Ionic Liquids

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J. Chromatog. A (2018) in press

Analysis of acetylcholinesterase inhibitors by extraction in choline saccharinate aqueous biphasic systems
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Ionic liquid-based aqueous biphasic systems (IL-ABS) formed by ILs composed of ions of low toxicity, choline ([Chol]+) coupled with saccharinate ([Sac]−) and acesulfamate ([Ace]−), and inorganic salts with distinct water-structuring properties were employed for simultaneous extraction and concentration of acetylcholinesterase (AChE) inhibitors – galantamine (gal), N-desmethyl galantamine (des) and ungiminorine (ung). Comprehensive experiments aimed to assess the influence of salt and IL type and concentration, as well as the pH and temperature on the phase-forming ability and distribution of the target alkaloids between the two phases formed reveled that the IL anion and pH are the most important factors. At the optimal conditions found a quantitative recovery into the IL-rich phase of gal, des and ung was achieved in a single extractive step. These results were further used as a platform for the development of a simple and safer sample pretreatment method for analysis of the three analytes, followed by RP-HPLC/UV detection. The method showed satisfactory analytical performance, the latter allowing quantitative determination of these AChE inhibitors in pharmaceutical dosage form and in human urine.
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Processes 5 (2017)

Distribution of N-methylimidazole in ionic liquids/organic solvents systems
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The partition coefficients, Kmim, of N-methylimidazole (mim) in two-component systems composed of ionic liquid (IL) and a series of organic solvents immiscible with ILs (butyl acetate, ethyl acetate, tert-butyl methyl ether, diethyl ether and cyclohexane) were determined by a shake-flask method. The influence of different factors such as temperature, solvent polarity, mim concentration, and water content on Kmim by using 1-butyl-3-methylimidazolium chloride {[C4C1im]Cl} as a model compound was comprehensively studied. The calculated thermodynamic functions of transfer (∆trG0, ∆trH0, ∆trS0) showed that the mim migration (IL→organic phase) is a thermodynamically unfavorable and enthalpy-determined process in the temperature range of 298.15 to 328.15K; however, the results suggested that mim partition toward the organic phase can be enhanced by the rational manipulation of the extraction conditions. Experiments conducted with other 1-alkyl-3-methylimidazolim chlorides (CnC1im]Cl (n = 6, 8, 10) revealed that mim possesses similar behavior and can be successfully washed out from the ILs by extraction with organic solvents. The results obtained in this study give some clues toward the choice of an appropriate solvent and conditions to be employed for the purification of halide-based ILs by means of a liquid-liquid extraction.
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Sep. Pur. Technol. (2017) in press

Efficient purification of halide-based ionic liquids by means of improved apparatus for continuous liquid-liquid extraction
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The purity level of Ionic liquids (ILs) is a question of immense importance both from fundamental and applied standpoint. In order to improve the purification process of halide-based ILs, the latter being starting materials for the synthesis of a vast number of other ILs, we constructed an apparatus for continuous liquid-liquid extraction to be used as a tool for purification after the quaternisation step. The apparatus employs the heat of the evaporating solvent to heat up the extraction chamber, thus allowing the liquid-liquid extraction to be conducted at elevated temperature. The latter improves the process efficiency due to facilitated mass transfer. The purification carried out with this tool proved successful in the removal of impurities such as residual starting compounds (N-methylimidazole and haloalkanes) under mild conditions and was shown to give ILs of high purity for considerably reduced consumption of organic solvent and technological time.
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Sep. Sci. Technol. (2017) 1–11

Ionic liquid-assisted micellar extraction for the quantitative determination of sesquiterpenic acids in Valeriana officinalis L. (Caprifoliaceae)
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A series of hydrophilic ionic liquids (ILs) were investigated as extractants for the quantitative determination of valerenic and acetoxyvalerenic acids in Valerianae radix. The influence of different factors, e.g. type of cation and anion, alkyl chain length, concentration, temperature, extraction time and solid–liquid ratio, was investigated. The results obtained showed that the extraction yield is strongly dependent on the cation type. The best outcome was obtained with IL capable of forming micelles in aqueous solution, e.g. 1-decyl-3-methylimidazolium chloride. As a result, an alternative protocol for the quantification of sesquiterpenic acids in valerian was developed and validated.
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Sep. Sci. Technol. 52 (2017) 812–823

Partitioning of α-amylase in aqueous biphasic system based on hydrophobic and polar ionic liquid: Enzyme extraction, stripping and purification
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Controlled partitioning of a commercial α-amylase is achieved in aqueous biphasic system (ABS) of a hydrophobic and polar ionic liquid, 3-methyl-1-octylimidazol-3-ium saccharinate ([C8C1im][Sac]). Studying the effects of pH and [C8C1im][Sac]-concentration, the IL interference in the amylolytic action is deduced. Liquid-liquid extractions into [C8C1im][Sac] at different pHs are carried out. The α-amylase extraction occurs below pH = pI (isoelectric point), and above pI other inactive proteins are preferably transferred. The extracted α-amylase is afterwards recovered, being partially purified from inactive protein and microbial pigment. In the ABSs of pHs > pI, the α-amylase remains concentrated and purified in the aqueous raffinates. (19) Partitioning of α-amylase in aqueous biphasic system based on hydrophobic and polar ionic liquid: Enzyme extraction, stripping and purification.
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in - Green Chemistry and Sustainable Technology 2016, pp. 161–181

Extraction of natural phenolic compounds with ABS
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Amongst natural compounds, phenolic compounds – the most abundant class of secondary plant metabolites – are commonly employed as additives in the manufacturing of various human commodities, such as dietary supplements, food and pharmaceutical and cosmetic products, and hence can be considered of high importance from an industrial standpoint. The extraction of these compounds proceeds according to well-established procedures, which are multistage, laborious and time and energy consuming and use organic solvents which are often flammable, volatile and toxic. Accordingly, there is the need to develop novel and sustainable procedures, so that the production of such value-added chemicals can be achieved in a more efficient and environmentally friendly manner. This chapter represents a comprehensive overview on the recent achievements in the extraction of natural compounds, and mainly phenolic compounds, by means of ionic-liquid-based aqueous biphasic systems (IL-based ABS). It considers factors that influence the extraction efficiency, such as inorganic salt type and concentration, IL type and concentration, pH value and temperature, and provides some clues towards the extraction yield improvement.
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Sep. Sci. Technol. 51 (2016) 2691–2699

Ionic liquid-supported solid-liquid extraction of bioactive alkaloids. IV. New HPLC method for quantitative determination of galantamine in Leucojum aestivum L. (Amaryllidaceae)
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A series of aqueous solutions of hydrophilic ionic liquids (ILs) were examined as extractive systems in the recovery of galantamine from plant material of Leucojum aestivum L. The extractions were carried out both at room temperature and conventional heating conditions. The influence of various factors on the extraction efficiency was comprehensively studied. The conducted comparative analysis with conventional methods showed higher extraction ability of the ILs-based extractive systems for significantly reduced extraction times. The results obtained were implemented in a new HPLC method for quantification of galantamine, avoiding the use of harmful organic solvents during the sample preparation step.
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Sep. Purif. Technol. 155 (2015) 13-19

Ionic liquid-supported solid–liquid extraction of bioactive alkaloids. III. Ionic liquid regeneration and glaucine recovery from ionic liquid-aqueous crude extract of Glaucium flavum Cr. (Papaveraceae)
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In continuation of a research project aiming at introducing ionic liquids (ILs) as an alternative to the widely applied for the recovery of natural products of industrial interest conventional molecular solvents, we developed a concise procedure for isolation of the biologically active alkaloid S-(+)-glaucine from IL-based aqueous crude extract. To this end, a comparative study of the behavior of 1 M [C4C1im][Ace]-aqueous solution and methanol in a series of consecutive extractions with the same extractant was conducted. The results obtained proved the better performance of the IL-based system in the solid–liquid extraction step, since the latter showed constantly higher extraction efficiency (ca. 35% enhanced) compared to methanol. The above procedure allows glaucine accumulation from at least ten successive extractions, while simultaneously reduces the total solid–liquid ratio from 1:40 to 1:7.2, without loss of efficiency. Furthermore, the loss of IL into the matrix pores after extraction was also considered, suggesting the need for IL recycling by posttreatment of the residual biomass. To recover glaucine from the crude IL-based aqueous extract, a series of non-miscible with water molecular solvents were tested. As a result, optimal conditions for quantitative extraction into chloroform were found, from which, after solvent removal and subsequent crystallization from ethanol, the target compound was isolated as a hydrobromide salt, the latter being the marketed form of glaucine.
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Processes 3 (2015) 769-778

Ionic Liquid-Based Aqueous Biphasic Systems—A Facile Approach for Ionic Liquid Regeneration from Crude Plant Extracts
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The possibility for simultaneous controlled partition of the biologically active alkaloid S-(+)-glaucine, presented in a crude ionic liquid-aqueous plant extract, and separation of the ionic liquid (IL) employed by means of ionic liquid-based aqueous biphasic systems (IL-ABS) was investigated in this study. The ABS were formed by the addition of inorganic salts with distinct water-structuring properties such as Na2CO3, MgSO4, (NH4)2SO4, and NaH2PO4 to an enriched of glaucine extract of Glaucium flavum Cr. (Papaveraceae). The influence of the salt type and concentration on the phase-forming ability, as well as the pH value on the partition of glaucine between the two phases formed, was comprehensively studied. It was found that the target alkaloid is predominantly transferred into the IL-rich phase, regardless the influential factors. The results obtained were further used as a platform for the development of an improved extractive procedure, ensuring simultaneous glaucine recovery, IL recycling and water removal in a single technological step. Thus, based on the formation of a three-phase system consisting of butyl acetate, IL-rich phase, and salt-rich phase, nearly quantitative recovery of glaucine (>99%), IL recycling (ca. 90%), and water removal (ca. 85%) were achieved by salt-induced separation of the crude plant extract.
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J. Mol. Catal. B-Enzym. 117 (2015) 62-68

Effect of two series ionic liquids based on non-nutritive sweeteners on catalytic activity and stability of the industrially important lipases from Candida rugosa and Rhizopus delemar
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This is the first study on the effect of ionic liquids (ILs) based on non-nutritive sweeteners on the catalytic efficiency and the structural and the thermal stability of lipases from Candida rugosa (CRL) and Rhizopus delemar (RhDL). Initially, we synthesized two series of ILs, namely 1-akyl-3-methylimidazolium saccharinates {[CnC1im][Sac]} and 1-akyl-3-methylimidazolium acesulfamates {[CnC1im][Ace]}, where the alkyl substituent was butyl, hexyl, octyl or decyl. The activities of the two enzymes were tested in two hydrolytic reactions using walnut oil and 4-nitrophenyl acetate as substrates. The activity of CRL toward walnut oil was strongly influenced by the chain-length of the N-alkyl substituents at the imidazolium cation of the compounds. The ILs with short alkyl substituents (butyl or hexyl) activated moderately (up to 30%) or had no effect on CRL activity, while those with medium chain-length substituents strongly inhibited CRL. In the case of CRL, we observed the same behavior pattern for the two tested series of ILs, while for RhDL the same tendency was displayed only for the series of saccharinates. The coating of RhDL with 0.1 M [C8C1im][Sac] or [C8C1im][Ace] resulted in up to 1.5-fold increase in the enzyme initial activity. In contrast, CRL was strongly inhibited by these two ILs. We found that the effect of [C8C1im][Ace] on enzyme activity adopted concentration- and time-dependent manner for the two lipases.We observed a moderate increase in hydrolytic activity (by 1.2-fold factor) and good storage stability of RhDL (more than 30 days at 25 °C) when small quantities of all ionic liquids (<0.04 M), were added to the enzyme solutions. At the same time, by adding of 0.02 M [C4C1im][Sac] or [C4C1im][Ace], CRL was also stabilized and its activity was preserved for more than 25 days at room temperature. For comparison, the activities of the stored at 25 °C non-treated with ILs soluble CRL and RhDL were reduced by half for 7 days and 5 days, respectively. In contrast, we observed rapid inactivation at higher temperatures for all ionic liquid-coated enzymes. For example, half-lives of 25 min and 57.3 min at 50 °C were estimated for the pre-treated with [C4C1im][Ace]-CRL and for the non-treated-CRL, respectively. In addition, applying Fourier transform infrared spectroscopy, we monitored the changes in the secondary structure of the two enzymes in presence of the tested ILs which explained the altered stability and the activities of the two enzymes. Interestingly, coating with small amounts of ILs prevents aggregation of the two lipases even at high protein concentration.
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Int. J. Chem. Mol. Nuclear Mater. Metallurgical Eng. 9 (2015) 526-530

Biocompatible Ionic Liquids in Liquid – Liquid Extraction of Lactic Acid: A Comparative Study
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—Ionic liquids consisting of a phosphonium cationicmoiety and a saccharinate anion are synthesized and compared withtheir precursors, phosphonium chlorides, in reference to theirextraction efficiency towards L-lactic acid. On the base ofmeasurements of the acid and the water partitioning in theequilibrium biphasic systems, the molar ratios between acid, waterand ionic liquid are estimated which allows to deduce the lactic acidextractive pathway. The effect of a salting-out addition thatstrengthens hydrophobicity in both phases is studied in view to revealthe best biphasic system with respect to IL low toxicity and highextraction efficiency.
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J. Int. Sci. Publ. 9 (2015) 442-451

Ionic liquid-based biphasic systems for enzyme extraction: preliminary data from ionic liquids’ screening
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Ionic liquids consisting of pairs of imidazolium or phosphonium cation and saccharinate or chloride anion were synthesized and examined for extraction efficiency towards the hydrolytic enzyme, α-amylase. The quantification of the enzyme partitioning in the equilibrated biphasic systems of ionic liquid and water was based on the α-amylase activity assay, performed where possible in both phases. The water transfer from the aqueous phase into the ionic liquid-rich phase was also followed. The effect of pH, which determines the electrostatic charge of the protein aminoacid chain, was studied. Backward extractions were also performed in order to evaluate the activity yield resulted from the enzyme transfer though the ionic liquid.
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In - Green Chemistry and Sustainable Technology, 2014, pp. 127-166

Ionic Liquids as Alternative Solvents for Extraction of Natural Products
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Ionic liquids (ILs) have been proved as promising substituents of the flammable, volatile, and toxic organic solvents in numerous processes. This chapter considers the role of ILs in the extraction of natural products from their native sources and represents a comprehensive overview on the recent achievements in the IL-assisted solid-liquid extractions of secondary metabolites from plant matrices. By analyzing the similarities and differences between the ILs and molecular solvents, important factors that influence the extraction efficiency are discussed, and some general conclusions regarding the advantages and disadvantages of the use of ILs are emphasized. The effect of the IL structure on the extraction efficiency and the possible extraction mechanism and the approaches for both IL recycling and solute recovery after extraction are also discussed.
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Sep. Purf. Technol. 125 (2014) 239-246

Hydrophobic 3-alkyl-1-methylimidazolium saccharinates as extractants for L-lactic acid recovery
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N-Octyl- and N-decylsubstituted N-methylimidazolium saccharinates ([C8/10C1im][Sac]) were synthesized and found to form biphasic systems after saturation with water. Therefore, they could be considered as hydrophobic ionic liquids (ILs), which suggests their potential application as extraction media. The performance of these ILs as extractants of l-lactic acid (LA) from aqueous solutions was evaluated. The pH dependence and the influence of additives such as kosmotropic salts or alcohols on the LA extraction yield (EY%) were comprehensively studied. As a result, EY = 90% was achieved with [C8C1im][Sac] in two extraction steps. Furthermore, based on the observed effects of pH and kosmotropic salt, successful LA re-extraction (95%) from the IL-rich phase was attained by means of K2HPO4-stripping solution. The latter represents the highest re-extraction efficiency for LA/IL system described so far in the literature. Based on the results obtained, a plausible mechanism of LA extraction, which considers the secondary structure of the water saturated long side chain imidazolium saccharinates, is proposed. As a result, the IL extraction capacity was attributed to the formation of polar channels, separated by non-polar domains, which channels are capable of swelling and liberating water and other hydrophilic solutes.
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Sep. Purif. Technol. 103 (2013) 279-288

Ionic liquid-supported solid–liquid extraction of bioactive alkaloids. II. Kinetics, modeling and mechanism of glaucine extraction from Glaucium flavum Cr. (Papaveraceae)
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Abstract: The temperature dependence on the global kinetics of both methanol and 1-butyl-3-methylimidazolium acesulfamate ([C4mim][Ace])-supported extraction of the bioactive alkaloid S-(+)-glaucine from plant material of Glaucium flavum Crantz (Papaveraceae) was measured and a comparative analysis in respect to the extractant type was performed. The experimental data was fitted with high coefficients of determination by means of an empirical model showing that the extraction process in both cases follows second-order kinetics. The concentration at saturation, Cs, extraction rate constants, k2, initial rates of extraction, h, and activation energies of extraction, Ea, were then calculated and discussed. The obtained results give a considerable advantage to the Ionic liquid-supported (IL-supported) extraction procedure due to the faster and quantitative glaucine transfer, regardless the temperature. A plausible extraction mechanism scenario, describing the whole system in terms of solute–solvent, solute–matrix and matrix–solvent interactions at every stage of the extraction process was proposed. As a result, the apparent kinetics and yield of the IL-supported extraction were attributed to the cell wall modification by H-bonding interactions between both ions of [C4mim][Ace] and cellulose, resulting in the plant tissues disruption. The latter was further unequivocally confirmed by means of scanning electron microscopy. The kinetics parameters obtained were then implemented into a model for the prediction of glaucine amount extracted in 1 M [C4mim][Ace] water solution at any temperature and time with good predictive ability.
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Sep. Purif. Technol. 97 (2012) 221-227

Ionic liquid-supported solid–liquid extraction of bioactive alkaloids. I. New HPLC method for quantitative determination of glaucine in Glaucium flavum Cr. (Papaveraceae)
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A series of hydrophilic 1-alkyl-3-methylimidazolium-based ionic liquids were used as extractants for the effective extraction of S-(+)-glaucine from plant material of Glaucium flavum Crantz (Papaveraceae). The extractions were carried out both under ultrasonic and conventional heating conditions and the extraction efficiency was monitored by HPLC. The influence of the anion (chloride, bromide, acesulfamate and saccharinate), alkyl chain length in the imidazolium ion, concentration, extraction time, and plant material/extractant ratio was investigated. A comparative study between conventional Soxhlet extraction with methanol as a solvent (total extraction) and water solutions of ILs shows the same extraction ability of ILs, but with significantly reduced extraction time. Moreover, the extraction efficiency was shown to be strongly anion dependent. The results obtained provide a fast and safe method for determination of glaucine in G. flavum Cr.
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Z. Naturforsch. 65b (2010) 873 – 906

Orthoamides, LXIX [1]. Contributions to the Synthesis of N,N,N',N',N''-peralkylated Guanidines and N,N,N',N',N'',N''-persubstituted Guanidinium Salts
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N,N,N',N'-Tetraalkyl-chloroformamidinium chlorides 6 are prepared from N,N,N',N'-tetraalkylureas5 and phosgene in acetonitrile. The iminium salts 6 react with primary and secondary aminesin the presence of triethylamine to give N,N,N',N',N''-pentasubstituted and N,N,N',N',N'',N''-hexasubstituted guanidinium salts 7 and 8, respectively, Treatment of the guanidinium salts 7 with sodium hydroxide in excess affords the N,N,N',N',N''-pentasubstituted guanidines 9a – 9aa. Additionally, the N,N,N',N',N''-pentasubstituted and N,N,N',N',N'',N''-hexasubstituted guanidiniumsalts 7l, 7p and 8a – c can be obtained from the reaction mixtures by addition of stoichiometricamounts of sodium hydroxide. A modified method is described for the preparation of guanidiniumsalts possessing dialkylamino substituents consisting of two long-chain alkyl groups (>C14). Some guanidines 9 were alkylated with allyl chloride and bromide, ethyl bromide, butyl bromide, benzyl bromide and chloride, dimethyl sulfate, diethyl sulfate, and methyl methansulfonate to give the corresponding guanidinium salts 11 – 15. By alkylation of the N,N,N',N',N''-pentasubstituted guanidine9v with triethyloxonium tetrafluoroborate the guandinium tetrafluoroborate 16a is accessible. N-Functionalized guanidinium salts 17 – 18a – c result from the reaction of N,N,N',N',N''-pentasubstitutedguanidines with ethyl bromoacetate and bromoacetonitrile, respectively, and subsequent anion exchange with sodium tetraphenylborate. N,N,N',N'-Tetramethylguanidine (21) adds to ethyl acrylate to give the labile guanidine 22, which forms the guanidinium salt 23a on treatment with methyl iodide. Zwitterionic guanidinium salts 25 result, when N,N,N',N',N''-pentasubstituted guanidines are treated with sultones 24.
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Z. Naturforsch. 65b (2010) 791 – 797

Empirical Polarity Parameters for Hexaalkylguanidinium-Based Room-Temperature Ionic Liquids
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The polarity of a series of 36 hexaalkylguanidinium-based room-temperature ionic liquids(RTILs), featuring different unbranched alkyl substituents in the cation and eight different anions,has been determined by means of Reichardt’s solvatochromic betaine dye; ET(30) andthe corresponding normalized ENT values are presented. The positively solvatochromic probe 5-dimethylamino-5-nitro-2,2-bithiophene was used to characterize unspecific solvent/solute interactions(effects of dipolarity/polarizability) of ten hexaalkylguanidinium and, for comparison, two 1-alkyl-3-methylimidazolium ionic liquids.
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Z. Naturforsch. 65b (2010) 37 – 48

New Guanidinium Based Room Temperature Ionic Liquids. Substituent and Anion Effect on Density, Polarity and Solubility in Water
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In order to examine the influence of the alkyl chain length on some physical properties of guanidiniumsalts, the synthesis of a homologous series of new N-n-alkylsubstituted N,N-diethyl-N,N-di-n-propyl-N-n-hexyl guanidinium ionic liquids (gILs), containing chloride (Cl), tetrafluoroborate(BF4), acesulfamate (Ace), saccharinate (Sac), and tosylate (Tos) as anions, is reported. Cn-gILAce,Cn-gILSac, and Cn-gILBF4 were obtained by ion exchange reaction of the corresponding hexasubstitutedguanidinium chlorides (Cn-gCl, n = 3, 4, 6, 8, 10), which were synthesized by a quaternizationreaction of the pentaalkyl-substituted guanidine 3 and the corresponding alkylchloride in DMF.The tosylates gILs Cn-gTos (n = 1, 2, 4, 6, 8, 10) were synthesized by alkylation of 3 with the correspondingalkyltosylates. Some physical properties, such as solubility in water and organic solvents,refractive index and density, are considered as a function of the length of the n-alkyl substituent Rand the nature of the anion.
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Z. Naturforsch. 64b (2009) 756 – 764

Residual Volume Approach II. Simple Prediction of Ionic Conductivity of Ionic LiquidsDescription
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The Residual Volume Approach (RVA), a recently developed method for the prediction of fundamentalphysical properties of ionic liquids (ILs) is extended and now allows the estimation of ionicconductivity of unknown ILs, using a simple linear correlation between the ionic conductivity andpreviously defined substituent parameters – β X. The proposed method is applied to the conductivitycorrelations of 61 n-alkyl substituted imidazolium, tetraalkylammonium, pyrrolidinium, piperidinium,sulfonium and phosphonium homologous ILs, containing [BF4]−, [Tf2N]−, [C2 F5PF]−,[CF3BF3]−, [C2H5BF3]−, [F(HF)2.3]−, [Br]−, [I]−, and [formate]− as anions. The influence of theion type – both anion and cation – on the property changes is discussed. Moreover, it is shown thatrelatively rigid cations with C2 symmetry decrease the expected conductivity in the same manner as they increase the viscosity of the ILs.
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Z. Naturforsch. 64b (2009) 215 – 222

Simple Prediction of Some Physical Properties of Ionic Liquids: The Residual Volume Approach
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A new method for prediction of fundamental physical properties of ionic liquids (ILs) is proposed.The Residual Volume Approach (RVA) allows the estimation of density and viscosity of unknown ILs,using a simple linear correlation between a given property and a newly defined substituent parameter β X. The proposed method has been developed for the density estimation of 50 n-alkyl-substitutedimidazolium and tetraalkylammonium salts in a homologous series of ILs and has been extended forthe estimation of viscosity, which also correlates linearly with the corresponding β X. In addition, the parameters β X are temperature and pressure independent, which allows the prediction of these values at any temperature and pressure.