Many thiosemicarbazones possess a wide spectrum of medicinal properties including activity against influenza, protozoa, small pox, certain kinds of tumour, tuberculosis, leprosy, bacterial and viral infections, psoriasis, rheumatism and tripamosomiasis, cocidiosis, malaria and have been suggested as possible pesticides and fungicides. Their activity has frequently been thought to be due to their ability to chelate trace metals. Thus the metal chelates with ligands of biological importance have been playing an important role in the development of new coordination chemistry. Complexes containing chelating ligands, which show promising biological activity, have been recently studied by ourselves1-11 and others.12-22 We have investigated the synthesis and characterization of cobalt(II),1-2 nickel(II),2-3 oxovanadium(IV),4-5 platinum(II)6 and some lanthanide(III)7 complexes that contain a range of ancillary ligands such as semicarbazones,7 thiosemicarbazones.1,2,4-6 Recently, we focused our attention to the investigation on transition metal complexes of N and O donor ligands.3,8,9 Very recently we reported the synthesis, characterization and biological activities of nickel(II) and cobalt(II) complexes of N and O donor of hydrazones derived from isonicotinic acid hydrazide viz., N-isonicotinamido-furfural-2'-aldimine (INH-FFL), N-isonicotinamido cinnamalidine (INH-CIN) and N-isonicotinamido-3',4',5'-trimethoxybenzalaldimine (INH-TMB) ligands.3,10,11 Although many thiosemicarbazones possess a wide spectrum of medicinal and biological properties23-26 still the metal complexes of the sulphur donor thiosemicarbazones have not been given as much attention as dithiophosphate, dithiocarbamates, dithiolates, dithio-β-diketonates, dithiooxamide or xanthates. Thus herein we present our studies on two new thiosemicarbazones N, N and S donor ligands i.e., 4[N-(4'-ethylbenzalidene)amino]antipyrine thiosemicarbazone (EBAAPTS) (Fig. 1) and 4[N-(2',4'-dimethylbenzalidene) amino]antipyrine thiosemicarbazone (DMBAAPTS) (Fig. 2) have been synthesized and their coordination behaviour towards Co(II) and Ni(II) are reported.
Fig. 1.4[N-(4'-Ethylbenzalidene)amino]antipyrine thiosemicarbazone (EBAAPTS) [Mol. formula C21H24N6S].
Fig. 2.4[N-(2',4'-Dimethylbenzalidene)amino]antipyrine thiosemicarbazone (DMBAAPTS) [Mol. formula C21H24N6S].
MX2·nH2O (M = Co2+ or Ni2+; X = Cl-, Br-, NO3-, NCS- or CH3COO-) were obtained from SD Fine Chemicals Ltd. (Mumbai, India) and were used as received. M(NCS)2 was prepared by mixing metal chloride (in ethanol) and ethanolic solution of potassium thiocyanate in 1:2 molar ratio. The precipitated KCl was filtered off and the filtrate having respective metal thiocyanate was used immediately for complex formation. The ligands EBAAPTS and DMBAAPTS were synthesized in the laboratory by our reported method.26
Synthesis of the complexes
A general method has been used for the preparation of all the complexes. A hot ethanolic solution of the corresponding cobalt(II) or nickel(II) salt was mixed with a hot ethanolic solution of the ligand (EBAAPTS or DMBAAPTS) in 1:1 molar ratio.1,2,10,11 The reaction mixture was refluxed on water bath for ca. 2 h. On cooling in ice cold water, the coloured complexes precipitated out in each case. The products were filtered, washed with ethanol, re-crystallized and dried over P4O10 under vacuum.
Instrumentation, physico-chemical measurements and analytical estimations
The cobalt(II) and nickel(II) in their metal complexes were estimated complexometrically with EDTA using murexide and eriochrome black-T as indicators respectively after decomposing the complexes with conc. H2SO4 and H2O2.2 The halogens and pseudohalogens were estimated by reported method.1,2,10,11 The sulfur content in the complexes was estimated gravimetrically as precipitated BaSO4 while the nitrogen content in the complexes was determined by the Kjeldahl method.
The molecular weight determination of the present complexes was carried out cryoscopically in freezing PhNO2 using a Beckmann thermometer of ±0.01 ℃ accuracy. A Toshniwal conductivity bridge and dip type cell was used for the conductivity measurements of the complexes in PhNO2 at room temperature. The magnetic susceptibility measurements on powder form of the complexes were carried out at 25 ℃ on Evan’s balance using anhydrous CuSO4 as calibrant. The infrared spectra of the complexes were recorded on a Perkin Elmer infrared spectrophotometer model 521 KBr pellets in the range of 4000-200 cm-1. Diffused reflectance spectra of the solid compounds were recorded on a Beckmann DK-2A spectrophotometer at C.D.R.I. Lucknow, India. Thermogravimetric analyses of the complexes were carried out on Perkin-Elmer Pyris Diamond in static air with an unlidded platinum boat sample holder, at the heating rate of 6 ℃/min. The antibacterial and antifungal activities of some representative cobalt(II) complexes and standards ampicillin, tetracycline and salicylic acid were screened by following our reported methods.1,2,10,11
RESULTS AND DISCUSSION
The reaction of Co(II) and Ni(II) with EBAAPTS and DMBAAPTS yielded the complex, [MX2(L)(H2O)] where M=Co2+ or Ni2+; X=Cl-, Br-, NO3-, NCS- or CH3COO- and L=EBAAPTS or DMBAAPTS. The analytical data of these complexes showed that they are stable and can be stored for months without any significant change. These complexes are generally soluble in common organic solvents. The molar conductance values of the complexes in nitrobenzene reveal that all the halo, nitrato, isothiocyanato and acetato complexes are essentially non-electrolytes.27 The cryoscopically determined molecular weights and conductivity data are presented in Table 1. In general, the molecular weight results are good agreement with the conductance data suggesting monomeric formulations.
The calculated magnetic moment based on magnetic susceptibility measurements of the cobalt(II) and nickel(II) complexes are given in Table 1. The observed values of magnetic moment for cobalt(II) complexes are generally diagnostic of the coordination geometry about the metal ion.1,2,11 The low spin square planar cobalt(II) complexes may be readily identified by values of μeff in the range 2.1-2.9 B.M., arising from one unpaired electron plus an apparently large orbital contribution. Both tetrahedral and high-spin octahedral cobalt(II) complexes possess three unpaired electrons but may be distinguished by the magnitude of the deviation of μeff from the spin only value1. The magnetic moment of the tetrahedral cobalt(II) complexes with an orbitally non-generate ground state is increased above the spin only value via contribution from higher orbitally degenerate terms and occurs in the range 4.2-4.7 B.M.1,2 The octahedral cobalt(II) complexes however maintain a large contribution due to 4Tg ground term and exhibit μeff in the range 4.8-5.6 B.M.1 Few data are available for high spin five-coordinate complexes, however, the range has been given as 4.5-4.8 B.M. The magnetic moments of the present cobalt(II) complexes are in the range of 4.8-5.1 BM (Table 1) which show that all cobalt(II) complexes are paramagnetic and have three unpaired electrons indicating a high-spin octahedral configuration.
Magnetic behavior of the octahedral nickel(II) complexes is relatively simple. Nickel(II) has the electronic configuration 3d8 and exhibit a magnetic moment higher than expected for two unpaired electrons in the octahedral environment (2.8-3.2 B.M.) and the tetrahedral (3.4-4.2 B.M.) complexes whereas its square-planar complexes would be diamagnetic.2,11 The paramagnetism observed for the present series of nickel(II) complexes ranges from 2.9-3.2 BM (Table 1), which is consistent with the octahedral stereochemistry of these complexes.
Table 1.Analytical, conductivity and molecular weight data of Co(II) and Ni(II) complexes of EBAAPTS and DMBAAPTS
It is known that the thiosemicarbazide molecule itself exists in the trans configuration (Structure a) and while complexing in this configuration it behaves as a monodentate ligand, bonding only through the sulphur atom.1,2,4,6,11 It is also known that bonding can also occur through the hydrazinic nitrogen and the amide nitrogen (Structure b), if the sulphur centre is substituted.1,2,4 On reinvestigating the crystal structure of thiosemicarbazide hydrochloride, these conformation changes on the basis of protonated deprotonated isomeric forms and steric effects. In most of the complexes studied, the thiosemicarbazone function coordinates to the metal ion in the cis-configuration (Structure c) as a bidentate ligand bonding through the thione/thiol sulphur atom and the hydrazine nitrogen atom in a bidentate manner.1,2,6,11.
When an additional coordinating functionality is present in the proximity of the N,S-donating centres, the ligands are found to act as tridentate species (Structure d) yielding a polymeric compounds in some cases. It is also shown that alkylation of the thiocarbonyl sulphur of thiosemicarbazone derivatives induces not only complexation through the terminal amino group, but also has enough acidic character for it to function as a mono acidic ligand. In the presence of various transitions metal ions, the ligands (EBAAPTS and DMBAAPTS) are capable of condensing at the terminal amino nitrogen atom through another aldehyde or ketone to yield quadridentate ligands, as shown in Structure e, using such template reactions.
Relevant to the bonding in thiosemicarbazone complexes is the ability to locate the various groups infra red (IR) frequencies corresponding to typical linkages. Although there have been many attempts to assign empirically a few infrared bands of metal complexes of thiosemicarbazone ligands,1,2,4,6,11 no complete assignment of their IR spectra have been available. A study and comparison of infrared spectra of EBAAPTS and DMBAAPTS and their [MX2(L)(H2O)] type complexes with Co(II) and Ni(II) are shown in Table 2 and 3 which imply that these ligands behave as neutral tridentate and coordinated through N and N of two azomethine groups and of S of thio-keto group. The strong bands observed at 3322-3200 cm-1 region in both thiosemicarbazones have been observed due to N-H vibrations. Practically, there is no effect on these frequencies after complexation exclude the possibility of complexation by this group in ligands; EBAAPTS and DMBAAPTS. The absorptions in 1622-1610 cm-1 range in free ligands (EBAAPTS and DMBAAPTS) may be attributed to C=N stretching vibrations of imine-nitrogen which is in agreement with the previous observations.28 On complexation of EBAAPTS (Table 2) and DMBAAPTS (Table 3) with Co(II) and Ni(II) these frequencies are shifted to lower energies. These observations suggest involvement of unsaturated nitrogen atoms of the two azomethine groups in bonding with the Co(II) and Ni(II) ions.
Table 2.Key infrared bands (cm-1) of EBAAPTS and Co(II) and Ni(II) complexes of EBAAPTS
In substituted thioureas, the C=S stretching vibrations contributed markedly to CN stretching and bending as well as N-C-S bending modes of vibrations. In the spectra of the present ligands (EBAAPTS and DMBAAPTS), the bands observed in the region 1290-1255 cm-1, 1130-1075 cm-1 and 840-760 cm-1 regions are assigned to [ν(C=S) + ν(C=N)+ν(C-N)], [δ(N-C-S)+δ(C=S)] bending and ν(C=S) stretching, respectively, which are in line with the observations of previous researchers.29 The coordination of sulfur with Co(II) and Ni(II) ions results in donation of electrons towards the metal ions. This results in the weakening of C=S bond. Hence on complexation C=S stretching vibrations should decrease and those of C-N should increase. In the present complexes of Co(II) and Ni(II) with EBAAPTS and DMBAAPTS, frequencies in the range 1290-1260 cm-1 increased by 40-50 cm-1. Similarly, bending modes of N-C-S and C=S also increased but to a lesser extent. On the other hand, on complexation the frequencies in region 840-760 cm-1 were shifted to lower wave numbers and intensity of the bands were also reduced. The changes described suggest coordination through S of C=S.
As there were no bands around 2700-2500 cm-1, in the infrared spectra, the possibility of thione-thiol tautomerism (H-N-C=S↽⇀C=N-SH) in the ligands, EBAAPTS and DMBAAPTS, has been ruled out. In the far infrared spectral region, some new bands with medium to weak intensity in region 450-335 cm-1 were assigned to ν(M-N) and ν(M-S). Thus the infrared spectral suggested the tridentate nature of the thiosemicarbazones and pointed out the N, N, S sites as possible donor atoms. The presence of coordinated water was confirmed by very broad absorptions around 3400 cm-1 in the infrared spectra of the complexes. Also the bands at ~ 930 and 770 cm-1 may be due to rocking and wagging modes of the coordinated water.30
Table 3.Key infrared bands (cm-1) of DMBAAPTS and Co(II) and Ni(II) complexes of DMBAAPTS
In thiocyanato complexes, the three fundamental absorption C-N stretch (ν1), C-S stretch (ν3) and N-C-S bending (ν2) were identified in regions 2045-2030, 845-840 and 475-460 cm-1, respectively. These frequencies are associated with the terminal N-bonded isothiocyanate ions.31 The appearance of two strong absorption bands in 1560-1520 cm-1 and 1310-1300 cm-1 region for nitrato complexes were attributed to ν4 and ν1 modes of vibrations, respectively, of the covalently bonded nitrate groups.32 The (ν4-ν1) values of ~220 cm-1 for these complexes suggested strong covalency for the metal-nitrate bonding.2 Lever et al. have shown that the number and relative energies of nitrate combination frequencies (ν1+ν4) in the region 1800-1700 cm-1 of the infrared spectrum, may be used as an aid to distinguish the various coordination modes of the nitrato group.33 It has been demonstrated that bidentate coordination of the nitrato group involves a greater distortion from D3h symmetry than unidentaten coordination, therefore, bidentate nitrate groups should show a larger separation of (ν1+ν4).33 Lever et al. confirmed that the separation for monodentate nitrate appeared to be 5-26 cm-1 and for bidentate nitrate 25-66 cm-1.33 A separation of 15-25 cm-1 in the combination bands (ν1+ν4) in the 1800-1700 cm-1 region in the present complexes confirmed the monodentate nitrate coordination. The acetato complexes showed infrared absorption frequency bands corresponding to νasym(COO-) and νsym(COO-) at ~1610 and 1370 cm-1, respectively2 confirming that both the acetate groups in the present complexes are unidentate.34
The electronic spectra of all the Co(II) complexes recorded were quite similar to each other and consist of two bands in the regions 18520-18000 cm-1 and 20840-20000 cm-1, which clearly indicated the octahedral stereochemistry of the complexes. The band maxima and their assignments are presented in Table 4. The energy of ν1 corresponds to 10Dq for weak field. The ligand field parameters, Dq, B and nephelauxetic effect (b) have also been calculated, using first order perturbation theory, from the ligand field spectra of octahedral Co(II) complexes, and reported in Table 4. The appreciable intensity enhancement in all the Co(II) complexes studied confirmed the distortion from a regular octahedral structure.
Table 4.Electronic spectral data and ligand field parameters of Co(II) complexes of EBAAPTS and DMBAAPTS
Table 5.Electronic spectral data and ligand field parameters of Ni(II) complexes of EBAAPTS and DMBAAPTS
The band maxima, their assignments, the calculated nephelauxetic effect (b) and the ligand field parameters B and Dq for some representative Ni(II) complexes are listed in Table 5. The absorption spectra of the Ni(II) complexes studied displayed bands in 10999-8200 cm-1 (ν1), 17700-15150 cm-1 (ν2) and 27500-24400 cm-1 (ν3) (Table 5) suggested the octahedral stereochemistry of these complexes.35 The comparison of the 10Dq values 7200, 7000 and 9700 cm-1 for [NiCl6]4-, [NiBr6]4- or [Ni(NCS 6]4- complexes, respectively with our results for the corresponding octahedral [MX2(L)(H2O)] (M=Ni2+, X=Cl-, Br- or NCS-) confirmed the distortion from a regular octahedral structure.2 This due to the fact that the equatorial ligand’s steric hindrance prevents axial ligands to form optimum covalent bonding with the Ni(II) and Co(II) central metal ions.
The thermogravimetric results of few representative cobalt(II) complexes of EBAAPTS (L1) are presented in Table 6. The thermogravimetric data indicated that the complexes were stable up to 85-90 ℃ and non-hygroscopic in nature. In the temperature range of 80-142 ℃, one coordinated water molecule is lost, after which decomposition and deligation processes started. Finally, at ~600 ℃, Co3O4 was obtained as final residue. The thermal decomposition may be represented by the following equations:
Table 6.Thermoanalytical results obtained for the Co(II) and Ni(II) complexes of EBAAPTS
The thermal results of few representative Ni(II) complexes of DMBAAPTS (L2) are also presented in Table 6. Ni(II) DMBAAPTS complexes are also stable upto the temp range 75-80 ℃. The careful analysis of thermogravimetric curves showed the following thermal equations:
The agar-cup method in DMF solvent at a concentration of 50 μg/mL was used to study the antibacterial activities of some representative cobalt(II) complexes and standard drugs. The antibacterial activities of EBAAPTS, DMBAAPTS, their cobalt(II) complexes, and standard: ampicillin and tetracycline were screened under identical conditions against gram positive bacteria Bacillus subtilis (B.s.) and Staphylococcus aureus (S.a.) and gram negative bacteria Escherichia coli (E.c.) and Salmonella typhi (S.t.). The results are presented in Table 7 in form of the diameters of zone of inhibition (mm). The data presented in Table 7 shows that the cobalt(II) and EBAAPTS or DMBAAPTS complexes have moderate antibacterial activities against these bacteria. It is important to note that these complexes exhibit greater activity than the parent ligand and the same was found during our previous studies.1
The thiosemicarbazones EBAAPTS, DMBAAPTS and their cobalt(II) complexes were also studied for their antifungal activities against two fungi: Aspergillus niger and Candida albicans (A. niger and C. albicans) and salicylic acid as standard. On the basis of the results presented in Table 7 it was found that almost all complexes showed nearly the same extent of activity, but they were found less active compared to salicylic acid. However, EBAAPTS complexes showed increased antifungal activity than that of DMBAAPTS complexes. It may be due to presence of furan ring and comparatively faster diffusion of EBAAPTS complexes. These compounds were found to be efficient antifungal agents.
Table 7.Antifungal and antibacterial activities of cobalt(II) complexes of EBAAPTS and DMBAAPTS
Few researchers have investigated the biological and medicinal properties of transition metal complexes of thiosemicarbazones36-41 where the antitumour activities of Mn(II), Co(II), Ni(II) and Cu(II) chelates of anthracene-9-carboxaldehyde thiosemicarbazone have been studied.37 The cytotoxic activity of phenylglyoxal bis(thiosemicarbazone) against Ehrlich ascites carcinona cells have also been studied.38 These compounds were also screened for antimicrobial activity on B. subtilis and E.coli. They inhibited the bacterial growth considerably.38 The antibacterial and antifungal activities of the present complexes were also compared with the activity results of some other cobalt(II) and nickel(II) complexes having different ligands.42-45 It was found that the present complexes are less potent bactericides with respect to reported cobalt(II) and nickel(II) complexes42,43 while some other complexes have almost comparable44,45 or less45 antibacterial and antifungal activities. However their experimental conditions are different.42,45
The compounds [MX2(L)H2O[ (M=Co2+ or Ni2+; X= Cl-, Br-, NO3-, NCS- or CH3COO-; =EBAAPTS or DMBAAPTS) epresent the first example of Co(II) and Ni(II) complexes involving N, N and S donor chelating agents EBAAPTS and DMBAAPTS and X forming six coordinated compounds and are stable in solid and solution states. The isolated complexes demonstrate that interactions of Co(II) and Ni(II) salts separately with EBAAPTS or DMBAAPTS i.e. thiosemicarbazones lead to 1:1 stoichiometries. Co(II) complexes of EBAAPTS or DMBAAPTS showed moderate antibacterial activities against Bacillus subtilis, Staphylococcus aureus, Escherichia coli and Salmonella typhi. The present compounds have antifungal activity against A. niger and C. albicans. DMBAAPTS complexes showed lesser antifungal activity than that of EBAAPTS complexes. The overall experimental evidence shows that these metal ions display a coordination number six and presumably have a distorted octahedral environment around the metal ion as shown in Fig. 3.
Fig. 3.Proposed structure of [MX2(L)H2O] M=Co(II) or Ni(II); X=Cl-, Br-, NO3-, NCS- or CH3COO-; L=EBAAPTS or DMBAAPTS.