Synthesis of Schiff Bases by Non-Conventional Methods

1. Introduction

Schiff bases are versatile C=N containing compounds possessing broad range of biological activities, and incorporation of metals in form of complexes show some degree of antibacterial, antifungal, antitumor, antiviral and anti-inflammatory properties [1]. Schiff bases are typically formed by the condensation of a primary amine and an aldehyde or ketone. Structurally, a Schiff base is a nitrogen analogue of an aldehyde or ketone in which the carbonyl group has been replaced by an imine or azomethine group. Schiff bases are some of the most widely used organic compounds. They are used as pigments and dyes, catalysts, intermediates in organic synthesis, and as polymer stabilisers [2]. They are fundamental materials for the synthesis of various ligands which can be used as chiral auxiliaries in asymmetric synthesis. Metal complexes of Schiff bases have also been used in oxidation reactions [3].

Imine or azomethine groups are present in various natural, natural-derived and non-natural compounds. The imine group present in such compounds has been shown to be critical to their biological activities (Figure 1) [4, 5, 6]. Schiff bases are represented by the general formula R₃R₂C=NR₁. The substituents R₂ and R₃ may be alkyl, aryl, heteroaryl or hydrogen while the substituent R₁ at the N-imino may be alkyl, aryl, heteroaryl, hydrogen or metallo (usually Si, Al, B, Sn).

The general approaches to the synthesis of Schiff bases are described in this report. Some unconventional methods of preparation and efficient practical techniques like microwave irradiation, solid-solid condensation, ultrasound irradiation, water suspension medium, infrared irradiation and the use of natural product as catalysts are discussed.

2. Preparation of Schiff bases

The most common method for the preparation of imines is the original reaction reported by Hugo Schiff in 1864 [7, 8, 9]. It is usually formed by the condensation of an aldehyde or ketone 5 with a primary amine 6 and elimination of water molecule in a Dean Stark apparatus. The formation of a Schiff base 8 is a reversible reaction and the dehydration of carbinolamine 7 generally takes place under acid or base catalysis, or upon heating. Molecular sieves are then used to completely remove water formed in the system (Figure 2) [10].

Aliphatic ketones react with amines to form imines more slowly than aldehydes; therefore, higher reaction temperatures and longer reaction time are required. Acid catalysts and water removal from the reaction mixture can significantly increase the reaction yields. Aromatic ketones are less reactive than aliphatic ones and require harsh conditions to be converted into imines.

Recently, a number of innovations and new techniques for the preparation of Schiff bases have been reported including solvent-free, clay, or microwave irradiation, solid-state synthesis, molecular sieves, liquid crystals, water suspension medium, infrared and ultrasound irradiation [11, 12, 13, 14, 15].

The mechanism of Schiff base formation is another variation of nucleophilic addition to the carbonyl group, where the nucleophile is the amine. The amine reacts with the carbonyl to give an unstable addition compound called carbinolamine. The carbinolamine loses water by either acid or base catalysed pathways. Since the carbinolamine is an alcohol, it undergoes acid catalysed dehydration (Figure 3) [16].

3. Synthesis of Schiff bases from various methods

The clay catalysed synthesis of imines and enamines under solvent-free conditions using microwave irradiation has been reported by Varma et al. [11]. A synthetic procedure catalysed by montmorillonite K 10 clay was employed for the preparation of imines and enamines. An equimolar mixture of the carbonyl compound and amine was placed in an open glass container and irradiated in a microwave oven at full power for 3 minutes. The product was extracted into DCM and removal of the solvent under reduced pressure gave the imines/enamines in 75–98% yield. This approach eliminates the need for the large excess of support usually employed in solid phase reactions and reduces considerably the longer times and large quantities of aromatic solvents required in the conventional solution phase chemistry which entails the azeotropic removal of water using Dean-Stark apparatus. This method was also employed by Vass et al. [17] for the synthesis of N-sulfonylimines 11 (Figure 4). The one-pot and high-yielding protocol for the preparation of N-sulfonylimines from aryl aldehydes 9 and sulfonamides 10 provided a better alternative to the existing methods due to its shorter reaction time, simple reaction procedure and the formation of cleaner products that can be used for synthetic applications without further purification.

The synthesis of imines has been carried out efficiently using silica gel supported sodium hydrogen sulfate (NaHSO₄.SiO₂), a non-toxic and inexpensive catalyst, as a reusable heterogeneous catalyst in solvent-free conditions under microwave irradiation [18]. Several substituted imines were prepared by this method (Figure 5). The NaHSO₄.SiO₂ catalyst can be reused by simple washing with diethyl ether after each use followed by activation in an oven at 120°C for 1 h prior to use, thus rendering the process more economical. This constitutes a green and efficient alternative to the MW assisted method described by Varma et al. [11] using K-10 clay as catalyst and the use of DCM or diethylether, which are the commonly used solvents for this reaction. The use of NaHSO₄.SiO₂ catalysed nucleophilic attack on the carbonyl group by the amine and served as a dehydrating agent to facilitate the removal of water in the final step. This eliminates the environmental disadvantages of using toxic drying agents such as TiCl₄.

Schmeyers et al. [12] reported the solid-state synthesis of various kinds of benylideneaniline derivatives 14 without passing through liquid phases. The solid-solid reactions were performed by grinding together equimolar mixture of the pure aniline 12 and aldehyde 13 in a mortar at room temperature for 2 h (Figure 6). Twenty preparatively useful imines were quantitatively (100% yield at 100% conversion) obtained as hydrates. The water produced in the reaction was removed at 80°C under vacuum. These solid-solid condensations, unlike (acid catalysed) imine synthesis in solution, proceed waste-free.

A mild and improved protocol for the preparation of imines by ultrasound irradiation has been developed by Guzen et al. [15]. A wide range of aromatic and heteroaromatic aldehydes were employed and all imines were obtained in excellent yields. The reaction was very efficient on a large scale, with the advantage of a very simple work-up and short reaction time (10 min). However, the process involved the use of a catalyst for activation and reaction solvent (Figure 7).

A new, simple, efficient, and environmentally benign method for the preparation of substituted N-benzylideneaniline derivatives, via condensation of several benzaldehydes and anilines, by means of infrared irradiation under solvent-free conditions has been developed [19]. The reactions proceeded with good yields and in considerably shorter times than those previously reported under classical thermal conditions with additional advantages of lower cost, ease of work-up, and the fact that activation of the reaction by an acid catalyst was unnecessary.

The synthesis of various kinds of imines by a simple and green procedure was reported by Tanaka and Shiraishi [13]. The process involved the condensation reactions of aldehydes and amines in a water suspension medium at room temperature. Water is a non-toxic, safe, and cheap medium. The use of water as solvent allowed the formation of imines without the need for catalysis, the use of a large excess of aromatic solvents, or the azeotropic removal of water. The reactions were completed in short reaction times, high-yielding and the products were isolated by filtration.

This procedure was also employed by Rao et al. [20] for the synthesis of Schiff bases via the condensation of 1,2-diaminobenzene with various substituted aromatic aldehydes in aqueous medium (Figure 8). The method was experimentally simple, clean, high-yielding, with reduced reaction times. The product was purified by simple filtration followed by washing with water and drying processes.

4. Synthesis of Schiff bases using natural catalysts

A green method for the synthesis of Schiff bases using natural acids found in tamarind extract and lemon juice as a catalyst has been reported (Figure 9) [21]. The condensation of benzaldehyde 23 with aniline 24 and with urea 26 gave benzylidene aniline 25 and benzylidene urea 27 respectively. The products which were identified by various spectroscopic techniques showed significant antimicrobial and antioxidant activities. The role of tamarind extract and lemon juice as catalysts which are important for the formation of these Schiff bases was observed in that the reaction carried out in the absence of the catalysts gave no products. The method was economical and gave high yield of product.

5. Conclusion

Some non-conventional methods of preparation of Schiff bases have been extensively discussed. These methods are environment friendly, free from organic solvents and without the drawbacks of long reaction time, special apparatus and cost of dehydrating agent.