Chiral ionic liquids: a compendium of syntheses and applications (2005-2012)

In recent years, the field of chiral ionic liquids (CILs) has undergone exponential growth. As the technology has advanced, new ways of synthesizing stable and structurally diverse ionic liquids have been established. This has led to heretofore unknown applications of CILs as well as in improving efficiency of previously identified applications. In this review article we have compiled a comprehensive database containing structures and physical properties of notable CILs that have been synthesized during the last 6 years. Their applications in the fields of asymmetric organic synthesis, spectroscopy, and chromatography are also illustrated. This is an expansion of our previous review, which covered the literature before 2005.     

New chiral imidazolium ionic liquids from isomannide

New chiral bis and mono-imidazolium ionic liquids derived from isomannide were synthesized. The structural features of the chiral organic cations impart a special arrangement of the chiral cavity. The new chiral chloride salts of isomannide derivatives are pivotal compounds for the synthesis of different organic ionic liquids. After metathesis different anions were associated to the chiral cations providing a new class of chiral ionic liquids.     

A rapid analytical method for monitoring the enantiomeric purity of chiral molecules synthesized in ionic liquid solvents

Ionic liquids (ILs) have been widely used as reaction solvents in asymmetric synthesis due to their interesting physical and chemical properties. However, monitoring reactant-to-product conversion and the enantiopurity of formed stereoisomers often involves a tedious extraction step before chromatographic analysis. In this study, a rapid and sensitive sampling method using headspace solid-phase microextraction (SPME) coupled to chiral gas chromatography was developed for the "on-line" analysis of chiral molecules in the IL solvent. Three different SPME sorbent coatings, namely polydimethylsiloxane, polyacrylate, and a polymeric ionic liquid-based fiber, were examined in this study. The analytical performance of the developed method was evaluated in terms of reproducibility, slope of calibration curve, linear range, calibration linearity, and the determination of detection limits. The SPME method was successfully applied in the determination of enantiomeric excess from selected mixtures of chiral molecules. A preliminary study was performed using an "on-fiber" derivatization approach revealing that the stereoisomers extracted by the SPME fiber can be efficiently derivatized using a short "on-fiber" derivatization step. The developed SPME method eliminates the need of sequestering the reaction, separating the compounds of interest from the IL solvent, and the addition of a derivatizing reagent.     

Biocatalytic synthesis of C3 chiral building blocks by chloroperoxidase‐catalyzed enantioselective halo‐hydroxylation and epoxidation in the presence of ionic liquids

The optically active C3 synthetic blocks are remarkably versatile intermediates for the synthesis of numerous pharmaceuticals and agrochemicals. This work provides a simple and efficient enzymatic synthetic route for the environment‐friendly synthesis of C3 chiral building blocks. Chloroperoxidase (CPO)‐catalyzed enantioselective halo‐hydroxylation and epoxidation of chloropropene and allyl alcohol was employed to prepare C3 chiral building blocks in this work, including (R)‐2,3‐dichloro‐1‐propanol (DCP*), (R)‐2,3‐epoxy‐1‐propanol (GLD*), and (R)‐3‐chloro‐1‐2‐propanediol (CPD*). The ee values of the formed C3 chiral building blocks DCP*, CPD*, and glycidol were 98.1, 97.5, and 96.7%, respectively. Moreover, the use of small amount of imidazolium ionic liquid enhanced the yield efficiently due to the increase of solubility of hydrophobic organic substrates in aqueous reaction media, as well as the improvement of affinity and selectivity of CPO to substrate. © 2015 American Institute of Chemical Engineers Biotechnol. Prog., 31:724–729, 2015     

Determination of enantiomeric composition by negative-ion electrospray ionization-mass spectrometry using deprotonated N-(3,5-dinitrobenzoyl)amino acids as chiral selectors

The ability to use mixtures of deprotonated N-(3,5-dinitrobenzoyl)amino acids as chiral selectors for the determination of enantiomeric composition by electrospray ionization-mass spectrometry is demonstrated. For each experiment, two N-(3,5-dinitrobenzoyl)amino acids were chosen such that each would have opposite selectivity for the enantiomers of the analyte. Electrospray ionization-mass spectrometry, monitored in the negative ion mode, of solutions containing the two N-(3,5-dinitrobenzoyl)amino acids, sodium hydroxide, and the analyte, in a one-to-one mixture of methanol and water, afford peaks in the mass spectrum that correspond to the deprotonated 1:1 analyte-selector complexes. The ratio of the intensities of the complexes in the mass spectrum can be related to the enantiomeric composition of the analyte. Additionally, the sense and extent of chiral recognition is consistent with chromatographic observations, using chiral stationary phases derived from N-(3,5-dinitrobenzoyl)amino acids. Each analysis of enantiomeric composition requires less than 10 s to complete, indicating that this method has great potential for the development of fast-/high-throughput chiral analyses.     

Chiral ionic liquids: synthesis and applications

Over the last ten years, interest and publications involving ionic liquids have expanded exponentially. Thus far, they have predominantly been used in organic synthesis and separations. However, their use is rapidly expanding into other areas of science and technology. Research involving chiral ionic liquids has been much more limited and only recently has come to the forefront. In this work, we review the synthesis of chiral ionic liquids and their use. Today, this is an area of research that is poised for rapid development and expansion.     

几种离子液体的微波法合成及其对脂肪酶催化效果的影响

采用微波法合成9种目标离子液体,对中间体[Bmim]Br的合成条件及其离子液体对全细胞催化剂催化效果的影响进行考察.直接将产脂肪酶真菌粗状假丝酵母(Candida valida) T2细胞固定在聚氨酯颗粒中,制备固定化细胞催化剂,将其应用于合成离子液体介质中催化甲醇与大豆油酯交换反应制备生物柴油.结果表明:微波功率200 W下间隙照射100 s,中间体[Bmim]Br的收率达95.16%,有效地提高了离子液合成产率;在[Bmim]PF6离子液中固定化细胞酶催化转酯化反应30 h,大豆油的转化率达42%,反应效果较其他8种合成离子液体好;固定化细胞颗粒和[Bmim]PF6重复使用4次,其油脂转化率和酶活保持率分别达到29%和69%,表现出较好的催化反应稳定性.     

Over-stabilization of Candida antarctica lipase B by ionic liquids in ester synthesis

Four different ionic liquids, based on dialkylimidazolium cations associated with perfluorinated and bis(trifluoromethyl)sulfonyl amide anions were used as reaction media for butyl butyrate synthesis catalyzed by free Candida antarctica lipase B at 2% (v/v) water content and 50 °C. Lipase had enhanced synthetic activity in all ionic liquids in comparison with two organic solvents (hexane, and 1-butanol), the enhanced activity being related to the increase in polarity of ionic liquids. The continuous operation of lipase with all the assayed ionic liquids showed over-stabilization of the enzyme. The reuse of free lipase in 1-butyl-3-methylimidazolium hexafluorophosphate in continuous operation cycles showed a half-life time 2300 times greater than that observed when the enzyme was incubated in the absence of substrate (3.2 h), and a selectivity higher than 90%.     

Application of L-proline derivatives as chiral shift reagents for enantiomeric recognition of carboxylic acids

Four proline-derived chiral receptors 5-8 were readily synthesized starting from L-proline. The enantiomeric recognition ability of chiral receptors was examined with a series of carboxylic acids by (1) H NMR spectroscopy. The molar ratio and the association constants of the chiral compounds with each of the enantiomers of guest molecules were determined by using Job plots and a nonlinear least-squares fitting method, respectively. The Job plots indicate that the hosts form 1:1 instantaneous complexes with all guests. The receptors exhibited different chiral recognition abilities toward the enantiomers of racemic guests. Among the chiral receptors used in this study, prolinamide 6 was found to be the best chiral shift reagent and is effective for the determination of the enantiomeric excess of chiral carboxylic acids.     

Enantioseparation of flurbiprofen enantiomers using chiral ionic liquids by liquid‐liquid extraction

Flurbiprofen is a kind of nonsteroidal anti‐inflammatory drug, which has been widely used in clinic for treatment of rheumatoid arthritis and osteoarthritis. It has been reported that S‐flurbiprofen shows good performance on clinic anti‐inflammatory treatment, while R‐enantiomer almost has no pharmacological activities. It has important practical values to obtain optically pure S‐flurbiprofen. In this work, chiral ionic liquids, which have good structural designability and chiral recognize ability, were selected as the extraction selector by the assistance of quantum chemistry calculations. The distribution behaviors of flurbiprofen enantiomers were investigated in the extraction system, which was composed of organic solvent and aqueous phase containing chiral ionic liquid. The results show that maximum enantioselectivity up to 1.20 was attained at pH 2.0, 25°C using 1,2‐dichloroethane as organic solvent, 1‐butyl‐3‐methylimidazole L‐tryptophan ([Bmim][L‐trp]) as chiral selector. The racemic flurbiprofen initial concentration was 0.2 mmol L^?1, and [Bmim][L‐trp] concentration was 0.02 mol L^?1. Furthermore, the recycle of chiral ionic liquids has been achieved by reverse extraction process of the aqueous phase with chiral selector, which is significant for industrial application of chiral ionic liquids and scale‐up of the extraction process.     

A fluorescent chiral chemosensor for the recognition of the two enantiomers of chiral carboxylates

A new 7-nitrobenz-2-oxa-1,3-diazole (NBD)-based fluorescent chiral chemosensor (NBD-1) was prepared and applied to the recognition of the two enantiomers of the tetrabutylammonium salts of N-t-Boc-α-amino acids and chiral carboxylic acids including naproxen. In particular, the chiral recognition by the new fluorescent chiral chemosensor for the two enantiomers of N-t-Boc-threonine (tetrabutylammonium salt) was quite excellent, the Stern-Volmer constant ratio (K(D)/K(L)) for the two enantiomers being as high as 4.89.     

Investigation of maltodextrin‐based synergistic system with amino acid chiral ionic liquid as additive for enantioseparation in capillary electrophoresis

The combined use of chiral ionic liquids (ILs) and chiral selectors in capillary electrophoresis (CE) to establish a synergistic system has proven to be an effective approach for enantioseparation. In this article, tetramethylammonium‐L‐arginine, a kind of amino acid chiral IL, was applied to investigate its potential synergistic effect with maltodextrin in CE enantioseparation. The established maltodextrin‐based synergistic system showed markedly improved enantioseparations compared with the single maltodextrin system. Parameters such as the chiral IL concentration, maltodextrin concentration, buffer pH, applied voltage, and capillary temperature were optimized. Satisfactory enantioseparation of the five studied drugs, including nefopam, duloxetine, ketoconazole, cetirizine, and citalopram was achieved in 50 mM Tris‐H₃PO₄ buffer solution (pH 3.0) containing 7.0% (m/v) maltodextrin and 60 mM tetramethylammonium‐L‐arginine. In addition, the chiral configuration of tetramethylammonium‐L‐arginine was also investigated to demonstrate the existence of a synergistic effect between chiral ILs and maltodextrin.     

Enzymatic activity and thermal stability of metallo proteins in hydrated ionic liquids

Hydrated choline dihydrogen phosphate (Hy[ch][dhp]) containing 30 wt% water was investigated as a novel protein solvent. The Hy[ch][dhp] dissolved some metallo proteins (cytochrome c, peroxidase, ascorbate oxidase, azurin, pseudoazurin and fructose dehydrogenase) without any modification. These proteins retained the surroundings of the active site after dissolution in Hy[ch][dhp]. Some metallo proteins were found to retain their activity in the Hy[ch][dhp]. © 2010 Wiley Periodicals, Inc. Biopolymers 93: 1093–1099, 2010. This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com     

Antibacterial activities of mono-, di- and tri-substituted triphenylamine-based phosphonium ionic liquids

We report the synthesis of new mono, di and tri phosphonium ionic liquids and the evaluation of their antibacterial activities on both Gram-positive and Gram-negative bacteria from the ESKAPE-group. Among the molecules synthesized some of them reveal a strong bactericidal activity (MIC?=?0.5?mg/L) for Gram-positive bacteria (including resistant strains) comparable to that of standard antibiotics. A comparative Gram positive and Gram negative antibacterial activities shows that the nature of counter-ion has no significant effects. Interestingly, the increase of phosphonium lateral chains (from 4 to 8 carbons) results in a decrease of antibacterial activities. However, the increase of the spacer length has a positive influence on the activity on both Gram-positive and Gram-negative bacteria except for E. aerogenes. Finally, the increased charge density has no effect on the Gram-positive antibacterial activities (MIC between 2 and 4?mg/L) but seems to attenuate (except for P. aeruginosa) the discrimination between Gram-positive and Gram-negative. Overall these results suggest a unique mechanism of action of these triphenylamine-phosphonium ionic liquid derivatives.     

Chiral mono and diamide derivatives of calix[4]arene for enantiomeric recognition of chiral amines

Novel chiral mono and diamide derivatives of calix[4]arene have been prepared from the aminolysis reaction of 5,11,17,23-tetra-tert-butyl-25,27-diethoxycarbonyl-methoxy-26,28-dihydroxycalix[4]arene 1 and 25,27-diethoxycarbonyl-methoxy-26,28-dihydroxycalix[4]arene 2 with chiral (S)-(-)-1-phenylethylamine (PEA) and (1S,2S)-(+)-2-amino-1-(4-nitrophenyl)-1,3-propanediol, respectively. Spectrophotometric titrations have been performed in CHCl(3) at 20-30 degrees C in order to obtain the binding constants (K) and the thermodynamic quantities (DeltaH and DeltaS) for the stoichiometric 1:1 inclusion complexation of various chiral amines with these new host compounds. Preliminary experiments were undertaken to confirm the complexation properties of receptors 9 and 13 with PEA by (1)H NMR in CDCl(3) at room temperature. The molecular recognition abilities and enantioselectivities for guests (R and S)-alpha-PEA and (R and S)-cyclohexylethylamine (CHEA) are discussed from a thermodynamic point of view.     

NMR studies of chiral recognition by cyclodextrins

Chiral recognition by cyclodextrins is of considerable importance, especially for pharmaceutical industry, in view of the possible side effects of the second enantiometer of chiral drugs. In general, it manifests itself in all NMR parameters (chemical shifts, coupling constants, NOE and ROE effects, and relaxation rates) on one hand. On the other hand, it allows one to determine the thermodynamic parameters characterizing diastereomeric complexes formed by cyclodextrins with enantiomeric guests. After an introduction and a general discussion of NMR manifestations of chiral recognition by cyclodextrin, the existing literature data on this problem will be discussed herein. Chirality 16:90-105, 2004.     

DABCO-based chiral ionic liquids as recoverable and reusable organocatalyst for asymmetric Diels–Alder reaction

New DABCO-based chiral ionic liquids were synthesized and evaluated in asymmetric Diels–Alder reaction of cyclopentadiene with α,β-unsaturated aldehydes or 4-phenyl-3-buten-2-one. Chiral ionic liquid of modified MacMillan catalyst having a DABCO cation and hexafluorophosphate anion acts as organocatalyst (5 mol%) for the Diels–Alder reaction of crotonaldehyde and cyclopentadiene producing 98% of the product and 87% ee (endo) in CH₃CN/H₂O (95/5) at 25°C in 2 h. The scope and limitations of the catalysis were also studied by using cyclopentadiene and α,β-unsaturated aldehydes, and the Diels–Alder products were obtained in 18%–92% yields with 68%–93% ee. The catalyst was recycled and reused up to 6 cycles with a slight drop in ee and conversion of the product.     

Conversion of hexose into 5-hydroxymethylfurfural in imidazolium ionic liquids with and without a catalyst

Conversion of fructose and glucose into 5-hydroxymethylfurfural (HMF) was investigated in various imidazolium ionic liquids, including 1-butyl-3-methylimidazolium chloride (BmimCl), 1-hexyl-3-methylimidazolium chloride (HmimCl), 1-octyl-3-methylimidazolium chloride (OmimCl), 1-benzyl-3-methylimidazolium chloride (BemimCl), 1-Butyl-2,3-dimethylimidazolium chloride (BdmimCl), and 1-butyl-3-methylimidazolium p-toluenesulfonate (BmimPS). The acidic C-2 hydrogen of imidazolium cations was shown to play a major role in the dehydration of fructose in the absence of a catalyst, such as sulfuric acid or CrCl₃. Both the alkyl groups of imidazolium cations and the type of anions affected the reactivity of the carbohydrates. Although, except BmimCl and BemimCl, other four ionic liquids could only achieve not more than 25% HMF yields without an additional catalyst, 60–80% HMF yields were achieved in HmimCl, BdmimCl, and BmimPS in the presence of sulfuric acid or CrCl₃ in sufficient quantities.     

Synthesis and HPLC chiral recognition of regioselectively carbamoylated cellulose derivatives

Four regioselective-carbamoylated cellulose derivatives having two different substituents at 2-, 3-, and 6-position were prepared and evaluated as chiral stationary phases (CSPs) for high-performance liquid chromatography. Investigations showed that the nature and arrangement of the substituents significantly influenced the chiral recognition abilities of the heterosubstituted cellulose derivatives and each derivative exhibited characteristic enantioseparation. Some racemates were better resolved on these derivatives than the corresponding homogeneously substituted cellulose derivatives including a commercial CSP, Chiralcel OD. Racemic compounds shown in this study were most effectively discriminated on cellulose 2,3-(3-chloro-4-methylphenylcarbamate)-6-(3,5-dimethylphenylcarbamate) and 2,3-(3,5-dimethylphenylcarbamate)-6-(3-chloro-4-methylphenylcarbamate).