A short, effective protocol for Shciff base synthesis using microwave

3 HNUE JOURNAL OF SCIENCE DOI: 10.18173/2354-1059.2017-0048 Chemical and Biological Science 2017, Vol. 62, Issue 10, pp. 3-10 This paper is available online at A SHORT, EFFECTIVE PROTOCOL FOR SHCIFF BASE SYNTHESIS USING MICROWAVE Duong Quoc Hoan and Nguyen Thi Lan Faculty of Chemistry, Hanoi National University of Education Abstract. Both nitration of vanillin and condensation of 5-nitrovanilllin with aniline derivatives were accelerated by using microwave oven. The nitration gave 5-nitrovanillin in 80% yield and the condensation gave twelve Schiff bases in excellent yield (80 - 97%) within short reaction time (4 - 10 min) along with other advantages like mild reaction condition and safer environmental conditions. Schiff base structures are confirmed by 1 HNMR analysis. Keywords: Condensation, microwave oven, nitration, 5-nitrovanillin, Schiff bases. 1. Introduction Schiff base plays an important role in organic synthesis as well as in medicinal chemistry. For example, reduction of >C=N bond gives a secondary amine [1]; cyclization gives thiazolidin-4-one [2], an important heterocyclic compound in pharmacological synthesis. Another example, condensation of acetyl chlorides (bearing an electron withdrawing group and at least one hydrogen atom at the α-position) with N-arylaldimines occurs by initial acylation at the nitrogen atom and leads to -lactams of interest in penicillin chemistry [3]. Aziridines are also the products of the reactions of Schiff bases with the Simmons-Smith reagent (methylene diiodide/zinc-copper couple) [4]. Recently, scientists have found that, the lipophilicity of the drug is increased through the formation of chelates [5] and drug action is increased due to effective permeability of the drug into the site of action. The effectiveness of compounds against organisms depends either on the impermeability of the microbe cells or on ribosome structure of microbial cells [6], therefore, Schiff base act as an antibacterial [7, 8]; antitumor [9]; anticonvulsant [10]; antiparasitic reagent [11]. It is, in fact, very important to synthesize Schiff base. One of the most popular Schiff base is a product of condensation reaction between aldehyde and amine. However, in the traditional method (Conventional Method) reaction reagents were refluxed in absolute ethanol in presence of acetic acid catalysts [12] and gave non-pure products that rise problems for purification. Recently, microwave has been used to synthesize Schiff bases [13, 14]. In these works the microwave oven was Qpro-M oven, Received July 20, 2017. Revised November 20, 2017. Accepted November 27, 2017. Contact Duong Quoc Hoan, e-mail address: hoandq@hnue.edu.vn Duong Quoc Hoan and Nguyen Thi Lan 4 specially build for scientific research and operating at 1000 W. Recently, we have reported the synthesis of Schiff bases but using conventional methods: heating in ethanol and in presence of some drops of acetic acid; heating in dichloromethane in presence of acetic acid and anhydrous magnesium sulfate [11]. In this paper, microwave oven was used to carry out the nitration and condensation to form Schiff bases with some advantages such as: short time, no solvent or limited solvent amount, high yield and easy purification. 2. Content 2.1. Experiments * Experimental section Solvents and other chemicals were purchased from Sigma-Aldrich, Merck Corp. were used as received, unless indicated. The 1 H NMR spectra were recorded on the Bruker Avance 500 NMR spectrometer in CDCl3 in The Vietnam Academy of Science and Technology. Chemical-shift data for each signal was reported in ppm units. Sanyo domestic microwave oven in middle power (400 W) was used as a synthesizer. * Synthetic procedure 5-nitrovanilline (1) [15] Nitration of vanillin: Vanillin (2 g, 13 mmol) mixed with 15mL of 10% aqueous nitric acid was irradiated in the Sanyo domestic microwave oven for 1 min at power level 400 W. The progress of the reaction was monitored by thin layer chromatography (TLC) till the disappearance of the starting material on TLC plate. The reaction mixture was cooled to room temperature and cold water (30 mL) was added to it when a light orange colored solid separated. This solid was filtered, washed with water till free from acid, dried. This compound obtained in 80% yield. * Synthesis of Schiff bases General procedure: Method 1: To a solution of 5-nitrovanillin (0.34 g, 2 mmol, 152 g/mol) and aniline (0.23 mL, 2.5 mmol, 93g/mol) in absolute dimethyl formamide (DMF) (5 mL) was added 2-3 drops of glacial acetic acid. The mixture was refluxed for 8h. The progress of reaction was monitored with TLC. After reaction completion, the mixture was added cold water (50 mL) to form solid. The solid was filtered, and purified with flash column chromatography. Method 2: To a mixture (for liquid aniline derivatives) or solution (for solid aniline derivatives) of 5-nitrovanillin (0.34 g, 2 mmol, 152 g/mol) and aniline derivatives (2.5 mmol) in limited amount DMF (1 mL, for solid case) was added 2-3 drops of glacial acetic acid. The mixture/solution was irradiated with Sanyo domestic microwave oven for 4-10 min in the middle power (400 W). The progress of reaction was monitored with TLC every minute. The products were collected after adding absolute ethanol (10 mL) and cooled down in ice bath. Products were pure enough for structural confirmation after washing with cold ethanol. A short, effective protocol for Shciff base synthesis using microwave 5 (E)-2-methoxy-6-nitro-4-[(phenylimino)methyl]phenol (2.1) 1 H-NMR (CDCl3, 500 MHz)  (ppm): 11.07 (br, 1H), 8.40 (s, 1H), 8.05 (d, J = 1.5 Hz, 1H), 8.01 (d, J = 1.5 Hz, 1H), 7.04 (td, J = 8.5, 2.0 Hz, 2H), 6.57 (d, J = 8.5 Hz, 2H), 6.62 (t, J = 8.5 Hz, 1H), 4.07 (s, 3H). (E)-2-methoxy-6-nitro-4-{[(3-nitrophenyl)imino]methyl}phenol (2.2) 1 H-NMR (CDCl3, 500 MHz)  (ppm): 11.00 (br, 1H), 8.48 (s, 1H), 8.05 (d, J = 1.5 Hz, 1H), 8.00 (d, J = 1.5 Hz, 1H), 7.38 (t, J = 8.0 Hz, 1H), 7.36 (m, 1H), 7.32 (t, J = 8.0 Hz, 1H), 7.01 (m, 1H), 4.07 (s, 3H). (E)-2-methoxy-4-{[(2-methoxyphenyl)imino]methyl}-6-nitrophenol (2.3) 1 H-NMR (CDCl3, 500 MHz)  (ppm): 11.07 (br, 1H), 8.48 (s, 1H), 8.05 (d, J = 1.5 Hz, 1H), 8.01 (d, J = 1.5 Hz, 1H), 7.36 (td, J = 8.0, 1.5 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 7.06 (td, J = 8.0, 1.5 Hz, 1H), 4.07 (s, 3H). (E)-2-methoxy-4-{[(3-methoxyphenyl)imino]methyl}-6-nitrophenol (2.4) 1 H-NMR (CDCl3, 500 MHz)  (ppm): 11.07 (br, 1H), 8.47 (s, 1H), 8.05 (d, J = 1.5 Hz, 1H), 8.01 (d, J = 1.5 Hz, 1H), 7.36 (td, J = 8.0, 1.5 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 7.06 (td, J = 8.5, 1.5 Hz, 1H), 6.58 (d, J = 8.0 Hz, 1H), 4.07 (s, 3H), 3.89 (s, 3H). (E)-2-methoxy-4-{[(4-methoxyphenyl)imino]methyl}-6-nitrophenol (2.5) 1 H-NMR (CDCl3, 500 MHz) (ppm): 11.03 (br, 1H), 8.60 (s, 1H), 8.08 (d, J = 2.0 Hz, 1H), 6.69 (d, J = 8.0 Hz, 2H), 6.53 (d, J = 8.0 Hz, 2H), 4.07 (s, 3H), 3.85 (s, 3H). (E)-4-{[(2-hydroxyphenyl)imino]methyl}-2-methoxy-6-nitrophenol (2.6) 1 H-NMR (CDCl3, 500 MHz) (ppm): 11.07 (br, 1H), 8.60 (s, 1H), 8.08 (d, J = 2.0 Hz, 1H), 7.82 (d, J = 2.0 Hz, 1H), 7.28 (td, J = 8.5, 1.5 Hz, 1H), 7.22 (td, J = 8.0, 1.5 Hz, 1H), 7.04 (br, 1H), 7.03 (dd, J = 8.0, 1.5 Hz, 1H), 6.92 (td, J = 8.0. 1.5 Hz, 1H), 4.05 (s, 3H). (E)-4-{[(3-hydroxyphenyl)imino]methyl}-2-methoxy-6-nitrophenol (2.7) 1 H-NMR (CDCl3, 500 MHz)  (ppm): 11.07 (br, 1H), 9.40 (s, 1H), 8.48 (s, 1H), 8.02 (d, J = 2.0 Hz, 1H), 7.05 (t, J = 8.0 Hz, 1H), 6.92 (dd, J = 8.5, 1.5 Hz, 1H), 6.22 (d, J = 1.5 Hz, 1H), 6.48 (dd, J= 8.0, 1.5 Hz, 1H), 4.05 (s, 3H). (E)-4-{[(4-hydroxyphenyl)imino]methyl}-2-methoxy-6-nitrophenol (2.8) 1 H-NMR (CDCl3, 500 MHz)  (ppm): 11.21 (br, 1H), 9.60 (s, 1H), 8.59 (s, 1H), 8.05 (s, 1H), 7.66 (s, 1H), 7.25 (d, J = 8.5 Hz, 2H), 6.82 (d, J = 8.5 Hz, 2H), 3.90 (s, 3H). (E)-2-methoxy-6-nitro-4-[(p-tolylimino)methyl]phenol (2.9) 1 H-NMR (CDCl3, 500 MHz)  (ppm): 11.04 (br, 1H), 8.42 (s, 1H), 8.00 (d, J = 1.5 Hz, 1H), 8.01 (d, J = 1.5 Hz, 1H), 6.86 (d, J = 8.0 Hz, 2H), 6.49 (d, J = 8.5 Hz, 2H), 4.07 (s, 3H), 2.11 (s, 3H). (E)-4-{[(4-bromophenyl)imino]methy}-2-methoxy-6-nitrophenol (2.10) 1 H-NMR (CDCl3, 500 MHz)  (ppm):11.07 (br, 1H), 8.46 (s, 1H), 8.05 (d, J = 1.5 Hz, 1H), 8.01 (d, J = 1.5 Hz, 1H), 7.18 (d, J = 9.0 Hz, 2H), 6.55 (d, J = 9.0 Hz, 1H), 4.07 (s, 3H). (E)-2-methoxy-4-[(naphthalen-1-ylimino)methyl]-6-nitrophenol (2.11) 1 H-NMR (CDCl3, 500 MHz)  (ppm): 11.08 (br, 1H), 8.45 (s, 1H), 8.29 (dd, J = 7.0, 2.5 Hz, 1H), 8.08 (d, J = 1.5 Hz, 1H), 8.03 (d, J = 1.0 Hz, 1H), 7.86 (dd, J = 7.0, 2.0 Hz, Duong Quoc Hoan and Nguyen Thi Lan 6 1H), 7.52 (m, 2H), 7.74 (d, J = 7.5 Hz, 1H), 7.46 (t, J = 8.0 Hz, 1H), 7.04 (d, J = 8.5 Hz, 1H), 4.09 (s, 3H). (E)-2-methoxy-4-[(naphthalen-2-ylimino)methyl]-6-nitrophenol (2.12) 1 H NMR (CDCl3, 500 MHz)  (ppm):11.07 (s, br, 1H), 8.42 (s, 1H), 8.28 (m, 1H), 8.04 (d, J = 1.5 Hz, 1H), 8.00 (d, J = 1.0 Hz, 1 H), 7.85 (m, 1 H), 7.73 (d, J = 8.5 Hz, 1H), 7.52 (t, J = 9.0 Hz, 2H), 7.45 (t, J = 8.0 Hz, 1H), 7.03 (d, J = 7.5 Hz, 1H), 4.06 (s, 3H). 2.2. Results and discussion * Synthesis The nitration was carried out with 10% HNO3 in water as protocol shown by Bose et al. [15]. Luckily, it took 1 minute for completion under irradiation. Although the yield was 80 % the same as reported with conventional method (con. HNO3/HOAc, 0ºC  rt., 1 h, 80%) [12], it was much greener because of using less corrosive 10% HNO3 instead of concentrated HNO3 and its solvent was water instead of acetic acid. Scheme 1. Synthesis of Schiff bases For Schiff base cases, a Schiff base was synthesized by both microwave and conventional methods for a comparative study. Synthesis of Schiff base is often carried out by acid-catalysis or generally by refluxing the mixture of aldehyde (or ketone) and amine. However, with the assistance of microwave irradiation, it was found that the condensation had more advantages than the conventional methods did. In order to optimize the microwave condition for Schiff base synthesis, the condensation of aniline and 5-nitrovanillin was selected for screening because aniline was popular and inexpensive. Table 1. Optimization of condensation reaction between aniline and 5-nitrovanillin Conventional method condition Microwave method Power levels Refluxed in absolute DMF Low Medium High Time 8 h 30 min 5 min Burned Yield (%) 78 82 97 0 A short, effective protocol for Shciff base synthesis using microwave 7 Solvent selection: Since the condensation reaction needs temperature to accelerate the elevation of water, therefore, selected solvent was anhydrous DMF following the result of Naeimia and Rahmatinejada [16]. Conventional method: the reaction was carried out in conventional method (see experimental section). It took 8h for completion and yield 78% after purification (Table 1). Solvent was DMF for comparison. Unfortunately, TLC showed that both starting materials (5-nitrovanillin and aniline) were remaining. Thus, column chromatography was used to purify the Schiff base. Table 2. Microwave assisted Schiff base synthesis Compound Microwave method in medium power level Melting point (ºC) Appearance Solvents Time (min.) %Yield 2.1 - 4 97 155-156 Brownish yellow 2.2 DMF 10 83 172-173 yellow 2.3 DMF 6 89 156-157 yellow 2.4 - 5 90 142-143 yellow 2.5 DMF 8 85 157-158 brown 2.6 DMF 6 85 160-161 Brownish yellow 2.7 DMF 10 83 136-137 Brownish yellow 2.8 DMF 5 87 182 red 2.9 - 7 143 yellow 2.10 DMF 7 163-164 yellow 2.11 DMF 10 87 145 Reddish yellow 2.12 DMF 10 80 161 Reddish yellow Microwave method: As mentioned above, the condensation of aniline and 5- nitrovanillin was also searched for effect of irradiation power. The Sanyo domestic microwave was designed in three power levels: low, medium and high. So the reaction was tested with each power level with and without DMF solvent. It was found that progress of reaction with and without solvent was the same. In other word, using either a limited solvent DMF (1mL) or no DMF solvent gave same results. In details, at low power level, completion of reaction took 30 minutes and the yield was 82%. At high power level gave a burn for reaction after 1 minute. The best power level was medium. It Duong Quoc Hoan and Nguyen Thi Lan 8 took 4 minutes for completing and yield was 97 % after purification (see table 1). Since these Schiff bases did not dissolve well in absolute ethanol but the excess aniline dissolved well in, therefore, absolute ethanol was added in to obtain product. Surprisingly, the obtained product was pure enough for next reactions or structure determination. Based on the optimization condition other reactions were carried out under irradiation at medium power level with DMF in case aromatic amines were solid and without DMF for liquid ones. Results were shown in the table 2. 2.3. Structural determination As reported in our previous paper [11], the Schiff bases structures were confirmed by IR, NMR, NOESY and MS spectral methods. In this work, the configuration of –CH=N- bond was anti [11]. Hence, twelve Schiff bases were only checked with 1 H NMR spectra. Results were shown in the experimental section of each compound. H3CO HO NO2 N 1 6 2 3 4 5 7 8 10 9 12 14 13 11HO 2.6 H8 H6 H2 H14 H12H11 H13 H7 H(OH) Figure 1. 1 H NMR spectrum of Schiff base 2.6 For example, in case of compound 2.6, its 1 H NMR spectrum showed the resonance signals for protons of two hydroxyl groups at  11.20 and  7.04 ppm as broad peaks; H2 and H6 were as doublet peaks at  8.08 (d, J = 2.0 Hz, 1H) and  7.82 ppm (d, J = 2.0 Hz, 1H) because of splitting each other; H7 was at  4.05 ppm (s, 3H); H8 was at  8.60 ppm (s, 1H). Four protons of amine part belonged to aniline part were addressed as expected structures: the doublet peaks at  7.28 ppm (J = 8.0, 1.5 Hz, 1H) and  7.04 (J = 8.0, 1.5 Hz, 1H) must be for H11 and H14 which were split by one proton at ortho and another one at meta positions. H12 and H13 were interacted with two proton at ortho and one proton at meta positions, therefore, they were triplet doublet peaks at  7.22 and 6.92 ppm (Figure 1). 1 H NMR data for each compound was shown in experimental section. The results agreed with all expected structures. A short, effective protocol for Shciff base synthesis using microwave 9 3. Conclusion Sanyo domestic microwave oven was employed to accelerate the nitration reaction of vanillin to yield 5-nitrovanillin in 80% yield at medium power level for 1 minute with 10% HNO3 in water. It was found that twelve Schiff bases were synthesized under microwave irradiation for 4-10 minutes gave in 80-97 % yield. 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