View of Syntheses, Characterization of a New Legend 2-Hydroxy-N'-(5-Phenyl-1,3,4-Oxadiazol-2-yl) Benzohydrazide with Some Transition Metal Complexes

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18167 http://annalsofrscb.ro

Syntheses, Characterization of a New Legend

2-Hydroxy-N'-(5-Phenyl-1,3,4-Oxadiazol-2-yl) Benzohydrazide with Some Transition Metal Complexes

Ahmed.M.I.Alsanafi

¹

, Dr.prof. Ibrahim.A.Flifel

¹

[email protected], [email protected]

University of Thi-Qar/College of Science

Abstract

In the current study, many new derivatives for 1.3.4-oxadiazole with its complexes using salts of transition metals such as nickel, copper, iron, cadmium, cobalt and chromium, were synthesized. The prepared ligands and their complexes were and identified using H-NMR and mass spectrometry in addition to FT-IR spectroscopy. Magnetic susceptibility and conductivity measurements were also performed. The hyperchem application was also used to perform theoretical calculations using the MP3 method

^[1]

to study the stability energy of the compounds to determine the binding sites of the ligand with the metallic elements to form complexes.

Key words: ligand, complexes, characterization, Hyperchem, electrostatic potential

Introduction

Oxadiazole and its derivatives were pentagonal heterocyclic compounds containing one oxygen and two nitrogen atoms. Oxadiazole was present in various forms as 1,2,5-oxadiazole, 1,2,4-oxadiazole, 1,2,3-oxadiazole and 1,3,4-oxadiazole

[2]

. The 1,3,4-oxadiazole isomer is attributed to the (unstable) diazoxitonotomer

^[3]

.

The compounds containing the nucleus 1,3,4-oxadiazole have an important benefit in the biological field as they have many biological activities such as anti- bacterial

^[4,5]

, anti-fungal

^[6]

, anti-inflammatory

^[7]

, anti-cancer

^[8]

, anti-cancer

^[8]

.

Figure 1: Oxadiazole Isomers

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anticonvulsant

^[9]

, interferon stimulator

^[10]

, anti-HIV

^[11]

, anti-diabetes

^[12]

, anti- tuberculosis

^[13]

, lipid peroxidation inhibitor

^[14]

, insecticides

^[15]

and antioxidants

[16]

. They were also used in many equipments and devices such as corrosion inhibitors

^[17]

, fluorescent and color chemical sensors

^[18]

, dyes

^[19]

, polymers

^[20]

, and light-emitting diodes

^[21]

.

Experimental

Synthesis of Benzohydrazide (A)

A mixture of Methyl benzoate (50.5 ml, 0.4 mol) and hydrazine monohydrate (20ml, 0.4 mol) in absolute ethanol (100 ml) were refluxed for 6 hours, the mixture was evaporated to half volume, cooled, filtered and washed with absolute ethanol

^[22]

, the solid (A) was lighting white with melting point 115

⁰

C, yield 95% . Synthesis of 5-phenyl-1,3,4-oxadiazole-2-thiol (B) and checked with TLC.

Benzohydrazide (A) (13.6 gm, 0.1 mol), potassium hydroxide (5.6 gm, 0.1 mol) and carbon disulfide (6ml, 0.1 mol) were refluxed in absolute ethanol (100 ml), the solvent was evaporated and acidified with HCl (10%), then the precipitate was filtered and the solid result was recrystallized from ethanol absolute

^[23]

. The solid (B) was white yellowish, melting point 220

⁰

C, yield 92.3%.and checked with TLC

Synthesis of 2-hydrazinyl-5-phenyl-1,3,4-oxadiazole(C)

5-phenyl-1,3,4-oxadiazole-2-thiol (B) (9gm, 0.5 mol) and hydrazine monohydrate (5ml , 0.1 mol) in ethanol absolute as solvent (50 ml) were refluxed for 15 hours.

White precipitate was appeared in round bottom

^[24]

. The precipitate was filtered and recrystallized from absolute ethanol, melting point 226

⁰

C, yield 72% .and checked with TLC.

Synthesis of 2-hydroxy-N'-(5-phenyl-1,3,4-oxadiazol-2-yl)benzohydrazide

The ligand was synthesized by condensation of 5g 0.028 mole of 2-hydrazinyl-5-

phenyl-1,3,4-oxadiazole(C) and 2.5ml 0.028 methyl salicylate (2-methylhydroxy

benzoate) in absolute ethanol (50 ml), then the mixture was refluxed for 10 hours

(monitored by TLC)

^[25][26]

. The ligand was precipitated, filtered and recrystallized

from absolute ethanol to get yellow-brown ligand melted at 230

⁰

C, yield

88%.and checked with TLC.

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O O

CH₃

+

^H²^N ^NH²

O NH

NH₂

+

methyl benzoate hydrazine benzohydrazide

methanol

O NH

NH₂

+

^CS² ^O

N N SH

benzohydrazide

C H₃ OH

A

B

+

^H2^S

5-phenyl-1,3,4-oxadiazole-2-thiol C₂H₅OH/Ref

KOH C₂H₅OH/Ref

A

O

N N

SH

+

^H2^N NH₂ O

N N

NH N H₂

hydrazine B

5-phenyl-1,3,4-oxadiazole-2-thiol

+

^H²^S

2-hydrazinyl-5-phenyl-1,3,4-oxadiazole Ethanol

c Ref

O N

N NH NH2

+

Ethanol Ref

2-hydrazinyl-5-phenyl-1,3,4-oxadiazole C

Ligand

+

O O

OH

CH₃

O

N N NH

NH

O O H

CH₃OH

methyl 2-hydroxybenzoate

2-hydroxy-N'-(5-phenyl-1,3,4-oxadiazol-2-yl)benzohydrazide

Preparation of complexes

The complexes were synthesized by mixing of (0.001 mol) from the ligand with salts (COCl

₂

.6H

₂

O, CdCl

₂

.6H

₂

O, CuCl2.6H

₂

O and NiCl

₂

.6H

₂

O) in (100 ml) absolute ethanol and refluxed for 2 hrs. The precipitate was filtered and wash several times with ethanol or aqueous ethanol to removed unreacted salts or ligand, then the precipitated complexes were dried, and checked with TLC

^[27]

.

Figure 2: steps of synthesis reactions

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Analysis and physical measurements

3.1 FT-IR spectral

FT-IR of the synthesized ligand and its complexes were carried out using KBr disc to ligand and CsI for complexes . The free ligand (L) exhibited six major bands which ware attributable to (υOH) (3298) cm

^-1

(υNH

2

) (3194) cm

^-1,

(υC=N) (14481) cm

^-1

, (υC-O-C) sym (1230Cm

^-1

), (υ C-O-C) asy (1319Cm

^-1

) and (1072Cm

^-1

) structure movement bands respectively, as shown below (table 2). New bands were formed Attributed to the coordinated (M- N) and (M-Cl) bonds and appeared at the region(601-327)cm

^-1

and (277-235)cm

^-1

respectively. This indicated that the coordinate occurred through the ( N), and (Cl) atoms .

3-2:Nuclear Magnetic Resonance

The

¹

H-NMR spectra of the ligand showed signals at (13.94ppm, H) and (5.81ppm, 2H) due to O-H protons and NH-NH protons respectively .signals at [(6.99-8.03)ppm, 9H] due to chemical shifts of aromatic ring protons linking the oxadiazole ring

^[29]

as showed in the figure below [figure 15] . 3.3 Mass spectra

The mass spectra of ligand showed the molecular ion peak at 296 m/z which was in conformity with the molecular formula C

15

H

12

N

4

O

3 .

Other peaks ware due to the subsequent fragments like [C

15

H

11

N

4

O

2

]

⁺

=279 m/z , [C

15

H

11

N

4

O]

⁺

=263 m/z , [C

8

H

7

N

4

O]

⁺

=175 m/z , [C

8

H

6

N

3

O]

⁺

=160 m/z ,

Λ Scm² mol^-1 M.p °C

M.Wt Color

formula No

--- 230

296 white

C15H12N4O2 (L) 1

23 10 3 454

green Cr( L) Cl3

2

12 215

444 White yellowish

Co ( L) Cl2H2O

3

220 11 425

Light green Ni( L)Cl2

4

10 217

430 Light gray

Cu(L)Cl2

5

Table 1: Analysis and physical measurements

M-Cl M-N

Str movmen

t C-O-C

SY C-O-C

ASY C=N

Hetro C=C

aromatic C-H C=O

aromatic

NH OH

1072 1230

1319 1481

1531 1631

3055 3194

3298 L1

235 327

1072 1230

1319 1500

1531 1631

3055 3194

3298 L1Co

277 601

1076 1288

1327 1431

1558 1616

3055 3236

3302 L1Ni

270 482

1010 1303

1384 1481

1531 1639

3055 3116

3271 L1Cu

Table 2 FT-IR spectra of ligand and it is complexes

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[C

8

H

5

N

2

O]

⁺

=145 m/z , [C

7

H

5

O

2

]

⁺

=121 m/z , [C

7

H

5

NO]

⁺

=119 m/z , [C

7

H

3

O]

⁺

=103 m/z, [C

6

H

6

]

⁺

=77 m/z,[C

₄

H

₃

]

⁺

=51 m/z.

The mass spectral of the Cr(III) complexes showed molecular ion peaks at 454 m/z corresponding to [[Cr(L) Cl

3

]

^.+

stoichiometry. This complex showed another fragmentation peaks at 419 m/z ,383 m/z , 348 m/z due to loss one , two and three chlorine atom respectively. The mass spectral of the Co (II) complexes showed molecular ion peaks at 444 m/z corresponding to [Co(L)H

2

OCl

2

]

^.+

stoichiometry.

This complex showed another fragmentation peaks at 426 m/z ,390 m/z due to loss one and two chlorine atom respectively . The mass spectral of the Ni(II) complexes showed molecular ion peaks at 424 m/z corresponding to [Ni(L)Cl

₂

]

^.+

stoichiometry . This complex showed another fragmentation peaks at 390 m/z ,354 m/z due to loss one and two chlorine atom respectively . The mass spectral of the Cu(II) complexes showed molecular ion peaks at 430 m/z corresponding to [Cu(L)Cl

₂

]

^.+

stoichiometry . This complex showed another fragmentation peaks at 395 m/z ,359 m/z due to loss one and two chlorine atom respectively .

Electrostatic potential(MEP) . Molecular

3-3:

Electrostatic potential is a very important in parameter finding the active site in the molecule system with a positive charge. The species that have positive charge tend to attack a molecule where the electrostatic potential is strongly negative (electrophilic attack). Electrostatic potential of free ligands were measured and plotted as 2D contour to find the active site of molecule

^[30]

as shown in figures[4-9].

4.1 Biological Study

The antibacterial and antifungal efficiency of ligand and its complexes were evaluated by using agar spread method. Two type of bacteria have been used, Gram positive bacteria as (Staphylococcus

aureus) and Gram negative bacteria as(Pseudomonas aeruginosa), using Ampicillin as standard drug ,and tow type of fungi (Candida albicans) and (Candida kruse), using Flucanazole and Itraconazole as standard drug.

The bacteria and fungi inhibition was calculated in millimeter. nutrient agar was used as culture

medium .dimethyl Sulfoxide used as diluent the concentration of all compounds in this dilwent was

10

^-3

, using disc susceptibility test. The dishes were put in the incubator for 24hr. at 37℃

^[31]

.

according to the results in table (3), all compound possessed good anti-bacterial and anti-fungal

activity. Out of all the synthesis compounds Nickel(II) complex mor more bactericidal than others

even the standard drug.

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Figure 2 anti-fungi

NO Flucanazole DMSO

Controle 1 Itraconazole

Control 2 Candida

albicans Flucanazole

Control 1 Itraconazole

C2 Candida

kruse

L3 1 0

15 20

10 14

22 15

2 L3Cr 0

15 20

11 14

22 10

L3Co 3 0

15 20

11 14

22 12

4 L3Ni 0

15 20

11 14

22 12

L3Cu 5 0

15 20

10 14

22 12

Table(3)Anti-fungal data of ligand and its complexes, data represented the diameter of the zone growth inhibition (mm)

NO Ampicilline DMSO

Controle Staph +Ve

Psedo -Ve

1 L3

0 15

18 18

L3Cr 2 0

15 8

0

3 L3Co 0

15 0

16

4 L3Ni

0 15

14 0

5 L3Cu 0

15 16

18

anti-bacterial data of ligand and its complexes,

data represented the diameter of the zone growth inhibition (mm)

Table(4)

A B C D

A: Candida albians with Fluconazole control1 C: Candida kruse with Fluconazole control1 B: Candida albians with Itraconazole control2 D: Candida kruse with Itraconazole control2 control2

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conclusion

A 1,3,4-oxidiazole derivative acts as a two-chelated ligand. The spectral data show the participation of two groups of N-H and C-N-C in coordination with a central transition metal ion. Various techniques such as 1H.NMR spectra as well as molar conductivity .

Figure 3 anti – bacterial A: against Staphylococcus aureus. B: against Pseudomonas aeruginosa

Figure 7 . Graphical presentation of stereochemistry of the complex [Co(L1)Cl2H2O]

Figure 6 . Graphical presentation of stereochemistry of the complexes [Cr(L1) Cl3]

HOMO Electrostatic Potential as Contours for L

Figure(5) Figure 4 . Graphical presentation of stereochemistry

of the Ligand

B A

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Figure 8 . Graphical presentation of stereochemistry of the complexes [Ni(L1) Cl2]

Figure 9 . Graphical presentation of stereochemistry of the complexes [Cu(L1) Cl2]

L Figure 10

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Cr(L1)Cl3 Figure 11

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Co(L)Cl2H2O

Ni(L1)Cl2

Figure 12

Figure 13

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Cu(L1)Cl

Figure 14

Figure 15 H-NMR spectra of Ligand

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Figure16 Mass spectra of ligand

Figure 17 Mass spectra of Cr(L)Cl3

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Figure 19 Mass spectra of Co(L)Cl2H2O Figure 18 Mass spectra of Ni(L)Cl2

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Refrence:

[1]- I. B. Foresman and C. Frisch,

^״

Exploring Chemistry with Electronic structure Methods

^״

,2

^nd

d,.Gaussian Inc., Pittsburgh, PA. (1996).

[2] C. S. De Oliveira, B. F. Lira, J. M. Barbosa-Filho, J. G. F. Lorenzo, and P. F. De Athayde-Filho, Synthetic approaches and pharmacological activity of 1,3,4-oxadiazoles: A review of the literature from 2000-2012, vol. 17, no. 9. 2012.

[3] S. M. Zachariah, M. Ramkumar, N. George, M. S. Ashif, and M. April, “Sciences A Review on Oxadiazole .,”

Res. J. Pharm. Biol. Chem. Sci., vol. 6, no. 2, pp. 205–219, 2015.

[4] P. W. Lei, Z. Jian, and Z. H. Fang, “Potent antibacterial agents : pyridinium-functionalized amphiphiles bearing 1 , 3 , 4-oxadiazole scaffolds,” Springer-Online, 2016.

[5] I.A.Flifel* A. H.Gatea, * S.A.ali “Synthesis , Characterization , Antimicrobial New 2,2'-[(1E,2E)-ethane-1,2- diylidenedi(2E)hydrazin-1-yl-2-ylidene]bis(5-methyl-1,3,4-oxadiazole) and their transition” J.Thi-Qar sci.Vol.6,pp. 1991-8690,2017.

[6] T. Zhang et al., “Antibacterial and Antifungal Activities of 2- ( substituted ether ) -5- ( 1- phenyl-5- ( tri fl uoromethyl ) -1 H -pyrazol-4-yl ) -1, 3,4-oxadiazole Derivatives,”Wiley Period., pp. 4–10, 2017.

[7] V. B. Iyer, B. M. Gurupadayya, K. V. Sairam, B. Inturi, R. S. Chandan, and A. K. Tengli, “Anti-Inflammatory Activity of 1,3,4-Oxadiazoles Derived from Benzoxazole,” J. Pharm. Sci. Pharmacol., vol. 2, no. 3, pp. 233–

241, 2015.

[8] M. Agarwal et al., “chemistry Design and synthesis of new 2 , 5-disubstituted-1 , 3 , 4-oxadiazole analogues Figure 20 Mass spectra of Cu(L)Cl2

(15)

as anticancer agents,” springer-Medicinal Chem. Res., pp. 0–1.

[9] N. Siddiqui, J. Akhtar, and M. S. Yar, “Substituted phenyl containing 1,3,4-oxadiazole-2-yl-but-2- enamides:

synthesis and preliminary evaluation as promising anticonvulsants,” Springer-medicinal Chem. Res., 2014.

[10] L. Dong, B. Song, J. Wu, Z. Wu, Y. Zhu, and D. Hu, “Synthesis and antiviral activity of novel thioether derivatives containing 1,3,4-oxadiazole/thiadiazole and emodin moieties,” Phosphorus. Sulfur. Silicon Relat.

Elem., vol. 191, no. 6, pp. 904–907, 2016.

[11] Z. Hajimahdi, A. Zarghi, R. Zabihollahi, and M. R. Aghasadeghi, “Synthesis, biological evaluation, and molecular modeling studies of new 1,3,4-oxadiazole- and 1,3,4-thiadiazole-substituted 4-oxo-4H-pyrido[1,2- a]pyrimidines as anti-HIV-1 agents,” Springer-medicinal Chem. Res., 2012.

[12] R. V Shingalapur, K. M. Hosamani, R. S. Keri, and M. H. Hugar, “European Journal of Medicinal Chemistry Derivatives of benzimidazole pharmacophore : Synthesis , anticonvulsant , antidiabetic and DNA cleavage studies,” Eur. J. Med. Chem., vol. 45, no. 5, pp. 1753–1759, 2010.

[13] N. C. D. A. R. Trivedi and H. V. V. H. C. Somani, “Synthesis and biological evaluation of 1 , 3 , 4-oxadiazole bearing dihydropyrimidines as potential antitubercular agents,” Med. Chem. Res., vol. 2, no. 25, pp. 329–338, 2015.

[14] S. J. Gilani, S. A. Khan, and N. Siddiqui, “Bioorganic & Medicinal Chemistry Letters Synthesis and pharmacological evaluation of condensed heterocyclic derivatives of isoniazid,” Bioorg. Med. Chem. Lett., vol. 20, no. 16, pp. 4762–4765, 2010.

[15] A. A. S. Chawla, G., B. Naaz, “Exploring 1, 3, 4-Oxadiazole Scaffold For Anti-inflammatory And Analgesic Activities: A Review Of Literature From 2005-2016,” US national library of medicine national institutes of health. 2017.

[16] N. Renuka, H. K. Vivek, G. Pavithra, and K. A. Kumar, “Synthesis of Coumarin Appended Pyrazolyl-1,3,4- Oxadiazoles and Pyrazolyl-1,3,4-Thiadiazoles: Evaluation of Their In Vitro Antimicrobial and Antioxidant Activities and Molecular Docking Studies,” Russ. J. Bioorganic Chem., vol. 43, no. 2, pp. 197–210, 2017.

[17] M. Bouanis, M. Tourabi, A. Nyassi, A. Zarrouk, C. Jama, and F. Bentiss, “Corrosion inhibition performance of 2,5-bis(4-dimethylaminophenyl)-1,3,4-oxadiazole for carbon steel in HCl solution: Gravimetric, electrochemical and XPS studies,” Applied Surface Science, vol. 389. Elsevier B.V., pp. 952–966, 2016.

[18] et al ZHOU, Gang, “Novel polyphenylenes containing phenol-substituted oxadiazole moieties as fluorescent chemosensors for fluoride ion.” Macromolecules, pp. 2148–2153, 2005.

[19] K. Hunger, Industrial Dyes Chemistry, Properties, Applications. Wiley-VCH, 2003.

[20] C. Anghel, M. Matache, C. C. Paraschivescu, A. M. Madalan, and M. Andruh, “A novel 1-D coordination polymer constructed from disilver-1,3,4-oxadiazole nodes and perchlorato bridges Catalin,” Elsevier- Inorganic Chem. Commun., vol. 76, pp. 22–25, 2017.

[21] N. Deshapande, N. S. Belavagi, S. I. Panchamukhi, M. Hussain, I. Ahmed, and M. Khazi, “Synthesis and optoelectronic properties of thieno[2,3-b]thiophene based bis 1,3,4-oxadiazole derivatives as blue fluorescent material for use in organic light emitting diodes,” ElsOPTICAL Mater., no. 2, pp. 5–8, 2014.

[22] Dina A. Najeeb, “Some Transition Metal Complexes with 2-thioacetic acid-5-pyridyl- 1,3,4-oxadiazol,” J. Al- Nahrain Univ., vol. 14, no. 3, pp. 35–39, 2011.

[23] K. Kishore et al., “European Journal of Medicinal Chemistry Design , synthesis and biological evaluation of 1 , 3 , 4-oxadiazole derivatives,” Eur. J. Med. Chem., vol. 45, no. 11, pp. 4963–4967, 2010.

[24] P. Derivatives, M. T. Abdel-aal, W. A. El-sayed, S. M. El-kosy, and E. S. H. El-ashry, “Synthesis and Antiviral Evaluation of Novel 5-(N-Aryl- aminomethyl-1,3,4-oxadiazol-2-yl)hydrazines and Their Sugars, 1,2,4-Triazoles, Tetrazoles and Pyrazolyl Derivatives,” Arch. Pharm. Chem. Life Sci, vol. 341, pp. 307–313, 2008.

[25] M. S. Yadawe, S. N. Unki, and S. A. Patil, “Synthesis , Spectral Characterization and Biological Studies of Lanthanum ( III ) Complexes with Schiff Bases,” Int. Lett. Chem. Phys. Astron., vol. 12, pp. 94–104, 2013.

[26] H. A. Mohamad, B. Mohamad, and H. Ameem, “Synthesis and Characterization of Co(II), Ni(II) and Cu(II)

(16)

Complexes with Thio-1,3,4-oxadiazole Derivatives,” Cryst. Ideas–The Role Chem. Springer Int. Publ., pp.

253–266, 2016.

[27] S. Menati, H. Amiri, B. Askari, M. Riahi, F. Jalilian, and G. Dini, “Synthesis and characterization of insoluble cobalt(II), nickel(II), zinc(II) and palladium(II) Schiff base complexes: Heterogeneous catalysts for oxidation of sulfides with hydrogen peroxide,” Comptes rendus - Chim.,pp.1-10, 2015.

[28] I.A .Flifel ,S.H. Kadhim “Synthesis and Characterization of 1,3,4- oxadiazole derivatives with some new transition metal complexes "Journal of kerbala university , vol. 10 no.3 scientific . 2012