Exploring Recent Advancements in Schiff Base Chemistry

Abstract

Recent advancements in synthesizing Schiff bases, including sustainable and highly customizable approaches, are examined, offering insights into how their structures can be tailored for specific purposes. Schiff bases find applications in various fields, such as materials science, which contribute to developing polymers, metal-organic frameworks, nanocomposites, and medicinal chemistry, which serve as promising drug candidates. Additionally, they play crucial roles in coordination chemistry catalysis and have potential applications in emerging areas like nanotechnology and renewable energy, contributing to the development of nanomaterials and energy storage systems. This chapter provides a comprehensive overview of this synthesis and its applications, catering to researchers, students, and professionals looking to explore the multifaceted landscape of Schiff base compounds in contemporary organic chemistry.

1. Introduction

The scientific community recently became fascinated by an intriguing group of versatile organic compounds known as Schiff bases [1, 2, 3]. These compounds, which originate from the condensation of primary amines with carbonyl compounds, are distinguished by a dynamic interplay of chemical properties supporting their diverse applications. This chapter is an in-depth look at the complex area of Schiff Base Chemistry [4, 5, 6]. It attempts to give a thorough analysis of the synthesis techniques and a broad picture of the numerous applications that have sprung from the latest developments in this exciting field. It is essential to comprehend Schiff bases’ historical roots to appreciate their contemporary relevance [7, 8, 9, 10]. Schiff bases have evolved dramatically since Hugo Schiff’s groundbreaking research in the late 1800s when he first described the condensation reaction between amines and aldehydes or ketones. Since their original discovery as synthetic intermediates, these substances have become adaptable building blocks with various functions. Revolutionary advancements in synthesizing Schiff bases have been made, indicating how organic chemistry constantly changes [10, 11, 12]. Green chemistry techniques, sonochemistry, and microwave-assisted synthesis are novel approaches that have enhanced conventional condensation reactions. Improving synthesis efficiency, these methods also correspond with the increasing focus on ecologically friendly and sustainable practices. These compounds’ versatility is highlighted by the fact that Schiff base synthesis can now use a wide range of starting materials, including heterocyclic compounds and unconventional amines [13, 14, 15].

Schiff bases are distinguished by their structural diversity, evidence of the abundant possibilities inherent in their chemistry. Researchers have deciphered the complex architectures of Schiff base compounds using sophisticated spectroscopic techniques like mass spectrometry, X-ray crystallography, and NMR spectroscopy [16, 17, 18, 19]. This structural realization makes understanding the relationship between molecular arrangement and properties possible, laying the groundwork for customizing Schiff bases for various uses. The emergence of Schiff bases as important participants in catalysis has greatly aided the development of effective and selective methods for organic synthesis. Schiff commands facilitate a spectrum of reactions by serving as ligands for transition metal catalysts, including oxidation, reduction, and cross-coupling [10, 20, 21, 22]. Changing the structure of the ligand allows for the modification of catalytic activity, which opens up new possibilities for synthesizing complex molecules with specific features. Schiff bases have emerged as an area of interest in medicinal chemistry due to their promising biological properties. Interest in using these substances for therapeutic purposes has increased due to their antimicrobial, antiviral, and anticancer characteristics. Structure-activity relationships are important in drug design because they have created hybrid compounds with improved pharmacological potential by combining Schiff bases with biologically active moieties [23, 24, 25].

The rich history, varied synthesis techniques, and plethora of applications of Schiff base chemistry become apparent as we progress through this chapter. There are many exciting developments and applications for Schiff bases, whose versatility inspires researchers to continue pushing the boundaries of chemical innovation. Join us as we explore the complexities of Schiff base chemistry and its revolutionary influence on modern organic chemistry, as scientists and enthusiasts are invited to participate (Figure 1).

Figure 1.

Recently developed Schiff bases have found significant applications in therapeutics.

2. Synthesis of unique Schiff bases and their applications

Ashraf S. Hassan, in 2023, a novel scientific finding [26], has demonstrated the possibility of a successful “one drug—multiple targets” strategy for treating complex medical conditions. 3-hydrazino-isatin was reacted with different aldehydes to form novel derivatives of isatin-based Schiff bases (2–7). Extensive in vitro evaluations encompassing antioxidant, antidiabetic, anti-Alzheimer, and anti-arthritic properties resulted from meticulous analyses that validated their structures. Compound 5a showed strong antioxidant activity, notable inhibition of α-amylase and acetylcholinesterase, and similar anti-arthritic properties to diclofenac sodium. Compound 5a’s therapeutic potential was highlighted by in silico ADMET predictions and molecular docking simulations (Figure 2).

Figure 2.

Synthesis and production of Isatin-Centered azomethine and Isatin-Centered azomethine-arylazo compounds.

In 2022, Maryam Fawzi Habeeb created N-anthranilic acid [27] by starting the process with the Ullmann reaction, which involved combining derivatives of o-chlorobenzoic acid with o- and p-phenylenediamine. These compounds were cyclized using poly(phosphoric acid) (PPA) to produce products of amino acridone. The next step was to create terphthaldehyde mono Schiff bases by reacting terphthaldehyde with panisidine, o-, m-, or p-toluidine. These were then mixed with the derivatives of amino acridone to form additional Schiff bases. Different compounds were produced by the amino acridone derivatives reacting independently with terphthaldehyde, 4-(dimethyl amino) benzaldehyde, 2-formyl benzoic acid, and methyl-4-formyl benzoate. The structural characterization was done using FTIR spectroscopy, 13C NMR, and 1H NMR. The synthesized products demonstrated potential applications in medicinal chemistry and antibacterial research, as demonstrated by their antibacterial efficacy tests against Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus. This thorough synthetic method yields a variety of compounds with various functions and possible biological applications (Figure 3).

Figure 3.

Investigations into the creation, properties, and biological functions of new Schiff bases from amino acridone.

Marijana Hranjec’s study from 2023 explores [28, 29] the antiviral, antibacterial, and antiproliferative properties of novel Schiff bases made from benzimidazoles that have been N-substituted. The study examines the nature of substituents at the N atom of benzimidazole nuclei and their impact on the phenyl ring. The research uses in vitro testing to determine structure–activity relationships to assess the synthesized Schiff bases’ antiviral efficacy against various antibacterial potentials, viruses against a range of bacterial strains, and antiproliferative effects on several human cancer cell lines. Although certain Schiff bases showed slight antiviral effects, these were noted at concentrations greater than those of reference medications. Precursor 23 showed broad efficacy against tested bacterial strains, while a subset of derivatives showed moderate antibacterial activity. Schiff base 40 stands out because it has a phenyl ring at the N atom and a 4-N, N-diethylamino-2-hydroxy substitution on the benzimidazole nuclei. IC50 ranges from 1.1 to 4.4 μM, indicating its potent antiproliferative action against multiple cancer cell lines. It was noted that Schiff base 40 had the strongest antitumoral effect against acute myeloid leukemia (HL-60). These results highlight the potential of the synthesized compounds, particularly Schiff base 40, as interesting subjects for additional investigation in creating cancer cell-targeting medicines (Figure 4).

Figure 4.

Schiff bases derived from N-substituted benzimidazole: Design and synthesis: Exploring novel antimicrobial agents.

Nazish Shahab [29], successfully synthesized in three steps a series of novel Schiff’s base hydrazone derivatives (1–24) based on polyhydroquinoline (PHQ) with good yields. Refluxing ethyl-2-(2-formylphenoxy)acetate, dimedone, ammonium acetate, and ethyl acetoacetate in ethanol for 6-7 hours produced the first compound (1). This was carried out in an unsymmetrical multi-component one-pot Hantzsch reaction. Compound 2 refluxed the resultant PHQ for 4–5 hours in absolute ethanol with hydrazine hydrate. The hydrazide was treated with various substituted aromatic/aliphatic aldehydes for the production of Schiff bases (3–24). Structural analysis was performed on all synthesized analogs using 1H, 13C, and LC-HRESI-MS spectroscopy. With IC50 values ranging from 5.26 to 25.17 μM, 12 compounds (10, 14, 7, 9, 8, 17, 12, 19, 13, 15, 21, and 11) demonstrated significant activity against α-glucosidase. The move was higher than that of acarbose, which has an IC50 of 873.34 ± 1.67 μM, a standard α-glucosidase inhibitor. Molecular docking studies demonstrated that these active compounds efficiently occupied the α-glucosidase acarbose binding pocket, suggesting their potential as α-glucosidase inhibitors (Figure 5).

Figure 5.

Characterization and synthesis of novel hydrazone Schiff Base derivatives based on Polyhydroquinoline nucleus: Potential antioxidants and antibacterial agents.

According to Najiah M. Alyamani, organic compounds’ structural [1] symmetry or asymmetry is one of their most fundamental characteristics. Z-geometrical isomers are kinetically preferred, promiscuous structures with many biological functions. Beginning with the ethyl acrylate ester derivative (Z)-1 starting material, a new series of hybrid molecules containing 3,4,5-trimethoxybenzamide moieties and Schiff base were synthesized, and elemental microanalysis, 1H-NMR, and 13C-NMR spectroscopic studies were used to confirm their structural integrity. Colchicine was the reference material, and the MCF-7 breast cancer line was used as a test subject for the target hybrids’ in vitro cytotoxic activity. Most recently developed combinations showed significant growth inhibition activity against the MCF-7 cells compared to the reference material (Figure 6).

Figure 6.

Optimized synthetic routes for the design and elaboration of Schiff Base–TMB derivatives.

As per Shahnazar Ali, in 2023, a novel class of thiazolidinones (TZD 5a-s) and azetidinones (AZT 6a-s) was developed, with their target being [2] the cox-2 enzyme (PDB protein 1PXX). 2-mercapto benzoxazole (1) was used as the starting material in conventional and microwave methods. The rat paw edema method was used to measure the anti-inflammatory activity in vivo, and DPPH free radical scavenging was used to evaluate the antioxidant activity in vitro. A comparative study compared microwave and conventional methods’ yield, purity, and reaction time. Key intermediates, including ethyl 2-(benzoxazol-2-ylthio)acetate (2) and 2-(benzoxazol-2-ylthio)acetohydrazide (3), were formed during the synthesis process. Schiff bases (4a-s) were then created, and thiazolidinones (5a-s) and azetidinones (6a-s) were produced as a result (6a-s). The substances underwent tests for their ability to cause ulcers and reduce inflammation in vivo and their antioxidant capabilities in vitro. Three dimensions, robust CoMFA and CoMSIA models were obtained through QSAR analyses using SYBYL-X 2.1.1 software. The best models displayed acceptable prediction values and significant coefficients for a test set of eight compounds. After docking studies, molecules 5c, 5q, 5j, 6q, and 6 g showed acute ulcerogenic activity in vivo and favorable interaction energy with the COX-2 enzyme (protein 1PXX). These molecules were considered promising candidates. These findings provide valuable information that can be utilized to predict the compound activity and guide the synthesis of new molecules (Figure 7).

Figure 7.

Design and synthesis of benzoxazole-substituted Thiazolidinones and Azetidinones.

In February 2023, Kiran Singh and his team produced a novel [30] Schiff base known as five-methyl-3-((5-bromosalicylidene) amino)-pyrazole (HMBP) by refluxing 3-amino-5-methylpyrazole and 5-bromosalicylaldehyde in methanol at a 1:1 M constitution. Elemental analysis and spectral techniques (1 H NMR, IR, and mass) were used to characterize the HMBP. The coordination behavior of certain transition metal ions with newly synthesized Schiff base is also described. 1H NMR, fluorescence, elemental analyses, infrared spectra, electronic spectra, UV–vis, mass, and magnetic moments have all been used to characterize the complexes. The thermogravimetric assay (TG-DTG) has been used to conduct and explain the thermal study of the complexes. T Infrared spectra show that the Schiff base is a bidentate ligand linked to the metal ions by protonated phenolic O and imine N. The presence of water molecules is confirmed by thermal analysis. Quantum yields were measured in addition to the HMBP and all metal complexes’ determined structures. According to a fluorescence study, metal complexes exhibit more intense fluorescence than the new Schiff base. To calculate the kinetics variables, the Coats-Redfern equation was applied. A variety of food-borne pathogens, such as Clostridium perfringens (MTCC 450), Escherichia coli (MTCC 433), Staphylococcus aureus sub aureus (MTCC 1144), Pseudomonas aeruginosa (MTCC 424), and fungi (Aspergillus niger, Aspergillus fumigatus, and Candida albicans), were tested against the synthesized ligand and its complexes. All of the complexes were found to have stronger biological activity toward individual organisms when compared to the new Schiff base (Figure 8).

Figure 8.

Extensive studies on the synthesis of new Schiff Base 5-Methyl-3-((5-Bromosalicylidene) amino)-pyrazole and its transition metal complexes.

In June 2022, Sheikh Abdul Majid’s Schiff bases were [31] recognized as essential chemical scaffolds for applications in both industry and medicine. Because carbamate derivatives have so many uses, we report here the synthesis and characterization of a new Schiff base ligand, (E)-ethyl 2-(4 methoxy benzylidene) hydrazine carboxylate, and 4-(nitrobenzaldehyde) methylcarbamate. The compound was characterized by combining B3LYP and 6-31 G(d,p)formalism with calculations from density functional theory and experimental data. The primary characterization techniques used for the elemental analysis of the mixture were FT-IR, UV-Vis, and NMR spectroscopic evaluations (Figure 9).

Figure 9.

Design and synthesis of Carbazate derivatives as innovative Schiff Base ligands for advanced coordination chemistry.

In 2023, Nandeshwarappa utilized condensation synthesis [32] to generate a sequence of (E)-1-methyl-3-((substituted phenylamino)methyl) quinoline-2(1H)-one Schiff bases (3a-j) containing the quinoline moiety (2a-j) from a solitary starting material, 1-methyl-2-oxo-1,2-dihydroquinoline-3-carbaldehyde (1). The structure of the recently synthesized compounds was verified by Fourier transformation infrared (FTIR), mass spectroscopy, elemental analysis, and proton (1H) and carbon (13C) nuclear magnetic resonance spectroscopy. The in-vitro antimicrobial activity of the synthesized compounds against gram-positive (Bacillus licheniformis and Bacillus cereus), gram-negative (Escherichia coli and Acinetobacter sp.), and antifungal (Aspergillus flavus and Pichnanomala) bacteria was tested using the agar well diffusion method. Furthermore, the compounds (3b, 3c, 3d, 3f, 3 g, and 3j) that show good activity are tested for in-vitro antitubercular activity against the mycobacterium tuberculosis H37Rv strain using the Micro-plate Almamar Blue Assay (MABA) method. Important information about the compounds’ effectiveness against these strains is obtained from this process. The structural activities of the synthesized compounds were also discussed. The distinct substituent affixed to the phenyl ring in compounds 3a, 3c, 3d, 3f, and 3 g provides a strong argument (Figure 10).

Figure 10.

Convenient synthesis, characterization, and biological evaluation of novel Schiff Base heterocycles.

3. Conclusion

In conclusion, investigating advances in Schiff base chemistry has shed light on the field’s dynamic evolution and potential to have a revolutionary effect in modern chemistry. The experience has highlighted structural adaptability, creative synthetic approaches, and a wide range of uses for Schiff bases in fields such as medicinal chemistry and materials science. Schiff bases will significantly impact the direction of environmentally friendly and sustainable chemistry as we look toward the future. Their potential in cutting-edge fields like supramolecular chemistry, nanotechnology, and renewable energy sources offers intriguing chances for additional study and development. To help researchers and enthusiasts navigate this dynamic and exciting field of organic chemistry, the chapter has attempted to provide a comprehensive understanding of Schiff base chemistry.