Synthesis, Spectroscopic, Thermal Characterization and Biological Activity of (E)-4-(4-Methoxybenzylideneamino)-N-(5-Methylisoxazol-3-Yl) Benzenesulfonamide and Its Copper Complexes.

 

M. Elnawawy, R.S. Farag, I.A. Sbbah and A.M. Abuyamine

Faculty of Science Al-Azhar University, Cairo, Egypt.

*Corresponding Author E-mail: abuyamin33@yahoo.com

 

ABSTRACT:

A Schiff base (E)-4-(4-methoxybenzylideneamino)-N-(5-methylis-oxazol-3-yl) benzene-sulfonamide (C18H17N3O4S), and its copper complex were synthesized and the structures  elucidated in the bases of elemental analysis, 1HNMR,  UV–VIS, IR, Mass spectroscopy, magnetic susceptibility, thermal  analysis and conductance measurements. The studies indicate an octahedral structure for the complexes with the (C22H27N3O10SCu) formula. The I.R. spectra suggest that the ligand acts as a tridentate (NNO) donor. Also, the biological activity of the Schiff base and its Cu complex are biologically active.

 

KEYWORDS: sulphamethoxazole, Schiff base, copper complex , antibacterial and antifungal  activities.

 


 

1. INTRODUCTION:

Schiff base compounds which contain the azomethine (imine) group (–RC=N–) are usually prepared by the condensation of a primary amine with an active carbonyl compound1.

 

It has been often used as chelating agents (ligands) in the field of coordination chemistry and their metal complexes are of great interest for many years. It is well known that O and  N  atoms play a key role at the active sites of numerous metallobiomolecules in the coordination with metals2.

 

Later, a great number of sulfanilamide derivatives were synthesized, characterized and tested as antibacterial agents, with many such derivatives currently used for the treatment of bacterial infections. Such sulfonamide derivatives widely used in clinical medicine as pharmacological agents with a wide variety of biological actions, were designed from the simple sulfanilamide lead molecule3, Also Schiff base known as anticancer and antiviral agents4, and its metal complexes have been widely studied because they have industrial, antifungal, antibacterial, anticancer herbicidal applications5, antitubercular activities6 and chelating abilities which give it attracted remarkable attention7.

 

Sulfa drugs had attracted special attention from their therapeutic importance as they were used against a wide spectrum of bacterial ailments8

.

2. EXPERIMENTAL:

2.1- Materials:

Sulphamethoxazole  (was obtained from Memphis Co. for Pharm. & Chemical Ind., Egypt.), and p-methoxybenzaldehyde was obtained from Morgan chemical IND, Co, Egypt. glacial acetic acid was obtained from El-Nasr pharmaceutical chemicals Co, Egypt), ethanol 99% (was obtained from Technolgene. Corp, Dokki, Egypt)  diethyl ether and N,N-dimethyl formamide (DMF) (was obtained from Sd finne-chem.limited India, copper acetate were chemically pure  of grade, Merck, Garmany.

 

2.2- Instruments:

IR spectra were obtained as KBr disc on a Pelkin. Elmer FTIR spectrophotometer 57928 RXIFT-IR system. The electronic spectra were recorded by Perkin Elmer Lambda 35 Spectrophoto-meter using DMF as solvent. The mass spectra were performed by Hewlett Packard mass spectrometer model MS 5988. Metal analyses were determined by atomic absorption (AAS Vario6). Conductance TDS Engineered system, U.S.A, was employed for the conductometric titration at Al-Azhar university, Cairo, Egypt. While  Elemental analysis, 1HNMR spectra were recorded by a Varian, USA, Gemini 200 MHz Spectrometer in DMSO-d6 at Micro-analytical Center, Cairo University, Cairo, Egypt and Magnet susceptibility measurement of the complexes were determined at room temperature  by the Faraday method and at Faculty of Science,  Cairo University.

 

2.3- Synthesis of Schiff base ( I ):

The Schiff-bases was prepared as in (scheme 1) by the usual condensation reaction9, in which p-methoxybenzaldehyde  (0.1 mole) was drop wisely added to the amine (Sulphamethoxazole ) (0.1 mole) with continuous stirring, (drops of glacial acetic acid10, was added).  After complete addition the reaction mixture was heated under reflux for about four hours. The products (imines) were separated after cooling at room temperature by filtration.  The isolated compound was purified by recrystallization from ethanol. After one week orange prisms of Schiff base (I) were obtained, and the melting point was found 202 ºC.

 

Scheme 1: Synthesis of Schiff base (I).

 

2.4- Synthesis Schiff-base metal complexes:

2.4.1- Molar ratio:

2.4.1.1-        Conductometric Titration:

The conductometric titration; illustrated in  Figure (1),  is performed by titrating 10 ml of 1x10-3 M metal ion solution with increasing volume of 1x10-3 M complexing agent solution of Schiff-base, using DMF as solvent, and the conductance was then recorded after stirring the solution for about 2 minutes. By plotting the conductance value, after correction for dilution as a result of addition of chelating agent. Vs. milliliter of the reagent added, and applying the least square equation11­­­­­.

 

Figure (1): conductometric titration of Schiff base (I) (1x10-3M) with

(CH3COO)2.Cu. H2O ( 1x10-3M) system.

 

2.4.1.2-    Spectroscopic Molar ratio testing:

In the present investigation, the concentration of the metal ion was kept constant, while that of the ligand was varied, the absorbance of the solution prepared was plotted versus the molar ratio [ligand] / [metal ion], one obtains straight lines, each two intersects at a certain ratio12.

 

A tow ml solution Cu+2 ion concentration were kept constant at 1x10-3 M, while that the ligands were regularly varied from 0.2x10-3  to 2x10-3  M using DMF as solvent. The absorbance of the mixed solutions was measured The results obtained represented graphically in Figs. (2).

 

Figure (2): Absorption spectra of Cu (II) complex molar ratio method

 

A plot of the absorbance as a function of molar ratio metal ion/ ligand is represented by two portions which indicate the formation of 1:1 ligand : metal complex.

 

2.4.2-: Preparation of Schiff-base metal complexes

A solution of the copper acetate (CH3COO)2.Cu. H2O (0.001 mole) in 25 ml absolute ethyl alcohol was added drop wise  to equimolar amounts of Schiff-base (0.001 mole) (I). After complete addition of the metal salt the reaction mixture was heated under reflux for six hours, the product separated after cooling, by filtration and recrystallization from ethanol to give solid products (Ia) (scheme 2).   Yield = 59.50 % (0.35g). where the m.p of the complex is >300 º C.

 

Scheme (2): synthesis of Cu complex(Ia) .

 

3.      RESULT AND DISCUSSION:

3.1-  The structure of Schiff base (I) was elucidated on the bases of:

3.1.1-        Elemental analysis C, H and N of Schiff base (ethyl 4-(2-hydroxy-benzylideneamino) benzoate) were (57.06, 6.03 and 11.53 respectively) which compatibles with that required (58.21, 4.61 and 11.31respectively).

 

3.1.2-        The 1H NMR spectrum of Schiff-base (I) , using DMSO d6 as solvent, showed the multiplet signals of the aromatic protons of tow phenyl rings, generally overlay the chemical shift range δ 7 - 8.2 ppm. The chemical shift of methoxy group appear at 3.9 ppm. The chemical shift of methyl group (CH3) appear at 2.5 ppm. The signal noticed at δ 9 ppm can be assigned for the azomethine proton and the single noticed at 9.7 ppm   represent NH group.

 

3.1.3-        The electronic spectrum of Schiff-base (I); exhibits the absorption band structure at λmax= 204-228 nm corresponding to π-π* transitions of the phenyl ring, The band at λmax= 267 nm corresponds to transitions of the C=N group, while the broad band at λmax= 337 nm corresponds to n-π* transitions of the azomethine and S=O  bonds.

 

3.1.4-        The IR spectrum exhibits a broad band in the region 3254 cm-1 characteristic to the stretching mode of vibrations of NH group. The band at 1590 cm-1 assigned to the  υ C=N stretching mode of vibration of the azomethine group12, 13. A sharp peak at 1704 cm-1 is due to C = O stretching mode of vibrations. SO2 group appear at 1162 cm-1 and N-O bond appear at 1470 cm-1. And stretching vibration of aromatic C =C at 1455 cm-1. Finally the bands at 2973, 2750 and 1361 cm-1 may be assigned as υ C-H aromatic, C-H aliphatic  and C-N respectively14.

 

3.1.5-        The mass spectrum of the Schiff-base (IV) (C18H17N3O4S) shows ion peak at m/e = 371.55 (47.02%) as the molecular peak, the ion peak at m/e = 289.95 (82.92%) is due to M+(C14H13N2O3S). The ion peak at m/e = 210.4 (100%) which is the base peak corresponds to M+ (C14H12NO).  The ion peak at m/e = 180.3 (2.05% ) is due to M( C13H10N ), and the ion peak at m/e = 104.75 (4.94%) corresponds to M+( C7H6N ) .

 

3.2-  The structure of Cu complex of Schiff base (Ia) was   elucidated on the bases of:

3.2.1-The element analysis:

The element analysis show that the percent of  N= 9.10 % and Cu= 9.8% which are compatible with required (N= 7.13 % and Cu =10.79%.

 

3.2.2- Electronic spectra:

The electronic spectra of the Schiff base complexes were carried out in DMF solutions at a concentration of 10-5 M. The spectrum of the complex exhibits the absorption band structure at λmax= 225 and 231 nm corresponds to π-π* transitions of the C=O and C=N groups respectively. The sharp band at λmax= 287 nm corresponds to n- π* transitions of the acetate group.  The sharp band at λmax= 330 nm corresponds to n- π* transitions of the azomethine group. Where the band at λmax= 615 nm15 corresponds to d→d transitions of the copper metal. The assignments are in conformity with the proposed octahedral geometry for the complex.

 

3.2.3- Magnetic Measurements:

Magnetic susceptibility was measured by the Faraday method at room temperature, the effective magnetic moment μeff, of complex Ia found to =1.9 BM; which confirms the octahedral geometric of the complex as expected.

 

3.2.4 IR spectra:

Comparing  the IR spectra of the complexes and the free ligand, the following differences were observed: (i) the strong  band at 3254 cm-1 in the ligand is assigned to NH group16, this band is shifted to lower frequency on chelating with metal ion indicating the NH group can act as coordinating site. (ii) the shift of the two sulfonamide vibration  (symmetric as well as the asymmetric one) toward lower wave numbers in the spectra of the complexes, as compared to the spectrum of the corresponding ligand (table 1) further support M-O bonding. (iii)The strong band at 1470 cm-1 assigned to N-O in heterocyclic exhibit lower shift as support M-N bonding, so the complexes were tridentate. (iv) The complexes Ia exhibit a broad bands at (3470 cm–1 simultaneously appeared with a bands at (832 cm–1) attributed to lattice held and / or coordinated water molecules17. The presence of coordinated water was also established and supported by TG/DT analysis of these complexes. (v)   New bands appear in the region 552 cm-1 and 480 cm-1 in the complexes (Ia-e) spectra can be attributed to the vibrations of M← N and M ←  O respectively.

 

3.2.5 Thermal analysis:

The copper complex C22H27N3O10SCu was thermally decomposed in three successive decomposition steps within the temperature range 140–898ºC. The first decomposition step with an estimated mass loss of 2% (=12 g/mol) within the temperature range 98-155ºC may be attributed to the liberation of 2/3 lattice water molecule. The second decomposition step with an estimated mass loss of 2.956% (=23 g/mol) within the temperature range 155- 181.35ºC may be attributed to the liberation of coordinated water molecule and 1/3 lattice water. The third step found within the temperature range 181–337.68ºC with an estimated mass loss of 34.388% (=192.5g/mol), which is reasonably accounted for by the removal of CH3OC6H4CH=NH and C3H4O. The fourth step found within the temperature range 337–720ºC with an estimated mass loss of 29.188% (=107.21g/mol), which is reasonably accounted for by the removal of N2H3C.

 

Finally, it is found within the temperature range 720- 898ºC with an estimated mass loss of 5.391% (=15g/mol), which is reasonably accounted by the removal of oxygen atom. The copper oxide reminded  and some residue .

 

3.2.6     Mass spectroscopy:

The first peak at m/e 585 represents the molecular ion peak of the complex[C22H27N3O10SCu]. The primary fragmentation of the complex takes place due to the loss of –( OCH3, 2H2O and C2H3O )  groups with peak at m/e 468. Further degrades with the subsequent loss of –(C6H5CH=N) species forming peak at m/e 365. Further degrades with the subsequent loss of -(benzene ring ) species forming species with peak at m/e 290. Then tow acetate group leaving a peak at 172 finally all atoms evaporate leaving copper oxide with peak at m/e 78. represents the stable species with 33.31% abundance.

The mass spectra data confirm that the complexes were present, when supported by our additional analyses. The formulae is in agreement with the mass spectral data.

 

4. BIOLOGICAL ACTIVITY:

The antibacterial and antifungal activity18 of the Schiff base(I) and its  Cu complex(Ia) was done in comparison with PENICILIN G and STRPTOMYCIN for antibacterial CLOTRIMAZOLE and  ITRACONA-ZOLE for antifungal as standard. All the 6 selected strains tow of bacteria and four of fungi namely; {Staphylococcus aureus and Bacillus (Gram + ) and Pseudomonas aeruginoca and Escherichia coli (Gram - ) and Aspergillus fumigates, Geotrichum candidum, Candida albicans and syncephalastrum racemosum} showed sensitivity to all derivatives and compound I and Ia has shown good activity against all the tasted bacterial and fungal except syncephalastrum racemosum.

 

5. CONCLUSION:

1.      {(E)-4-(4-methoxybenzylidene-amino)-N-(5-methylisox-azol-3-yl)benzenesulfonamide} (Schiff base (I)) was synthesized from reaction between a mixture of Sulphamethoxazole  and p-methoxybenzaldehyde, the Schiff base (I) reacted with copper  acetate monohydrate, and the result of all previous physiochemical measurements show that the structure of 1:1 complex may be represented as in scheme2

 

2.      The Schiff base Behaves as tridentate ligand one from oxygen of carbonyl, one from NH and the other from nitrogen from heterocyclic  nitrogen to form distorted octahedral structure.  Finally the tow compounds I and Ia show more effected on both  bacterial and fungal than the basic drug ( sulphamethoxazole ).

 

Table 1: IR of Schiff base and its complex.

 

νH2O

νN-H

νSO2

νC=N

νN-O

νM-O

νM-N

M-H2O

I

3470

3254

1162

1590

1470

 

 

 

Ia

3448

3244

1144

1590

1434

480

552

832

 

6. REFERENCES:

1.       A. V. Kurnoskin, J. Macromol. Sci., Rev. Macromol. Chem. Phys.36, 457 (1996).

2.       K. Singh, M.S. Barwa, P.Tyagi, Eur. J. Med. Chem. 42 , 394,(2007)

3.       Joumal of Enzyme Inhibition and Medicina! Chemistry,. 19 , 263-267 (2004).

4.       Cheng, L et al. Bioorg. Med. Chem. Lett.,20, 2417-2420 (2010).

5.       P.G. Cozzi, Chem. Soc. Rev. 33, 410 (2004).

6.       D. Lednicer, The Organic Chemistry of Drug Synthesis, Vol-III, Wiley Interscience Publication, New York, 90, 283 (1984).

7.       Jarrahpour AA, Motamedifar M, Pakshir K et al.. Molecules 9, 815-824 (2004).

8.       David C.Eaton. Investigation in organic chemistry. McGraw-Hill Book Company (1994).

9.       A. L. Vogel, A Text book of practical Organic Chemistry   p. 653 (1973).

10.     A. Y. Vibhute. et al, Bulletin of the catalysis Society of India, 8, 164-168 (2009).

11.     J. Chalt and H. R. Waston, J. Chem. Soc. 2, 545 (1962).

12.     J. Rydbarg, Acta Chem. Second, 13, 2023 (1959).

13.     Z.H. Chohan et al, Journal of Enzyme Inhibition and Medicinal Chemistry, 21(6) 741–748 ( 2006).

14.     Santosh Kumar et al. Journal of Current Pharmaceutical Research; 1, 39-42 (2010).

15.     Umit C akır. et.al. spectroscopy letters, 36 (5), 429 -440 (2003).

16.     S. S. SHARMA, et al, E-Journal of Chemistry, , 8(1), 361-367 (2011).

17.     Pragnesh K. et al, synthesis and reactivity in inorganic and metalorganic chemistry, 34 (7), 1223–1235 (2004).

18.     Bauer, A, W, et al., American journal of clinical pethology, 45, 493-496 (1966).

 

 

 

 

Received on 23.08.2011        Modified on 05.09.2011

Accepted on 11.09.2011        © AJRC All right reserved

Asian J. Research Chem. 4(10): Oct., 2011; Page 1578-1581