Chiral NMR discrimination of piperidines and piperazines using (18-crown-6)-2,3,11,12-tetracarboxylic acid

Enantiomeric discrimination is observed in the (1)H and (13)C NMR spectra of piperidines and piperazines in the presence of (-)-(18-crown-6)-2,3,11,12-tetracarboxylic acid. The amines are protonated by the carboxylic acid groups of the crown ether to produce the corresponding ammonium and carboxylate ions. Association of the ammonium ion with the crown ether likely involves two hydrogen bonds with the crown ether oxygen atoms and an ion pair with the carboxylate anion. Methyl, hydroxymethyl, phenyl, carboxyl, pyridyl, and cyclohexyl substituent groups alpha to the nitrogen atom do not inhibit binding of the ammonium ion to the crown ether. The NMR spectra of piperidines with the stereogenic center alpha or beta to the nitrogen atom exhibit substantial enantiomeric discrimination. Dibasic substrates such as the piperizines are likely converted to their diprotonated form in the presence of the crown ether, and both nitrogen atoms appear to associate with the crown ether moiety.     

Enantioselective separation of racemic secondary amines on a chiral crown ether-based liquid chromatography stationary phase

The first general enantioselective separation of racemic secondary amines on a crown ether-based liquid chromatography chiral stationary phase (CSP) is presented. The CSP is based on (+)- or (-)-(18-crown-6)-2,3,11,12-tetracarboxylic acid covalently bonded to silica gel. A mobile phase containing methanol, acetonitrile, triethylamine and acetic acid was employed in these separations of secondary amines with crown ether CSPs. The separation mechanism is believed to be the secondary amine forming a complex which includes crown ether coordination and electrostatic interaction of the positively charged amine with a carboxylate anion of the immobilized crown ether.     

Chiral NMR discrimination of pyrrolidines using (18-crown-6)-2,3,11,12-tetracarboxylic acid

The compound (18-crown-6)-2,3,11,12-tetracarboxylic acid is shown to be an effective chiral NMR solvating agent for determining the enantiomeric excess of chiral pyrrolidines. Enantiomeric discrimination is observed in both the ¹H and ¹³C NMR spectra. The neutral amine is mixed with the crown ether in an NMR tube and a neutralization reaction between the two produces the corresponding ammonium and carboxylate ions. An association of these ions accounts for the chiral recognition. Pyrrolidines with one or two substituent groups α to the nitrogen atom are not inhibited from binding to the crown ether. Chiral discrimination was observed in the NMR spectra of pyrrolidines that have a stereogenic center α or β to the nitrogen atom. Dibasic substrates are likely converted to their diprotonated form in the presence of the crown ether, and both ammonium sites appear to associate with the crown ether moiety.     

Evaluation of A Chiral Crown Etherlc Column For the Separation of Racemic Amines

Abstract

Enantiomeric resolution of more than fifty racemic primary amines can be achieved on a column that utilizes a crown ether as a chiral selector. the racemic solute is solubilized in an acidic solvent, forming an ammonium ion from the primary amine functional group. an interaction between the lone pair electrons on the oxygens of the crown ether and the positive charge of the ammonium group leads to the formation of an inclusion complex. Due to the chirality of the crown ether there is stereoselective interaction resulting in enantiomeric separation. Excellent resolution is possible for amino acids, amino alcohols, amino esters and amines. Compounds are separated that were poorly resolved by conventional ligand exchange columns and by other means.     

Alternative approach to enhancing cation selectivity in ion chromatography

A new approach to enhance cation selectivity in ion chromatography (IC) is described. Two packings, one carrying a conventional carboxylate cation exchanger and the other carrying a crown ether (CE) phase are packed into two separate columns and used in series. The resolution between sodium and ammonium and between ammonium and potassium is increased significantly. The two stationary phases may also be mixed and packed into a single column. The selectivity of the cations can be adjusted easily by varying the dimensions of the carboxylate and CE columns (in the two-column configuration), or by changing the ratio of the carboxylate cation exchanger to the CE packing (in the single-column configuration). These new systems separate ammonium and sodium, even when the sodium concentration is 5000 times higher. Amines such as ethanolamine and triethanolamine can also be separated from the alkali and alkaline-earth cations.     

Improvement of chiral stationary phases based on cinchona alkaloids bonded to crown ethers by chiral modification

To improve the chiral recognition capability of a cinchona alkaloid crown ether chiral stationary phase, the crown ether moiety was modified by the chiral group of (1S, 2S)‐2‐aminocyclohexyl phenylcarbamate. Both quinine and quinidine‐based stationary phases were evaluated by chiral acids, chiral primary amines and amino acids. The quinine/quinidine and crown ether provided ion‐exchange sites and complex interaction site for carboxyl group and primary amine group in amino acids, respectively, which were necessary for the chiral discrimination of amino acid enantiomers. The introduction of the chiral group greatly improved the chiral recognition for chiral primary amines. The structure of crown ether moiety was proved to play a dominant role in the chiral recognitions for chiral primary amines and amino acids.     

Chiral separation of gemifloxacin in sodium-containing media using chiral crown ether as a chiral selector by capillary and microchip electrophoresis

Chiral crown ether, (+)-(18-crown-6)-tetracarboxylic acid (18C6H(4)), is an effective chiral selector for resolving enantiomeric primary amines owing to the difference in affinities between 18C6H(4) and each of the amine enantiomers. In addition to the destacking effect of sodium ion in the sample solution, the strong affinity of sodium ion to the polyether ring of crown ether is unfavorable to chiral capillary electrophoresis using 18C6H(4) as a chiral selector. In this report, the chiral separation of gemifloxacin dissolved in a saline sample matrix using 18C6H(4) was investigated. Adding a chelating agent, ethylenediaminetetraacetic acid (EDTA), to the run buffer greatly improved the separation efficiencies and peak shapes. The successful chiral separation of gemifloxacin in a urinary solution was demonstrated for both capillary and microchip electrophoresis.     

New epoxy-terminated oligoesters: Precursors to totally biodegradable networks

Two types of novel biodegradable epoxy resins, carrying cycloaliphatic-epoxy and glycidyl ester end-groups, have been synthesized from hydroxy-telechelic oligoesters. The cycloaliphatic-epoxy end-groups were based on either methyl cis-4-cyclohexene-2-(carboxylic acid)-1-carboxylate or 3-cyclohexene-1-carboxylic acid. These compounds were reacted with hydroxy-telechelic poly(ε-caprolactone-co-D ,L -lactide) oligoesters, yielding cycloaliphatic-olefin-terminated oligomers. Conversion of the olefin to the epoxide groups was achieved using a phase transfer epoxidation with an inorganic peracid derived from the reaction of phosphoric acid, sodium tungstate, and hydrogen peroxide. Aliquat 336, a quaternary ammonium salt, acted as the phase transfer catalyst. Nearly theoretical conversion of hydroxy to epoxy end-groups was achieved in only one case, however, alternative variations of this method of synthesis show promise. To prepare glycidyl ester-terminated prepolymers, hydroxy-telechelic poly(ε-caprolactone) oligoesters were reacted with succinic anhydride, in 1,2-dichloroethane with 1-methylimidazole as catalyst, resulting in (carboxylic acid)-terminated oligomers. After conversion of the end-groups to the potassium carboxylate salt by titration with methanolic KOH, the isolated salt was dried and reacted with epibromohydrin in acetonitrile at reflux, using an 18-C-6 crown ether as the phase transfer catalyst, thus preparing the (glycidyl ester)-telechelic prepolymer. Epoxide equivalent weights differed by 2.7–7.1% from the theoretical values. These cycloaliphatic-epoxide and glycidyl ester-terminated prepolymers may be crosslinked with anhydrides or amines, respectively, to produce totally bioabsorbable networks. © 1993 John Wiley & Sons, Inc.     

Determination of sodium and ammonium ions in disproportionate concentration ratios by ion chromatography

In ion chromatography, samples of very different ammonium-to-sodium concentration ratios are difficult to quantify since these two cations have similar selectivities for stationary phases containing commonly used sulfonate or carboxylate cation-exchange functional groups. The IonPac CS15 cation-exchange column, with carboxylate and phosphonate functional groups as well as a crown ether group, was developed to address this limitation. Selectivity for the common inorganic cations on this column is different from that of conventional cation-exchange columns in that the separation between sodium and ammonium ions has been greatly increased, allowing for determinations of low levels of one in the presence of high levels of the other with an isocratic eluent. For larger than 4000:1 sodium-to-ammonium concentration ratios, an eluent step change or gradient elution is needed. For moderate ratios, combinations of this column with a carboxylate column, containing no crown ether group, can be used at room temperature with an isocratic eluent containing no organic solvent.     

(+)-(18-Crown-6)-2,3,11,12-tetracarboxylic acid and its Ytterbium(III) complex as chiral NMR discriminating agents

The compound (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid (I) and its ytterbium(III) complex are evaluated as chiral NMR discriminating agents. The crown ether is a useful chiral discriminating agent for protonated amino acid esters, amines, and amino alcohols. The crown can also be used with neutral primary amines since amines are protonated through a neutralization reaction with a carboxylic acid moiety of the crown. Enantiodiscrimination with the crown is observed in methanol and acetonitrile. Addition of ytterbium(III) nitrate to crown-substrate mixtures causes upfield shifts in the NMR spectrum of the substrate and often enhances the enantiomeric discrimination. Evidence indicates that the ytterbium(III) bonds to the carboxylic acid moieties of the crown, but enhancements in enantiomeric discrimination result from either the different association constants of the enantiomers with the crown or diastereomeric nature of the resulting crown-substrate complexes. The ytterbium complex with the crown is suitable for use in methanol but precipitates in acetonitrile.     

Modular synthesis of di- and tripeptides of luminescent crown ether aminocarboxylic acids

Luminescent benzo crown ether aminocarboxylic acids with ammonium ion affinity were prepared and converted into linear bis- and tris benzo crown ether amides using standard peptide coupling protocols. The affinities of the new crown ethers to ammonium ions and di- and tetrapeptides bearing ammonium ion moieties were determined by emission titration in methanol and buffered water.     

4]Pseudorotaxanes with remarkable self-sorting selectivities

The synthesis and characterization of several self-assembled [4]pseudorotaxanes is reported, some of which form in a programmed way based on two similar yet orthogonal crown ether/secondary ammonium ion binding motifs. A preference for the formation of a [4]pseudorotaxane with an antiparallel rather than parallel alignment of crown ether building blocks is observed even in the absence of such orthogonal binding sites, when a homodivalent axle is used.     

Enantiomeric discrimination of cyclic β-amino acids using (18-crown-6)-2,3,11,12-tetracarboxylic acid as a chiral NMR solvating agent

(18-Crown-6)-2,3,11,12-tetracarboxylic acid is an excellent chiral NMR solvating agent for cyclic β-amino acids with cyclopentane, cyclohexane, cycloheptane, cyclopentene, cyclohexene, bicyclo[2.2.1]heptane, and bicyclo[2.2.1]heptene rings. The crown ether was added to the neutral β-amino acids in methanol-d₄. A neutralization reaction between the crown ether and β-amino acid forms the ammonium ion needed for favorable association. Enantiomeric discrimination of the two hydrogen atoms α to the amine and carboxylic acid moieties of the β-amino acid was observed with every substrate studied. Trends in the order of the enantiomeric discrimination of certain hydrogen atoms for substrates of similar structures correlate with the absolute configuration.     

Side arm participation in lariat ether carboxylate-alkali metal cation complexes in solution

Lariat ether carboxylic acids of structure CECH₂OCH₂C₆H₄-2-CO₂H with crown ether (CE) ring sizes of 12-crown-4, 15-crown-5 and 18-crown-6 are prepared and converted into alkali metal-lariat ether carboxylate complexes. Absorptions for the diastereotopic benzylic protons in the ¹H NMR spectra of the complexes in CDCl₃ are utilized to probe the extent of side arm interaction with the crown ether-complexed metal ion as a function of the crown ether ring size and identity of the alkali metal cation.     

The use of immobilized crown ethers as in-situ N-protecting groups in organic synthesis and their application under continuous flow

In addition to their high affinity for inorganic cations, crown ethers have been shown to efficiently sequester ammonium ions, forming a stable adduct via hydrogen bonding. Using this principle, several authors have reported the use of crown ethers as protecting groups for amines however to date, their widespread use has been somewhat precluded by the difficulties associated with removal of the crown ether from the resulting reaction mixture. In order to address this problem, we report the preparation of an immobilized 18-crown-6 ether derivative and its incorporation into a flow reactor, demonstrating the ability to use and recycle the reagent for the chemoselective O-acylation and alkylation of bifunctional compounds such as 4-(2-aminoethyl)phenol and 4-nitrophenol.     

Application of crown ethers as modifiers for the separation of amines by capillary electrophoresis

The separation of amines with capillary electrophoresis (CE) was made possible by applying crown ethers such as 18-crown-6 and 15-crown-5 as modifiers. Crown ether 18-crown-6 performed better as a modifier than 15-crown-5. The mobility change of primary amines with 18-crown-6 was larger than that for secondary and tertiary amines. The mobility change of various amines with 18-crown-6 were in the order: 1-aminobutane>2-aminobutane>2-amino-2-methylpropane. Effects of crown ether concentration, pH and cations in the eluent of CE were also investigated and discussed. Some neurotransmitters such as dopamine, serotonin, epinephrine, isoproterenol and phenylalanine were separated successfully by using crown ethers in CE analysis.     

Sequential O- and N-acylation protocol for high-yield preparation and modification of rotaxanes: synthesis, functionalization, structure, and intercomponent interaction of rotaxanes

A pseudorotaxane consisting of a 24-membered crown ether and secondary ammonium salt with the hydroxy group at the terminus was quantitatively acylated by bulky acid anhydride in the presence of tributylphosphane as catalyst to afford the corresponding rotaxane in high yield. Large-scale synthesis without chromatographic separation was easily achieved. The ammonium group in the resulting rotaxane was quantitatively acylated with excess electrophile in the presence of excess trialkylamine. Various N-functionalized rotaxanes were prepared by this sequential double-acylation protocol. 1H NMR spectra and X-ray crystallographic analyses of the rotaxanes showed that the crown ether component was captured on the ammonium group in ammonium-type rotaxane by strong hydrogen-bonding intercomponent interaction. The conformation around the ammonium group was fixed by the hydrogen-bonding interaction. Meanwhile, the conformation of the amide-type rotaxane was determined by the weak CH/pi interaction between the methylene group in crown ether and the benzene ring of the axle component. The N-acylation of ammonium-type rotaxane is useful for the preparation of both functionalized rotaxanes and weak intercomponent interaction-based rotaxanes.     

Magic ring catenation by olefin metathesis

[reaction: see text]. Olefin metathesis has been employed in the efficient syntheses of a [2]catenane with the templation being provided by the recognition between a secondary ammonium ion and a crown ether. In one approach, a crown ether precursor has been clipped around an NH2+ center situated in a macrocyclic ring, yielding the mechanically interlocked compound. In the other approach, the reversible nature of olefin metathesis allows for a magic ring synthesis to occur wherein two free macrocycles can be employed as the stationary materials, leading to the formation of the same [2]catenane.     

Solvation-thermodynamic effects of the water-methanol solvent on the coordination of Na+, K+, NH 4 + , and Ag+ ions with 18-crown-6: Gibbs energies of complexation and resolvation of reagents

The results of solvation-thermodynamic monitoring of aqueous-methanol solutions of electrolytes (NaCl, KCl, NH₄Cl, AgNO₃) and 18-crown-6 ether (L) in the mole fraction scale are summarized and systematized. The stability of sodium mono(crown ether) complexes in water-methanol solvents is due to both enthalpy and entropy contributions, and the stability of the ammonium and silver complexes, to the enthalpy contribution. The solvent effects in formation of crown ether complexes of sodium, potassium, ammonium, and silver are subjected to solvation-thermodynamic and correlation analyses. An equation is suggested for estimating the ion selectivity of crown ethers, and the contributions of energy constituents (the Gibbs energy of transfer of reagents) to varation of the ion selectivity of 18-crown-6 toward M-Na⁺ pairs in the water-methanol solvent are revealed.     

Polycarboxylate crown ethers: Synthesis,complexation, applications

Crown ethers derived from tartaric acid present a number of interesting features as receptor frameworks and offer a possibility of enhanced metal cation binding due to favorable electrostatic interactions. The synthesis of polycarboxylate crown ethers from tartaric acid is achieved by simple Williamson ether synthesis using thallous ethoxide or sodium hydride as base. Stability constants for the complexation of alkali metal and alkaline earth cations were determined by potentiometric titration. Complexation is dominated by electrostatic interactions but cooperative coordination of the cation by both the crown ether and a carboxylate group is essential to complex stability. Complexes are stable to pH 3 and the ligands can be used as simultaneous proton and metal ion buffers. The low extractibility of the complexes was applied in a membrane transport system which is a formal model of primary active transport.