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Journal of the Chilean Chemical Society

versão On-line ISSN 0717-9707

J. Chil. Chem. Soc. v.53 n.4 Concepción dez. 2008 

J. Chil. Chem. Soc, 53, N° 4 (2008) págs: 1653-1657





a*Department of Chemistry, Central College Campus, Bangalore University, Bangalore-560001.e-mail:
b,c,d Biochemistry Section, Department of Chemistry, Central College Campus, Bangalore University,Bangalore-560001


A new tetradentate Schiff base, 3-[(Z)-2-piperazin-l-yl-ethylimino]-l, 3-dihydro indol-2-one was synthesized by the condensation of isatin(Indole-2,3-dione) with l-(2-aminoethyl)piperazine(AEP). Its complexes with Co(II), Ni(II), Cu(II), Zn(II), Cd(II), Hg(II), U02(VI) and Th(IV) have been synthesized and characterized by microanalysis, conductivity, UV-visible, FT-IR, 'H NMR, TGA and magnetic susceptibility measurements. The complexes have 1:1 metal to ligand stoichiometry. The complexes of Cu(II) and Th(IV) are 1:1 electrolytes whereas the complexes of Co(II), Ni(II), Zn(II), Cd(II), Hg(II) and U02(VI) are nonelectrolytes. ITie spectral data revealed that the ligand acts as a neutral tetradentate, coordinating through the azomethine nitrogen, two piperazine nitrogen atoms and carbonyl oxygen. Octahedral geometry for Co(II), Ni(II), Cu(II), Zn(II), Cd(II) and Hg(II) complexes and a coordination number of 8 for U02(VI) and Th(IV) complexes are proposed. The ligand and its metal complexes were screened for antibacterial activity against Bacillus subtilis, Staphylococcus aureus (S. aureus), Escherichia Coli (E. Coli) and Pseudomonas aeruginosa and the complexes are more potent bactericides than the ligand. The anthelmentic activity of the ligand and its complexes against earthworms was also tested.

Key words: Isatin, Schiff base, 1-(2-aminoethyl )piperazine and complexes.


Isatin thiosemicarbazone derivatives were found to exhibit interesting applications in physiological studies1. Many isatin-derived compounds possess a wide spectrum of medicinal properties and thus, have been studied for activity against tuberculosis2,3, leprosy4, fungal5,6, viral7 and bacterial infections8,9etc. Weinberger and coworkers10 synthesized a novel mixed valence copper(I)-copper(II)-bis(N,N'-antipyril-methyl)-piperazine complex and characterized by spectroscopic and X-ray diffraction technique. In this case the ligand acts as tetradentate in which the piperazine ring adopts a "boaf'-confirmation. In this paper, the synthesis and characterization of a new Schiff base and its complexes with cobalt (II), nickel(II), copper (II), zinc(II), cadmium(II), mercury(II), dioxouranium(VI) and thorium(IV) are presented in which piperazine ring adopts boat confirmation. The ligand and its metal complexes were screened for antibacterial activity agamstBacillus subtilis, Staphylococcus aureus (S. aureus), Escherichia Coli (E.Coli) and Pseudomonas aeruginosa. Anthelmentic activity of the compounds was tested on earthworms (Peretima posthuma).



The chemicals employed were of AR or LP grade. All the solvents were purified by standard methods. l-(2-aminoethyl) piperazine (AEP) (Aldrich Chemicals) and isatin (S.D Fine chemicals) were used.

Preparation of Schiff base: The Schiff base was prepared by the reported method n. Equimolar ethanolic solutions (50 mi each) of isatin and l-(2-aminoethyl) piperazine were mixed and refluxed for about 1 hour. The reaction mixture was concentrated to a small volume and allowed to cool. The Schiff base ligand precipitated out. It was filtered, washed with ethanol and recrystallised from ethanol. The purity of the Schiff base ligand was monitored by TLC using eluants 1:1 ethyl acétate and petroleum ether and separated by column chromatography (Yield 90%). The mass spectrum of the ligand (IsAEP, L) (Fig. 1) shows the molecular ion peak at 259 u corresponding to the macrocyclic moiety [(C14H18N40)+ atomic mass 258].

Preparation of the complexes: The metal complexes were prepared by adding ethanolic solution (50 mi) of the metal salt to the ligand (100 mi) in 1:2 molar ratio and heating under reflux for about 3 hours. The reaction mixture was concentrated to a small volume. On cooling, the metal complexes precipítate out. They were filtered, washed with ethanol and dried in vacuo.

Antibacterial and anthelmentic activity measurements
The ligands and its complexes with Cu(II), Co(II), Ni(II), Zn(II), Cd(II) and Hg(II) were screened for antibacterial activity against Bacillus subtilis, Staphylococcus aureus (S. aureus), Escherichia Coli (E. Coli) and Pseudomonas aeruginosa at a concentration of lmg/0.02ml in DMF by cup píate method12. Anthelmentic activity of the compounds was measured on earthworms(Peretima posthuma) using 5mg/ml concentration by reported method13.

Analysis and physical measurements: The micro analysis of the samples was carried using Cario Ebra analyser. The metal contents were estimated by standard methods14. The conductivity measurements were made using a Systronics Conductivity Meter 304 with a dip type conductivity cell with a cell constant lcm"1. The magnetic susceptibility measurements were carried out at room temperature using Faraday balance. Electronic spectra were recorded in DMF in the range 900-350 nm using Shimadzu UV-3101 PC UV-VIS-NIR scanning spectrophotometer. 1H NMR spectra of the ligand and its complexes were obtained using Bruker AMX 400MHz FT NMR spectrometer. IR spectra of samples in KBr pellets were recorded in the región 4000-600 cm"1 on a Nicolet Impact 400-D FT-IR spectrometer. The far IR spectra of the complexes in the región 600-250 cm"1 were recorded using a Perkin Elmer Instruments, Spectrum one FT-IR spectrometer. The mass Spectrum of the ligand was recorded using a ESI-MS Bruker Daltronics mass spectrometer. TGA studies of the complexes were carried out using Perkin-Elmer Thermo gravimetric analyser TGA 7 with a sean rate of 10°C per minute in nitrogen atmosphere.


All the metal complexes are coloured solids and are stable towards air and have high melting points (above 250°C). The complexes have the general formula [MLC1J where M= Co(II) or Ni(II) while with Cu(II) salt, gives complex of the type [CuLCl(H20)]C1.2H20, [MLC1J.2H20 where M = Zn(II), Cd(II) and Hg(II) and with U02(VI) and Th(IV) salts the complexes of the type [U02L(N03)2]and [ThL(N03)3 2H20]N03 respectively were obtained. The complexes are insoluble in water and common organic solvents but are partly soluble in DMF and DMSO. Henee the molecular weights could not be determined. Elemental analysis and analytical data of the complexes suggest that the metal to ligand ratio in all the complexes isl:1 (Table 1). The conductivity for 10"3M solution of the complexes in DMF show Cu(II) and IR spectra: Selected IR spectral bands for the ligand and its complexes are given in Table 2. The IR spectrum of the free ligand is characterized mainly by the strong bands at 3221, 1717, and 1618 cm"1 which are attributed to the stretching frequencies of NH (aromatic), C=0 and C=N(azomethine) respectively15,16. The band at 1717cm'' due to C=0 stretching in the spectrum of the ligand shifts to lower wave numbers by 8-16 cm"1 in the metal complexes indicating that the carbonyl oxygen atom is coordinated to the central metal ion1617. The band at 1618cm_1 due to C=N stretching in the spectrum of the ligand shifts to lower wave numbers in all the metal complexes by 7-10 cm' 1 indicating that the azomethine nitrogen atom is coordinated to the metal ion16,". The band due to N-H (aliphatic) in the complexes appears at lower wave numbers relative to its position in the free ligand, thus clearly indicating the coordination of the ligand through the nitrogen atom of the N-H group.

The band due to the C-H stretching frequeney of the N-CH2 group in the complexes either disappears or shifts to lower wavelength región. In the case of disappearance, these bands probably shift to lower wave number región (2,900 cm"1) and overlap with stretching vibrational bands of other C-H bonds of the complexes. This shift indicates that the nitrogen atom of the N-CH2 group no longer has a lone pair of electrons and it acquired a partial positive charge due to its coordination with the metal ion. Similar observations were made by earlier authors10,26. A broad band around the 3450-3340 cm"1 is observed in the infrared spectra of the complexes of Cu(II), Zn(II), Cd(II), Hg(II) and Th(IV). This may be assigned to OH stretching frequencies of water molecule. Further the i.r spectra of the complexes of Cu(II), Co(II), Ni(II), Zn(II), Cd(II) and Hg(II) exhibit new bands at 480-540, 420-460 and SSO^Scm1, which may be assigned to M-O, M-N and M-Cl (terminal) stretching modes respectively18.

The IR spectra of U02(VI) nitrate complex showed no absorption bands due to free nitrate groups, where as the spectra of Th(IV) nitrate complex showed an absorption band at 1382cm1, where the free nitrate is known to absorb19. Both the complexes exhibit bands around 1480, 1300, 1030 cnr1 corresponding to monodentate nitrate groups19. The sharp bands at 932 and 759 cnr1 observed in the case of the uranyl complex correspond to the asymmetric (v3) and symmetríc (v:) stretching vibrations respectively. Thus the Schiff baseligand, is acting toward the central metal ions as neutral ONNN tetradentate ligand via carbonyl oxygen of isatin moiety, azomethine nitrogen and two piperazine nitrogen atoms forming three five-membered chelating rings.

1H NMR Spectra

The ^ NMR spectrum of the ligand and its diamagnetic Zn(II), Cd(II), Hg(II), U(VI) and Th(IV) complexes were recorded in DMSO-d6 and the spectral data are reported in Table 3. The protons of the isatin moiety, methylene groups and piperazine ring were assigned according to Chohan et al20. These protons shifted downfield due to the coordination to the metal ions20. The number of protons calculated from the integration of ^ NMR spectra is in accord with that expected from CHN analyses.


UV- visible and magnetic susceptibility measurements:

The cobalt(II), nickel(II) and copper(II) complexes show magnetic moments of 3.92, 3.15 and 1.92 B.M respectively which is characterístic of mononuclear, octahedral cobalt(II), nickel(II) and copper(II) complexes21. Zinc(II), cadmium(II), mercury(II), dioxouranium(VI) and thoríum(IV) complexes are diamagnetic. The electronic spectral data of the complexes in DMF are presented in Table 2.

The broad band centered at 14390 cnr1 appearing as an envelope in the copper (II) complex, assigned to the 2E 22.The electronic spectrum of the cobalt (II) complex shows two bands at 15748, 19230 cnr1

which are assigned to 4T1 —► 4A2 (F) (v2) and 4T1 (F) —► 4T1 (P) (v3) transitions, respectively, as expected for an octahedral cobalt(II) complex22. The electronic spectrum of the nickel (II) complex exhibits three bands at 10050, 14925 and 23529 cnr1, attríbutable to 3A2g(F) -► 3T2g(F) (v^, 3A2g(F) -► 3Tlg(F)(v2) and 3A2 (F) —,'3T1 (P) (v3) transitions, respectively, for an octahedral nickel(II) complex23. The electronic spectra of the U(VI) and Th (IV) complexes in DMF solution exhibit no bands in the 450-750nm región. The absorption bands obtained below 450nm correspond to the ligand % —► te* transitions and are not of help in deciding the geometry around the central uranium and thorium ions.

Thermo gravimetric studies

TGA studies of the complexes were carried out in nitrogen atmosphere at the rate of 10° per minute up to 700 °C. In the thermal decomposition studies of the complexes a general pattern is observed where the water of hydration is lost followed by the loss of uncoordinated chloríde/nitrate, coordinated chloríde/nitrate, ligand molecules and the decomposition of the complex to finally yield the respective metallic oxides at higher temper atures (Table 4).

Antibacterial Activity

The ligand and its metal complexes have been screened for their antibacterial activity and the results are presented in Table 5. The complexes Cu(II) and Co(II) shows very good activity against bacillus subtilis, S. aureus and E. Coli and least activity against Pseudomonas aeruginosa. The Ni(II) complex shows modérate activity against Bacillus subtilis and Pseudomonas aeruginosa and least active against S. aureus and E. Coli. On the other hand the complexes of Zn(II), Cd(II) and Hg(II) have shown least to modérate activity against both gram positive and gram negative bacteria. The enhanced activity of the complexes overthe Schiff base can be explained on the basis of chelation theory24. Chelation reduces the polarity of the metal ion considerably, mainly because of the partial sharing of its positive charge with donor groups and possible k- electrón delocalization on the whole chelate ring. The lipid and polysaccharides are some important constituents of cell walls and membranes, which are preferred for metal ion interaction. In addition to this, the cell wall also contains amino phosphates, carbonyl and cysteinyl ligands, which maintain the integrity of the membrane acting as a diffusion barrier and also provides suitable site for bonding. Chelation can reduce not only the polarity of the metal ion, but increases the lipophilic character of the chelate, and the interaction between the metal ion and the lipid is favoured. This may lead to breakdown of the permeability barrier of the cell, resulting in interference with the normal cell process. If the geometry and charge distribution around the molecule are incompatible with the geometry and the charge distribution around the pores of the bacterial cell wall, penetration through the wall by the toxic agent cannot takes place and this will prevent the toxic reaction within the pores. Chelation is not only criterion for antibacterial activity. Some important factors such as nature of the metal ion, nature of ligand, coordinating sites, hydrophilicity, lipophilicity and presence of co-ligands have considerable influence on antibacterial activity. Certainly, Steric and pharmacokinetic factors also play a decisive role in deciding the potency of an antimicrobial agent. The higher toxicity of the metal complex can attributed to the effect of metal ion on the normal cell process. The widespread interaction of metal ions with cellular compounds is due to the fact that all these structures contain a variety of functional groups that can act as metal binding agents. The problem is how to obtain those interactions in cells and organisms where non-polar membrane exist to hinder the movement of charged metal ions into the cell, where myriad of metal binding sites exist to compete for the metal ion, and where specificity of cellular interaction must occur in order to obtain therapeutic valué25. The presence of lipophilic and polar substituents is expectedto enhance antibacterial activity. Heterocyclic ligands with multifunctionality have a greater chance of interaction either with nucleoside bases (even after complexation with metal ion) or with biologically essential metal ions present in the biosystem can be promising candidates as bactericides since they always tend to interact especially with some enzymatic functional groups, in order to achieve higher coordination numbers25,26. Thus the antibacterial activity of metal complexes cannot be ascribed to chelation alone, but it is an intricate blend of all the above contributions.

Anthelmentic activity (in vitro)

The anthelmentic activity was tested on earthworms (Pheretima Posthuma). Amongst the complexes Cu(II), Co(II), Ni(II), Zn(II), Cd(II) and Hg(II) the complexes Cu(II), Co(II), Cd(II) and Hg(II) showed more activity than the standard and the remaining complexes are less active. Based on the above results, it may be stated that the activity of the Schiff base is enhanced on complexation with Cu(II), Co(II), Cd(II) and Hg(II) ions(Table 6).


As discussed above the Schiff base ligand acts as tetradentate with carbonyl oxygen, azomethine nitrogen and piperazine nitrogen atoms as donors. The probable structures are shown below, Fig 1-3. The antibacterial activity of the isatin Schiff base is enhanced upon complexation with metal ions particularly for Co(II). The anthelmentic activity of the Schiff base is also enhanced on complexation with metal ions.


The authors thank the Sophisticated Instruments Facility, Indian Institute of Science, Bangalore for providing NMR facility and Raman Research Institute, Bangalore for CHN analysis, and the UGC for the DRS and FIP(RKR) programs.


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(Received: June 6, 2007 - Accepted: March 24, 2008)

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