Overview of Schiff Bases

*Nuriye Tuna Subasi*

## **Abstract**

Schiff bases, which were first obtained by the German chemist H. Schiff in 1864, are used in the paint industry, polymer technology, pharmaceutical industry, medicine, agriculture, preparation of rocket fuel, and explanation of biological events, and in many other areas due to the groups in their structures. This chapter will be a guide that contains a summary of general information that should be known about these compounds, which have a wide range of use in our daily life. In this chapter, the following topics are planned to be explained. (1) Schiff bases, physical and chemical properties, (2) the formation mechanism of Schiff bases, (3) Schiff base reactions, (4) metal complexes of Schiff base, (5) classification of Schiff bases, (6) biological activity of Schiff bases, and (7) usage of Schiff bases.

**Keywords:** Schiff bases, azomethine, biological activity, metal complexes, formation mechanism

### **1. Introduction**

Compounds that are formed as a result of the nucleophilic addition reaction of aldehydes and ketones with primary amines under suitable conditions and which have carbon-nitrogen double bonds (dCH]Nd) in their structure are called Schiff bases. Schiff bases, which were first obtained by the German chemist H. Schiff in 1864 [1], were started to be used as ligands by Pfeiffer in the 1930s [2, 3] (**Figure 1**).

Aldehydes react very easily with primary amines to form Schiff bases, but this process is not so easy for ketones. In order to obtain Schiff bases from ketones, it is necessary to pay attention to factors, such as the choice of catalyst, the appropriate pH range, the selection of a solvent that can form an azeotrope mixture with the water to be formed in the reaction, and the appropriate reaction temperature. The carbonnitrogen double bond in Schiff bases formed as a result of the reaction of primary

$$\begin{array}{c} \mathsf{R}\_1\\ \mathsf{C}\_2\\ \mathsf{R}\_2\\ \mathsf{R}\_1, \mathsf{R}\_2, \mathsf{R}\_3 = \mathsf{Alkyl} \text{ or } \mathsf{A} \mathsf{Nd} \end{array}$$

**Figure 1.** *General representation of Schiff bases.* amines with aldehydes is called azomethine or aldimine, while the bond formed as a result of reaction with ketone is called imine or ketimine.

Schiff bases are selective toward metal ions and form complexes by transferring electrons from the active ends they contain to the metal. Schiff bases are known as a good nitrogen donor ligand (dCH]Nd). During the formation of the coordination compound, one or more electron pairs are donated to the metal ion by these ligands. Schiff bases can form highly stable 4-, 5-, and 6-ring complexes if they donate more than one electron pair. For this, a second functional group with a displaceable hydrogen atom must be found as close as possible to the azomethine group. This group is preferably the hydroxyl group [4].

### **2. Physical properties of Schiff bases**

Schiff bases are usually colored and transparent solids. They are used in the determination of metal amounts and in the identification of carbonyl compounds due to their precise melting points.

The carbon-nitrogen double bond in Schiff bases rotates more easily than the carbon-carbon double bond, which allows stereoisomers to transform into each other. The reason for this: polarization occurs in the azomethine bond due to the fact that nitrogen is more electronegative than carbon (**Figure 2**).

The stereoisomers of Schiff bases cannot be isolated with a few exceptions due to the very small energy difference between them. If only an electronegative group is attached to the nitrogen atom, stereoisomers become isolated, since this group reduces the ease of rotation around the azomethine bond. Since the electronegative group attached to the nitrogen atom in the azomethine group will push the negative charges of the nitrogen atom toward the carbon, this will cause a decrease in polarization and an increase in the character of the covalent double bond.

All compounds containing an azomethine group show basic properties due to the unshared electron pairs on the nitrogen atom and the electron donating feature of the double bond. Schiff bases show weaker basic properties compared to their corresponding amines. The reason for this is that while the nitrogen atom in amines undergoes sp<sup>3</sup> hybridization, this hybridization turns into sp2 hybridization when the imine structure is formed. Since the s character will increase in hybridization, the basicity will decrease greatly.

The C]N system is a weak chromophore that shows absorption in the ultraviolet field. Conjugation with phenyl groups shifts absorption to the visible region. When there is a deactivating substituent in the aromatic ring, such as a halogen, the wavelength of absorption decreases. Generally, aryl alkyl ketimines are absorbed at values between dialkyl and diaryl ketimines [5]. The IR stretch bands of the C]N system are generally observed at 1610–1635 cm<sup>1</sup> and that of C]N<sup>+</sup> at 1665–1690 cm<sup>1</sup> [6].

**Figure 2.** *Polarization of azomethine bond.*

### **3. Chemical properties of Schiff bases**

Schiff bases have many properties that vary according to the substituents attached to the azomethine group. The stability of the azomethine compound increases when there is an electronegative group attached to the nitrogen atom. The best example of this is that oximes carrying hydroxyl groups on the nitrogen atom along with phenylhydrazone and semicarbazones carrying dNH groups are much more stable to hydrolysis than Schiff bases carrying alkyl or aryl substituents on the nitrogen atom. Although Schiff bases are stable against alkalies, they are separated into amine and carbonyl compounds by hydrolysis in acidic environment.

The Schiff base formation reaction is reversible. As a result of the reaction, one mole of water is formed and the water in the environment shifts the direction of the reaction to the left. Therefore, the reaction is usually carried out in solvents where water can be removed from the environment by distillation, forming an azeotrope. If the reaction is carried out using amines containing an electronegative atom with unpaired electrons in the nitrogen atom, the reaction is completed and since hydrolysis will not occur, Schiff bases can be isolated with high efficiency (**Figure 3**).

The structures of Schiff bases are determined by the tautomeric transformations that occur depending on the polarity of the solvent and the hydrogen bonds that occur in the molecule. The preferred conformation in terms of the stability of Schiff bases is the nonplanar structure seen in **Figure 4.** This conformation has also been confirmed by quantum mechanics calculations [7].

In the studies, it has been reported that there are two types of tautomer forms, phenol-imine and ketone-amine, in Schiff bases obtained by using aldehydes containing ortho hydroxy group (**Figure 5**). The presence of these two tautomeric structures was determined by spectroscopic methods such as 13CNMR, <sup>1</sup> H-NMR, UV-Vis, and X-ray crystallography [8].

In studies with Schiff bases prepared from 2-hydroxy-1-naphthaldehyde and some aromatic and aliphatic amines (ammonia, methylamine, and phenylamine), it has

**Figure 3.** *Schiff base formation reaction.*

**Figure 4.** *Preferred conformation of Schiff bases.*

**Figure 5.** *Tautomeric structure of Schiff bases.*

been observed that the keto form is dominant in polar solvents, such as chloroform, and the enol form is dominant in nonpolar solvents [9, 10].

### **4. Formation mechanism of Schiff bases**

The most widely used method discovered by Schiff for the preparation of Schiff bases is the reaction of aliphatic or aromatic aldehydes or ketones with aliphatic or aromatic primary amines. The synthesis of Schiff bases obtained from the reaction of carbonyl compounds with primary amines takes place in two main steps. In the first step, a carbinolamine intermediate is formed from the condensation of the carbonyl group with the primary amine, and in the second step, a Schiff base is formed from the dehydration of the intermediate seen in **Figure 6** [12–14].

The formation of Schiff base is a pH-dependent reaction. Since the amine will form salt at low pH, the free amine concentration decreases and the fast addition step slows down and becomes the step that determines the rate of the reaction mechanism (**Figure 7**). In the case of a decrease in acidity, the addition step is faster and the

*Mechanism of condensation of carbonyl compounds with amines [11].*

**Figure 7.** *Increase in electrophilic power and decrease in nucleophilic power in acidic medium.* *Overview of Schiff Bases DOI: http://dx.doi.org/10.5772/intechopen.108178*

#### **Figure 8.**

*Decrease in electrophilic power and increase in nucleophilic power in basic medium.*

elimination step is slower (**Figure 8**). The optimal pH is the pH between these two extremes (pH 34). This pH is suitable for both starting the nucleophilic addition reaction and performing elimination reaction at a sufficient speed [7].

The effect of substitution is great on the stability of Schiff bases. Since smallmolecular-weight aliphatic imines without substituents on the nitrogen atom are easily polymerized, detailed information about these imines is not available. Schiff bases containing aryl substituents can be synthesized more stable and easily due to the electron feeding of the imine bond through ring conjugation, while those containing alkyl substituents are relatively unstable, synthesized in a long time, and polymerization is observed.

In the formation of imine; aldehydes are more reactive than ketones because they are less sterically hindered. In addition, in ketones, groups attached to the carbonyl carbon donate electrons, reducing the electrophilic character of the carbonyl carbon, thus reducing the reaction tendency and causing the reaction to take place more slowly. Therefore, although aldehydes and primary amines can easily form Schiff bases, it is quite difficult to obtain Schiff bases from ketones. In order to obtain Schiff base from ketones, many factors, such as choosing a solvent that can form an azeotrope mixture with the water released during the reaction, choosing a catalyst, choosing the appropriate pH range and the appropriate reaction temperature, must be taken into account. Particularly in order to obtain Schiff base from aromatic ketones, high temperature, long reaction time, and catalyst are required [4, 15].

Aromatic aldehydes and ketones can form highly stable Schiff bases. Aromatic aldehydes react with amines at low temperature and in a suitable solvent environment. In the reaction of aromatic aldehydes with aromatic amines, it has been indicated that the reaction rate increases in the presence of an electron-withdrawing substituent in the para position of the aldehyde and decreases in the presence of para position of the amine. While the water formed in the reaction must be removed during the production of Schiff base from aromatic ketones, there is no need to remove water in the synthesis of Schiff base from aldehydes and dialkyl ketones. While the water formed in the reaction must be removed during the generation of Schiff base from aromatic ketones, there is no need to remove water in the synthesis of Schiff base from aldehydes and dialkyl ketones [16].

### **5. Synthesis methods of Schiff bases**

#### **5.1 Reaction of aldehydes and ketones with primary amines**

The reaction of primary amines with carbonyl compounds is usually carried out by reflux. Since the reaction is reversible, the water formed in the reaction medium must be removed to prevent hydrolysis. Dean-Stark apparatus is generally used to remove water. In addition, the reaction was carried out successfully by using dehydration agents such as sodium sulfate and molecular sieve [17]. Moreover, methods using solvents, such as tetramethyl orthosilicate or trimethyl orthoformate, which remove water in the reaction medium, have also been reported in the literature [18, 19].

The reaction can be accelerated by acid catalysis. In such cases, mineral acids, such as H2SO4 or HCl, organic acids, such as p-toluene sulfonic acid, pyridinium ptoluenesulfonate, acidic resin, montmorillonite, or Lewis acids (ZnCl2, TiCl4, SnCl4, BF3Et2O, Mg(ClO4)2, MgSO4), can be used [15, 20–25].

The reaction of aliphatic ketones with amines to form a Schiff base occurs more slowly than with aldehydes. When the reaction rates of the same primary amine and aldehydes and ketones are compared, it was found that the rate order was; the rate order is aromatic aldehyde>aliphatic aldehyde>aliphatic ketone>aromatic ketone [26]. Recently, new solvent-free techniques have been developed for imine formation, including clay, microwave irradiation, water suspension media, liquid crystal, molecular sieve, and infrared and ultrasonic irradiation [27–34].

#### **5.2 Reaction of organometallic compounds with nitriles**

Grignard reagents can react with nitriles to form ketimines. Anhydrous hydrogen chloride or anhydrous ammonia is added to the reaction medium to prevent the hydrolysis of the intermediate products into ketones. With this method, intermediate products can be isolated with an efficiency of 5090% (**Figure 9**) [26].

#### **5.3 Reaction of phenols and phenol ethers with nitriles**

The alkyl or aryl nitriles react with phenol and phenol ethers with high efficiency under acid catalysis to form ketimines [35]. The reaction is carried out by saturating a solution of nitrile and phenol dissolved in ether with HCl gas. ZnCl2 should be used in reactions with lower reactivity phenols (**Figure 10**).

**Figure 9.** *Addition of organometallic reagents to nitriles.*

**Figure 10.** *Reaction of phenols with nitriles.*

## **5.4 Aerobic oxidative synthesis method**

Since aldehydes and ketones can be obtained from their corresponding alcohols by oxidative methods, it is also possible to prepare imines from alcohols and amines using oxidative processes (**Figures 11** and **12**) [36–43].

Following this general approach, Huang and Largeron developed new catalytic processes that convert primary and secondary amines to imines by aerobic oxidation under mild conditions [38–44].

#### **5.5 Reaction of metal amides**

Calcium or alkali metal salts of primary amines react with aromatic ketones to form Schiff bases [26].

### **6. Reactions of Schiff bases**

#### **6.1 Polymerization reaction**

Many studies have been carried out on poly (Schiff bases) over time due to their thermal, conductive [45–47], fiber forming [48], liquid crystal [49, 50], and nonlinear optical properties [51, 52]. One of them is poly (Schiff base) formed by the reaction of diamines and dialdehydes by Catanescu et al. (**Figure 13**) [53].

#### **6.2 Reaction with Zn and haloesters**

β-Lactams are formed as a result of the reaction of Schiff bases with Zn and haloesters at room temperature [54].

**Figure 11.**

*Oxidative synthesis of imines from alcohols and amines.*

**Figure 12.** *Oxidative synthesis of imines from amines.*

**Figure 13.** *Polymer synthesis.*

#### **6.3 Reaction with HCN**

Nitrile derivatives are formed from the reaction of Schiff bases with HCN, and α-amino acids are formed by their hydrolysis [54].

#### **6.4 Reduction reactions**

Schiff bases are reduced with LiAlH4, NaBH4, and Na-EtOH reagents to form secondary amines [54].

#### **6.5 Hydrolysis**

Since the reaction steps of Schiff bases synthesized with carbonyl compounds and amines are reversible, starting materials are obtained by hydrolysis of Schiff bases. In the first step of hydrolysis, the intermediate product, carbinolamine, is formed. In the second step, the carbinolamine is decomposed to form the reaction products aldehyde (or ketone) and amine. Hydrolysis reactions are mostly acid-catalyzed and the rate of the reaction depends on the acidity strength [5].

*Overview of Schiff Bases DOI: http://dx.doi.org/10.5772/intechopen.108178*
