Chiral ionic liquids from their inception have been a compound of particular interest leading researchers to describe them accordingly. Few called them "organic salts with melting points under 1000C, often below room temperature" or "Liquids, composed of entirely anions and cations with a wide temperature range and no vapour pressure".
Properties and applications:
temperature Chiral ionic liquids are liquids, which mainly consists of ions, e.g. molten sodium chloride. But unlike other molten salts, ionic liquids melt at a very low temperature making it an advantage over other solvents. This feature of ionic liquid is achieved by instilling a bulky chiral ionic (anion/cation) group into the structure in order to prevent the ions packing up and thereby lowering the lattice energy. Due to the low lattice energies of these compounds, the melting points are low, thus making ionic liquids distinct among other solvents. Reactions performed in such solvents often give outstanding results when compared to other solvents.
green solvents In the previous years, ionic liquids have been honoured immense importance at different levels considering their capacity as green solvents.
Ionic liquids are being used as an alternative for other regular solvents employed in catalytic reactions and organic synthesis. Their use is so immense that they can actually be substituted into the class of green solvents which also includes water and other supercritical fluids.
vapor pressure: Chiral ionic liquids have remarkably very low or no vapour pressure, which contributes as a positive aspect in regards to green house effect. In simple terms, no vapour pressure means no vaporization of the solvent, thus no effect on environment.
(Ionic liquids. Green solvents for the future* Martyn J. Earle and Kenneth R. Seddon)
largeliquid range (thermally stable over a very wide temperature range): Ionic liquids are thermally stable up to 3000C and possess immense mechanical strength.
solvation ability Ionic liquids are potentially good solvents for many chemical reactions where practical solubilisation of compounds is not possible. Ionic liquids also come in handy as a solvent for thermo labile compounds. Ionic liquids are also known as "designer solvents" as they give a chance to adjust their chemical properties for a specific necessity. An ionic liquid can be designed by choosing either a negatively or positively charged ion and once created these ionic liquids can be used to solubilise chemicals or to extract residues from another material.
(A review of ionic liquids towards supercritical fluid applications
Seda Keskin, Defne Kayrak-Talay, Ug˘ur Akman âˆ-, O¨ ner Hortac¸su
Department of Chemical Engineering, Bo˘gazi，ci University, Bebek 34342, ˙Istanbul, Turkey)
Ionic liquids potentially good solvents for many chemical reactions in the cases where distillation is not practical, or water insoluble or thermally sensitive products are the components of a chemical reaction
versatility of their physico-chemical properties
multiphase bioprocess operations: Ionic liquids such as 1-butyl-3-methylimi-diazolium hexafluorophosphate were employed for the first time successfully in the liquid-liquid extraction of erythromycin-A instead of other conventional solvents.
(S.G. Cull, J.D. Holbrey, V. Vargas-Mora, K.R. Seddon, G.J. Lye, Biotechnol. Bioeng. 69 (2000) 227)
Liquid-liquid separations: Yet to be included.
Electrolytes for batteries and fuel cells: Yet to be included
Mobile phase additives in liquid chromatography: Yet to be included
RTILs are recyclable: Yet to be included
Chiral solvents for asymmetric synthesis:
Baylis-Hillman reaction: The reaction of benzaldehyde (aldehyde) and methyl acrylate (α, β- unsaturated electron withdrawing groups) in the presence of one equivalent of 1, 4-diazabicyclo octane and a chiral ionic liquid derived from N- methyl ephedrine resulted in an alkoxy ester with about 44% yield. The hydroxyl group is very important in order to attain high enantio selectivity.
The chiral ionic liquid can be regained by dissolving in dichloromethane and washing with liberal amounts of water.
Chiral solvents for stereo selective polymerization:
Ionic liquids have the capacity to lower the level of undesirable side reactions in polymerization reactions. Therefore when the reverse atom transfer radical polymerization (ATRP) of methyl meth acrylate (monomer) was performed in presence of 1-(-)-menthoxy carbonyl methylene-3-methylimidazolinium hexafluoro phosphate (chiral ionic solvent) in presence of azobis isobutyronitrile (initiator) at 800C along with copper chloride complex of bipyridine (transition metal complex) as catalyst, the conversion of monomeric form into a polymeric chain was uniform with the polymer's poly dispersity being far better than that of the chiral ionic solvent itself.
Chiral phases for gas chromatography:
Chiral ionic liquids have also been proved useful in the field of gas chromatography(a). They were successfully tested as stationary phases for the firm determination of organic compounds basing on the enantiomeric property of the compound. Ephedrium salt reported by Wasserscheid(b) was used in the capillary columns as a coating by employing static method at 400C with a solution of 0.25% (w/v) of ephedrium salt in dichloromethane. The chiral ionic liquid showed retention depending on enantio selectivity of alcohols, diols, sulfoxides and acetylated amines.
(a)- Ding, J.; Welton, T.; Armstrong, D.W. Anal.Chem. 2004, 76, 6819-6822,
(b)- Wasserscheid, P.; Bosmann, A.; Bolm, C. Chem. Commun. 2002,200-201
Chiral shift reagents in NMR:
Chiral shift reagents are otherwise known as chiral resolving reagents. They have the capacity to convert a mixture of enantiomers into diastereomers thereby making it easy to analyse the quantity of enantiomers.
Chiral ionic liquids were employed as chiral shift reagent for the ephedrium salt study under the influence of the ionic liquid in deuterated dichloromethane. This resulted in splitting of signals at a concentration of 0.3 mol/L of ionic liquid. In fact there was an increase in signal splitting when a small amount of water was added.
Chiral liquid crystals:
Ionic liquids with thermo tropic mesophases are one of the latest interests as they are considered as highly structured solvents. Such ionic liquids could increase the possibilities in a reaction by altering reactants or they can do the job of a template where, they can be worked upon for further modifications. The anionic part of the chiral ion liquid has an important role on the physical properties as it controls the melting point, viscosity and solubility. The interesting part of chiral ionic liquids is that they have a high thermal stability and bear a liquid crystalline state in wide temperature range.
Cyclo addition reactions:
A Cycloaddition reaction is defined as "a reaction which includes two or more unsaturated molecules combine with formation of a cyclic adduct with a net reduction of the bond multiplicity. Cycloaddition type of reactions is very useful in the synthesis of organic molecules with a monocyclic ring system or a polycyclic ring system as the addition occurs in between a double or triple bond as in straight addition reactions. Cycloaddition reactions differ from other reactions as they form a cyclic product which is as a result of introduction of two new σ bonds.
Cycloaddition reaction include few important reactions, such as that of Diels Alder reaction and 1, 3 dipolar cycloaddition reaction.
Diels alder reaction results in a six member ring from that of a conjugated diene and dienophile. The six member ring obtained as an outcome is a carbocyclic compound.
However, there has been a slight modification of the Diels Alder reaction, where, formaldehyde was used as a dienophile which resulted in the production of a six member hetero cycle.
1, 3 Dipolar cycloaddition reactions are very effective for the synthesis of five member heterocyclic compounds by employing 1, 3-dipoles and dipolarophile.
Cycloaddition reactions can be classified based on the size of the ring formed. This is usually represented as (I +J), where "I" and "J" represent the number of atoms given by the reactant species into the ring system. Therefore, Diels-Alder reactions can be classified as (4 +2) cycloaddition, whereas 1, 3-dipolar cycloaddition type of reaction can be classified as (3 +2) cycloaddition. The alternative and the most common method of classification are based on the number of reactant electrons that participate in the ring formation. In this type of classification, the Diels Alder reaction and 1, 3-dipolar cycloaddition are classified as (4 + 2) cycloaddition reactions. Therefore, it can be said that 1, 3 dipolar cycloaddition involves four pie electrons from the dipole part and two pie electrons from the dipolarophile part.
The development and recount of the concept of 1, 3-dipolar cycloaddition reactions:
Huisgen in his systematic studies of 1960's was the first to establish the general features of 1, 3-dipoles along with its applications. Even though Buchner (1888) studied the reaction with that of α, β-unsaturated esters and described the first 1, 3-dipolar cycloaddition reaction. A review of systems undergoing the 1, 3 additions was published by Smith after about five decades, where he discussed the structure, preparation and reactions of some of the 1, 3 systems but could not mention about the development of the 1, 3- systems. Smith also declared that the central element of all the 1, 3 systems was a pentavalent nitrogen atom and that a true 1, 3-cyclo addition occurred only when at least one end of the 1, 3 system terminates in a carbon atom.
Huisgen generalised the reaction procedure of 1, 3-dipolar cycloaddition in an attempt to improve the prediction and discovery of new classes of 1,3 dipoles. Huisgen gave rise to the idea of 1,3 dipolar cycloaddition as an occurrence involving the union of a 1,3 dipole i.e. a-b-c, with that of a dipolarophile d-e, resulting in the formation of a five member ring. In opposition to the reports of Smith, Huisgen in 1963 discovered 1, 3 dipolar cycloaddition reactions and reported their kinetics and mechanism. Also, Huisgen confirmed that not all 1, 3 dipoles hold nitrogen as a central atom but as a matter of fact some even had oxygen as the central atom and also, not all 1, 3 systems terminate in a carbon atom.
Huisgen proposed a coordinated addition mechanism where the new sigma bonds were formed simultaneously but not at the same rate. The stereo selectivity of cis-trans isomeric dipolarophile, the effect of the solvent and the substituent's on the rate constant, the activation parameters and the orientation of cycloadducts were all being favoured in them mechanism. But this mechanism was subject to a debate after Firestone proposed an alternative mechanism basing on the thermo chemical and regiochemical data i.e. the discrepancies between the calculated and experimental enthalpies. Huisgen then responded to this issue by highlighting several other features of the 1, 3 dipolar cycloaddition reactions that conform to the proposed mechanism but were found to be incompatible with the diradical intermediates such as the retention of configuration of 1, 3 dipoles and dipolarophiles.
A reactivity model for the coordinated cycloaddition reaction was presented by Sustmann in 1974. This reactivity model classified 1, 3 dipolar cycloaddition's into three types based on the interactions between Higher Occupied Molecular Orbital's (HOMO) and Lower Unoccupied Molecular Orbital's (LUMO) of dipoles an dipolarophiles.
Dipoles and Dipolarophiles:
Cycloaddition reactions that involve dipolar species reacting with pie bonds in order to give a five member ring are often termed as 1, 3 dipolar cycloaddition. A 1,3 dipole is a three atom system which can be represented by a Zwitterionic resonance structure. Huisgen classified the 1,3-dipoles into two types, the bent-allyl anion and the linear-allenyl type. A allyl anion usually consists of a heteroatom and has four pie electrons distributed over three atoms. The dipolarophile is usually an alkyne or alkene derivative. The dielectric constant of the solvent does not influence the rate of bimolecular reactions and thereby proceeds with high stereo selectivity and regioselectivity. The propagyl-allenyl anion type is linear and the central atom in the 1, 3-system is limited to nitrogen atom.
The most commonly named 1, 3 dipoles include nitrones, azomethine ylides, carbonyl ylides, nitrile oxides and diazoalkanes. Eventhough nitrones have been described as the most commonly referred 1, 3 dipole for the synthesis of a five member heterocyclic rings, the choice of a 1,3 dipole entirely depends on the target cycloadducts and their reactivity with possible dipolarophiles.
Majority of nitrones are stable compounds and can be in stored under normal room conditions. Whereas, it would be a bit of a trouble storing a cyclic nitrone as it is less stable than that acyclic nitrones. Azomethine ylides are highly unstable have to be prepared in situ and adhering to the standards. Carbonyl ylides undergo 1, 3 dipolar cycloaddition with a variety of dipolarophiles in order to give a tetrahydrofuran derivative. Nitrile oxide is a common 1, 3 dipole and is easily obtained from aldoxime or primary nitro compound. They are needed to be prepared in situ,because of their high reactivity. Diazoalkanes undergo 1, 3 dipole cycloaddition with a variety of dipolarophiles in order to give pyrazolines or pyrazole derivatives. The choice of dipolarophile depends on the target molecule and reactivity of the dipolarophile with the 1, 3 dipole.
Classification of 1,3-Dipoles consisting of carbon, nitrogen, and oxygen centres:
Selectivities:
Regioselectivity, enantioselectivity and diastereoselectivity are the three types of selectivity considered in 1, 3 dipole cycloaddition. These terms refer to the relative formation of a particular regiomer, enantiomers or diastereomers respectively among others.
Regioselectivity usually occurs in the 1, 3 dipolar cycloaddition's of unsymmetrical 1, 3 dipoles with unsymmetrical dipolarophiles. Regiochemistry is controlled by both steric and electronic effects. For example, 1, 3 dipolar cycloaddition of nitrones to terminal alkenes produces two possible regiomers. The sterically more crowded end of the 1, 3 dipole tends to add up more readily to the terminal carbon atom of the alkene thereby producing a five substituted regiomer. However, this effect may be dominated by strong electronic effects.
Enantioselectivity and diastereoselectivity can be controlled by the use of chiral 1, 3 dipole, chiral alkenes or chiral metal ligand complex catalyst. For coordinated reactions like 1, 3dipolar cycloaddition's, the geometry of the double bond in the alkene can be used in predicting relative stereochemistry in the cycloadducts. The reactions tend to be stereo specific as trans alkenes result in anti isomers whereas, cis alkenes give the syn product.
Nitrones:
Beckmann in 1890 for the first time synthesized nitrones. Nitrones were earlier known as azomethine oxides. "Nitrones" was coined from "Nitrogen ketone" in 1916 by Pfeiffer as he conceived a similarity between the N-O bind and the C=O bond. Though the name was accepted, it was actually the C=N-O group that behaved as n extended carbonyl group. It was difficult to name individual compounds as nitrones, therefore the name was adopted for all compounds containing the C=N-O group either in open or close chains. Even though some nitrones were named with the ending nitrones, the proper way of naming nitrones is not yet fully established.
Nitrones as 1, 3 dipoles-Structure and features:
International union of pure and applied chemistry has defined nitrones as the "the N-oxide of imines" because of the main structural difference of imines (R1R2 C=NR3) having a N-Oxide bond.
The stabilized resonance system (C=N-O) consists of four pie electrons delocalised over three atoms, thus acting as 1, 3 dipoles in 1, 3 dipolar cycloaddition.
1,3 dipolar cycloaddition reactions are the most common reactions of nitrones and were been used in the formation of isoxazolidines. The reaction is particularly significant as three new chiral centres can be formed and also the isoxazolidine obtained can be used in the production of numerous other attractive building block molecules like that of 3-amino alcohols.
An illustration of the cycloaddition reaction of that of a nitrones with an alkene resulting in the production of an isoxazolidine is as follows:
Cyclic nitrones are very important in organic synthesis due to their use in the synthesis of cyclic and polycyclic ring systems. Cyclic nitrones result when the C=N of the nitrones is part of a ring system. Among these, the five member cyclic nitrones have gained particular importance due to their application as precursors in the synthesis of pyrollizidine alkaloids.
Experimental Section:
Materials:
List of reagents:
L-Menthol
Chloro Acetic Acid
4-Di Methyl Amino Pyridine
Di Cyclo Hexyl Carbido Imide
1- (n-butyl) imidazole
Potassium Tetra Fluoro Borate
Triethylamine
Chloroform
Ethyl Acetate
Dry Di chloro methane
10% HCl
Sodium bi carbonate
Sodium Sulphate
Apparatus Used:
Separating funnels
Measuring cylinders
Conical flasks
Beakers
Round bottom flask
Condenser
Syringes
Test tubes
TLC plates
Pasteur pipettes
List of Equipment:
JoelTM FT-NMR Spectrometer, JNM-ECP 400
Rotary Evaporator
Vacuum Desiccators
Methodology:
General procedure for the synthesis of Chiral Ionic Liquid:
A solution of menthol (10 grams, 64.0 mmol) in dry dichloro methane (50ml) was prepared in a 250 ml round bottomed flask under stirring at 00C. After the menthol crystals had completely dissolved in the dichloro methane, chloro acetic acid (7.82 grams, 83.2 mmol), N N1- Di cyclohexyl carbodiimide (17.2 grams, 83.2 mmol) , and 4-Dimethyl pyridine (0.78 grams, 6.4mmol) was added into the round bottomed flask and stirring was continued at room temperature for 18 hours (overnight) and was turned off the next morning.
The reaction mixture was turned off and was filtered under vacuum and the precipitate was washed with dichloro methane. The filtrate (organic layer) was washed with 50 ml of 10% hydrochloric acid in a separating funnel and the lower layer was collected. Thus obtained organic layer was washed with 50 ml of saturated sodium bicarbonate, followed by a wash with 50 ml of brine solution. The lower layer from the separating funnel was collected and was subjected for drying over sodium sulphate which was later filtered over vacuum. The pale brown liquid obtained after vacuum filtration was taken into a round bottomed flask and concentrated over rotary evaporator at 400C for 15 minutes. This resulted in a thick brown oily substance which was left over night in the vacuum desiccators at 650C and reduced pressure.
The residue was heated to 800C and was set for stirring in the presence of (8.4 ml, 1.0 equiv.) butyl imidazole for 4 hours. This resulted in a thick brown oily substance.
The brown oily substance turned into a sticky solid which had to be heated at 500C for 30 minutes before proceeding with ion exchange. For the ion exchange step, 10 ml of water was added along with potassium tetra fluoro borate (8.05 grams, 1.0equiv) and set for stirring at room temperature for 3 hours.
After the water had evaporated, the brown residue was diluted in 10 ml of dichloro methane and filtered over a pad Celite® and dried over sodium sulphate under vacuum to produce a chiral ionic liquid which was concentrated over a rotary evaporator at 400C and 50 rpm speed for 15 minutes. This chiral ionic liquid was further dried at 800C under reduced pressure (-30 lb) in a vacuum desiccator for 48 hours.
Column chromatography was performed on the sample in order to isolate a purified form. The column was packed with silica gel and the mobile used was a solvent mixture of 210 ml of hexane and 90 ml of ethyl acetate. As the product was too thick for the pipette to suck, it was a diluted with a few drops of ethyl acetate. A thin layer of the chiral ionic liquid was carefully dropped on to the silica. This layer was protected with a thin layer of treated sand in order to avoid agitation while refilling. The solvent moved downwards as the air pressure was applied. Layers of solvent were collected in various test tubes. A total of 29 test tubes of samples were collected which were then evaluated using thin layer chromatographic technique. Samples from test tube number 4-16 showed a positive sign. These volumes of sample were taken into a round bottomed flask and condensed on a rotary evaporator at 400C and 50 rpm. This resulted in a thick oily liquid.
General procedure for Menschutkin quarterisation:
All the reactions were to be performed under anhydrous conditions. The round bottomed flask used for the experiment was thoroughly dried using a hot air gun on the exteriors and pulled up using a vacuum for the insides.
Distillation of tri alkyl amine: The distilled tri alkyl amine was taken into a two neck round bottomed flask on sodium carbonate crystals. It was then connected to the reflux condenser with a vacuum. The condenser lead into another round bottomed flask with potassium hydroxide pellets. This RBF was maintained at -700C and was meant for the distilled tri alkyl amine to collect.
A solution of freshly distilled tri alkyl amine (5.01 grams, 0.036 mol) in hexane (30 ml) was prepared. To this, chloromethyl (1R, 2S, 5R)-(-) - menthyl ether (7.49 ml, 0.036 mol) was slowly pumped over a period of 20 minutes. The clear solution until then began to get cloudy and started forming white precipitate. The reaction mixture was stirred for 3 hours in presence of nitrogen environment.
The white precipitate produced was separated by filtration and the filter cake was washed with hexane. Previously re-crystallising the crude product from ethyl acetate was problematic as it was difficult to get hold of the formed crystals. Therefore the reaction was altered by directly evaporating the solvent from the crude product by drying the same at 450C under reduced pressure.
After drying over night, the weight of the obtained product after successful Menschutkin quaternisation was 9 grams.
Preparation of tri alkyl [(1R, 2S, 5R)-(-)-menthoxy methyl] ammonium salt:
2 grams of the ammonium salt obtained through Menschutkin quaternisation was weighed and dissolved in 15 ml of water
To this Potassium tetra fluoro borate (4.70 grams) was added and stirred at room temperature for 2 hours. The phases were separated and the salt was obtained after decantation. This salt was washed with cold water until all the chloride ions were no longer detected using silver nitrate. The obtained salt was analysed using NMR as the re-crystallisation proved problematic earlier.
General considerations:
Reaction monitoring
Reactions were monitored by thin layer chromatography using a solvent mixture of hexane and ethyl acetate in 5:1 ratio.
Sample preparation:
NMR
20 mg of sample was weighed into a vial and 0.7ml of respective NMR grade solvent was added. This was then equilibrated and transferred into a NMR tube.
