Physicochemical characterization of benzalkonium chloride and urea

Journal of Molecular Liquids 224 (2016) 1249–1255

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Physicochemical characterization of benzalkonium chloride and urea based deep eutectic solvent (DES): A novel catalyst for the efficient synthesis of isoxazolines under ultrasonic irradiation Mohammed Afroz Bakht a,⁎, Mohammad Javed Ansari b, Yassine Riadi a, Noushin Ajmal c, Mohamed Jawed Ahsan d, Mohammed Shahar Yar e a

Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University, P.O. Box-173, Al-Kharj 11942, Saudi Arabia Department of Pharmaceutics, College of Pharmacy, Prince Sattam Bin Abdulaziz University, P.O. Box-173, Al-Kharj 11942, Saudi Arabia c Department of Basic Sciences and Humanities, Pratap University, Jaipur 303104, Rajasthan, India d Department of Pharmaceutical Chemistry, Maharishi Arvind College of Pharmacy, Ambabari Circle, Jaipur, Rajasthan 302039, India e Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Hamdard University, New Delhi 110062, India b

a r t i c l e

i n f o

Article history: Received 18 August 2016 Received in revised form 19 September 2016 Accepted 21 October 2016 Available online 24 October 2016 Keywords: Benzalkonium chloride Urea DES Ultrasound Isoxazoline

a b s t r a c t Various novel deep eutectic solvents (DESs) have been prepared by combining different molar ratio of benzalkonium chloride and urea, subsequently characterized for some physical and spectroscopic properties. Among newly formed DESs, one of the mixture (1:2) was employed in combination with ultrasound (US), for the synthesis of selective isoxazoline derivatives. The reactions were also performed by nonultrasonic (NUS)/ thermal method using conventional solvent system for comparison purposes. Applying DES, as a reaction medium in either of the thermal and ultrasonic assisted methods, an appreciable improvement in the product yield was achieved in a shorter time. The results show some advantages in terms of reaction time and energy consumption when DES and ultrasound combination was used for the synthesis of isoxazolines. Recyclability attributes of DES were also studied which revealed that a marginal decrease in the yield (%) was recorded up-to four runs. The findings of this study support the use of DES in combination with ultrasound technique as a viable green route for the synthesis of isoxazoline derivatives. © 2016 Elsevier B.V. All rights reserved.

1. Introduction The five member heterocyclic isoxazolines constitute an important class of compounds, being rich in biological potential including neuroprotective [1], antibacterial, anthelmimtic, analgesics [2,3], anti-inflammatory [4], antitubercular [5], anticancer [6] and many more. Several isoxazoline derivatives have been prepared using tedious routine organic solvents [4,5]. Isoxazoline moieties are synthesized under acidic or basic reaction media, which are believed to be more hazardous and time consuming [6,7]. The use of conventional volatile solvents not only cause environmental pollution but are also injurious to health [8]. Therefore less toxic, stable biocompatible solvents such as deep eutectic solvent (DES) would be a valuable choice. DES is a mixture of two or more component having melting point lower than individual component [9]. Usually, deep eutectic solvents (DESs) are prepared from organic halide salts (Quaternary ammonium salts e.g. Choline chloride) with the compounds able to donate hydrogen bond such as urea, thiourea, and Glycerol etc.) [10]. Therefore, interaction of both the ⁎ Corresponding author. E-mail address: [email protected] (M.A. Bakht).

http://dx.doi.org/10.1016/j.molliq.2016.10.105 0167-7322/© 2016 Elsevier B.V. All rights reserved.

component through hydrogen bonding led to the depression in freezing and melting point makes the eutectic mixture called DES [11,12]. Over the years, ionic liquids (IL's) were solvents of choice as these are green solvents with desirable properties such as - broad solubility range [13], high thermal stability, inflammability [14,15] and low volatility [16]. Despite of these advantages, certain limitations (high cost, toxicity, purification) of IL's prompt the researchers to discover deep eutectic solvents (DESs) [17–20]. Great attention has been made over the past few years towards application of ultrasound technology in organic and material synthesis [20, 21]. Ultrasound technique enhanced the reaction rate even at milder conditions as compared to conventional thermal process [22,23]. Principally, ultrasound work by the mechanism of acoustic cavitation generated through the repeated formation, growth and collapse of millions tiny vapor bubbles during chemical reactions [23,24]. It has been experimentally proved that acoustic cavitation creates high pressure (18,000 atomic pressures) and temperature (2000–5000 K) [25] which affect the chemical transformations [24,26]. In the present research, Benzalkonium chloride was used as ingredient with urea to prepare various deep eutectic mixtures. Benzalkonium chloride (BZK), is a member of the quaternary ammonium compounds

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M.A. Bakht et al. / Journal of Molecular Liquids 224 (2016) 1249–1255

and is a mixture of alkyl benzyl dimethyl ammonium chlorides designated as [C6H5CH2N (CH3)2R] Cl, having R group, n-octyl (n-C8H17; C8) to higher homologues. It is used as preservative in various dosage forms including aqueous ophthalmic formulations [27]. It also belongs to an economically important class of industrial chemicals such as disinfectants, biocides, detergents, anti-electrostatics, and phase transfer catalysts [28]. We have explored benzalkonium chloride and urea in different molar ratios to prepare novel DES systems. Successfully prepared DESs were characterized for some important physical parameters like density, viscosity, conductivity, refractive index, freezing point and pH. In order to observe the interaction or bonding between components of mixture, we elucidated the structure of benzalkonium chloride and urea separately along with DES by IR, NMR and XRD spectroscopic data. Our aim of the research is to develop an effective, economical and environmentally viable DES that can be employed as a green solvent to large sector. Furthermore, we have also evaluated the effect of DES combined with ultrasound on the synthesis of some isoxazoline derivatives and percent yield, time of reaction, temperature and energy were compared with those prepared using conventional method. To the best of our knowledge only few reports are available on the combined use of ultrasound and DES for the exploration of organic synthesis [10]. Many other heterocyclic belongs to azole family such as triazole, tetrazole, pyrazole was synthesized using different catalyst [29–32]. Methodology of these biologically important scaffolds could be developed utilizing newly prepared DES. Besides isoxazoline, we have recently reported the synthesis of some pyrazolines using biocompatible DES [33]. In the present research we are going to report novel DES with ultrasound to synthesize some isoxazoline derivatives. 2. Materials and methods 2.1. Materials All the chemicals used in present research were purchased from Loba Chem (India) and Sigma Aldrich (USA). These chemicals were used in the experiments without any subsequent purification. Density was measured using pycnometre; Viscosity was measured using Ostwald viscometer. The refractive indices were measured using automatic refractrometer (Rudolph, J-257, NJ, USA). Conductivity measurement was done by using Jenway conductivity meter (model 4520). pH of samples was calculated using Lovibond sense direct pH meter (model SN 10/5401, Germany). Deionized water was used for dilution, calculation, or calibration purposes wherever required. All the physical properties were measured at 20 °C, 30 °C, 40 °C and 50 °C (freezing point was calculated by laboratory manual thermometer). Spectroscopic data of all the three selected DESs and benzalkonium chloride & urea were generated through IR spectra using KBr discs by FT/IR - 4100 JASKO model in the ratio of 1:100 and NMR spectra by BRUCKER-PLUS (500 MHz) using TMS as internal standard. X-ray diffraction (XRD) patterns were recorded on a Rigaku Ultima IV X-ray Diffractometer at angles between 2° and 80°, with a scan rate of 2°/min. Sonochemical syntheses were carried out with the help of ultrasonic set-up (Probe) using operating frequency of 20 kHz with 130 W power. The progress of the reaction and purity of the compounds were monitored by thin layer chromatography in a solvent system (n-hexane: EtOAc, 80:20 v/v). Mass spectra were calculated on micromass (LCT Premier, waters).

Table 1 Physical appearance of deep eutectic mixtures at different molar ratios. Ratio

Abbreviation

Appearance

1:1 1:2 1:3 1:4 1:5

DES 1 DES 2 DES 3 DES 4 DES 5

Colorless clear liquid Colorless clear liquid Colorless clear liquid Turbid liquid Turbid liquid with some solid

30 min. Prepared DESs were kept in airtight container until further analysis. 2.3. Mechanochemical synthesis of chalcone (3a–e) All the required chalcones (3a–e) were synthesized by Claisen– Schmidt condensation using 2-bromo-4-chlorocetophenone with substituted aldehydes (2a–e) through solvent-less mechano chemical grinding method in presence of solid NaOH. An observable color change within 5 min indicates the chalcone formation which was further confirmed by TLC and spectroscopic data. 2.3.1. Spectroscopic data of synthesized chalcone (3a–e) 2.3.1.1. 1-(2-Bromo-4-chlorophenyl)-3-(4-chlorophenyl) prop-2-en-1one (3a). White solid; IR (KBr, cm−1): υmax 1689 (C_O), 1636 (CH_CH); 1H NMR (500 MHz, DMSO-d6): δ 8.05–8.04 (1H, d, _CH\\Ar, J = 8.6 Hz), δ 7.65–7.64 (1H, d, \\CO\\CH_, J = 8.6 Hz), 7.93–7.37 (7H, m, Ar\\H), 13C NMR (500 MHz, DMSO-d6): δ 121.3, 144.8 (2C, CH_CH), 186 (1C, C_O). 2.3.1.2. 1-(2-Bromo-4-chlorophenyl)-3-(2,4-dichlorophenyl) prop-2-en1-one (3b). Pale yellow solid; IR (KBr, cm−1): υmax 1689 (C_O), 1636 (CH_CH); 1H NMR (500 MHz, DMSO-d6): δ 8.22–8.21 (1H, d, _CH\\Ar, J = 8.05 Hz), δ 7.50–7.48 (1H, d, \\CO\\CH_, J = 6.75 Hz), 8.42–7.36 (6H, m, Ar\\H), 13C NMR (500 MHz, DMSO-d6): δ 121.6, 145.2 (2C, CH_CH), 184 (1C, C_O). 2.3.1.3. 1-(2-Bromo-4-chlorophenyl)-3-(2-hydroxy-3-methoxyphenyl) prop-2-en-1-one (3c). White solid; IR (KBr, cm−1): υmax 1670 (C_O), 1616 (CH_CH); 1H NMR (500 MHz, DMSO-d6): δ 7.28–7.27 (1H, d, _CH\\Ar, J = 7.58 Hz), δ 7.11–7.10 (1H, d, \\CO\\CH_, J = 8 Hz), 7.95–7.39 (5H, m, Ar\\H), 13C NMR (500 MHz, DMSO-d6): δ 121.9, 145.1 (2C, CH_CH), 184 (1C, C_O). 2.3.1.4. 4-(3-(2-Bromo-4-chlorophenyl)-3-oxoprop-1-en-1-yl) benzoic acid) (3d). White solid; IR (KBr, cm−1): υmax 1662 (C_O), 1616 (CH_CH) 1H NMR (500 MHz, DMSO-d6): δ 7.78–7.76 (1H, d, _CH\\Ar, J = 8.08 Hz), δ 7.77–7.75 (1H, d,\\CO\\CH_, J = 6.77 Hz), 8.35–7.86 (7H, m, Ar\\H), 13C NMR (500 MHz, DMSO-d6): δ 121.7, 144.1 (2C, CH_CH), 182 (1C, C_O). 2.3.1.5. 2-(3-(2-Bromo-4-chlorophenyl)-3-oxoprop-1-en-1-yl) benzoic acid (3e). White solid; IR (KBr, cm− 1): υmax 1666 (C_O), 1619 (CH_CH) 1H NMR (500 MHz, DMSO-d6): δ 7.68–7.63 (1H, d, _CH\\Ar, J = 7.88 Hz), δ 7.42–7.39 (1H, d,\\CO\\CH_, J = 6.58 Hz), 7.98–8.82 (7H, m, Ar\\H), 13C NMR (500 MHz, DMSO-d6): δ 122.3, 145.5 (2C, CH_CH), 186 (1C, C_O). 2.4. Synthesis of isoxazoline derivatives (4a–e)

2.2. Preparation of DESs Different molar ratios of BZK and urea were selected to prepare DES samples (Table 1). An automated shaker (Ultra Turrax-25, Ikea, Germany) was used to mix both components of DES. Each sample mixture of DES was shaken at 500 rpm at room temperature for the period of

To the synthesis of desired isoxazoline derivatives (4a–e), three different approaches were adopted- (i) Synthesis by thermal method using two conventional solvent (glacial acetic acid and sodium hydroxide), (ii) synthesis by thermal method using deep eutectic solvent (DES) and (iii) synthesis by ultrasonic method using DES. A mixture of


benzalkonium chloride as a salt and urea as a hydrogen bond donor were used prepare deep eutectic solvent for the present study as per literature method [10,12]. 2.4.1. Synthesis of isoxazoline derivatives by thermal method using conventional solvents In first attempt synthesis of isoxazoline derivatives (4a–e) by refluxing mixture of purified chalcone (3a–e) (0.005 M) and hydroxylamine hydrochloride (0.005 M) either in glacial acetic acid and/ or sodium hydroxide (20 mL) by classical thermal method. Reactions were continuously monitored by TLC in a solvent system (n-hexane: EtOAc, 80:20 v/v). An excess of solvent was removed and crude mass poured into crushed ice. Reaction was acidified in case sodium hydroxide used as a medium. Resultant reaction mixture was washed with water dried and recrystallized from ethanol. 2.4.2. Synthesis of isoxazoline derivatives by thermal method using DES In this approach, reaction was repeated using DES (8 g) as a solvent. On completion, reaction was extracted by dichloromethane using separating funnel. The dichloromethane layer was collected separately and evaporated to get final product. DES keeps aside and reused up to four cycles. 2.4.3. Synthesis of isoxazoline derivatives by ultrasonic method using DES Above reaction was performed again using ultrasonic method in a flask under sonication probe (ACE probe, 20 kHz frequency) at 40% amplitude with 130 W power for necessary time with a 5 s ON and 5 s OFF cycle from time t = 0 h. The temperature of the reaction was maintained at 30 ± 2 °C by using jacketed reactor having water circulation, especially designed for synthesis. Rest of the procedure was followed as described earlier in thermal method. 2.4.4. Spectroscopic data of synthesized isoxazoline derivatives (4a–e) 2.4.4.1. 4-(3-(2-Bromo-4-chlorophenyl)-5-(4-chlorophenyl)-4,5dihydroisoxazole (4a). White solid; IR (KBr, cm − 1 ): υ max 1648 (C_N), 1590 (C\\C); 1 H NMR (500 MHz, DMSO-d 6 ): δ 3.46–3.43 (2H, dd, CH 2 J = 12 Hz), 4.37–4.35 (1H, t, CH J = 10 Hz), 8.12– 7.27 (7H, m, Ar\\H); 13 C NMR (500 MHz, DMSO-d 6 ): δ 39.98 (1C, CH 2 isoxazoline), 86.94 (1C, CH isoxazoline), 125.9–135.8 (12C, Ar\\C), 153.47 (1C, isoxazoline); MS: m/z 372 (M+ + 1). 2.4.4.2. 3-(2-Bromo-4-chlorophenyl)-5-(2, 4-dichlorophenyl)-4, 5dihydroisoxazole (4b). White solid; IR (KBr, cm−1): υmax 1666 (C_N), 1570 (C\\C) 1H NMR (500 MHz, DMSO-d6): δ 4.05–4.02 (2H, dd, CH2 J = 15.2 Hz), 4.88–4.62 (1H, t, CH J = 11.4 Hz), 8.32–7.46 (6H, m, Ar\\H); 13C NMR (500 MHz, DMSO-d6): δ 39.97 (1C, CH2 isoxazoline), 86.74 (1C, CH isoxazoline) 126.75–134.88 (12C, Ar\\C), 156.93 (1C, isoxazoline); MS: m/z 406 (M+ + 1). 2.4.4.3. 2-(3-(2-Bromo-4-chlorophenyl)-4,5-dihydroisoxazol-5-yl)-6methoxyphenol (4c). Creamish white solid; IR (KBr, cm−1): υmax 1670 (C_N), 1616 (C\\C); 1H NMR (500 MHz, DMSO-d6): δ 3.89–3.72 (2H, dd, CH2 J = 12.5 Hz), 5.23–5.11 (1H, t, CH J = 10.7 Hz), 7.98–7.40 (6H, m, Ar\\H); 13C NMR (500 MHz, DMSO-d6): δ 39.91 (1C, CH2 isoxazoline), 87.56 (1C, CH isoxazoline), 128.86–137.69 (12C, Ar\\C), 155.98 (1C, isoxazoline); MS: m/z 383 (M+ + 1).

2.4.4.5. 2-(3-(2-Bromo-4-chlorophenyl)-4,5-dihydroisoxazol-5-yl)benzoic acid (4e). IR (KBr, cm− 1): υmax 1680 (C_N), 1592 (C\\C); 1H NMR (500 MHz, DMSO-d6): δ 5.12–5.25 (2H, dd, CH2 J = 12.8 Hz), 6.08– 5.81 (1H, t, CH J = 9.5 Hz), 8.07–7.36 (7H, m, Ar\\H), 12.56 (1H, s, COOH); 13C NMR (500 MHz, DMSO-d6): δ 39.96 (1C, CH2 isoxazoline), 88.11 (1C, CH isoxazoline), 127.55–142.22 (12C, Ar\\C), 158.43 (1C, isoxazoline), 165.85 (1C, Ar\\COOH); MS: m/z 381 (M+ + 1). 3. Results and discussion There are different molar ratios of salt (benzalkonium chloride) and hydrogen bond donor (urea) was used to prepare DES (Table 1). The amount of benzalkonium chloride (BZK) was fixed with the change in the concentration of urea. Among different DESs prepared, the first three DES was colorless clear liquid event at room temperature. But rest of the DESs (DES 4, DES 5) was found to be turbid with some solid particles. The solid appeared in these DESs might be urea particles which was unreacted and precipitated as such. Excess urea particles create hindrance to make hydrogen bond with their counterpart's i.e. benzalkonium chloride. The two unsuccessful ratios of DESs (DES4 and DES5) were not considered for any physical or spectroscopic study. The other higher molar ratio of DESs was not prepared due to precipitation of urea particles from the mixture. Moreover, three successful molar ratios, 1:1, 1:2 and 1:3 were selected for measuring the physical (density, viscosity, conductivity, refractive index, pH and freezing point) and spectroscopic (IR, NMR, XRD) properties. 3.1. Physical properties of DESs 3.1.1. Refractive index Refractive index (RI) is an important property. It is measured in terms of speed of light travelled through vacuum and given sample. Refractive index depends on electrical and magnetic permeability of substances. It provides material purity or concentration as a function of temperature of three prepared DESs. In general, the value of RI increased with the rise in temperature. The effect of hydrogen bond (HBD) in the RI was very marginal observed (Table 2). 3.1.2. Conductivity Conductivity is another important physical properties needs to be discussed. Generally high viscosity substance exhibits poor ionic conductance [2]. Ionic conductance was determined as a function of temperature in mS/cm. Conductivity of all the tested DES mixture was increased with increasing temperature. Simple kinetic energy theory involved in these phenomena, where frequency of collision between molecules randomly increased with the rise in temperature and that leads Table 2 Physical properties of DESs against different temperature. Physical properties

Refractive indices

Conductivity (mS)

pH

2.4.4.4. 4-(3-(2-Bromo-4-chlorophenyl)-4,5-dihydroisoxazol-5-yl)benzoic acid (4d). IR (KBr, cm− 1): υmax 1689 (C_N), 1600 (C\\C); 1H NMR (500 MHz, DMSO-d6): δ 5.43–5.55 (2H, dd, CH2 J = 14.5 Hz), 6.39– 6.00 (1H, t, CH J = 9.8 Hz), 8.13–7.45 (7H, m, Ar\\H), 12.85 (1H, s, COOH); 13C NMR (500 MHz, DMSO-d6): δ 39.93 (1C, CH2 isoxazoline), 89.19 (1C, CH isoxazoline), 125.69–143.28 (12C, Ar\\C), 156.76 (1C, isoxazoline), 166.94 (1C, Ar\\COOH); MS: m/z 381 (M+ + 1).

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Density (g/cm3)

Viscosity (cP)

Molar ratio (BZK:UREA)

1:1 1:2 1:3 1:1 1:2 1:3 1:1 1:2 1:3 1:1 1:2 1:3 1:1 1:2 1:3

Temperature (°C) 20

30

40

50

1.457 1.446 1.452 12.6 11.90 2.27 8.29 8.33 8.32 1.10 1.18 1.28 128 133 141

1.453 1.443 1.449 14.03 12.32 3.03 7.63 7.77 8.01 1.07 1.16 1.23 115 126 136

1.448 1.440 1.444 14.82 12.90 3.33 7.32 7.55 7.78 1.04 1.11 1.20 111 119 132

1.439 1.438 1.441 15.89 14.01 3.52 7.30 7.46 7.42 1.02 1.09 1.12 107 116 129

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to weaken the intermolecular forces due to which ionic conductivity was increased [19]. Amount of hydrogen bond donor also affects ionic conductivity of the different molar ratios of BZK:urea (Table 2). The maximum and minimum conductivity of DESs was 15.89 mS/cm at 50 °C and 2.27 mS/cm at 20 °C respectively. It has been clearly observed that as the concentration of urea increased, the conductivity was drops accordingly. The ionic conductivity was found almost similar in the molar ratios of 1:1 and 1:2 (BZK:urea) in respective temperatures, but it was drastically decreased 5–6 folds. This was again due to the weak intermolecular bonds between hydrogen bond donor (Urea) and accepter (BZK). As we increased the amount of urea it weakens the bonds between the two, and conductivity decreased proportionally. 3.1.3. pH pH dictates the properties such as catalysis, acidity, basicity, solubility in various organic reactions and pharmaceutical formulations. Basicity drops down with increasing temperature (Table 2) in all three DESs under study. Effect of HBD was observed in the molar ratio of 1:3 where concentration of urea was high and the value of pH (basicity) was also found highest among DESs. 3.1.4. Density Density is one of the important physical properties which define the mobility of solvents. Temperature has significantly affects the properties of substances and three selected DES are formed by BZK and urea has same case. Many experimental and theoretical studies have proved that as the temperature raises hydrogen bonding life time per molecule and density decreases [34,35]. Density of selected DESs has been found decreasing linearly with increasing temperature (Table 2).

Fig. 2. ORTEP diagram: dashed line showed intermolecular hydrogen bonding between urea and BZK (1:2).

as concentration of hydrogen bonds donor increases the depression in freezing point value was enhanced. 3.2. Spectroscopic properties

3.1.5. Viscosity Viscosity is an important measurement of fluids internal frictional properties which relates the resistance of a substance to flow [35]. DES viscosity is higher in comparison to organic solvents [35]. In this experiment viscosity of three selected DESs as expected decreases with increasing temperature (Table 2). It was also found that as the amount of hydrogen bond donor (urea) increases the viscosity values dampened.

3.2.1. FT-IR There are all FT-IR spectra of urea (A), BZK (B), and three mixtures 1:1 (C), 1:2 (D), 1:3 (E) was evaluated to predict possible complex formation. There was a prominent NH stretching and NH bending vibrations were observed at 3424 and 1635 cm− 1 respectively of urea molecule (Fig. 1). These characteristic peaks of NH were either blurred or almost disappeared in all prepared BZK:urea mixtures. Association of BZK with urea largely depends on the hydrogen bonding this in turn depends on the concentration of urea. It was postulated that as the concentration of hydrogen bond donor (urea) increases, interaction between two (BZK and urea) decreases and hydrogen bond life time was best when the ratio of benzalkonium chloride and urea is 1:2 [12, 18,24] and melting point was also decreased.

3.1.6. Freezing point (Tf) DES is formed by mixing of two components by self-association through hydrogen bonds. New mixture is generally characterized by a lower in freezing point than their individual component. Here, benzalkonium chloride has freezing point −1 °C and urea has 133 °C. The freezing point of eutectic mixture was −6 °C, −12 °C and −16 °C for the molar ratios 1:1, 1:2 and 1:3 respectively which is considerably much lower than individual component. Results clearly indicated that

3.2.2. NMR NMR is an important technique to elucidate molecular structure identification. In present research NMR spectra of urea and the mixtures was evaluated to confirm the stability of prepared DESs. In proton NMR, characteristics peak of urea was observed due to NH at δ 5.68 ppm. Considering the ideal DES (1:2) same peak was downfield by some margin and appeared at δ 5.74 ppm. 13C NMR of carbonyl carbon of urea was observed at δ 160.44 ppm, in complex it was downfield and appeared at

Fig. 1. FT-IR Spectra of (A) BZK:Urea (1:1), (B) BZK:Urea (1:2), (C) BZK:Urea (1:3), (D) BZK and (E) Urea.

Fig. 3. XRD pattern of (A) Urea (B) BZK:Urea (1:2) (DES).

M.A. Bakht et al. / Journal of Molecular Liquids 224 (2016) 1249–1255 Table 3 Effect of DES and other conventional solvents in the synthesis of isoxazoline derivatives by NUS and US methods. Entry

Reaction medium

Reaction conditions

Temperature (°C)

Yield (%)

1. 2. 3. 4.

Glacial acetic acid Sodium hydroxide DES (BZK:Urea) DES (BZK:Urea)

NUSa NUSa NUSb USc

155 162 80 RT.

65 48 77 85

Table 4 Synthesis of isoxazoline derivatives (4a–e) by thermal (NUS) and ultrasonic method catalyzed by deep eutectic solvent (DES).

Reaction time

a

NUS (thermal method): chalcone (0.005 mol), hyrdoxylamine hydrochloride (0.005 mol), solvent (20 mL), reaction time = 15 h. b NUS (thermal method): chalcone (0.005 mol), hyrdoxylamine hydrochloride (0.005 mol), DES as solvent (BZK:Urea: 1:2, 8 g), reaction time = 5 h. c US (ultrasonic method): chalcone (0.005 mol), hyrdoxylamine hydrochloride (0.005 mol), DES as solvent (BZK:Urea: 1:2, 8 g), reaction time = 1 h.

160.81 ppm. Shifting of peak in both cases was again due to intermolecular hydrogen bond between BZK and urea. Most stable mixture (1:2) of DES was also confirmed by ORTEP diagram (Fig. 2) representing intermolecular hydrogen bonding between benzalkonium chloride and urea.

3.2.3. X-ray diffraction study In order to clarify the prepared structure one of the DES (1:2) was selected for X-ray diffraction study. There was a sharp peak of urea was observed, but disappeared in XRD pattern of DES and looks hazy (Fig. 3). This phenomenon demonstrates that there was a certain intermolecular hydrogen bond between the BZK and urea formed through self-assembly.

3.3. Mechanochemical method for the synthesis of chalcone Mechanochemical, grinding technology was used for the synthesis of chalcone. This approach is a cost effective and energy saving as compared to conventional heating. This method also improved the yield up to 95% in just 5 min without involving lengthy work up procedure.

Yield (%)

NUS (h)

US (min)

NUS

US

NUS

US

Energy saved (%)

4a 4b 4c 4d 4e

4 5 4.5 4 4.5

55 49 60 52 50

71 58 66 69 63

85 83 81 80 78

4.78 4.62 5.35 4.48 5.67

0.66 0.60 0.67 0.58 0.66

86 87 87.5 87 88

3.4. Study of significant attributes of benzalkonium chloride and urea (1:2) based DES in the synthesis of isoxazolines To facilitate the efficiency of the method with conventional routes, we have conducted synthesis of isoxazoline derivatives (4a–e) in two classical solvents, glacial acetic acid & sodium hydroxide and other biocompatible solvent called deep eutectic solvent (DES) prepared from benzalkonium chloride and urea (BZK:urea: 1:2) as presented in Table 3. The most stable mixture of DES (1:2) was selected for the present reactions as suggested by physical and spectroscopic properties. It was also evidenced by some literature [10,12,25] that ratio (1:2) is better in terms of solubility, toxicity and cost effective as compared to ionic liquids. A schematic representation has been shown in scheme 1. The results obtained in conventional method were low in terms of yield, even after heating continuously for several hours. There was improvement in yield% using DES (BZK:Urea) as compared to conventional solvents. In order to observe the effect of ultrasound, in second experiment repeated the same using only DES. In this method, the yields of desired compounds were markedly improved at the expense of less time i.e. around 1 h. Furthermore, the results also indicated the combined effect of ultrasound and DES to be better than their individual effect (Table 3).

Ar

O

Cl

Grinding method

+

+

H O

Energy utilized (kJ/g)

Entry

Cl H3C

1253

Br

Ar

Br

O

2a-e

1

NH2OH/ HCl

NaOH

3a-e

Ar 4-chlorophenyl 2,4-dichlorophenyl

US Method NUS Method DES, room temp. GAA/NaOH/DES

2-hydroxy-3-methoxyphenyl 4-carboxyphenyl 2-carboxyphenyl

Cl

Br N Ar

O 4a-e

Scheme 1. Thermal and ultrasonic mediated synthesis of isoxazoline derivatives catalyzed by Benzalkonium chloride and urea (1:2) based deep eutectic solvent (DES).

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(reaction). It was noticed that there was slight decrease in % yield in each run (Fig. 4). This may be due to-(i) decrease in the efficiency of DES, (ii) effect of ultrasound and eutectic combination after each run, (iii) some amount of DES may be wasted during work up. 3.6. Plausible mechanism involved in the formation of isoxazolines 3.6.1. Role of DES Mechanism involved in the formation of isoxazoline needs to be justified. Many of existing literature explain the role of DES in the formation of their desired product [10,12,18,24] but still the exact mechanism is not clear. Although, the mechanism involved in the formation of isoxazoline derivatives (4a–e) could be explained by the reaction sequence (Scheme 2). Catalytic nature of DES might be due to weak acidic nature of benzalkonium chloride (BZK) and hydrogen bond donor ability of urea which influence the formation of desired compounds. The stepwise chemical rearrangement, dehydration and cyclization leads to the product under investigation.

Fig. 4. Recyclability study of DES-US catalyzed reactions of isoxazoline derivatives.

Considering the thermal method (NUS) reaction took 15 h to complete using glacial acetic acid and sodium hydroxide, but the yield was found to be 65 & 48%, respectively. Repeating the same reaction guided by thermal method using DES as reaction medium, there was 10% rise in the yield and time of reaction also decreased by three fold (Table 4). In another way, combining DES and ultrasound showed marked improvement in the % yield with reduced reaction time. Reaction took just around 49–60 min compared to 4–5 h by thermal method (Table 4). DES and US led reactions were also found better in terms of energy efficiency against thermal method. Energy utilized by each reaction in the present scheme (4a–e) is shown in Table 4. All the energy calculations were found in Appendix A in supplementary material. A maximum of 88% energy was saved in this process.

3.6.2. Role of ultrasound Moreover, role of ultrasound in the synthesis of isoxazoline derivatives was also addressed. Under sonic condition, there is growth and generation of plenty tiny bubbles as a result of high pressure and temperature for a very short time inside the reaction medium [10,24,26]. Superiority of ultrasound comparison to other energy sources (such as heat, light) in duration, pressure and energy per molecule were also highlighted [36]. The immense local temperature and pressure creates extraordinarily heating and cooling generated through cavitation bubble collapse. As a result, extreme microscopic conditions are created within these bubbles such that substrates participating in reactions are converted to highly reactive species, thereby assisting in faster rearrangement, dehydration and cyclization process [10].

3.5. Recyclability of Benzalkonium chloride and urea (1:2) based DES Recyclability of attribute of deep eutectic solvent was also studied. The DES recovered from each batch was re-used for the next run Ar

H

H

H

O

N H N

O

H3C

O

Br

N

H O

CH3 -Cl

Cl

H

Br Ar

N H

H

N

O-:NH2

H Cl HO

O

N H

Br

H Ar O-:NH2

Cl Cl

Br

Cl -H2O

Ar

N O

Ar

O

O

H Br

H

N

Scheme 2. Plausible reaction mechanism involving role of DES in the formation of isoxazoline derivatives.


It has been postulated that ultrasound and its secondary effect of cavitation produces physical and chemical effect on a reaction system, which largely help to the enhancement of the kinetics and yield [37]. Physical effects are observed through intense micro-convection generation in reactions which gives rise to improvements in mass transfer of the system. Chemical effects include formation of solvent vapor molecules due to thermal decomposition in the cavitation bubble resulting in generation of smaller molecular species that may leads to product formation. 4. Conclusions In conclusion, we developed a novel deep eutectic solvent by mixing of benzalkonium chloride and urea. The new DESs has well characterized by physical and spectroscopic properties. One of the most stable DES (BZK:urea, 1:2) was used to synthesized isoxazoline derivatives under ultrasonic irradiation. These studies also explore various possibilities for the synthesis of isoxazoline derivatives including greener alternative of deep eutectic solvent with ultrasound driven reactions. Successfully five derivatives of isoxazoline were synthesized by thermal method (NUS) and ultrasonic (US) method using conventional solvents and benzalkonium chloride based deep eutectic solvent (DES). Performance evaluation was observed in terms of reaction time, % yield and energy utilization by each method. US-DES took maximum 60 min to afford the product as compared to NUS and NUS-DES driven reactions which took 15 h & 5 h, respectively. The yield of the product was also improved in case of US-DES method and it was as high as 88%. In short, deep eutectic solvent prepared from benzalkonium chloride and urea can be a good alternative to harsh organic solvents (Ionic liquids) with cost effective, biodegradable, and recyclable nature. This new DES will be a hope for large sector of industry as solvent as well as catalyst. Acknowledgments Authors are thankful to the Prince Sattam bin Abdulaziz University for providing necessary facilities for the present research. Appendix A. Supplementary data Supplementary data to this article can be found online at http://dx. doi:10.1016/j.molliq.2016.10.105. References [1] P. Conti, M.D. Amici, G. Grazioso, G. Roda, A. Pinto, K.B. Hansen, B. Nielsen, U. Madsen, H. Bräauner-Osborne, J. Egebjerg, V. Vestri, D.E. Pellegrini-Giampietro, P. Sibille, F.C. Acher, C.D. Micheli, J. Med. Chem. 48 (2005) 6315–6325.

1255

[2] D. Nauduri, G.B. Reddy, Chem. Pharm. Bull. 46 (1998) 1254–1260. [3] P. Mondal, S. Jana, A. Balaji, R. Ramakrishna, L.K. Kanthal, J. Young Pharm. 4 (2012) 38–41. [4] I. Filali, J. Bouajila, M. Znati, F. Bousejra-El Garah, H. Ben, Jannet, J. Enzyme Inhib. Med. Chem. 30 (2015) 371–376. [5] M. Shaharyar, M.A. Ali, M.A. Bakht, V. Murugan, J. Enzyme Med. Chem. 23 (2008) 432–436. [6] L. Shi, R. Hu, Y. Wei, Y. Liang, Z. Yang, S. Ke, Eur. J. Med. Chem. (2012) 549–556. [7] J.S. Ghomi, M.A. Ghasemzadeh, J. Serb, Chem. Soc. 77 (2012) 733–739. [8] A. Tarraga, P. Molina, D. Curiel, M.D. Velasco, Tetrahedron 57 (2001) 6765–6774. [9] X. Lian, S. Guo, G. Wang, L. Lin, X. Liu, X. Feng, J. Org. Chem. 16 (2014) 7703–7710. [10] S.S. Balvant, R.L. Hyacintha, V.P. Dipak, J.J. Krishna, B.P. Aniruddha, S.S. Ganapati, Ultrason. Sonochem. 20 (2013) 287–293. [11] M. Hayyan, F.S. Mjalli, M.A. Hashim, I.M. Al Nashef, Fuel Process. Technol. 91 (2010) 116–120. [12] Q. Zhang, V.K. De Oliveira, S. Royer, F. Jerome, Chem. Soc. Rev. 41 (2012) 7108–7146. [13] R.M. Lau, F.V. Rantwijk, K.R. Seddon, R.A. Sheldon, Org. Lett. 2 (2000) 1–3. [14] K.P. Dhake, Z.S. Qureshi, R.S. Singhal, B.M. Bhanage, Tetrahedron Lett. 50 (2009) 2811–2814. [15] H. Olivier-Bourbigou, L. Magna, D. Morvan, Appl. Catal. A 373 (2010) 1–56. [16] J.T. Gorke, F. Srienc, R.J. Kazlauskas, Chem. Commun. 10 (2008) 1235–1237. [17] M. Hayyan, M.A. Hashim, A. Hayyan, M.A. Al-Saadi, I.M. AlNashef, M.E.S. Mirghani, O.K. Saheed, Chemosphere 90 (2013) 2193–2195. [18] A.P. Abbott, D. Boothby, G. Capper, D.L. Davies, R.K. Rasheed, J. Am. Chem. Soc. 126 (2004) 9142–9147. [19] B.S. Singh, H.R. Lobo, G.S. Shankarling, Catal. Commun. 24 (2012) 70–74. [20] S.Y. Wang, S.J. Ji, X.M. Su, Chin. J. Chem. 26 (2008) 22–24. [21] J.T. Li, X.L. Li, T.S. Li, Ultrason. Sonochem. 13 (2006) 200–202. [22] H. Zang, Y. Zhang, Y. Zang, B.W. Cheng, Ultrason. Sonochem. 17 (2010) 495–499. [23] A.B. Pandit, G.S. Shankarling, Ultrason. Sonochem. 18 (2011) 617–623. [24] T.J. Mason, Ultrason. Sonochem. 14 (2007) 476–483. [25] D.M. Gao, W.L. Ma, T.R. Li, L.Z. Huang, Z.T. Du, Molecules 17 (2012) 10708–10715. [26] J.S. Yadav, B.V.S. Reddy, K.S. Reddy, Tetrahedron 59 (2003) 5333–5336. [27] S.H. Chung, S.K. Lee, S.M. Cristol, S.M. Lee, E.S. Lee, D.W. Lee, K.Y. Seo, E.K. Kim, Mol. Vis. 12 (2006) 415–421. [28] B. Grillitsch, O. Gans, N. Kreuzinger, S. Scharf, M. Uhl, M. Fuerhacker, Water Sci. Technol. 54 (2006) 111–118. [29] S. Hosseyni, L. Wojtas, M. Li, X. Shi, J. Am. Chem. Soc. 138 (2016) 3994–3997. [30] D.W. Piotrowski, A.S. Kamlet, A.-M.R. Dechert-Schmitt, J. Yan, T.A. Brandt, J. Xiao, L. Wei, M.T. Barrila, J. Am. Chem. Soc. 138 (2016) 4818–4823. [31] P. Lederhose, N.L. Haworth, K. Thomas, S.E. Bottle, M.L. Coote, C. Barner-Kowollik, J.P. Blinco, J. Organomet. Chem. 80 (2015) 8009–80017. [32] N. Kumarswamyreddy, V. Kesavan, Org. Lett. 18 (2016) 1354–1357. [33] M.A. Bakht, Der. Pharm. Chem. 7 (2015) 274–278. [34] S.W. Dorota, P. Anna, S. Joanna, Cent. Eur. J. Chem. 6 (2008) 555–561. [35] Y. Rizana, A. Emilia, S. Kamaliah, R. Mohd, Basyaruddin Abdul, Molecules 19 (2014) 8011–8026. [36] J. Webster (Ed.), Ultrasonic Physical Mechanisms and Chemical Effects, Wiley Encyclopedia of Electrical and Electronics Engineering, John Wiley & Sons 1999, pp. 646–647. [37] V.S. Moholkar, H.A. Choudhury, S. Singh, S. Khanna, A. Ranjan, S. Chakma, J. Bhasarkar, R.L. Qi, Physical and Chemical Mechanisms of Ultrasound in Biofuel Synthesis, in: Z. Fang, J. Smith (Eds.),Production of Biofuels and Chemicals with Ultrasound, Biofuel. Bioref 2015, pp. 35–86.