Oxovanadium(IV) complexes of medicinal relevance: Synthesis, characterization, and 3D-molecular modeling and analysis of some oxovanadium(IV) complexes in O,N-donor coordination matrix of sulfa drug Schiff bases derived from a 2-pyrazolin-5-one derivative

2.1 Materials

Vanadyl sulfate pentahydrate, calcium hydroxide, butyryl chloride, dimethyl formamide, sulfa drugs, viz., sulfamerazine (Thomas Baker Co. Ltd., Mumbai, India), sulfadiazine, sulphaguanidine and sulfanilamide (Sigma Chemicals Co., USA), and 3-methyl-1-phenyl-2-pyrazolin-5-one (Lancaster Research Chemicals, England) were used as supplied. All other chemicals used were of analytical grade.

2.2 Preparation of 3-methyl-1-phenyl-4-butyryl-2-pyrazolin-5-one (bumphpH)

It was prepared by the method reported elsewhere (Jensen, 1959a,b) with modification. Into a 1-L 3-necked quick fit flask containing DMF (100 mL) and carrying a dropping funnel, a mechanical stirrer, and a reflux condenser was placed 3-methyl-1-phenyl-2-pyrazolin-5-one (17 g, 0.098 mol). A solution was obtained by gentle heating and stirring. Calcium hydroxide (10 g, 0.14 mol) was added and butyryl chloride (10.33 mL) was added drop wise within 2–3 min. The reaction was exothermic and the reaction mixture became a paste. The mixture was allowed to cool and then refluxed with stirring for 1 h on a sand bath, during which period, the bright yellow complex, formed initially, turned yellowish brown. The complex was decomposed by pouring the reaction mixture into chilled dilute hydrochloric acid solution (500 mL, 2 N). A yellowish brown solid settled, which was filtered on a sintered glass crucible, washed with distilled water until the washings were colorless and dried in air and recrystallized from n-heptane. Melting point, 65 °C, yield, 70%.

2.3 Synthesis of Schiff bases

The Schiff bases with sulfa drugs were prepared as follows: An ethanolic solution (15 mL) of bumphpH (0.488 g, 2 mmol) was added to the solution of sulfadiazine (0.500 g, 2 mmol), sulfanilamide (0.344 g, 2 mmol), sulfaguanidine (0.428 g, 2 mmol), or sulfamerazine (0.528 g, 2 mmol) in ethanol. The resulting solution was refluxed with stirring for 4–5 h and then filtered to remove the insoluble sulfa drug, if any. The filtrate so obtained was concentrated on a water bath and left overnight at room temperature when colored crystals of Schiff bases separated out from their respective solutions. The crystals thus obtained were washed with ethanol and dried in vacuo. The characterization data of Schiff bases are given in Tables 1 and 2.

2.4 Synthesis of complexes

The following general procedure was used in the synthesis of all the complexes. The salt VOSO₄·5H₂O (0.253 g, 1 mmol) was dissolved in 5 mL of water and this solution was added to a warmed, stirred ethanolic solution (∼15 mL) of the corresponding Schiff bases, bumphp-sdzH (0.952 g, 2 mmol), bumphp-sgnH (0.880 g, 2 mmol), bumphp-snmH (0.796 g, 2 mmol) or bumphp-smrH (0.980 g, 2 mmol). The resulting solution was refluxed for 10–12 h and then concentrated to half of its volume. The resulting colored precipitate was filtered and washed several times with ethanol to remove the unreacted ligand and the metal salt. The product was dried in vacuo. The analytical data are given in Table 3.

2.5 Analyses

Carbon, hydrogen, and nitrogen were determined micro-analytically at SAIF, Indian Institute of Technology, Mumbai. The vanadium content of each of the complexes was determined as follows. One hundred milligrams of the sample of the compound were placed in a silica crucible, decomposed by gentle heating and then was added 1–2 mL of concentrated HNO₃, 2–3 times. An orangish mass (V₂O₅) was obtained after decomposing and complete drying. It was dissolved in minimum amount of dilute H₂SO₄, and the solution so obtained was diluted with distilled water to 100 mL in a measuring flask. The vanadium content of each of the complexes was determined volumetrically using decinormal KMnO₄ solution as an oxidizing agent in the presence of sulfurous acid. The amount of vanadium in the sample solution was calculated using the standard (Furman, 1962) relationship: 1 mL of 0.1 N KMnO₄ = 5.094 mg vanadium.

2.6 Physical methods

The following physical methods were used in the present investigation. Thermogravimety of a complex was performed on a Perkin–Elmer Thermoanalyser at S.A.I.F., Indian Institute of Technology, Mumbai. The solid-state infrared spectra were obtained using KBr pellets with a Perkin–Elmer model 1620 FT-IR spectrophotometer at the Central Drug Research Institute, Lucknow. Electronic spectra were recorded on an ATI Unicam UV-1–100 UV/vis Spectrophotometer in our laboratory. Conductance measurements were made in DMF solution using a Toshniwal conductivity bridge and dip-type cell with a smooth platinum electrode of cell constant 1.02. Magnetic measurements were done by a vibrating sample magnetometer at the Regional Sophisticated Instrumentation Centre, Indian Institute of Technology, Chennai. The decomposition temperatures of the complexes were recorded by an electrically operated melting point apparatus (Kumar Industries, Mumbai) of heating capacity up to 360 °C. Cyclic voltammetric measurements were carried out on an ECDA-001 basic electrochemistry system. A three-electrode system consisting of (i) a platinum disk working electrode, (ii) a platinum wire counter electrode and (iii) a Ag/AgCl reference electrode was used. A 10 mL glass cell with a Teflon cell cover holding working, counter, and reference electrodes and deoxygenating purge tube formed the sample cell. Prior to each run, the working electrode was polished using polishing nylon cloth over a glass plate. The sample solution was deoxygenated by passing purified nitrogen gas through the solution. The X-Band and EPR spectra of the complexes were measured on a Bruker ESP X-band EPR spectrometer using powdered samples at the Regional Sophisticated Instrumentation Centre, Indian Institute of Technology, Chennai.

2.7 3D Molecular modeling studies

The 3D molecular modeling of one of the synthesized compounds was carried out on CS Chem 3D Ultra Molecular Modeling and Analysis Programme (www.cambridgesoft.com). It is an interactive graphics program that allows rapid structure building, geometry optimization, and molecular display. It has the ability to handle transition metal compounds.

3.1 Infrared spectral studies

The important spectral bands of the synthesized ligands as well as the complexes are presented in Tables 2 and 4, respectively. All of the Schiff base ligands in the present investigation exhibit a broad band centered at 3328–3486 cm⁻¹. This suggests the involvement of the 5-OH group in intramolecular hydrogen (Maurya et al., 1997) bonding with the lone pair of azomethine nitrogen. It also suggests that the ligands exist in enol form in the solid state (Maurya et al., 2002a,b,c).

The Schiff base ligands used in the present investigation contain six potential donor sites: (i) the enolic oxygen; (ii) the cyclic nitrogen, N¹; (iii) the cyclic nitrogen, N²; (iv) the azomethine nitrogen; (v) the sulfonamide (–SO₂NH) oxygen or nitrogen and; (vi) the ring nitrogen of sulfa drug. All the Schiff base ligands show a sharp and strong band due to ν(C⚌N) of the azomethine group at 1627–1630 cm⁻¹. The observed low-energy shift of this band in the chelates and appearing at 1607–1617 cm⁻¹, suggests the coordination of the azomethine nitrogen (Maurya et al., 2002a,b,c).

The ν(C⚌N²) (cyclic) band arising from the pyrazolone moiety of the ligands appears at 1581–1596 cm⁻¹ and does not show any appreciable change in its respective positions in the complexes. This observation indicates the non-participation of the ring nitrogen N² in coordination. The coordination of the ring nitrogen N¹ is unfavorable due to the steric demand of the bulky phenyl ring attached to it.

The ν(NH) mode of the sulfonamide group/amino group in the uncoordinated Schiff bases remains almost unchanged in the spectra of their complexes (see Tables 2 and 4). This suggests that the sulfonamide nitrogen/amino group is not taking part in coordination. The band appearing at 1388–1410 cm⁻¹ in the ligands is assigned to ν_as(O⚌S⚌O). This band remains almost at the same position in the complexes and hence suggests that the sulfonamide oxygen is not taking part in coordination with the metal center. The reaction of the enolic Schiff bases with VO²⁺ ion with the elimination of a proton is revealed by the presence of a new band in the complexes at 1150–1195 cm⁻¹ as compared to that of the Schiff bases at 1138–1179 cm⁻¹ due to ν(C–O) (enolic) (Maurya et al., 1996). The appearance of a broad band centered at 3313–3475 cm⁻¹ and assignable as ν(OH) suggests the presence of lattice/coordinated water molecules in the complexes.

Most of the oxovanadium(IV) complexes exhibit a strong band near 1000 cm⁻¹, which has been assigned to ν(V⚌O) (Selbin, 1966). In contrast, several oxovanadium(IV) complexes have been reported in which this stretching mode appears at quite lower (Maurya et al., 2001) wave numbers, around 900 cm⁻¹. The shift of ν(V⚌O) band to lower wave numbers has been suggested due to the presence of a slight ⋯V⚌O⋯V⚌O⋯ type interaction occurring between a vanadyl oxygen of one molecule with a vanadium metal in another molecule (Boas and Pessoa, 1987). In the present work, the ν(V⚌O) mode is found at 975–990 cm⁻¹ thereby suggesting the absence of ⋯V⚌O⋯V⚌O⋯ type interaction in these complexes. The IR spectra of the Schiff base ligand (bumphp-snmH, III) and its complex,[VO(bumphp-snm)₂(H₂O)]·H₂O (3) are given in Figs. 2 and 3, respectively.

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Figure 2

IR spectrum of bumphp-snmH (III).

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Figure 3

IR spectrum of[VO(bumphp-snm)₂(H₂O)]·H₂O (3).

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3.2 Electronic spectral studies

The electronic spectra of these compounds were recorded in 10⁻³ M dimethylformamide solutions in the range of 280–800 nm. The λ_max of the electronic spectral peaks and the respective molar extinction coefficients along with the tentative assignments are given in Table 5. Besides high intensity charge transfer transitions, all these complexes displayed one low intensity d–d transition which may be assigned to $b_2\to {}^1{a}_1^{*}$ transition (Lever, 1984). The assignment of $b_2\to {}^1{a}_1^{*}$ transition in each case assumes idealized C₂v symmetry. These spectra are typical of oxovanadium(IV) complexes (Maurya and Rajput, 2004; Dutta et al., 1997). The electronic spectrum of the compound,[VO(bumphp-sgn)₂(H₂O)]·H₂O (2) is shown in Fig. 4.

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Figure 4

Electronic spectrum of[VO(bumphp-sgn)₂(H₂O)]·H₂O (2).

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3.3 ESR spectral studies

The X-band EPR spectra of compounds, (2) and (4) were recorded using the microwave frequencies 9.09 GHz and 9.10 GHz, respectively in frozen DMF solution without DPPH at LNT. Each spectrum shows an eight-line pattern, a characteristic of an unpaired electron being coupled with a vanadium nuclear spin (I = 7/2). This means that the unpaired electron is in the vicinity of I = 7/2 of its own mother nucleus. Thus, the isotropic ESR spectrum of a magnetically dilute oxovanadium(IV) complex gives (2 × 7/2 + 1 = 8 lines). The calculated ESR parameters from the spectra of both the complexes are given in Table 6.

The observed g_av values for both the complexes deviate from the free ion value 2.0036, which suggest that the resulting complexes are covalent in nature (Dutta and Syamal, 1993). Moreover, the features of the spectra of these complexes are indicative of monomeric oxovanadium(IV) complexes (Maurya et al., 2002a,b,c). The ESR spectrum of compounds,[VO(bumphp-sgn)₂(H₂O)]·H₂O (2) and[VO(bumphp-smr)₂(H₂O)]·H₂O (4) is given in Fig. 5a and b, respectively.

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Figure 5a

ESR spectrum of[VO(bumphp-sgn)₂(H₂O)]·H₂O (2).

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Figure 5b

ESR spectrum of[VO(bumphp-smr)₂(H₂O)]·H₂O (4).

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3.4 Thermogravimetric studies

The thermogram of one of the representative compounds,[VO(bumphp-snm)₂(H₂O)]·H₂O (3) were recorded in the temperature range from 30 to 1000 °C at a heating rate of 15 °C/min. This compound shows a weight loss of 4% in the temperature range 80–140 °C (calcd. wt. loss for 2 mol of H₂O, 4%). As this weight loss starts from 80 °C and completes around 140 °C, this shows the presence (Maurya et al., 2003; Zhao et al., 2008) of one lattice water and one coordinated water molecule in the complex. After this weight loss, the compound remains stable up to 300 °C and thereafter, shows a steep weight loss. The ultimate weight loss of 84% at ∼950 °C roughly corresponds to the removal of all the ligand moieties from the complex (calcd. wt. loss for removal of all the ligand moieties, 92.7%). The final residue attaining a constant weight (observed, 16%) over 950 °C roughly corresponds to V₂O₅ (calculated, 20.27%). This weight loss data, thus, agree well with the IR results for this complex. The thermogram of compound,[VO(bumphp-snm)₂(H₂O)]·H₂O (3) is given in Fig. 6.

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Figure 6

Thermogram of[VO(bumphp-snm)₂(H₂O)]·H₂O (3).

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3.5 Magnetic measurements

The magnetically dilute oxovanadium(IV) complexes usually exhibit magnetic moments in line with spin-only value of 1.73 B.M. At room temperature, the observed value of the magnetic moments for the present complexes, are in the range 1.74–1.76 B.M. These data suggest that the complexes under this investigation are mononuclear (Dutta et al., 1997).

3.6 Conductance measurements

The observed molar conductances (12.5–19.7 ohm⁻¹ cm² mol⁻¹) in 10⁻³ M DMF solutions of these Schiff base complexes are given in Table 3, and are consistent with the non-electrolytic nature of the complexes. Such a non-zero molar conductance value for each of the complexes in the present study is most probably due to the strong donor capacity of DMF, which may lead to the displacement of anionic ligand and change of electrolyte (Geary, 1971) type.

3.7 Cyclic voltammetric studies

Cyclic voltammetric measurements of two representative complexes,[VO(bumphp-sdz)₂(H₂O)]·H₂O (1) and[VO(bumphp-snm)₂(H₂O)]·H₂O (3), were carried out on an ECDA-001 basic electrochemistry system in order to assess the suitability of ligand environments in the present complexes to facilitate electron transfer reactions. The complexes were dissolved in dimthyformamide and the cyclic voltammograms were recorded in the scan range of 2000 to −2000 mV. The reduction of these complexes to +III oxidation state (usually expected in such complexes) were achieved by waves with E_r values (Maurya and Rajput, 2004; Dai et al., 1996) in the range from −788.45 to −913.45 mV against the saturated Ag/AgCl electrode (Table 7). Other important parameters are also included in this table. The deviations of i_pc/_ipa from 1 in the present cases suggest that the redox couple is not reversible. This may be due to a slow electron transfer reaction. This is again reflected by the unusually high values of ΔE in the range of 346.3–403.9 mV, not following the reversibility criterion (Kissinger and Heineman, 1984), $$\mathrm{\Delta }{E}_{\text{p}}=E_{\text{pa}}-E_{\text{pc}}=\frac{0.059}{n}$$ The cyclic voltammogram of compound (3) is shown in Fig. 7.

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Figure 7

Cyclic voltammogram of[VO(bumphp-snm)₂(H₂O)]·H₂O (3).

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3.8 3D-Molecular modeling and analysis

In view of the hexa-coordination of all the complexes (vide infra), and also taking into account the well established square pyramidal structure (Sakurai et al., 1995) of bis(picolinato)oxovanadium(IV)[having two monoprotic bidentate (O,N-donor) picolinate ligand, similar to two monoprotic O,N-donor sulfa drug based Schiff base ligands (LH) used in the present investigation, and occupying equatorial positions cis to each other, and oxo group at one of the axial positions], the molecular modeling of a representative compound,[VO(bumphp-sdz)₂(H₂O)]·H₂O (1) is based on its octahedral structure with an axial oxo group and water molecule trans to O (oxo) and two O,N-donor LH ligands at the equatorial positions cis to each other. The details of bond lengths and bond angles as per the 3D structure (Fig. 8) are given in Tables 8 and 9, respectively. For convenience of looking over the different bond lengths and bond angles, the various atoms in the compound in question are numbered in Arabic numerals. In all, 382 measurements of the bond lengths (140 in number), plus the bond angles (242 in number) are listed in the Tables 8 and 9. Except few cases, optimal values of both the bond lengths and the bond angles are given in the Tables along with the calculated ones. The actual (calculated) bond lengths/bond angles given in Tables are obtained as a result of energy optimization in CHEM 3D Ultra, while the optimal bond length/optimal bond angle values are the most desirable/favorable (standard) bond lengths/bond angles established by the builder unit of the CHEM 3D. The missing of some values of standard bond lengths/bond angles may be due to the limitations of the software, which we had already noticed in modeling of other systems (Maurya et al., 2007, 2008, in press). In most of the cases, the actual bond lengths and bond angles are close to the optimal values, and thus the proposed structure of the compound (1) as well as of the others are acceptable (Maurya and Rajput, 2007; Maurya et al., 2007, 2008, in press).

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Figure 8

3D structure of[VO(bumphp-sdz)₂(H₂O)]·H₂O (1).

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