METAL COMPLEXES OF HETEROCYCLIC UNSATURATED 1, 3- DIKETONES

METAL COMPLEXES OF HETEROCYCLIC UNSATURATED 1, 3- DIKETONES

K.L. Krishnakumar*¹ and Mathew Paul ²

Research and Development Centre, Bharathiyar University ¹, Coimbatore – 641 046, Tamil Nadu, India

Department of Chemistry, Christ College ², Irinjalakuda, Kerala-680125, India

ABSTRACT: The present investigation is mainly on the synthesis, characterization and anti-microbial screening of certain new curcuminoid analogues containing imidazole, pyrrole and thiophene rings and their metal complexes. The ability of such heterocyclic β-dicarbonyl compounds and their metal ions to influence many of complex reaction upon which the vital processes of micro-organisms depends is the motivation behind the work. A series of 5- hetero aryl-1-phenyl-4-pentene-1,3-diones(1a-c) and their Cu (II), Ni (II)  complexes of ML₂ stoichiometry were synthesized and characterized by  UV, IR, mass and ¹H NMR spectroscopies. Analytical and spectral data suggest neutral bidentate coordination for unsaturated diketone with metals.  Anti-microbial screening was carried out by using Kirby-Bauer disc plate method. All the ligands and their metal complexes showed significant anti-microbial action. Further complexation; seem to augment the antimicrobial activity of the compounds.

ML₂ stoichiometry, IR spectra, H NMR, Mass, Complexation, Anti-microbial screening, Ligands

INTRODUCTION: Several synthetic metal complexes which mimic the behavior of complicated bimolecules are known and at present the study of such compounds are receiving much attention. One such example is curcuminoids, the active chemical component present in traditional Indian plant curcuma longa (turmeric). They are 1, 3-diketones in which the diketo function is directly attached to olefinic groups. Here all efforts were made to synthesize heterocyclic analogues of such β-dicarbonyl compounds and their metal complexes.

Very few literatures were available with the use of heterocyclic aldehydes for the synthesis of curcumin related compounds ¹. Pharmacological significance of hetero rings was the reason behind selecting different heterocyclic aldehydes like imidazole-2-carboxaldehyde, pyrrole-2-carboxaldehyde and thio phene-2-carboxaldhyde as one of the reactant to condense with benzoyl acetone.

Transition metals like Cu(II), Ni(II) were used as metals for present work. The reaction proceeded via condensation of heterocyclic aldehydes with benzoyl acetone through boric anhydride mediated esterification ². These compounds were subjected to anti microbial tests against the test organisms; bacterial cultures Staphylococcus aureus, Bacillus subtilis, Escherichia coli and pseudomonas aeruginosa and fungal cultures Candida albicans, Aspergillus niger respectively.

MATERIALS AND METHODS: The chemicals required were obtained from Lancaster, Sigma and Aldrich chemical suppliers.UV spectra’s were recorded in methanol solution (10^-4M) JASCO V-530 UV/VIS spectrophotometer.IR spectra(KBr pellets) were recorded on Schimadzu 81101A FTIR Spectrophoto-meter. Carbon and hydrogen percentages reported are by microanalysis and the metal percentage by using a Perkin-Elmer 2380 Atomic Absorption Spectrophoto- meter.

NMR   on Jeol 400 NMR spectrometer,mass spectra on a Jeol/Sx-102(FAB) mass spectrometer. Micro analysis of the compounds was performed on a Perkin Elmer model 240 analyzer. Bacterial cultures Staphylococus aureus, Bacillus subtilis, Escherichia coli and pseudomonas aeruginosa and fungal cultures Candida albicans,Aspergillus niger were procured from National chemical laboratory,Pune.

Preparation of 5-hetero aryl-1-phenyl-4-pentene-1, 3-diones: The compounds (structure-I) were prepared by the condensation of three different heterocyclic aldehydes with benzoyl acetone as reported earlier for structurally related 5-aryl compounds ^{3, 4}. Benzoyl acetone (0.005 mol) mixed with boric oxide (0.005 mol) and dry ethyl acetate (5 ml) was stirred for ca. 1 h. The stirring  was further continued for 1 h with slow addition of a solution of aromatic aldehyde(0.005) mol in dry ethyl acetate (5 mL), followed by tri-(sec-butyl)borate (0.01 mol) and N-butylamine (0.05 mL). After stirring for an additional period of ca.3 h. The solution was set aside overnight.

Hot ca.( 60^oC) hydrochloric acid (0.4 M, 7.5 mL)was then added to the reaction mixture and again stirred for ca .1 h, before extraction with ethyl acetate, the washed extracts were combined, concentrated and the residual paste obtained was stirred with hydrochloric acid(2M,10 mL).The separated solid product was collected, washed with water, ethanol and dried under reduced pressure. The compounds were recrystalliized from hot benzene to get chromatographically (TLC) pure material. Structural details of 1(a-c) are presented in table 1.

5-HETEROARYL-1-PHENYL-4-PENTENE-1, 3- DIONES           (1)

TABLE 1:

M= Cu²⁺, Ni²⁺ for n=2              

(2)Preparation of metal complexes: Cu(II), Ni(ii) chelates of diketones were prepared by the following general method ⁵. To a refluxing ethanolic solution of the compound (0.002 mol, 20 mL),an aqueous solution of metal (II)acetate(0.001  mol, 5 mL) was added and the reaction mixture was refluxed for ca. 2 h. and the volume was reduced to half. The precipitated complex on cooling to room temperature was filtered, washed with water and dried in vacuum. The complexes were recrystalliised from hot methanol. The metal salts used were acetates of Cu²⁺and Ni²⁺.

Anti-microbial bio assay of ligands and its metal complexes: These three ligands and their metal complexes were assayed for their antimicrobial activities against six test organisms, namely, Bacterial cultures Staphylococus aureus, Bacillus subtilis, Escherichia coli and pseudomonas aeruginosa and fungal cultures Candida albicans, Aspergillus niger. Concentrations of 500mg/disc and 250 mg/disc were used for all the test compounds and results were compared with the standard drug ciprofloxacin (10 mg/disc) and fluconazole (20mg /disc) for anti bacterial and anti fungal screening respectively. Dimethyl formamide was used as the vehicle. The results were interpreted as per Kirby-Bauer method ⁶.

RESULTS AND DISCUSSION: The 5-hetero aryl-1-phenyl-4-pentene-1, 3-diones formed by above method were crystalline in nature with sharp melting points. The analytical data of ligands and their complexes were discussed here. The yield, melting points and the carbon, hydrogen percentages are presented in Table 2. These ligands formed stable complexes with Cu²⁺, Ni²⁺. They were crystalline in nature with sharp melting points. Carbon, hydrogen percentages are in agreement with ML₂ stochiometry. The electronic, IR, NMR and mass spectral data of complexes are compatible with the structure that would result when the chelated enol proton of the ligand is replaced by metal ion as in structure 2.

TABLE 2: ANALYTICAL AND PHYSICAL DATA OF 5-HETERO ARYL-1-PHENYL-4-PENTENE-1, 3-DIONES AND THEIR METAL COMPLEXES

The UV spectra of the compounds in 95% ethanol (10^-3 M) showed two broad band’s at ca. 410  and 225 nm respectively due to n→π* and π→ π* transitions. As expected these band shifted to higher wavelength compared to benzoyl acetone due to conjugation of the double bond to indole ring. In the metal complexes the former bond showed a bathochromic shift (5-16 nm) indicating the involvement of dicarbonyl function in complexation⁷.

The IR spectra of the diketones show two prominent bands at ca.1647 and 1605 cm^-1 respectively due to  benzoyl and cinnamoyl ѵ(C=O) vibrations ⁸. The observed position and intensity of bands indicate that the compounds exist entirely in the enol form and are enolised towards cinnamoyl function. However, the heterocyclic group and phenyl group may lower the carbonyl frequency. Thus the net effect is to lower the stretching of both carbonyl groups.

Therefore, it is difficult to assign precisely even the carbonyl stretching frequencies. The most striking feature in the IR spectra of complexes is the absence of any band in the region 1630-2000 cm^-1 due to free or hydrogen bonded carbonyl groups. However in the spectra of all complexes, a new strong band appeared at at ca. 1580 cm^-1 assignable to metal bonded carbonyl group.

This is further supported by the appearance of medium intensity bands at ca.450 and ca.463 cm^-1 presumably due to ѵ (M-0) vibrations ⁹. The important infrared bands and their assignments are given in table 3 and 4.

TABLE 3: CHARACTERISTIC IR DATA (cm-1) OF 5-HETERO ARYL-1-PHENYL-4-PENTENE-1, 3-DIONES

TABLE 4: CHARACTERISTIC IR DATA (cm^-1) OF METAL COMPLEXES 5-HETERO ARYL-1-PHENYL-4-PENTENE-1, 3-DIONES

The ¹H NMR spectra of all unsaturated ligands displayed a one proton signal at ca. δ 15 ppm due to the intramolecularly hydrogen bonded enolic proton. Other signals appearing are in the range δ 7(methine protons), 6.8-7.5 (alkenyl protons) and 7.2-8.2 (aryl protons). In the H NMR spectra of metal complexes, the low field signal due to the enol proton of the ligand is absent indicating its replacement by the metal ion during complexation. The assignments of various proton signals observed are assembled in Table 5 and 6.

TABLE 5: ¹H-NMR SPECTRAOF (δ,ppm) OF 5-HETERO ARYL-1-PHENYL-4-PENTENE-1, 3-DIONES

 TABLE 6: ¹H-NMR SPECTRAOF (δ,ppm) OF METAL COMPLEXES 5-HETERO ARYL-1-PHENYL-4-PENTENE-1, 3-DIONES

Mass spectra of all the unsaturated diketones showed intense molecular ion P ⁺/(P+1)⁺ peaks in conformity with their formulation. Peaks due to (Ar-CH=CH-CO) ⁺, (P-C₆H₅) ⁺, (P-C₆H₅CO)⁺,etc  are characteristic of all the spectra. The mass spectrum of complexes shows the step wise removal of aryl groups. The molecular ion peeks obtained from these compounds were in agreement with ML₂ stochiometry. The anti bacterial and anti fungal activity of ligands and their metal complexes were illustrated in table 7.

TABLE 7: ANTI MICROBIAL ACTIVITY OF 5-HETERO ARYL-1-PHENYL-4-PENTENE-1, 3-DIONES AND  THEIR METAL COMPLEXES

The  data (table 8) revealed that large number of synthesized  ligands and their metal complexes possess comparable anti bacterial and anti fungal activities comparable to that of standard drugs. Amoung the compounds, 1b, which contain Pyrrole substitution found to be highly active against all six strains studied.In many cases metal complexation increased the activity of the unsaturated diketones. Amoung the complexes, Cu (II) complexes are found to be highly active. This can be explained on the basis of chelation theory ¹⁰. They thought to act by favoring the breakdown of permeability barrier of cell wall of micro organisms.

CONCLUSION: Three heterocyclic synthetic analogues of curcumin and their Cu, Ni  complexes were obtained in this research as a result of experiments. The existence of the unsaturated diketones in the intramolecularly hydrogen bonded enol form has been well demonstrated from their analytical and spectral data.Analytical and spectral data of metal complexes with Cu(II) and Ni(II) showed the monobasic bidendate coordination, in which the intramolecularly hydrogen bonded enolic proton is replaced by metal cation.

Anti microbial studies reveal that the compounds possesses significant activity against all the tested organisms. Further compound 1b and its Cu complex were found to be highly active. The present study proves that the title compounds may find application for therapeutic purposes in human diseases provided they are non toxic to human body.

REFEERENCES:

1. Krishnankutty K, Joseph J and Babu J: Metal chelates of 1, 7-diindolyl-1,6-heptadiene-3,5-dione. Journal of Indian chemical Society. 2007; 84:478-47.
2. Magda GB: synthesis of curcumin derivatives.Acta Universitatis Cibiniensis , Series E:Food technology. 2005; 1: 11-16.
3. Mathew PU, Venugopalan P  and Krishnankutty K : Metal chelates of 5-aryl-1-phenyl-4-pentene-1,3-diones. Asian Journal of Chemistry.2002; 14:1335-1340.
4. Muhammed BU, Anjali K and Mathew PU: Metal complexes of unsaturated polycarbonyl compounds derived from benzoyl acetone and aromatic aldehydes.Journel of the Iranian Chemical Research. 2010;3;71-81
5. Pooja NV, Javed IS and Harjit DJ : Synthesis of $-diketone and Its Metal Complexes. World Applied Sciences Journal.2011; 14(8): 1154-1157.
6. Prescott LM, Harley JP and Klein DA: Microbiology,WCB,Pubuque(USA),First Edition 1990.
7. Krishnankutty K, Muhammed BU and Mathew PU: Some unsaturated β-diketones and their metal chelates. Trade Science Inc. Inorganic Chemistry. 2009; 4(2): 78-82.
8. Nakamoto K:Infrared Spectra of Inorganic and Coordination Compounds. Wiley (Newyork), Fourth Edition 1976.
9. Bellamy LJ: The Infrared Spectra of Complex Molecules, Academic Press (London), First Edition 1980.
10. Mathews C, Mohanan K: Synthesis and Characterization of Complexes of Cobalt(II), Nickel(II), Copper(II) and Zinc(II) with2-(2-carboxyphenylazo)-1, 3-diketones.Asian Journal of Chemistry.2007; 19 :2831-2838.
    

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    How to cite this article:

    Krishnakumar KL and Paul M: Metal complexes of Heterocyclic unsaturated 1, 3- diketones. Int J Pharm Sci Res 2013; 4(3); 1154-1158.

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