Research Journal of Chemical Sciences ______________________________________________ ISSN 2231-606X Vol. 5(5), 85-88, May (2015) Res. J. Chem. Sci. International Science Congress Association 85 Ionic liquid as Green solvent for aa-alkylation of Active Methyelne Compounds Kotian Geeta* Department of Chemistry, St. Xavier’s, Autonomous, College, Mumbai 400 001, INDIAAvailable online at: www.isca.in, www.isca.me Received 11th May 2015, revised 14th May 2015, accepted 18th May 2015 AbstractA selective monoalkylation of active methylene compounds with various alkyl halides in 1-butyl-3-methylimidazolium hexafluorophosphate [bmim] [PF] ionic liquid is reported here. The product can be recovered by vacuum distillation and the ionic liquid can be recycled without any loss in yield. Keywords: Alkylation, phenylacetonitriles, diphenylacetonitrile, ionic liquid, ethyl acetoacetate, diethyl malonate. Introduction Organic reactions have been studied in conventional molecular solvents for decades. Release of these volatile organic solvents in the atmosphere causes detrimental effects on environment and human health. In today’s environmentally conscious world, the focus is on developing ‘greener technologies’ that would solve dual purposes, i.e. develop modern techniques, that are not only eco-friendly but also solve the purpose of advancement of science in a truer sense. Room temperature ionic liquids (RTILs) are a new class of solvent formed by the direct combination of organic cation such as N-alkyl-pyridinium or 1-alkyl-3-methylimidazolium and inorganic anions like haloaluminate, hexafluorophosphate and tetrafluoroborate. With the increasing global demand for developing environmentally safer technology as well as the replacement of VOC’s, ionic liquids are gaining immense popularity. This is due to their negligible vapor pressure, non-flammability, unique solvating power and recyclability. Hence, they are rightly considered as ‘greener solvents’. Reports show a variety of reactions having been carried out in room temperature ionic liquids ranging from electrophilic reactions1,2, hydrogenation, Wittig reaction, heterocyclic synthesis5,6, to nucleophilic substitution reactions7,8. Several reviews on this novel solvent have been reported9-12. C-C bond formation is an important reaction in organic synthesis. The -alkylation reaction of phenylacetonitrile is of commercial importance due to the use of the -alkylated derivatives as pharmaceutical intermediates13. Drugs like oxeladine, pentapiperide, phenoperidine, dicyclonine, etc. have been synthesized through alkylation of phenylacetonitrile with various alkyl halides. Methods for the alkylation of esters and nitriles have been reviewed14. These procedures generally involve the use of hazardous and expensive condensing agents like NaNH, metal hydrides, triphenylmethide, potassium tertiary butoxide, alkoxides, etc, and use of strictly anhydrous organic solvents, ether, benzene, DMF, DMSO, liq. NH. These reagents demand an inert atmosphere. Without protection from atmosphere afforded by the solvent vapour or by an inert gas, many of the bases are rapidly attacked by molecular oxygen, resulting in lowering of yields. Besides this, solvents like DMSO and DMF pose general problems of odour as well as the difficulty encountered in separating these solvents from the products. Till date, use of phase transfer catalysts is the simplest method for the alkylation of various active methylene compounds15. Our continued search for ‘greener methods’ of synthesis and the established utility of RTILs, as environmentally benign solvents, prompted us to study alkylation of a few active methylene compounds, phenylacetonitrile (1), diphenylacetonitrile (5), ethyl acetoacetate (8) and diethyl malonate (9) with different alkyl halides in 1-butyl-3-methylimidazolium hexafluorophosphate [bmim] [PF] ionic liquid using KOH as a base. The [bmim] [PF] was prepared by the procedure reported in literature16. The results of alkylation of (1) and (5) with different alkyl halides (2) are given in table-1. Materials and MethodsMaterials: All the reagents and chemicals were procured from commercial sources (SD Fine Chemicals, India). 1-methylimidazole (Merck-India) was dried, distilled and stored over KOH and ethyl acetate was dried over CaH. 1-butyl chloride (Aldrich, USA) was used without further purification. MARS 5 microwave oven digester supplied by CEM Corporation was used for preparation of quaternary salt 1-butyl-3-methylimidazolium chloride17. Research Journal of Chemical Sciences ___________________________________________________________ ISSN 2231-606XVol. 5(5), 85-88, May (2015) Res. J. Chem. Sci. International Science Congress Association 86 CNRX KOH[bmim][PF CN CN R + 1 2 3a: R = Et 4a: R = Et R= Et, nPr, 3b: R = nPr 4b: R = Pr nBu, PhCH- 3c: R= nBu 4c: R = Bu X= Br, Cl 3d: R= PhCH- 4d: R=PhCH- CN PhRX KOH[bmim][PF CN Ph 5 6 7a: R = Et R= Et, nPr, allyl 7b: R = nPr X = Br 7c: R = allyl RCHCOOEt + nPrBrCO or KOH[bmim][PF RCHCOOEt + RCCOOEtnPrBr nPrBr nPrBr 8: R = COCH 10 11a: R = COCH 12a: R = COCH3 9: R = COOEt 11b: R = COOEt 12b: R = COOEtScheme-1 Alkylation of active methylene compounds with different alkyl halides in [bmim] [PF] ionic liquid Preparation of 7c: In a typical reaction, diphenylacetonitrile (5) (0.97 g, 5 mmol) was dissolved in 2 ml of [bmim][PF] ionic liquid, to it allylbromide (0.73 g, 6 mmol) and KOH (0.56 g, 10 mmol) were added and stirred at 70C for 50 min. The reaction mixture was neutralized by adding dil. HCl, followed by extraction with EtO and washing twice with HO. The EtO layer was then passed through sodium sulphate and evaporated. The resultant product was obtained in the pure form, analyzed by GC (SE-30 column on Eshita model with FID and N as gas-carrier) and no further purification was necessary. The ionic liquid was recovered andreused.Yield 99%, IR (KBr): = 2237 cm-1 (CN stretching) ; H NMR of 7c, (300 MHz, CDCl): = 3.12 (d, 2 H, J=1.08 Hz, C-CH), 5.14-5.25 (m, 2H, =CH), 5.62 (m, 1H, CH), 7.3- 7.42 (m, 10 H, arom) H NMR of 3a, (300 MHz, CDCl): = 1.06 (t, 3 H, CH), 1.93-1.98 (m, 2H, -CH), 3.73 (m, 1H, CH), 7.3- 7.4 (m, 5H, Harom). Note: In case of entries 1-4 (table-1) and 1-2 entries (table-3) the products were purified by column chromatography using CHCl/ Petroleum-ether (3:2) as the eluent. Results and Discussion We observed that with equimolar amount of KOH the reaction did not proceed, it was only with 2 equivalents of KOH that the product formation (monitored on TLC) was observed. Hence, we kept the concentration of KOH in all cases as 2 equivalent. Besides this, solid KOH was present in the system during the entire course of the reaction. This could be attributed to the low nucleophilicity of the ionic liquid-KOH mixture which allows only surface reactivity. Research Journal of Chemical Sciences ___________________________________________________________ ISSN 2231-606XVol. 5(5), 85-88, May (2015) Res. J. Chem. Sci. International Science Congress Association 87 Table -1Results of alkylation of 1 and 5 in [bmim] [PF] Entry Substrate RX Time (h) Temp ( 0 C) Product Yield (%) b 1. 1 EtBr 3.5 40 3a 73 c 2. 1 n - PrBr 1.5 70 3b+4b 84 d 3. 1 n - BuBr 1.7 75 - 80 3c+4c 75 e 4. 1 PhCH 2 Cl 4.5 75 - 80 3 94 5. 5 EtBr 2.5 40 7a a 95 6. 5 n - PrBr 1 70 7b a 100 7. 5 CH 2 =CHCH 2 Br 0.8 70 7c a 99  \n  Yields are based on GC analysis 100 % selectivity of 3a 88 % selectivity of 3b and 12 % 4b 99.7 % selectivity of 3c and 0.3 % 4c The reaction of 1 with n-PrBr was carried out both at room temperature as well as at 70 C. At both the temperatures the reaction took place, but at rt it took 3.5h to give 62 % 3b and 4.5 % of 4b; whereas at 70 C within 1.5 h 75 % 3band 9 % of 4b were obtained. In order to avoid the use of a solvent during the work-up, we carried out a 15 mmol reaction of with n-PrBr under identical conditions. After the reaction was complete, the ionic liquid layer containing the reactants and product was transferred to a micro distillation assembly and the product was vacuum distilled. To compare the preference of the ionic liquid [bmim][PF] with a molecular solvent in the nucleophilic reaction, we carried out the reaction of 1 with 1-BuBr under identical conditions in DMSO, which is highly polar solvent and highly favourable for an nucleophilic substitution reaction. When DMSO was used as a solvent 67 % 3c and 14 % 4c were formed; whereas in the case of ionic liquid 75 % 3c and just 0.2 % 4cwere obtained. Though the yields were nearly the same in both the cases, still ionic liquid certainly has an advantage over DMSO as an aprotic polar solvent; since the latter poses general problems of odour, interference in the product isolation, and non- recovery. The major advantage that ionic liquid offers over other conventional organic solvents is the recyclability (table-2). Ionic liquid could be reused even after 5 cycles. We did not observe any loss in yield of the product nor in the nature of ionic liquid (confirmed by IR and H NMR). Table -2 Reuse of recovered [bmim] [PF] in the reaction of 1 with n-PrBr Cycles Combined yield (%) 1 84 2 84 3 84 4 83 5 83 With esters 8 and 9, similar results were obtained with selectivity towards mono alkylated product (table-3). Table- 3 Results of alkylation of esters 8 and 9 in [bmim] [PF] with nPrBr Entry Ester Product Combined yield (%) Selectivity (%) Mono- di- 1 8 11a+12a 73 87 13 2 9 11b+12b 86 68 32 Alkylation of both the esters was carried out at 70 C for 2 h, Yields are based on GC analysis Conclusion In conclusion, we have demonstrated an efficient method of the alkylation of active methylene compounds in [bmim] [PF], without the use of a phase transfer catalyst or any dangerous condensing agents. The ionic liquid acts both as solvent as well as catalyst, and hence an excellent substitute for classical aprotic solvent as well as PTC catalyzed alkylation of active methylene compounds. The [bmim] [PF] offers the additional benefit of cleaner reaction and solvent recovery. The yields obtained are excellent. Selectivity as well as ease of product isolation by vacuum distillation provides a greener method of synthesis. 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