**2. Synthetic approach for Schiff base**

Any primary amine can react with an aldehyde or a ketone under appropriate circumstances to produce Schiff bases. Hugo Schiff (1834–1915), a great chemist who was honored by having Schiff base named in his honor, was born in Frankfurt/Main, Germany's thriving Jewish community. The Schiff base generally has the following common structure (**Figure 1**). A Schiff base is a nitrogen analog of an aldehyde or ketone in which the carbonyl group (CO) has been replaced by an imine or azomethine group. It is also known as an imine or an azomethine [42].

The library of organic chemistry has a number of amines and carbonyl compounds that make it possible to create Schiff bases with a variety of structural characteristics.

**Figure 1.**

*General structure of Schiff Base (R1 and R<sup>2</sup> both would be hydrogens. Alkyl or aryl members made up R<sup>3</sup> .) [https://en.wikipedia.org/wiki/Schiff\_base].*

**Figure 2.** *Schiff base formation reaction scheme [45].*

The basic carbonyl group for the production of Schiff bases can be an aldehyde (aromatic or aliphatic) or a ketone [43, 44]. The presence of substituent groups connected to the (>C=N) linkage regulates the stability of the imine group. The general reaction for the synthesis of the Schiff base is shown in (**Figure 2**) where R denotes an alkyl, aryl, cycloalkyl, or heterocyclic group, which might be variably substituted, and R1 may be an alkyl, aryl group, or H atom [46]. Refluxing the mixture under neutral conditions or with acid or basic catalysts usually causes the Schiff base to develop, which is a reversible process. Usually, the product separation or water removal is what brings the formation to completion [47].

Schiff bases are still synthesized by chemists, and today, active and well-designed Schiff base ligands are referred to as "privileged ligands." The bridging Schiff's bases have the following structure, which has a variety of functional groups that can be altered to suit different needs. R" is phenyl or a substituted phenyl, H is an alkyl or aryl group, and X is a phenyl or substituted phenyl group. In fact, Schiff bases have the ability to stable a wide range of metals in a variety of oxidation states, regulating the performance of metals in a wide range of advantageous catalytic transformations. The oxygen atoms in Schiff bases can be changed to sulfur, nitrogen, or selenium atoms; however, NO or N2O2-donor groups are the most frequent donor groups [48].

The mechanism of forming a Schiff base (**Figure 3**) is an additional application of the nucleophilic addition to the carbonyl group. The amine is the nucleophile in this situation. The amine interacts with the aldehyde or ketone in the first step of the process to produce carbinolamine, an unstable addition product. By bases or acids catalyzing the process, the carbinolamine loses water. The dehydration of the carbinolamine is acid-catalyzed because it is an alcohol. The reaction is typically catalyzed by acids because the dehydration of the carbinolamine is the ratedetermining step in the production of the Schiff base. However, because amines are basic molecules, the acid concentration cannot be too high. The equilibrium is pulled to the left, and carbinolamine production is prevented if the amine is protonated and turns non-nucleophilic. As a result, low acidity is preferred for many Schiff base

synthess. Base can also catalyze the dehydration of carbinolamines. Despite not being a concerted reaction, this reaction is somewhat comparable to the E2 elimination of alkyl halides. Through an anionic intermediate, it moves forward in two steps. The process of creating a Schiff base actually involves two different types of reactions, addition and elimination [48, 49].

In the meantime, a number of methods and systems for the synthesis of Schiff base have been described, including NaHCO3 [44], CuSO4 [46], P2O5/Al2O3 [47], MgClO4 [45], ZnCl2 [50], and MgSO4-PPTS [51]. In these systems, metal species act as Lewis acids to activate the carbonyl group and facilitate the removal of water. A few developments have been reported in recent years due to the advancement of experimental procedures, such as solid-state synthesis [52], solvent-free/clay/microwave irradiation [53], water suspension medium [54], reflux/solvent [55], infrared irradiation/no solvent [56], and K-10/microwave. The mentioned methods/systems revealed some drawbacks, including the need for high reaction temperatures, prolonged reaction times, and moisture-sensitive catalysts, huge amounts of aromatic solvents, expensive dehydrating reagents/catalysts, and specialized equipment [57]. NaHSO4.SiO2/ microwave/solvent-free [58], dirhodium caprolactamate [59], [bmim] BF4/molecular sieves [60], silica/ultrasound irradiation [61], silica/microwave [19], and silica/solvent-free [62].

**Conventional Method for synthesis of Schiff Base:** In order to make Schiff bases, aldehyde (0.004 mol) and different aromatic amines (2a–e) (0.004 mol) were condensed in water (10 ml) and agitated at room temperature. TLC has taken note of the reaction's progression. After the reaction was complete, a yellow-color, amorphous product was left behind. This product was filtered, dried, and then recrystallized from methanol [48].

**Microwave synthesis for Schiff Base**: A mixture of aldehyde (0.004 mol) and substituted aromatic amines (0.004 mol) in water (1 ml) was added and microwaved at 200 W for 30–60 seconds. TLC made note of how the reaction was progressing. Following the completion of the reaction, the reaction mixture contained a solid product, which was filtered and recondensed with methanol [48].

### **3. Spectroscopic analysis of Schiff base**

A Schiff base is a compound with the general structure R1R2C=NR'. They can be considered a subclass of imines, which is also synonymous with azomethine [63]. In order to investigate hybrid composites, spectroscopic analysis is used. The analysis reveals useful details such as elemental type, chemical composition, optical and electronic properties, and crystallinity. Ultraviolet and visible light (UV-vis) spectroscopy, elemental analysis, differential scanning calorimetric (DSC), hydrogen nuclear magnetic resonance (1H NMR), and Fourier transform infrared (FTIR) studies are used to evaluate these Schiff bases [64].

In the IR spectra, C=N is most commonly reported in the 1690–1640 cm<sup>1</sup> region as a strong and a sharp band at somewhat lower frequencies than the bands of C=O groups and close to C=C stretching frequencies. With angle strain, steric repulsion, other complicated local factors, solution concentration and nature of solvent, the stretching frequency of C=N is found to be at 1670 cm<sup>1</sup> . The frequency is usually lowered in the absence of one or more groups in conjugation with the C=N [65]. The multinuclear (<sup>1</sup> H and 13C) NMR spectral analyses are helpful to characterize and confirm the structure of Schiff bases. The upfield and downfield shifting of the signal is dependent upon the substituents present over the Schiff bases. In the CHN analysis of the Schiff bases, the elemental and sometimes isotopic compositions were found out for the confirmation of the structure of the synthesized derivatives.

It is important to note that the nitrogen atom in the Schiff base has a lone pair, which gives it the characteristics of a Lewis base and allows it to participate in the creation of hydrogen bonds, either intramolecularly or with polar molecules. This characteristic encourages the development of intramolecular hydrogen bonding, particularly when suitable non-polar solvents are present [66].

### **4. Schiff-base metal complexes**

Schiff-base metal complexes have been considered the active topic of research in coordination chemistry during a few decades of extensive research on metal-based pharmaceuticals, owing to their useful applications in numerous disciplines of science. They have potential therapeutic applications as antibiotics, antimicrobials, antitumors, antivirals, anti-inflammatory medicines, analgesics, antifungals, and many others [47]. Schiff bases are versatile pharmacophores that trap in metal ions within their structural units due to the presence of multiple donor atoms [67]. Schiff bases (azomethines) are formed by combining amino and carbonyl groups with multidentate ligands and forming highly significant complexes with metal ions. By using azomethine nitrogen, they can coordinate with metal ions. In organic synthesis, the Schiff base reaction is fundamental for the synthesis of C-N bonds. (**Figure 4**) They exhibit chelation property with O, N, and S donors, and metal complexes have a diverse biological action against many infections and cancers. Schiff base complexes with multidentate ligands are capable of chelating any metal ions. These ligands are effective in the exciting unique therapeutic approach to better understanding diseases and their therapy. The complexes of Schiff base of both transition metal ions (i.e., inner and outer) containing NO or NOS donor atoms were described as playing a significant role in biological activities. Because they are colorful and very stable for biological activities, certain of these metal complexes have attractive physical and chemical properties [69]. Some of the recently synthesized Schiff-base metal complexes are enlisted in **Table 1**.

**Figure 4.** *Formation of Schiff-base metal complexes [68, 69].*
