their
by mass spectroscopy.
IC50 value was less than BHT, as displayed in
Table 3
The FRAP value of compounds (2) and
(3a-e) as depicted in Figure 3, were compatible
with DPPH results as displayed in Figure 3. The
FRAP value of compound (2) showed the highest
antioxidant activity than their alkyl derivatives. The
decreasing in FRAP value of compounds (3a-e)could
be attributed to losing the NHCS group as mentioned
earlier.Compound (3b) with thio methylbenzimidazole
exhibited higher antioxidant properties than the other
thioalkeys in both assays and that could be attributed
Fig. 4: Relationship between structure of
hydrazones and the antioxidant activity
Fig. 5: FRAp value of compounds (4a-e) and (5a-i)

1795
SAOUD et al., Orient. J. Chem., Vol. 33(4), 1781-1798 (2017)
to precipitation of NH of banzimidazole in antioxidant group (ring A), the NH as secondary amine which
properties40-42. Assuming that the formation of considered as alternative secondary antioxidant,
oxadiazole ring at position six of the 2-methyl phenol the imine group (N=CH) as shown in Figure 4 which
could play an pivotal role to enhances the antioxidant enable resonance with aromatic (ring B) and their
ability by increasing the steric hindrance which lead substituted group such as 4-CH3 ,4-OH,3-OMe-4-
to increase the antioxidant capacity43.
OH, 3,5-di-OMe-4-OH and 2-OH-3,5-di-tert-butyl
group which act as electron donating group (EDG)
The hydrazones (4a-e) exhibited antioxidant to immerse the radical scavenging activity of
ability in both assays higher than their corresponding phenols15.These EDGs enable to lowering the bond
oxadiazole(5a-e) and that could be attributed to dissociation enthalpy (BDE) of the phenol (ring B) as
the generic structure of the newly synthesized well increase the stabilization of the phenoxyl44.
hydrazones (4a-e), as depicted in Table 4.
Compound (4a) with 4-methyl group
The structure of these hydrazons include exhibited lowest antioxidant among the hydrazons
a recognized free radical scavenger as phenol however; their DPPH scavenging activity was
Table 5: Antibacterial activities of synthesized compound
NO
Bacteria/MICs (mg/mL)
Gram-positive bacteria
Gram-negative bacteria
Acineto
bacter
calcoaceticus
Escherichia pseudo
Salmo
nella
Bacillus Enteroc Strepto
subtilis occus coccus
aeruginosa typhimurium faecalis pyogenes aureus
Staphyl
coli
monas
2
0.3
nd
0.35
>0.5
nd
>0.5
nd
>0.5
0.5
>0.5
0.5
>0.5
>0.5
0.5
0.05
0.3
>0.5
0.5
0.35
0.1
>0.5
nd
>0.5
nd
0.35
>0.5
nd
>0.5
0.35
0.4
0.2
0.4
>0.5
>0.5
>0.5
0.2
0.4
>0.5
nd
>0.5
>0.5
>0.5
nd
0.4
nd
0.05
>0.5
0.15
0.25
>0.5
0.4
0.35
0.20
0.15
0.05
0.2
0.1
nd
0.2
0.1
>0.5
0.1
0.4
>0.5
0.5
0.15
>0.5
0.05
0.5
>0.5
>0.5
0.35
0.3
0.2
0.1
0.25
>0.5
0.5
0.2
0.2
0.4
>0.5
>0.5
0.25
0.2
3a
3b
3c
3d
3e
4a
4b
4c
4d
4e
5a
5b
5c
5d
5e
5f
>0.5
>0.5
>0.5
0.5
>0.5
0.25
>0.5
0.15
0.15
>0.5
0.5
0.35
>0.5
>0.5
0.5
0.35
0.25
0.2
0.35
nd
0.4
0.5
>0.5
0.35
0.3
0.1
0.2
>0.5
0.4
0.4
015
0.3
nd
0.3
0.25
0.05
0.15
0.25
0.5
0.3
0.25
0.1
0.3
0.4
>0.5
0.2
0.3
0.5
0.35
0.30
0.15
0.25
0.45
>0.5
0.3
>0.5
0.1
0.5
02
0.05
0.25
>0.5
0.5
0.35
0.3
nd
5g
5h
5i
>0.5
>0.5
0.3
>0.5
0.5
0.5
>0.5
>0.5
0.25
<0.05
0.25
<0.05
Amox, 0.05
icillin
<0.05
<0.05
0.05
<0.05
Kana <0.05
mycin
<0.05
<0.05
<0.05
<0.05
>0.5
<0.05
<0.05
nd; not detected

1796
SAOUD et al., Orient. J. Chem., Vol. 33(4), 1781-1798 (2017)
slightly similar to BHT. Compound (4d) with two compounds displayed significant antibacterial
substituted methoxy group at the ortho-position of activity against gram positive bacteria, while few
phenol displayed inhibition percentage in DPPH compounds exhibited significant activities against
assay slightly higher than ascorbic acid, while gram negative bacteria. The results showed the
DPPH scavenging activity of compound (4c) with relationships between the structure and the reactivity
one substituted methoxy group at ortho phenol against microorganisms. The 1,3,4-oxadiazole-
showed less antioxidant activity than ascorbic acid. 5-thione(2) gave significant anti-bacterial activity
Both compounds (4d) and (4c) showed antioxidant towered gram positive and negative bacteria while
activity higher than compound (4b) without any ortho this reactivity decreased with their alkyl derivatives
substituted of the phenol group as depicted inTable 4. (3a-e). This result shows that the hydroxyl group of
These results are consistent with the concept that the phenol and thioamide group are play an important
number of hydroxyl group and the electron donating role to enhance the anti-bacterial activity.Compound
group enhance the antioxidant capacity5. Although (3b)exhibited highest activity among the thio alkyl
compound (4e) have di tert butyl group flanking the derivative and that could be attributed to the existence
OH, it displayed DPPH inhibition percentage less of the benzimidazole group.Compound (3a) with thio
than compound (4d) and that could be attributed to ethyl group do not exhibited any activity towered any
presence of the second tert butyl group at position microorganisms under the test as well compound
para which has a detrimental effect on the antioxidant (3d). Although, compounds (3c) and (3e) consist
properties45. The FRAP value of the hydrazones aromatic group in their alkyl structure exhibited low
consistent with the DPPH results Figure 5 and it activity against Gram-positive bacteria.These results
showed same sequence.4d>4e>4c>4b.
represented the relationship between the structure
and the anti-bacterial activities. Furthermore, the
The DPPH scavenger activity and FRAP biological activity of compounds (4a-e) clearly
values of the 1,3,4-oxadiazoles(5a-i)exhibited less demonstrated this relationship between the structure
activities than their corresponding hydrazone and that and the anti-bacterial activities. The anti-bacterial
could attributed to evanescence the CONHN=CHAr activity enhances with the existence of hydroxyl
group which involved to enhances the antioxidant group of phenol in hydrazone as well the methoxy
activity. However, the oxadiazoles included hydroxyl group at ortho position of the phenol. Compound
group shows antioxidant capacity more than without (4a) showed the lowest activity (with 4-methyl
hydroxyl group.Furthermore, the antioxidant capacity substituted), while the antibacterial activity increased
of these oxadiazoles declined with decreases of the when the substituted was 4-OH as in compound
hindrances around the hydroxyl group of phenols. (4b). Compound (4c) showed higher reactivity than
The DPPH inhibitions of oxadizoles without hydroxyl (4d)with one methoxy group at ortho position of
substituted (5a,5f and 5g) exhibited antioxidant phenol.The significant anti-bacterial activity against
ability depend on the substituted group and it takes (gram negative and gram positive) appeared with
the following order 4-Me> 4-OMe>4-Cl. The FRAP compound (4d) which is possessing two methoxy
value of these oxadiazoles was in agreement groups at ortho position. The reactivity decreased
with the DPPH inhibition percentage as shown in with compound (4e) compared to (4d),this believed to
Figure 5.
be due to the effect of the steric hindrance of tert-butyl
group at ortho position of phenol which reduced the
effect of hydroxyl group and reduce their toxophoric
Antibacterial activity
The antibacterial activities for synthesized effect .The 2,5-disubstituted1,3,4-oxadiazoles (5a-i)
compounds were screened by micro broth dilution showed antibacterial activity slightly less than the
assays. Standard strains of Gram-negative and hydrazones.The minimum inhibitory concentrations
Gram-positive bacteria were used. Amoxicillin and of these compounds demonstrated the importance
Kanamycin were used as references. Minimum of the effect of increasing the hydroxyl and the
inhibitory concentrations ((MIC) mg/mL) of effect of methoxy group as well. Compounds (5d)
the synthesized compounds against the test and (5c) exhibited the highest activity against both
microorganisms were established and the results gram positive and negative bacteria flowed by
were tabulated in Table 5. Most of synthesized compounds (5b) and (5i). Even though, compound

1797
SAOUD et al., Orient. J. Chem., Vol. 33(4), 1781-1798 (2017)
(5h) possesses high antioxidant activity, while their secondly from cyclization the hydrazide(2) with
antibacterial was lower than compounds(5d), (5c) arylcarboxylic acid in the presence of POCl3. The
and (5b).Furthermore, the activity of compound (5d) antioxidant activities of the newly synthesized
was higher than compound (5c), and compound (5b) compound were tested by DPPH and FRAP.Results
higher than (5h).These results clearly exhibited that showed the close relationship between structure
the antibacterial activity depend on the toxophoric of and antioxidant ability. The antibacterial activities
phenol and the hindrances of this phenol constringe for these compounds were tested against eight of
the toxophoric effect and the antibacterial effect microorganisms (gram negative and gram positive).
doesn’t correlate with the antioxidant activity of the The results demonstrated that the increasing of
synthesized compounds.
free phenol as well the methoxy group near by the
hydroxyl of phenol enhances the antibacterial activity
while, the increase in the hindrance around the
hydroxyl of phenollower the antibacterial activity.
CONCLUSION
Two Series of 1,3,4-oxadiazole bearing
2-methyl phenol were successfully synthesized.
The first one, 6-(5-thio-1,3,4-oxadiazol-2-yl)-2-
methylphenol(2)andtheirthioalkyl(3a-e).Thesecond
ACKNOwLEdGMENT
The authors would like to acknowledge
of 6-(5-(Aryl)-1,3,4-oxadiazol-2-yl)-2-methylphenol University of Baghdad for supported this research,
(5a-i)were synthesized by two methods firstly from as well great thanks to University of Malaya for their
cyclization their corresponding hydrazones(4a-e) great help.
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