Introduction

Schiff base reaction was investigated by Hugo Schiff 155 years ago, and these compounds are still of high significance for both scientists and researchers due to their applications in different fields. Schiff base compounds are prepared from the reaction of a primary amine with the carbonyl group of aldehyde (RHC=O) or ketone (R₂C=O). Schiff bases have a functional group carbonnitrogen double bond (-C=N-) called azomethine or imine, this imine group is very important for complex reaction and gives an important application in biological activity [1-4]. The Schiff base mechanism is nucleophilic addition reaction throw the carbonyl group (C=O). The nucleophile is the primary amine which is reacts with the aliphatic or aromatic aldehyde or ketone to give an intermediate compound called carbinolamine. This intermediate compound was loses water molecule by hydrolyses process with acidic or basic media as a catalyst [5]. Schiff bases metal complex are widely used in medicine for treating multiple viral diseases due to their transition metal complexes, which is play a key role in several areas, including antibacterial, antifungal, anticancer, and anti-inflammatory [6-8]. Schiff base ligands are an important class of ligands because of their several effective features, such as modifying by adding different donor groups and good flexibility [9, 10]. These readily available ligands, determined by their intrinsic chemical structures and the starting materials used for their synthesis, give functional diversity and different coordination numbers. The various advantages of imines have prompted scientists in the fields of magnetochemistry, bioinorganic chemistry, analytical chemistry, encapsulation, catalysis, separation and transport science to synthesize metal complexes [11-19]. They have good biological features and thus have been used in various catalytic, anti-cancer, and anti-microbial studies [20]. Pyrimidine derivatives of metal ion complexes with biological activity, such as antimalarial, antibacterial, antitumor, and antiviral properties have inspired researchers’ attention recently [21]. The real need in the drug sector is to find new pharmacological agents with different mechanisms and low side effects. In this manuscript, we aimed to prepare a series of metal complexes for the next metal ions Mn(II), Co(II), Ni(II), Cu(II), and Zn(II) with Schiff base derived from 2-hydroxy benzaldehyde making use of Schiff base derivatives as antibiotics.

Materials and Method

Methodology

All reagents and chemicals used in this study were in the analytical grade and purchased from (Sigma-Aldrich). Isatin (1H-indole-2,3-dione) 97%, Hydrazine monohydrate 99%, 2-hydroxybenzaldehyde, MnCl₂.2H₂O 99%, NiCl₂.6H₂O 99%, CuCl₂.2H₂O 99%, CoCl₂.6H₂O 99%, and ZnCl₂ 98% were provided from BDH and used once received. The employed FTIR apparatus operates in the range (200-4000) cm^-1 Shimadzu-3800 model. Electronic spectral inform were accomplished depending on Shimadzu160-meter. LC/MSS incomes are also established by Mass100P_Shimadzu contribution. Proton-NMR was published using Bruker 400-MHz-meter and elemental micro analysis was done on a perkin_Elmer_automatical instruments model_240B. Minerals were determined obeying a Shimadzu_(A-A)_680G AA_spectrometer. Magnetic features were measured using balance magnetic susceptibility model MSR-MK.

Ligand

A: Preparation of 3-hydrazone-1,3-dihydro-indole-2-one (L)

Compound (L) was prepared by putting (2 g, 0.0134 mol) of isatin in 20 mL ethanol and added dropwise with continuous stirring to (0.68 g, 0.0067 mol) of hydrazine monohydrate in 20 mL ethanol a100 mL round bottom flask. The mixture of the reaction was refluxed under stirring for 5 hours and monitored by TLC. Upon cooling at room temperature, the precipitate formed was filtered, washed with ethanol and ethyl ether, recrystallized, and then dried at 60 °C. The yield of the prepared compound was 80%, as provided in Scheme 1. 

B: Preparation of Schiff base (HL)

This ligand has synthesis using the general strategy that used in Schiff base synthesis and carried out in round bottomed flask of a100 mL in volume. At which (1 g, 1 mol) of main substance (L) is dissolved in 10 mL of MeOH and a drop of DMF with continuous stirring and heating to perform the dissolution of the main substance. Then, (0.757 g, 1 mol) of 2-hydroxy benzaldehyde is added onto the main substance solution with reflux and continuous stirring about 4 hours. Finally, adding two drops of glacial acetic acid to obtain Schiff base ligand, as depicted in Scheme 1.

Metal complexes synthesis

Copper complex of the obtained Schiff base was prepared using the following approach: dissolving (0.1 g, 0.01 mol) of ligand (HL) in 10 mL of MeOH and a drop of DMF. The dissolution process occurred immediately gaining transparent solution. Then, (0.064 g, 0.01 mol) of copper salt (Cu(II) Cl₂.2H₂O) and a drop of tri ethyl amine were added onto ligand’s solution in round flask of 100 mL volume. Thereafter, the mixture was refluxed, heated, and continuously stirred for 6 hours. After completely reflux, mixture was left to perform cooling at room temperature for one hour. After solvent evaporation, the resultant was kept in ice bath to accumulate the precipitate. Then, the precipitation was filtered. The other complexes of the following metal salts: NiCl_2.6H₂O (0.089 g, 1 mol), CoCl_2.6H₂O (0.089 g, 1 mol), MnCl₂.4H₂O (0.074 g, 1 mol), and ZnCl₂ (0.051g, 1 mol) were prepared, as depicted in Scheme 1 using the same approach that used in copper complex synthesis. With exception of their corresponded salts usage instead of copper salt, center fugue usage to separate the precipitate of Zn complex from its solution and desiccator to perform the dryness of zinc complex was done. Ni(II), Mn(II) and Co(II) complex were dried using ether during filtration and left for 4-5 hours.

Scheme 1: Ligand and metal complexes synthesis

Metal complexes synthesis

Copper complex of the obtained Schiff base was prepared using the following approach: dissolving (0.1 g, 0.01 mol) of ligand (HL) in 10 ml of MeOH and a drop of DMF. The dissolution process occurred immediately gaining transparent solution. Then, (0.064 g, 0.01 mol) of copper salt (Cu(II)Cl₂.2H₂O) and a drop of tri ethyl amine were added onto ligand’s solution in round flask of 100 mL volume. Thereafter, the mixture was refluxed, heated, and continuously stirred for 6 hours. After completely reflux, mixture was left to perform cooling at room temperature for one hour. After solvent evaporation, the resultant was kept in ice bath to accumulate the precipitate. Then, the precipitation was filtered. Other complexes of the following metal salts: NiCl_2.6H₂O (0.089 g, 1 mol), CoCl_2.6H₂O (0.089 g, 1 mol), MnCl₂.4H₂O (0.074 g, 1 mol), and ZnCl₂ (0.051g, 1 mol) were prepared, as indicated in Scheme 1 using the same approach applied in copper complex synthesis. With exception of their corresponded salts usage instead of copper salt, center fugue usage to separate the precipitate of Zn complex from its solution and desiccator to perform the dryness of zinc complex. Ni(II), Mn(II) and Co(II) complex were dried using ether during filtration and left for 4-5 hours.  

Results and Discussion

Physical and chemical properties

The reaction between Schiff base and metal salts gave the structural complexes in Scheme 1. The results of element-analysis and physical properties of Schiff base and complexes are provided in Table 1.

FT-IR studies

The FT-R spectrum of newly obtained ligand HL depicted in Figure 1 displays a distinguishable absorption band at 1622 cm^-1 contributes to azo-methine formation, which can be strong evidence about ligand (HL) synthesis. In addition to the absence of asymmetrical absorption band of NH₂-amino group. This can be strong indication that proves the formation of ligand through the interaction between carbonyl group of salysaldehyde and amino group of isaten.

It is important to note that the absence of C=O absorption band of 2-hydroxy benzaldehyde which can also supports the formation of ligand through this group. Other absorption bands were detected at 3155, 2891, 3248, 1739, and 1496 cm^-1 that belonging to the stretching vibrational mode of the following functional groups: C-H aromatic, C-H aldehydic, N-H amine, C=O of amide, and C=C of alkene, respectively [22]. As demonstrated in Table 2.

Copper complex [Cu(L)(Cl)(H₂O)] in Figure 2 demonstrates many changes including shifting in stretching vibrational mode of  C=N and disappearing of stretching vibrational mode of penolic group because of the occurrence of coordination through N of C=N and O of O-H groups, to be detected at 1612 cm^-1.

In addition, appearing new absorption bands at 592, 464 and 314 cm^-1 attributed to the vibration of M-N, M-O and M-Cl, respectively. Besides the bands of coordinated water molecule that observed at 3444-3447, 1533, and 756. Those new bands can strongly prove the formation of complex and the presence of H₂O aqua inside coordination sphere [23, 24]. The other complexes in Figures 3, 4, 5, and 6 also display individually such modifications happened in copper complex, as listed in Table 2.

UV-Vis studies

Figure 7 demonstrates UV-Vis spectrum of ligand (HL), at which π→ π* transition occurred at 269 nm, 30959.752 cm^-1. This transition may attribute to the presence of unsaturated bonds and aromatic rings in ligand’s structure. The other electronic transition occurred in ultraviolet region is n→ π* electronic transition at 323 nm, 30959.752 cm^-1. This transition may causes by the presence of hetero atoms in ligand’s structure such as (-N-) containing nonbonding electrons [25]. Figure 8 illustrates UV-Vis spectrum of [Ni(L)(Cl)(H₂O)] complex at which ultraviolet transitions that referred to as π→ π* and n→ π* were shifted compared with the same transitions that observed in ligand’s spectrum to be observed at 265 nm, 37735 cm^-1 and 306 nm, 32679 cm^-1 for both transitions, respectively. This modification causes by the occurrence of coordination with metal ion through Schiff base group and O atom of phenol. Another electronic transition which observed at 354 nm, 28248.587 cm^-1 is n→ π*+ (C.T). Moreover, single transition observed at visible region 423 nm, 23640.661 cm^-1 denoted as ³T_1F→³T_2F the transition that found in metal itself. This transition and the magnetic moment [3.81B.M] can support (td) geometry of the complex [26]. By the same approach, we can apparently discuss the electronic transitions for the rest complexes that displayed in Figures 9, 10, and 11 as well as Table 3.

Figure 12 illustrates the UV-Vis spectrum of [Mn(L)(Cl)(H₂O)] in diluted form complex at which ultraviolet transitions that referred to as π→ π* and n→ π* were shifted compared with the same transitions that found in ligand’s spectrum to be observed at 265 nm, 37735.849 cm^-1 and 326 nm, 30674.846 cm^-1 for both transitions, respectively. This modification causes by the occurrence of coordination with metal ion through Schiff base group and O atom of phenol. Moreover, in concentrated form of the complex in Figure 13, the transitions that observed at visible region are as follows: ⁶A₁→⁴T_1G at 437 nm, 22883.295 cm^-1 and ⁶A₁→⁴A₁+⁴E_G at (520 nm, 19230.769 cm^-1 those transitions are found in metal itself. Those transitions and the magnetic moment [2.79 B.M] can support (td) geometry of the complex [27].

Nuclear magnetic resonance spectrum of ligand ¹³C-NMR and ¹H-NMR

¹H-NMR spectrum is indicated in Figure 14 and Table 4 and demonstrates the next signals: singlet signal at δ 11.93 ppm belongs to (1H) Ar-OH, doublet signal at δ 9.03-8.01 ppm belongs to (1H) N-H group, triplet signal at δ 11.01-10.70 ppm belongs to azomethene proton (1H) N=C-H, and multiplet signal at δ 8.01-6.89 ppm belongs to (8H) Ar- H. This measurement was carried out using DMSO as solvent which in turn gave a signal δ at 2.31-2.64. TMS is used as reference [28, 29]. ¹³C-NMR spectrum in Figure 15 demonstrates the next signals: (100.622 MHz, DMSO-d₆) that gave a signal at δ 40 ppm. δ 110-140 ppm belong to (C₁-C₁₀) of aromatic ring, δ 140-150 ppm belong to (C₁₁ and C₁₂), δ 150 belongs to C₁₃, δ 160 attributed to C₁₄, and δ 165 attributed to C₁₅ [30].

Mass spectrum of ligand

In organic chemistry, mass spectroscopy is widely used as a potent structural characterization tool. Mass spectra fragmentation analogues for free Schiff base ligand [C₁₅H₁₁N₃O₂] were in good agreement with the structure in Scheme 1 characterized the mass spectrum an intense peak at 266.200 m/z that matches to its calculated molecular weight 265.27 m/z (Figure 15) [31].

Bioactivity evaluation of the ligand (HL) and its complexes

Two types of bacteria were tested (-Bacteria (Escherichia_coli) and +Bacteria (Staphellococcus_aureus)). The effect of the synthesized Schiff base and its complexes on the mentioned bacteria were tested and compared in 0.001M (DMSO-solvent) as control and the results are recorded in Table 5. These results indicate that the Schiff bases (ligand HL) has a negative inhibitory action toward both types of bacteria besides, [Mn(L)(Cl)(H₂O)] complex is also ineffective toward gram positive bacteria (Staphellococcus aureus). In addition, Cu-complex has the highest inhibition activity among all prepared complexes toward both types of bacteria, as illustrated in the table. The other complexes have variable positive effect toward both types of bacteria [32]. All the details are demonstrated in Figure 17.

Conclusion

This study involved the synthesis and characterization of Schiff's bases and complexes metal ions such as Mn(II), Co(II), Ni(II), Cu(II), and Zn(II) that were successfully gained using common condensation reaction between 2-hydroxybenzaldehyde and (Z)-3-hydrazineylideneindolin-2-one. The synthesis of Schiff bases ligand and metal ions complexes was done using various analytical and spectroscopic techniques like elemental microanalysis CHN, ¹³C, ¹H-nuclear magnetic resonance, infrared spectra FT-IR, electronic spectra, and mass spectrum. The molar conductance value of metal complexes shows their non-electrolytic nature. The complexes were found to be stable at room temperature. Based on the spectroscopic data, it was concluded that M⁺² coordinates to the oxygen atoms, nitrogen azomethine (C=N), and bidentate ligand. Likewise, the biological activity of the free ligand and its complexes were studied and showed that the prepared compounds have good ability to be used as antibacterial and antifungal.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Authors' contributions

All authors contributed to data analysis, drafting, and revising of the paper and agreed to be responsible for all the aspects of this work.

Conflict of Interest

The author declared that they have no conflict of interest.

ORCID

Nuha Ayad Abd AL_Qadir

https://www.orcid.org/0000-0002-0830-6608

Naser Dheyaa Shaalan

https://orcid.org/0000-0002-2875-5056

HOW TO CITE THIS ARTICLE

Nuha Ayad Abd AL-Qadir, Naser Dheyaa  Shaalan. Synthesis, characterization, and Biological Activity of New Metal Ion Complexes with Schiff Base (Z)-3((E)-2-hydroxybenzylidene) hydrazineylidene)indolin-2-one. J. Med. Chem. Sci., 2023, 6(7) 1660-1674

https://dx.doi.org/10.26655/JMCHEMSCI.2023.7.16

URL: http://www.jmchemsci.com/article_162542.html