Novel chiral hexaazamacrocycles for the enantiodiscrimination of carboxylic acids

New enantiopure amines (R,R)-1 and (S,S)-1 were obtained from (R)- or (S)-2,2′-diamino-1,1′-binaphthyl and 2,6-diformylpyridine in a synthesis templated by lead(II) or lanthanide(III) ions, reduction with NaBH₄ and subsequent demetallation. Similarly new amines (R,R,R,R)-2 and (S,S,S,S)-2 were obtained from (1R, 2R)- or (1S, 2S)-1,2-diphenylethylenediamine. The X-ray crystal structure of the Pb(II) complex with macrocyclic Schiff base precursor of (R,R)-1 indicates helical twisted conformation of this macrocycle, while the ROESY spectrum of R,R-1 suggests less twisted conformation. (R,R)-1 and (R,R,R,R)-2 were tested as chiral shift reagents (chiral solvating agents) for various α-substituted carboxylic acids, including non steroidal anti-inflammatory drugs. Enantiodiscrimination of carboxylate ¹H NMR signals was observed with ΔΔδ values up to 0.1 ppm.     

Urea-tetrahydrobenzoxanthene receptors for carboxylic acids

Hydrogen-bonding receptors for carboxylic acids have been prepared based on a cis tetrahydrobenzoxanthene skeleton. X-ray diffraction study of one of these compounds revealed that the cleft is suitable for establishing strong linear hydrogen bonds with the oxygen of a water molecule. Complexes that set only three H-bonds with the guests showed no chiral recognition with amino acid derivatives. However, suitable functionalization of the receptor provided a fourth H-bond with certain amino acid derivatives, leading to significant enantioselective complexation in this case.     

A fundamental study on the fluorescence-quenching effect of nitro groups in tetraphenylethene AIE dyes with electron-withdrawing groups

A nitro group is a common fluorescence quencher, but its quenching efficiency can be easily affected by the surrounding environment. To date, there has been no systematic study on the effects of electronwithdrawing groups on the quenching efficiency of nitro groups. Herein, by virtue of experimental validation and theoretical calculations, we found that strong electron-withdrawing groups, such as pyridinium and dicyanovinyl groups, are detrimental to the quenching effect of nitro groups. Decreasing the electron-withdrawing ability could restore the nitro group's quenching effect.     

Synthesis of new chiral fluorescent sensors and their applications in enantioselective discrimination

Five novel sensors (R,R)-3–6 and (S, S)-6 were synthesized and developed for enantioselective recognition of chiral compounds. Sensor 6 with two thiourea groups and steric π-conjugation frameworks could discriminate different chiral substrates, including acidic compounds, basic compounds, and neutral compounds. These results disclosed that the outstanding performance of enantioselective discrimination could be attributed to the thiourea group which acted as a hydrogen-bonding donor and the bulky steric moiety of the hosts which provided appropriate chiral environment. This result will be of great practical value in the designation of chiral sensors and high-throughput assay of chiral products.     

Quantitative HPTLC analysis of carboxylic acids in wine and juice

The need for quick and specific assay of carboxylic acids in wine and non-fermented beverages is explained. The method developed in this work is based on high performance thin-layer chromatography (HPTLC) followed by densitometric evaluation. Untreated samples, with the exception of red wines which were destained, were directly sprayed onto the cellulose layer. The chromatogram was developed with ethyl acetate-toluene-water-formic acid 60:20:20:15, then stained with xylose-aniline reagent. Densitometric scanning is by absorbance at 546 nm. The method is quick, sensitive, and has a wide dynamic range for the acids analyzed.     

Exceptional chiral recognition of racemic carboxylic acids by calix[4]arenes bearing optically pure alpha,beta-amino alcohol groups

Calixarenes bearing optically pure alpha,beta-amino alcohol groups at their lower rim exhibit exceptional and efficient chiral recognition ability in discrimination of racemic mandelic acid, 2,3-dibenzoyltartaric acid and 2-hydroxy-3-methylbutyric acid. [structure: see text]     

Synthesis of new chiral fluorescent sensors and their applications in enantioselective discrimination

New chiral fluorescent sensors derived from tetraphenylethylene and proline hydrazide were synthesized and applied in the chiral recognition of various chiral compounds, including unprotected amino acids, acidic compounds, chiral amines and even neutral alcohols. These results demonstrated that the excellent enantioselective response ability to various chiral substrates could be attributed to the –NH moieties of pyrrolidine ring and thiourea unit which acted as hydrogen-bonding donors. This result is of potential significance in enantiomeric discrimination and high-throughput analysis of the enantiomeric purity of chiral guests.     

Advanced dress-up chiral columns: New removable chiral stationary phases for enantioseparation of chiral carboxylic acids

This paper describes the preparation of new dress-up columns featuring reproducibly removable and replaceable chiral stationary phases. After synthesizing perfluroalkylated quinine and quinidine derivatives as chiral stationary phase compounds (F-CSPs), we adsorbed them reversibly onto a fluorous LC column through pumping of their solutions. Using this dress-up chiral column and fluorophobic elution of aqueous ammonium formate/MeOH mixtures, we could enantioseparate four racemic N-acetyl amino acids, dichlorprop, and sixteen fluorescent 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate (AQC)-derivatized amino acids. Dressing and undressing of the coated F-CSPs could be controlled by varying the fluorophilicity and fluorophobicity of the eluent. The relative standard deviations of the retention times, the retention factors, the number of theoretical plates, the enantioseparation factors, and the resolutions of each of four preparations of such dress-up columns were all less than or equal to 5.26% (from 20 repeated analyses); the reproducibilities from four different preparations were all less than or equal to 10.6%. These columns also facilitated highly sensitive and selective analyses of AQC-amino acids when detected using LC–MS/MS.     

Synthesis and study of a heterocyclic receptor designed for carboxylic acids

The synthesis of a tricyclic receptor having a bowl shape and three binding points for carboxylic acids has been achieved starting from readily available 1-tetralone derivatives according to two different methods. This host possesses a six-membered lactam moiety and a carboxamide at the end of a flexible arm. Association constant with benzoic acid and stoichiometry of the complex have been determined using ¹H NMR dilution experiments.     

Determination of low-molecular-weight carboxylic acids in aqueous samples by gas chromatography and nitrogen-selective detection of 2-nitrophenylhydrazides

A gas chromatographic method was developed for the determination of low-molecular-weight carboxylic acids in aqueous samples based on a derivatization procedure compatible with aqueous solutions. The technique uses nitrogen-selective detection with a thermionic-specific detector after derivatization of carboxylic acids as 2- nitrophenylhydrazides. The hydrazides were extracted with ethyl acetate prior to injection into the gas chromatograph. The derivatives appear to be stable in ethyl acetate at 0–5° C for long periods and, therefore, can be stored for analysis at a later date. The detection limits of different short-chain acids are in the range 0.8–1.4 pmol per injected sample. The relative standard deviation is less than 10% at the 1 μM level. Examples of the use of the method are given for the determination of carboxylic acids in anoxic marine sediment pore waters, coastal sea water and Black Sea water samples.     

Analysis of carboxylic acids by gas chromatography. Derivatisation using chloroacetone

Summary The preparation of the acetonyl esters of nine aliphatic carboxylic acids is described, the general formula of the derivatives being RCOOCH₂COCH₃ where R=alkyl or H. The derivatives show good chromatographic properties on both packed and capillary columns. The electron impact and chemical ionisation mass spectra of the derivatives are discussed.     

Chiral amines as reagents for HPLC-MS enantioseparation of chiral carboxylic acids

Mass spectrometry (MS) has become a popular analytical technique because of its high sensitivity and specificity. Therefore, the use of a chiral derivatization reagent for the MS detection seems to be efficient for the enantiomeric separation of racemates. However, the number of chiral reagents for the liquid chromatography (LC)-tandem mass spectrometry (MS/MS) analysis is very limited. The applicability of commercially available chiral amines as the derivatization reagents for the enantiomeric separation of chiral carboxylic acids is reported in this paper by using non-steroidal anti-inflammatory drugs (NSAIDs), i.e. ibuprofen, flurbiprofen, and loxoprofen. The efficiency of the chiral reagents was evaluated in terms of tagging easiness, separation by reversed-phase chromatography, and detection sensitivity by electrospray ionization (ESI)-MS/MS. Among the tested eight chiral amines, i.e. (R)-(+)-4-(3-aminopyrrolidin-1-yl)-7-(N,N-dimethylaminosulfonyl)-2,1,3-benzoxadiazole (DBD-APy), (S)-(+)-1-(2-pyrrolidinylmethyl)-pyrrolidine (PMP), L-prolinamide, (3R)-(-)-1-benzyl-3-aminopyrrolidine, (S)-(+)-1-cyclohexyl-ethylamine, (3R)-(+)-3-(trifluoroacetamido)-pyrrolidine (TFAP), (R)-(-)-1-aminoindan (AI), and (S)-(+)-tetrahydrofurfuryl-amine, DBD-APy, PMP, AI, and TFAP could be used as the chiral reagents for the enantiomeric separation of the NSAIDs. The Rs values and the detection limits of the derivatives were in the range of 1.29-3.85 and 0.57-0.96 fmol, respectively. These four reagents were applied for the determination of the NSAIDs in rat plasma.     

Fully automated reagent peak‐free liquid chromatography fluorescence analysis of highly polar carboxylic acids using a column‐switching system and fluorous scavenging derivatization

In this study, we combined a column‐switching system with a fluorous scavenging derivatization method to develop a fully automated reagent peak‐free LC fluorescence detection protocol for the analysis of highly polar carboxylic acids. In this method, highly polar carboxylic acids were derivatized with fluorescent 1‐pyrenemethylamine in the presence of 1‐ethyl‐3‐(3‐dimethylaminopropyl)carbodiimide and 1‐hydroxy‐1H‐benzotriazole. Residual excess of the unreacted reagent was tagged with 2‐(perfluorooctyl)ethyl isocyanate and then removed selectively using a fluorous column‐switching system placed in front of an analytical reversed‐phase column. The signal of the fluorous‐tagged unreacted reagent was completely absent in the resulting chromatograms; therefore, it did not interfere with the quantification of each acid especially those eluted before 20 min. The detection limits (S/N = 3) for the examined acids were in the range from 4.0 to 22 fmol per injection. We have applied this method to comparative analysis of highly polar carboxylic acids in urine samples obtained from diabetes mellitus type‐II model mice and their control.     

Development of new isothiocyanate-based chiral derivatizing agent for amino acids

Summary (1S,2S)-1,3-Diacetoxy-1-(4-nitrophenyl)-2-propylisothiocyanate [(S,S)-DANI] has been developed as a new chiral derivatizing agent for resolution of compounds containing an amino group. The reagent is readily available in both enantiomeric forms. Its applicability was demonstrated by the resolution of representative α-amino acids. The diastereomeric thiourea derivatives produced were separated by reversed-phase (C₁₈) high-performance liquid chromatography, with mixtures of 0.1% aqueous trifluoroacetic acid (pH∼2) and methanol as eluents.     

Determination of carboxylic acids by ion-exclusion chromatography with non-suppressed conductivity and optical detectors

Summary Determination of carboxylic acids using non-suppressed conductivity and UV detections is described. The background conductance of 1-octanesulfonic acid, hexane sulfonic acid and sulfuric acid at varying concentrations was determined. Using 0.2 mM 1-octanesulfonic acid as a mobile phase and an injection volume of 300 l, the detection limits range from 1 M for formic acid to 10 M for butyric acid. The conductivity detector was connected in tandem with a Waters 484 optical detector at 210 nm, which allowed the analysis of carboxylic acids from 0.01 mM to 10 mM. The dependence of the retention of carboxylic acids on the eluent pH is discussed.     

Determination of carboxylic acids in water by gas chromatography using several detectors after flow preconcentration

A novel analytical method is reported that combines continuous solid-phase extraction and gas chromatography for the determination of 22 carboxylic acids in water. The highly polar and hydrophilic analytes were preferentially sorbed on a mixture of LiChrolut EN-Supelclean ENVI-18 (1:1) sorbent column and eluted with methanol; this extraction process did not require derivatisation. The extract was analysed by gas chromatography coupled to a flame ionisation detector as well as a mass spectrometer with electron impact (EI) or positive chemical ionisation modes. The highest sensitivity was achieved when using MS-EI, with good linearity in calibration curves and low detection limits (2-40ngL(-1)) for 50mL of sample. The entire procedure from raw aqueous sample to a ready-to-inject methanol solution of the acids requires less than 15min. Another benefit of this method is the good accuracy (recoveries between 93 and 102%) and precision (relative standard deviation, 3.4-6.2%), which allows the determination of carboxylic acids in environmental water and in real chlorinated and ozonated drinking water.     

Enantiomer elution order reversal of fluorenylmethoxycarbonyl-isoleucine in high-performance liquid chromatography by changing the mobile phase temperature and composition

In this paper the elution order reversal of enantiomers of fluorenylmethoxycarbonyl- or FMOC-isoleucine is described depending on the separation temperature and composition of the mobile phase when using the polysaccharide-based chiral column Lux Cellulose-1 in HPLC with normal-phase eluent. Reversal of the enantiomer elution order (EEO) in HPLC depending on the column temperature and content of the polar modifier in the mobile phase has been reported before in the literature. However, EEO reversal by changing the content of acidic modifier in the mobile phase seems to be described for the first time in the present work.     

Determination of C4-C14 carboxylic acids by capillary zone electrophoresis. Application to the identification of diamide degradation products and partitioning studies.

Capillary zone electrophoresis (CZE) was investigated for the determination of linear saturated carboxylic acid homologues ranging from C₄ to C₁₄. Separation conditions were optimised to overcome the problems of decreasing solubility and decreasing selectivity between successive homologues with increasing chain length. Separations were performed at 20°C, using a 20 kV separation voltage and a pH 8 electrolyte containing 30% methanol. A suitable chromophore (4-aminobenzoate) was added to ensure indirect UV detection of the analytes. Calibration curves and repeatability were established. Minimum detectable concentrations of 3·10⁻⁶ mol l⁻¹ were achieved. Resolution between successive homologues was better than 2. The electrophoretic mobility of each homologue (n=7–14) was assessed and a quasi-linear relationship between the mobility value and 1/n was observed. The quantitative analysis of a diamide degradation solution was performed and compared to potentiometric results. The CZE method was also applied to the determination of C₇–C₁₄ partitioning between an organic medium containing tributylphosphate in n-dodecane and different basic solutions. Their behaviour was established according to the chain length and the pH of the aqueous phase. For C₁₀–C₁₄ compounds, results were validated by comparison with gas chromatographic analysis of the organic phases.