Synthesis, Spectroscopic, Molecular Modeling and Anti-Fungal Studies of Some Divalent Metal Complexes of 4-Hydroxyacetophenone Isonicotinoyl Hydrazone


A novel ligand N-4-hydroxyacetophenone isonicotinoyl hydrazone and its manganese(II) and nickel(II) metal complexes have been synthesized. The synthesized Schiff base and its metal complexes have been characterized by physical state determination, melting point and solubility measurements in different solvents, infrared, proton nuclear magnetic resonance, mass spectrometric and powder X-ray spectroscopic techniques. The thermal properties of the prepared compounds were obtained from TG/DTG measurements. On the basis of the analytical techniques, the ligand was found to be bidentate in nature coordinating to the metal ions through the azomethine nitrogen and carbonyl oxygen atoms leading to distorted octahedral geometries of the metal complexes which were modeled using MM2 force field. The ligand and its metal(II) complexes were evaluated for antifungal activity against Aspergillus fumigatus, Aspergillus niger, Candida albicans and Rhizopus stolonifera. The antifungal evaluation results revealed an enhanced activity upon coordination of the ligand with the metal(II) ions. The activity of the metal complex to the tested fungal strains was in the order Ni(II) > Mn(II).

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Toh-Boyo, G. , Njong, R. , Babette, E. and Nfor, E. (2021) Synthesis, Spectroscopic, Molecular Modeling and Anti-Fungal Studies of Some Divalent Metal Complexes of 4-Hydroxyacetophenone Isonicotinoyl Hydrazone. Open Journal of Inorganic Chemistry, 11, 95-109. doi: 10.4236/ojic.2021.113007.

1. Introduction

Hydrazones Schiff base compounds are formed usually through the condensation reaction of stoichiometric amounts of the appropriate hydrazine/hydrazide with carbonyl compounds such as aldehydes and ketones in alcoholic solvents like ethanol [1] to yield a product with the general formula, R-CO-NH-N=CR’R’’ [2]. These compounds have been found to possess interesting biological properties, such as anticonvulsant [3] [4], anti-inflammatory and antimicrobial [5], anti-tuberculosis [6], antitumor [7] [8], and antiviral [9] activities. Furthermore, they are important compounds for drug design, as possible ligands for metal complexes, organo-catalysis and also for the syntheses of heterocyclic compounds [10]. In recent years, a lot of biologically important hydrazide-hydrazones derivatives have been synthesized from different carbonyl compounds [11] [12] [13] [14] [15]. The biological activities of many of these compounds have been shown to be related to their metal-chelating abilities [16] [17] [18]. Therefore this class of compounds could be a good starting point to develop new led compounds in the treatment of multidrug-resistant bacteria.

Inspired by these considerations and in continuation with our studies on hydrazones ligands [19] [20], we herein report on the synthesis, spectroscopic, molecular modeling and antifungal activity of 4-hydroxyacetophenone isonicotinoyl hydrazone nickel(II) and manganese(II) metal complexes.

2. Materials and Method

All the reagents and chemicals used in this work were of analytical grade and used without further purification. Perkin-Elmer spectrum 100-FT-IR spectrometer was used for functional group identification. 1H-NMR spectra were obtained on a variant unity plus 400 MHz instrument. PXRD analysis was conducted using the Brucker D8 Advance for crystal structure determination and 6545 QT used for mass spectroscopy. Thermogravimetric analysis experiments were performed on a Shimadzu simultaneous TGA/DTG-60A compositional analysis instrument and the GallenKampe melting point apparatus fitted with a mercury-in-glass thermometer having a temperature range of 10˚C to 360˚C was used for melting point determination.

2.1. Synthesis of 4-Hydroxyacetophenone Isonicotinoyl Hydrazone

A solution of 4-hydroxyacetophenone (1.36 g, 0.01 mol) in 15 mL of methanol as solvent was added to a solution of isoniazid (1.37 g, 0.01 mol) in 15 mL methanol. Three drops of glacial acetic acid were added to the resulting mixture and refluxed for 6 hours at a temperature of 70˚C. On cooling, the precipitate was filtered and washed several times with methanol and dried over CaCl2 in a desiccator. Percentage yield was 84.2% (Scheme 1).

2.2. Synthesis of Manganese(II) Complex

The ligand (0.286 g, 1.12 mmol) dissolved in 10 mL of methanol was added to

Scheme 1. Synthesis of ligand 4-hydroxyacetophenone isonicotinoyl hydrazone.

Mn(Cl)2·4H2O (0.197.6 g, 0.559 mmol) dissolved in 10 mL of methanol. Three drops of glacial acetic acid were added to the mixture and refluxed at a temperature of 70˚C for 5 hours. On cooling, a yellow precipitate was filtered and washed several times with methanol and dried over CaCl2 in a desiccator. Percentage yield 86.7%.

2.3. Synthesis of Nickel(II) Complex

The ligand (0.286 g, 1.12 mmol) dissolved in 10 mL of methanol was added to NiCl2 (0.0724 g, 0.559 mmol) dissolved in 10 mL of methanol followed by the addition of three drops of glacial acetic acid. The resulting mixture was refluxed at a temperature of 70˚C for 5 hours. On cooling, a greenish-white precipitate was filtered and washed several times with methanol and dried over CaCl2 in a desiccator. Percentage yield 74.8%.

2.4. Solubility Test

About 0.1 g of the ligand and complexes were added separately to 1mL portion of the following solvents; ethanol, methylene chloride, distilled water, DMSO, and hexane, then shaken vigorously upon each addition. When all solute particles dissolved to form a homogeneous mixture, the compound was said to be very soluble in the solvent. If only part of the solute dissolved, the compound was said to be sparingly soluble in the solvent. If the solute remained unaffected after agitation in the solvent, then the compound was said to be insoluble in the solvent.

2.5. Antifungal Test for the Ligand and Its Metal(II) Complexes

The antifungal activities of the compounds were evaluated in vitro against the fungal strains: Aspergillus fumigatus, Aspergillus niger,Candida albicans and Rhizopus stolonifera cultured on Sabouraud dextrose agar seeded with 105 mL−1 fungal spore suspension and transferred to petri plates. Discs soaked in 20 mL (10 µg/mL in DMSO) of all compounds were placed at different positions on the agar surface. The plates were incubated at 32˚C for 7 days. The results were recorded as zones of inhibition in m and compared with the standard drug Nystatine. In order to clarify any participating role of DMSO in the biological screening, separate studies were carried out with the solutions of DMSO alone and they showed no activity against any fungal strains [21].

3. Results and Discussion

3.1. Physical Properties of Ligand and Its Metal(II) Complexes

Table 1 shows the physical properties of the ligand and its metal complexes. The colours were all intense and different from those of the metal salts used. The high melting points (265˚C to 290˚C) suggest the compounds exist in some polymeric forms and all melt with decomposition by apparent colour changes. All the prepared compounds were insoluble in methylene chloride, hexane and distilled water, sparingly soluble in ethanol and very soluble in DMSO.

3.2. Spectral Analysis of Ligand and Its Metal(II) Complexes

3.2.1. Mass Spectra

The ESI-Mass spectrum of the ligand (Figure 1) showed the molecular ion peak [M+H]+ at m/z 256 confirming the exact molecular weight of the ligand at m/z 255. The ESI mass spectrum for the manganese(II) complex showed a peak at m/z 311 due to [M+H]+1 which confirmed its exact molecular weight at m/z 310. With the nickel(II) complex, the spectrum exhibited a peak at m/z 314 due to [M+H]+1 confirming the molecular weight at m/z 313.

3.2.2. Infrared Spectra

In the IR spectrum of the ligand (Figure 2), the formation of the Schiff base is confirmed due to the presence of a broad signal of a secondary amide (NH) at 3300 cm−1 [22]. A strong band at 1665 cm−1 indicates the presence of an amide I carbonyl band in the ligand [23]. The band at 1545 cm−1 is assigned to N-H moiety [24] [25]. The band at 1020 cm−1 is identified the presence of N-N group.

The Infrared spectra of the manganese(II) and nickel(II) complexes (Figure 3 & Figure 4) show abroad band signal of a secondary amide (NH) in the 3275 - 3300 cm−1 as observed in the ligand spectrum precluding the possibility of complexation through the imine-nitrogen atom [25] [26]. A relatively strong band at 1653 cm−1 and 1665 cm−1 in the Ni(II) and Mn(II) complexes respectively indicates coordination through the carbonyl oxygen atom of the free base [23] [25]. The absorption band at 1545 cm−1 in both complexes was assigned to NH moiety as in the ligand confirming that the NH group does not take part in coordination [24] [25]. The band at 1020 cm−1 and 1040 cm−1 for the Mn(II) and Ni(II) complexes respectively was assigned to the N-N group. The shift to higher wave number in the nickel complex is very characteristic for many hydrazine ligands coordinating through the azomethine nitrogen atom which is as a result of the repulsion between the lone pairs of electrons on the adjacent nitrogen atoms, reduced after complexation [27] [28].

Table 1. Physical Properties of the Schiff Base and its Metal(II) Complexes.

Figure 1. Mass spectrum of the ligand.

Figure 2. IR spectrum of the ligand.

Figure 3. IR spectrum of the Mn(II) complex.

Figure 4. IR spectrum of the Ni(II) complex.

3.2.3. Proton-NMR

The H1 NMR analysis of the ligand in DMSO solution had seven intense peaks as shown in Figure 5. The peak at 2.31 ppm is assigned to the methyl protons. The multiplets at 6.83 and 7.78 ppm, and 7.80 and 8.76 ppm are assigned to methine protons (Aryl-C-H) on the phenyl ring and the pyridyl (Py-C-H) protons respectively [24]. The peak at 10.91 ppm is due to the highly deshielded hydroxyl proton (Aryl-OH) on the benzene ring while the peak at 9.84 ppm is assigned to the highly deshielded proton of the imino group (CON-H) involved in hydrogen bond formation since in solution the ligand exist in the keto-enol form with the enolic form being dominant and highly deshielded [29].

3.3. TG/DTG Analysis of Ligand and Its Metal(II) Complexes

Thermogravimetric (TG) and differential thermogravimetric analyses (DTG) were carried out for the ligand in N2 atmosphere at atemperature range 40 to 800˚C at the heating rate of 10˚C·min−1. The data from TG and DTG clearly indicated that the decomposition of the ligand proceeds in one step. The weight losses for each complex were calculated within the corresponding temperature ranges [30]. The TG curve of the ligand as shown in Figure 6 indicated a 81.31% weight loss in a single step that starts around 285˚C to 450˚C. The DTG showed an inflation point of 311˚C representing the exact decomposition temperature.

The data from the TG and DTG curves for Mn(II) and Ni(II) complexes (Figure 7 & Figure 8) clearly indicate that the decomposition proceeds in one and three steps respectively. The weight losses for each complex were calculated within the corresponding temperature ranges [30] [31]. The manganese complex was stable up to 250˚C but started decomposing around 260˚C up to 450˚C in a single step with the percentage weight loss of 78.97%. Its DTG curve showed an inflation point of 298˚C. The TG curve of the nickel complex exhibits a number of decomposition stages and this is confirmed by numerous inflation points on its DTG as shown in Figure 8. The first stage with estimated mass loss of 3.17% within the temperature range 75˚C to 160˚C corresponding to the loss of hydrochloric acid molecules. It DTG showed an inflation of 98˚C. While the second step goes from 245˚C to 380˚C with a mass loss of 53.46% corresponding to the loss of parts of the ligand with an inflation point of 275˚C, the third step goes from 380˚C to 560˚C with a mass loss of 42.18% with an inflation point of 465˚C. The DTG curve showed another inflation point at 500˚C marking the last decomposition step [30] [31].

Figure 5. Proton NMR spectrum of the ligand.

Figure 6. TG/DTG curve of ligand.

Figure 7. TG/DTG curve of Mn(II) complex.

Figure 8. TG/DTG curve of Ni(II) complex.

3.4. Powder X-Ray Diffraction of Ligand and Its Metal(II) Complexes

Inorder to test the degree of crystallinity of the metal complexes, powder X-ray diffraction pattern were recorded using CuKα (wave length of 1.5406), as source in the range 4˚ - 60˚ (2θ). In both ligand and the metal complexes, the trend of the curves (Figures 9-11) decreases from maximum to minimum intensity indicating the amorphous nature of the complexes in the metal-ligand formation [32]. The X-ray diffraction pattern of Ni(II) complex recorded numerous reflections between the range 4˚ - 60˚ (2θ), which arouse from diffraction of X-ray by the plane of the complex from which 10 were chosen. The inter-planar spacing

Figure 9. Powder X-ray spectrum of the ligand.

Figure 10. Powder X-ray of manganese(II) complex.

Figure 11. Powder X-ray of nickel(II) complex.

was calculated by using Bragg’s equation: = 2d sinθ. The unit cell calculations were done for cubic symmetry from all-important peaks and the method yielded hkl (Miller indices) unit cell parameter values. The h2 + k2 + l2 values for the Ni(II) complex are 1, 4, 8, and 10, 15, 18, 32, 46, 56, 74. The presence of forbidden number 15 was observed in the Ni(II) complex indicating that the complex may belong to the hexagonal or tetragonal systems. The h2 + k2 + l2 values for Mn(II) complex are 1, 2, 4, 5, 6, 8, 10, 17, 26, 41 and no forbidden numbers were found for the chosen reflections.

On the basis of the infrared, proton NMR, mass spectroscopic, TG/DTG and powder X-ray diffraction analysis, the proposed structures of the ligand and its metal complexes were modeled as depicted below in Figures 12-14.

3.5. Molecular Modelling Studies of Ligand and Its Metal(II) Complexes

Since the single crystals structures of the ligand and its metal(II) complexes were not available, an attempt to gain more insight on the molecular structure of the complexes, geometrical optimization and conformational analysis, 3D molecular modelling of the proposed structures of the complexes was performed using MM2CS Chem3D Ultra 11.0 version software and using pm3 programme. The correct stereochemistry was assured through the exploitation and modification of the molecular coordinates to attain reasonable low energy molecular geometries. The potential energies of the complexes were considered as the sum of the following equation:

Figure 12. Optimized geometry of ligand. Hydrogen atoms are omitted for clarity.

Figure 13. Optimized geometry of manganese(II) complex.

Figure 14. Optimized geometry of nickel(II) complex.

E = Estr + Eang + Etor + Evdw + Eoop + Eelec

where E represents, the energy value corresponding to the given interactions (kcal/mol). The subscripts str, ang, vdw, oop, and elec represent bond stretching, angle boding, torsion deformation, van der Waals interaction, out of plane bending and electronic interaction respectively. The analytical and spectral studies revealed hexa-coordinated manganese and nickel complexes which were further confirm by molecular modelling studies. The 3D optimized geometrical structures of the ligand and its metal(II) complexes are presented in Figures 12-14. The minimum steric energy were repeated severally to obtain the global minimum energies of 147.314 kcal/mol for ligand and 375.801 and 1890.106 kcal/mol for manganese(II) and nickel(II) complexes respectively.

In the optimized structure of the manganese(II) complex, the Mn(39) – O(19), Mn(39) – Cl(40), Mn(39) – N(29) bond lengths are 3.8048, 1.5268, and 4.5215 Ǻ respectively. The O(38) – Mn(39) – O(19), O(38) – Mn – N(29), O(38) – Mn(39)– Cl(40), Cl(41) – Mn(39) – N(29), Cl(41) – Mn(39) – Cl(40) bond angles are 167.9463˚, 29.1981˚, 96.8685˚, 118.1159˚ and 171.9214˚ respectively. For the optimized structure of nickel(II) complex, the Ni(39) – O(19), Ni(39) –Cl(41), Ni(39) – N(10) bond lengths are 1.8156, 2.1574 and 1.8491 Ǻ respectively. The O(38) – Ni(39) – O(19), O(38) – Ni(39) – N(29), O(38) – Ni(39) – Cl(40), Cl(41) – Ni(39) – N(29), Cl(41) – Ni(39) – Cl(40) bond angles 175.9353˚, 89.4096˚, 87.7844˚, 83.8496˚ and 178.5292˚ respectively.

3.6. Antifungal Activity

The antifungal screening of the ligand and its metal(II) complexes was carried out against Aspergillus fumigatus, Aspergillus niger, Candida albicans and Rhizopus stolonifera according to the literature protocol. The results were compared with the standard drug Nystatine. The diameter of inhibition zones of the ligand ranged from 16 to 23 mm against the tested organisms, that of nickel

Table 2. Antifungal activity of ligand and its metal complexes.

complex from 17.5 to 25.5 mm and manganese complex from 19.5 to 24.5 mm. All these values compared to that of Nystatine (reference drug) which ranged from 25 to 30 mm as in Table 2. This result reveals that the complexes are more reactive than their parent ligand. The order of activity of metal complexes is Ni > Mn. The nickel complex had the higher activity against Candida albicans (25.5 mm) than manganese (24.5 mm) complex as compared to the ligand (23 mm). A similar trend was observed in the activity of metal complexes against the other fungal strands. When we compared the inhibition diameter of the ligand and the metal complexes, it was revealed that the metal complexes exhibit higher antifungal activity against the fungal strains used than the free ligand. An acceptable reason for this may be considered in the light of overtones and coordination theory proposed by [33]. According to overtone’s concept of cell permeability, the lipid membrane that surrounds the cell favours the passage of only lipid soluble materials. So, liposolubility is an important factor which controls antifungal activity. On chelation, the polarity of metal ions will be reduced to a greater extend due to the overlap of the ligand and partial sharing of the positive charge of the metal ion with the donor groups.

4. Conclusion

The ligand, N-(4-hydroxylacetophenone) isonicotinoylhydrazone and its Mn(II) and Ni(II) complexes have been prepared and characterized. The melting points of the synthesized compounds were generally high and range from 260˚C to >300˚C and decomposition temperatures of the metal complexes range from 250˚C to 600˚C revealing the stability of the metal complexes which are common to such hydrazones complexes due to coordination of ligand in different tautomeric forms. On the basis of the infrared, proton NMR, mass spectroscopic, TG/DTG and powder X-ray diffraction analysis, the ligand was found to be bidentate in nature, coordinating to the metal ions through the azomethine nitrogen and the carbonyl oxygen in a hexa-coordination mode. Antifungal screening revealed that the synthesized complexes were more active than the parent ligand.


The authors are grateful to Professor Andrew D. Burrows of the Department of Chemistry, University of Bath, Bath Spa, United Kingdom, for the assistance with spectroscopic measurements.

Conflicts of Interest

The authors declare no conflicts of interest regarding the publication of this paper.


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