Aza-Micheal Reaction in Glycerol as a Sustainable Hydrotropic Medium

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ScienceDirect Materials Today: Proceedings 2 (2015) 1792 – 1798

4th International Conference on Materials Processing and Characterization

Aza-Micheal Reaction in Glycerol as a Sustainable Hydrotropic Medium Santosh Kamble a*, Arjun Kumbharb, Sanjay Jadhav cand Rajashri Salunkhec a

Department of Chemistry, Yashavantrao Chavan Institute of Science, Satara-415001, India b Department of Chemistry, P.D.V.P. College, Tasgaon-416312, India c Department of Chemistry, Shivaji University Kolhapur-416004, India

Abstract The organic transformation carried out in suitable solvent as well as in presence of catalyst is more important due to its environmental impact. We try to optimize the organic transformation in aqueous hydrotropic solution because of it is a sustainable technique. Now days, the glycerine used as hydrotrope and it shows excellent hydrotropic properties. Glycerine has been show combine advantages of water like non-toxic, colourless, odourless liquid, large availability, renewability due to this important properties it recently proposed as a valuable green solvent. © 2014 The Authors. Elsevier Ltd. All rights reserved. © 2015 Elsevier Ltd. All rights reserved. Selection and under responsibility of theofconference committee membersmembers of the 4th International conference onconference Materials on Selection andpeer-review peer-review under responsibility the conference committee of the 4th International Processing and Characterization. Materials Processing and Characterization. Keywords: Glycerol, Hydrotropic Medium, Aza-Micheal Reaction

1.

Introduction

The elimination of hazardous solvents in chemical processes and their replacement by environmentally more benign reaction is important goal of modern synthetic chemistry. Aqueous solution of hydrotropes can be considered to be environmental benign reaction medium and is non-toxic, non-flammable, inexpensive and being a nonexhaustible. Hydrotropes are highly water soluble surface active organic salts that at higher concentration enhance the solubility of sparingly soluble as well as practically insoluble organic compounds in aqueous medium. This phenomenon was first reported by Neuberg in 1916 [1].The phenomenon of increasing solubility of normally insoluble or sparingly soluble compounds in water by a third component or additive is termed as Hydrotropy or Hydrotropism. The substance that causes the solubility enhancement is called Hydrotrope or Hydrotropic agent. The hydrotropes are characterized by an amphiphilic association structure [2]. Importance of hydrotropes and their many synergistic properties appeared when it combined with other amphiphilic molecules [3, 4]. * Corresponding author. Tel.: +91-02162-234392; fax: +91-02162-234392.. E-mail address:[email protected]

2214-7853 © 2015 Elsevier Ltd. All rights reserved. Selection and peer-review under responsibility of the conference committee members of the 4th International conference on Materials Processing and Characterization. doi:10.1016/j.matpr.2015.07.022

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Hydrotropes normally comprise hydrophilic and hydrophobic moieties, the hydrophobic moiety being typically too small to induce micelle formation [5]. The volume of the hydrophobic parts of the studied additives roughly evaluated by simple calculations which shows efficiency of hydrotrope. Generally larger is the parts of additives better is the hydrotropic efficiency and in contrast the hydrophilic part carrying a charge or not is of minor importance. Therefore the hydrophobic part of the molecule is the key matter in hydrotrope [6]. The mechanism of self association of hydrotropes being suggested by non-cooperative[7] as well as cooperative self aggregation [810]. Hydrotropes form aggregates in aqueous solution that are reminiscent of surfactant micelles and the formation of associated structures important to show hydrotropic effect. The characteristic aggregation of hydrotrope induces the origin of the solubilization process of sparingly soluble hydrophobic compound in water in analogy to a micillization process [11].The ability of hydrotrope to increase the solubility of organic compounds in water is strongest when the hydrotrope concentration is sufficient to induce the formation of associated structure and after which solubilities remain unchanged [12]. After certain threshold concentration the sudden increase in solubilisation by hydrotropes, called as minimum hydrotrope concentration (MHC). Minimum hydrotropic concentration changes when solution properties changes such as, viscosity, conductivity, surface tension and solubility. The relatively high concentration required to reach MHC. Kumar et.al reported a novel approach for reducing the MHC [13]. Aggregation and MHC are the exact mechanism of solubilisation by hydrotropes [14]. The most important is the presence of minimum hydrotrope concentration (CHC or MHC) analogues to minimum micellar concentration (CMC). The solubilisation of organics in hydrotropes differ from the other typical salting-in compounds and cosolvents, in this the solubility increases sigmoidally depending on the concentration of hydrotrope. The salting-in cosolutes and cosolvents at higher concentration usually cause a monotonic increasing solubility without leveling off [15]. Hydrotropes are more effective in solubilising organic solutes and more selective than the micelle-forming surfactant [16, 17]. The self aggregation of hydrotropes are differs from that for micelles [18]. A crucial difference between hydrotrope and micelle-forming surfactant becomes distinguish from the phase diagram of their respective aqueous solution. The micelle-forming surfactant shows lamellar liquid crystal region in their aqueous solution while this region are not observed in the aqueous solution of hydrotropes. The lamellar region separates the normal micellar solution from the inverse micellar one. Phase diagram of aqueous solution of hydrotropes display a single continuous isotropic liquid phase [19-21]. Hydrotrope have been applied in household liquid detergents, shampoos, degreasing compounds and printing paste, used to extract pentosans and lignins in the paper industry and additives for glues used in leather industry [22]. The various areas have been benefited by the use of hydrotropes. Aqueous solution of hydrotropes represents the unique properties of an alternative reaction media for organic synthesis. Besides being a cheap, non-toxic and environment friendly, aqueous hydrotropic solutions possess the other physico-chemical characteristics required to be an alternative greener solvents for organic transformations. The various organic transformations carried out in hydrotropic aqueous medium are beneficial, for example, Claisen-Schmidt reaction in hydrotropic aqueous solution [23], in the microwave-enhanced Hantzsch dihydropyridine ester synthesis [24], in synthesis of quinolines by Friedlander′s Heteroannulation method [25]. In addition, hydrotrope enhance the rate of multiphase reaction [26,27] which can lead to autocatalysis in the biphasic alkaline hydrolysis of aromatic esters [28].The hydropes are also used in variety of applications other than organic synthesis such as, in formulation of pharmaceuticals [29-33], extraction and separation processes [34-35] and the most recent research of hydrotropic action has been performed on these above two processes. They show influence on oil-in-water (OW) for microemulsions [36-37] and related cleaning and washing processes. Their biological action has also received more attention [38].

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The glycerine is higly stable and compatable with other solvents. Kaila Westerman [39]reported that, many things are soluble in glycerine easier than water and alcohol, therefore it acts as excellent solvent. Royal Society of Chemistry investigated the most widespread hydrotropes are ethers which come from ethylene glycol but problem with these compounds is that they are toxic and have been banned for pharmaceutical, medical and domestic use. Glycerol derivatives are good non-toxic substitutes which possesses comparable hydrotropic properties. As a solvent, when glycerol dissolves in water, it prevents the liquid from attaining any staying power, and so the liquid can no longer coat or attach itself to another surface. 2. Experimental Melting points were determined in an open capillary and are uncorrected. Infrared spectra were recorded on a Perkin-Elmer FTIR spectrometer. The samples were examined as KBr discs ~5% w/w. 1H NMR,13CNMR and DEPT spectra were recorded on a Bruker Avon 300 MHz spectrometer using CDCl3 as solvent and TMS as internal reference. The 50% glycerin solution prepared from commercially available glycerin in distilled water. All other chemicals were obtained from local suppliers and used without further purification.

General procedure for synthesis of β-amino nitrile A mixture of and α, β-unsaturated compound (1mmol) and amine (1 mmol) in 5 mL of aqueous 50 % glycerin solution was stirred at room temperature. The completion of the reaction as monitored by thin layer chromatography. After completion of the reaction the product was extracted in ether after evaporating ether the crude β-amino nitrile is obtained. 3. Result and Discussion We focused our attention on the use of glycerin in aqueous medium for Aza-micheal reaction. Initially we prepared the different concentration of glycerin in water and carry out the reaction for each concentration to observe that, the 50% concentration is suitable for this transformation and gives high yield of the product (Fig.1.1). Therefore we opted to use 50 % aqueous solutions of selected hydrotropes. Next, we turned our attention to the synthesis β-amino nitriles by Aza-micheal reaction in 50% glycerin solution (Scheme1). The dilution of glycerin because of it restricte the staying power of liquid, and liquid dose not attach itself to another surface.

Fig.1.1

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A series of experiments were undertaken in which a mixture of α, β-unsaturated compound and amine was stirred in 5 mL of 50 % of aq. glycerin solution in an open air at room temperature. Preliminary investigations carried out at room temperature yielded quantitative results. The hydrotropic solution of glycerin was found to be better alternative as compared to other existing method. The stupendous increase in the percentage conversion as well as rate of reaction in 50% glycerin solution.

R1 N

H

R

+

R2

R

R1

50% Glycerine Solution

N R.T.

R = -CN, -COO-nBu

R2

Scheme1 We employed this particular hydrotrope for subsequent studies. To explore versatility of the protocol, a series of β-amino nitrile were synthesized by the reaction of α, β-unsaturated compound with differently substituted amines in 50 % glycerin solution. The results of the reactions are summarized in Table 1.1.With both electron-poor and electron-rich amines, the corresponding β-amino nitrile was obtained in good to excellent yields. The Aromatic, benzylic, Primary, secondary (cyclic, acyclic and heterocyclic) amines gives excellent yield. Reaction of the sterically hindered amines even gave higher yield of the product highlightening the general applicability of the protocol. Table 1.1: Synthesis of β-amino carbonyl compound in 50% of aq. glycerin solution. Entry

Amine

α, β-unsaturated compound

1 O

2

N

H

Et N

H

CN

CN

N

CN

N

Et N

N

CN

Time (Min.)

Yield%

3

95

4

93

2

94

2

96

CN

N

N H

CH2-CH2-CN

N

4

O

Et

Et

3

Product

N

CN

N

N

H

CH2-CH2-CN

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5

CN N

N

H

N

H

CN

7

O

O

Me

O

N

H

N

Me

O

86

7

87

6

93

8

88

7

91

4

94

Me

O

N

H

N

O

O

N

N

O N

O

O

H

O

Et

O

O

N Et

12

5

O

N

O

N

11

95

O

O

O

Me

CN

N

O

O

10

3

CH2-CH2-CN

6

9

90

N

H

8

5

NH2

H

Et N

O

O

Et

CN

H

N

CN

a

All products were characterized by 1H NMR and IR spectroscopy. Isolated yields after chromatography c Literature values in parenthesis b

The note worthy feature of all these reactions was ease of product separation. It can be separated from aqueous solution by ether extraction method. The product obtained by evaporating ether. The identity of all the compounds was ascertained on the basis of IR, 1H NMR, 13C NMR and mass spectroscopy data and is in consistent with the literature.

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Spectral Analysis N-Cynoethyl imidazole (Table 1.1Entry-4) IR (neat, thin film): υ = 3093,2971, 2924,2245, 1895,1736. 1 H NMR(300Mz, CdCl3):δ 2.79 (m, 2H), 4.39 (m, 2H), 7.2 (m, 2H,), 7.7 (m, 2H). 13 C NMR: 19.159, 40.587, 108.85, 120.90, 122.85, 123.60, 142.43 DEPT: The two –CH2 carbon appeared at 19.159 and 40.58 N-Cynoethyl aniline (Table 1.1 Entry-12) IR (neat, thin film): υ = 3360,3004, 2926, 2249, 1603,1505. 1 H NMR(300Mz, CdCl3):δ2.59 (m,2H),4.09(m,2H), 6.5(m, 2H,),7.1(m3H). 13 C NMR: 18.04, 39.77, 113.02, 115.02, 118.05, 118.50, 118.60,129.25, 129.52, 146.11, 146.32, 170.85 DEPT: The two –CH2 carbon appeared at 18.04 and 39.77 Conclusion We develop efficient and green methodology for Aza-Micheal reaction. The 50% glycerin solution acts as green solvent without causing any environmental issue. Synthesis of β-amino nitrile achieved by simple experimental procedure in short reaction time with high yield.

Acknowledgments We gratefully acknowledge the financial support from the Department of Science Technology (DST-SERB) for awarding major research project under the scheme Empowerment and Equity Opportunities for Excellence in Science and the Y. C. Institute of Science, Satara for providing necessary facilities.

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