Syntheses, Crystal Structures and Antimicrobial Activities of Vanadium(V) Complexes with Similar Tridentate Hydrazone Ligands①

LI Ke LI Shu-Jing②YAO Xin-Jin NIU Jing-Jing QIU Xio-Yng

a (School of Chemistry & Chemical Engineering,Zhoukou Normal University, Zhoukou 466000, China)

b (Department of Chemistry, Shangqiu Normal University, Shangqiu 476000, China)

1 INTRODUCTION

Hydrazones are a kind of biological active compounds, which can be prepared by the condensation reactions of carbonyl-containing compounds with hydrazides. The compounds have attracted considerable attention for their wide range of biological activities, such as antibacterial[1-3], antifungal[4,5],and antitumor[6,7]. It was reported that hydrazone compounds bearing electron-withdrawing groups can improve their antimicrobial activities[8,9]. Rai and co-workers reported a series of fluoro, chloro,bromo, and iodo-substituted compounds, and found that they have significant antimicrobial activities[10].Vanadium complexes with Schiff bases and hydrazones have been reported with interesting antibacterial activities[11-14]. As a continuation of work on the exploration of novel complexes based antimicrobial agents, in this paper, two hydrazone ligands (E)-N?-(2-hydroxy-5-methoxybenzylidene)-2-hydroxybenzohydrazide (HLa) and (E)-N?-(3,5-dichloro-2-hydroxybenzylidene)-4-methoxybenzohydrazide (HLb) were prepared. Based on the hydrazone ligands, two new structurally similar vanadium(V) complexes, [VOLaL]·CH3OH (1) and[VOLbL] (2), were obtained and their antimicrobial activities were investigated.

2 EXPERIMENTAL

2.1 Materials and methods

Vanadyl acetylacetonate and organic materials were purchased from Sigma-Aldrich and used as received. All other reagents were of analytical reagent grade. Elemental analyses of C, H and N were carried out in a Perkin-Elmer automated model 2400 Series II CHNS/O analyzer. FT-IR spectra were obtained on a Perkin-Elmer 377 FT-IR spectrometer with samples prepared as KBr pellets. UVVis spectra were obtained on a Lambda 900 spectrometer. X-ray diffraction was carried out on a Bruker APEX II CCD diffractometer.

2.2 Synthesis of HLa

To the methanolic solution (30 mL) of 5-methoxysalicylaldehyde (0.02 mol, 3.04 g) was added a methanolic solution (20 mL) of 2-hydroxybenzohydrazide (0.02 mol, 3.04 g) with stirring. The mixture was stirred for 30 min at room temperature, and left to slowly evaporate to give colorless crystalline product, which was recrystallized from methanol and dried in vacuum containing anhydrous CaCl2.Yield 87%. IR data (cm–1): 3441, 3230, 1645, 1614,1570, 1492, 1453, 1363, 1311, 1272, 1228, 1156,1040, 963, 898, 813, 756, 640, 473. UV-Vis data(MeOH, λmax, nm): 293, 311, 358. Anal. Calcd. for C15H14N2O4: C, 62.9; H, 4.9; N, 9.8%. Found: C,62.7; H, 5.0; N, 9.7%.1H NMR (300 MHz,d6-DMSO): δ 12.02 (s, 1H), 11.79 (s, 1H), 10.60 (s,1H), 8.66 (s, 1H), 7.89 (1 H, dd, J = 7.8, 1.2). 7.45(m, 1H), 7.15 (d, 1H), 7.0～6.8 (m, 4H), 3.73 (s,3H).

2.3 Synthesis of HLb

To 30 mL methanolic solution of 3,5-dichlorosalicylaldehyde (0.02 mol, 3.84 g) was added a methanolic solution (20 mL) of 4-methoxybenzohydrazide (0.02 mol, 3.32 g) with stirring. The mixture was stirred for 30 min at room temperature,and left to slowly evaporate to give colorless crystalline product, which was recrystallized from methanol and dried in vacuum containing anhydrous CaCl2. Yield 91%. IR data (cm–1): 3440, 3273, 1647,1614, 1544, 1498, 1356, 1260, 1182, 1027, 963, 840,765, 685, 608, 479. UV-Vis data (MeOH, λmax, nm):288, 298, 327. Anal. Calcd. for C15H12Cl2N2O3: C,53.1; H, 3.6; N, 8.3%. Found: C, 53.2; H, 3.5; N,8.1%.1H NMR (300 MHz, d6-DMSO): δ 12.02 (s,1H), 11.39 (s, 1H), 8.64 (s, 1H), 7.95 (d, 2H), 7.54(d, 1H), 7.32 (m, 1H), 7.10 (d, 2H), 6.95 (t, 2H),3.86 (s, 3H).

2.4 Synthesis of [VOLaL]·CH3OH (1)

HLa(0.1 mmol, 28.6 mg) and vanadyl acetylacetonate (0.1 mmol, 26.5 mg) were mixed in methanol(10 mL). The mixture was refluxed for 1 h and then cooled to room temperature. Single crystals of the complexes, suitable for X-ray diffraction, were grown from the solution upon slow evaporation within a few days. The crystals were isolated by filtration, washed with methanol and dried in vacuum containing anhydrous CaCl2. Yield 37%. IR data (cm–1): 3447, 3208, 1693, 1536, 1496, 1433,1384, 1290, 1249, 1152, 1095, 1031, 974, 915, 756,693, 578, 483, 452. UV-Vis data (EtCN, λmax, nm):268, 314, 453. Anal. Calcd. for C23H22N3O8V: C,53.2; H, 4.3; N, 8.1%. Found: C, 53.0; H, 4.1; N,8.2%.

2.5 Synthesis of [VOLbL] (2)

HLb(0.1 mmol, 33.8 mg) and vanadyl acetylacetonate (0.1 mmol, 26.5 mg) were mixed in methanol(10 mL). The mixture was refluxed for 1 h and then cooled to room temperature. Single crystals of the complexes, suitable for X-ray diffraction, were grown from the solution upon slow evaporation within a few days. The crystals were isolated by filtration, washed with methanol and dried in vacuum containing anhydrous CaCl2. Yield 37%. IR data (cm–1): 3213, 1682, 1528, 1493, 1427, 1382,1241, 1165, 1093, 1018, 974, 760, 576, 483, 446.UV-Vis data (EtCN, λmax, nm): 293, 311, 358. Anal.calcd. for C22H16Cl2N3O6V: C, 48.9; H, 3.0; N, 7.8%.Found: C, 48.8; H, 3.1; N, 7.7%.

2.6 X-ray crystallography

X-ray diffraction was carried out at a Bruker APEX II CCD area diffractometer equipped with MoKα radiation (λ = 0.71073 ?). The collected data were reduced with SAINT[15], and multi-scan absorption correction was performed using SADABS[16]. The structures of the complexes were solved by direct methods with SHELXS-97[17], and refined against F2by full-matrix least-squares method using SHELXL-97[18]. All of the non-hydrogen atoms were refined anisotropically. The amino hydrogen atoms were located from electronic density maps and refined isotropically. The remaining hydrogen atoms were placed in the calculated positions and constrained to ride on their parent atoms. The crystallographic data and refinement parameters for the compounds are listed in Table 1.Selected bond lengths and bond angles are listed in Table 2.

Table 1. Crystallographic and Refinement Data for the Complexes

a R = Fo – Fc/Fo, wR = [∑w(Fo2 – Fc2)/∑w(Fo2)2]1/2

Table 2. Selected Bond Distances (?) for the Complexes

2.7 Antimicrobial assay

The antibacterial activities of the compounds were tested against B. subtilis, S. aureus, E. coli, and P.fluorescence using MH (Mueller-Hinton) medium.The antifungal activities of the compounds were tested against C. albicans and A. niger using the RPMI-1640 medium. The MIC values of the tested compounds were determined by a colorimetric method using the dye MTT[19]. A stock solution of the compound (150 μmol·L–1) in DMSO was prepared and graded quantities (75, 37.5, 18.8, 9.4,4.7, 2.3, 1.2, 0.59 μmol·L–1) were incorporated in specified quantity of the corresponding sterilized liquid medium. A specified quantity of the medium containing the compound was poured into microtitration plates. Suspension of the microorganism was prepared to contain approximately 1.0 × 105cfu·mL–1and applied to microtitration plates with serially diluted compounds in DMSO to be tested and incubated at 37 ℃ for 24 and 48 h for bacterial and fungi, respectively. Then the MIC values were visually determined on each microtitration plate,with 50 μL of PBS (phosphate buffered saline 0.01 mol·L–1, pH = 7.4) containing 2 mg of MTT·mL–1being added to each well. Incubation was continued at room temperature for 4～5 h. The content of each well was removed, and 100 μL of isopropanol containing 5% 1 mol·L–1HCl was added to extract the dye. After 12 h of incubation at room temperature, the optical density was measured with a microplate reader at 550 nm.

3 RESULTS AND DISCUSSION

3.1 Synthesis and characterization

The hydrazone ligands HLaand HLbwere readily prepared by the condensation reaction of 1:1 molar ratio of 5-methoxysalicylaldehyde with 2-hydroxybenzohydrazide, and 3,5-dichlorosalicylaldehyde with 4-methoxybenzohydrazide, respectively in methanol. Complexes 1 and 2 were prepared by the reaction of hydrazone ligands with vanadyl acetylacetonate in methanol, followed by recrystallization.Elemental analyses of the complexes are in accordance with the molecular structures proposed by X-ray analysis.

3.2 Spectroscopic studies

In the spectra of hydrazone ligands and the complexes, the weak and broad bands centered at about 3440 cm-1are assigned to the vibration of O–H bonds, and the weak and sharp bands located in the range of 3200～3300 cm-1are assigned to the vibration of N–H bonds. The position of the bands demonstrates that the N–H hydrazone protons are engaged in hydrogen bonds. The intense bands at 1645 cm-1of HLaand 1647 cm-1of HLbare generated by ν(C=O) vibrations, whereas the bands at 1614 cm-1by the ν(C=N) ones. The non-observation of ν(C=O) bands, present in the spectra of hydrazone ligands, indicates the enolization of amide functionality upon coordination to the V-center. Instead strong bands at 1693 cm-1for 1 and 1682 cm-1for 2 are observed, which can be attributed to the asymmetric stretching vibration of the conjugated CH=N–NH–C–O groups, characteristic for the coordination of enolate form of the ligands.The strong ν(V=O) bands at 974 cm-1could be clearly identified for both complexes[20].

In the electronic spectra of the complexes, the lowest energy transition bands are observed at 453 nm for 1 and 358 nm for 2, which are attributed to LMCT transition as charge transfer from p-orbital on the lone-pair of ligands’ oxygen atoms to the empty d-orbital of the vanadium atoms. The other strong bands in the range of 310～330 nm in the spectra of both complexes are similar to the absorption bands in the spectra of the corresponding hydrazone ligands, so they are attributed to the intra-ligand π→π* absorption peak of the ligands. The other main LMCT and to some extent π→π* bands appear at 268 nm for 1 and 293 nm for 2, and this is due to the oxygen donor atoms bound to vanadium (V)[20].

3.3 Structure description of the complexes

The molecular structures of complexes 1 and 2 are shown in Figs. 1 and 2, respectively. The coordination geometry around the vanadium atoms can be described as distorted octahedral with the tridentate hydrazone ligand coordinated in a meridional fashion, forming five- and six-membered chelate rings with bite angles of 74.95(18)° (1) and 74.67(16)° (2) (N(1)–V(1)–O(2)), and 84.11(19)° (1)and 84.09(17)° (2) (N(1)–V(1)–O(1)), respectively,typical for this type of ligand systems[21]. Each chelating hydrazone ligand lies in a plane with one hydroxylato ligand which lies trans to the hydrazone N(1) atom. One carbonyl atom of the benzohydroxamate ligand trans to the oxo group completes the distorted octahedral coordination sphere at a rather elongated distance of about 2.2 ?, due to the trans influence of the oxo group. This is accompanied by a significant displacement of the vanadium atom from the plane defined by the four basal donor atoms towards the apical oxo oxygen atom by 0.29 ?. As expected, the hydrazone ligands coordinate in their doubly deprotonated enolate form which is consistent with the observed O(2)–C(9) and N(2)–C(9) bond lengths of 1.29 and 1.31 ? in 1, and O(2)–C(8) and N(2)–C(8) bond distances of 1.29 and 1.30 ? in 2. This agrees with the reported vanadium complexes containing the enolate form of this ligand type[21-23]. In the crystal packing structure of complex 1, hydrazone molecules are linked by methanol molecules through intermolecular hydrogen bonds of N–H···O and O–H···O (Table 3),leading to the formation of 1D chains along the a axis (Fig. 3). In the crystal packing structure of complex 2, hydrazone molecules are linked together through intermolecular hydrogen bonds of N–H···N(Table 3), leading to the formation of 1D chains along the c axis (Fig. 4). In addition, there are π···π stacking interactions (Table 4) among the chains along the b axis in both structures. The hydrogen bonds as well as the π···π stacking interactions lead to the formation of 2D sheets parallel to the ab plane for 1 and bc plane for 2.

Table 3. Distances (?) and Angles (o) Involving Hydrogen Bonding of the Complexes

Table 4. Parameters between the Planes for the Complexes

Fig. 1. A perspective view of complex 1 with atomic labeling scheme.Thermal ellipsoids are drawn at 30% probability level

Fig. 2. A perspective view of complex 2 with atomic labeling scheme.Thermal ellipsoids are drawn at the 30% probability level

Fig. 3. Molecular packing structure of complex 1, with hydrogen bonds shown as dotted lines

Fig. 4. Molecular packing structure of complex 2, with hydrogen bonds shown as dotted lines

3.4 Antimicrobial activity

The hydrazone ligands and vanadium complexes were screened for antibacterial activities against two Gram (+) bacterial strains (Bacillus subtilis and Staphylococcus aureus) and two Gram (–) bacterial strains (Escherichia coli and Pseudomonas fluorescence) by MTT method. The MIC (minimum inhibitory concentration) values of the compounds against four bacteria are listed in Table 5. Penicillin G was used as the standard drug. The hydrazone ligands show medium activities against the bacteria B. subtilis, S. aureus, and E. coli. HLbhas weak activity against P. fluorescence, while HLahas no activity. The two complexes have from strong to medium activities against B. subtilis, S. aureus, and E. coli, while no activity against P. fluorescence. In general, the complexes have stronger activities against B. subtilis, and weaker activities against S.aureus, E. coli and P. fluorescence when compared with the hydrazone ligands. It should be noted that complex 2 has stronger activity against B. subtilis than Penicillin G.

Table 5. Antimicrobial Activities of the Compounds

The antifungal activities of the hydrazone ligands and the complexes were also evaluated against two fungal strains (Candida albicans and Aspergillus niger) by MTT method. Ketoconazole was used as a reference material. However, both hydrazone ligands and the complexes have no activity against the fungal strains.

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