A Universal 19F NMR Probe for Enantiomeric Discrimination of Primary, Secondary, and Tertiary Amines

Enantiomeric discrimination is observed in the 1H and 13C NMR spectra of secondary and tertiary amines in the presence of (-)-(18-crown-6)-2,3,11,12-tetracarboxylic acid (1). Nonequivalence of the resonances of prochiral nuclei in primary and secondary amines is also observed when they associate with 1. The amines are added in their neutral form and are protonated by the carboxylic acid groups of 1 to produce the corresponding ammonium and carboxylate ions. Secondary amines associate with 1 through two hydrogen bonds and an ion pair interaction. Tertiary amines can only form one hydrogen bond to accompany the ion pairing. Chiral discrimination in the 1H and 13C NMR spectra of a series of aryl-containing secondary amines is of sufficient magnitude to determine enantiomeric purities. The discrimination in the spectra of tertiary amines with 1 is smaller, but 13C NMR spectra provided enough distinction for the determination of enantiomeric purity.

The specific fluorescent detection of α-methyltryptamine (AMT) presents a great challenge because similar amine groups and benzene rings exist in a variety of amines. Here, we show the precise modulation of the electron-withdrawing strength of the π-conjugate bridge in aldehyde-containing Schiff base-based fluorescent probes for ultratrace AMT discrimination. It is found that different electron-withdrawing groups -C6H4, -C6H2N2, and -C6H2Br2 as the π-conjugate bridge of the 2-dicyanomethylidene-3-cyano-4,5,5-trimethyl-2,5-dihydrofuran (TCF)-based probes can classify and identify organic amines with different amine nucleophilicities. Notably, the probe with -C6H2Br2 as the π-conjugate bridge, denoted as BrFS-TCF, which has the highest electrophilicity of the recognition site, shows a superior nM-level limit of detection (LOD) and an instant response time (<0.1 s) toward AMT. Especially, it shows an excellent selectivity facing the secondary amines, tertiary amines, aromatic amines, and even primary amines. The present strategy would provide a new pathway for chemical substances with similar structures and properties and especially for fighting against illegal drugs.

[reaction: see text] Enantiomeric discrimination is observed in the (1)H NMR spectra of chiral secondary amines in the presence of (R)-(+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid. Secondary amines are protonated by one of the carboxylic acid groups of the crown ether to produce the corresponding ammonium and carboxylate ions. The secondary ammonium ion likely forms two hydrogen bonds to crown ether oxygen atoms and an ion pair with the carboxylate anion.

Calix[4]arenes, calix[4]resorcarenes, and anionic cyclodextrin derivatives were examined as chiral NMR solvating agents. The calix[4]arenes were prepared by attachment of amino acids through the hydroxyl groups of the phenol rings. Chloroform-, methanol-, and water-soluble derivatives were prepared and tested with a range of substrates. Chloroform-soluble chiral calix[4]resorcarenes were prepared by attachment of chiral primary and secondary amines and examined in NMR applications with a variety of substrates. Sulfated and carboxymethylated beta-cyclodextrin are effective at causing enantiomeric discrimination in the (1)H NMR spectra of organic cations. Lanthanide ions associate at the carboxymethyl groups and cause sizeable shifts and enhancements in enantiomeric discrimination in the spectra of organic cations. The enhancements caused by the lanthanide ion are large enough that much lower concentrations of the cyclodextrin can be used as compared to conventional analyses.

A C2-symmetric host (host 1) was synthesized by derivatization of chiral diphenylethylenediamine with phenylisocyanate. High-resolution proton nuclear magnetic resonance (1H NMR) was used to investigate whether the chiral host could be used for enantiomeric discrimination of its structural analogues:α-phenylethylamine (guest 2), α-(p-methoxyphenyl)ethylamine (guest 9) and their derivatives (guests 3~8 and 10~13), and hydrogen-bonding interactions underlying the enantiomeric discrimination. It was observed that the host was able to recognize the urea and amide derivatives of the two primary amines, except for guests 7 and 12 bearing two NO2 groups. The host had stronger hydrogen-bonding interactions with the urea derivatives of guests 2 and 9 than with the corresponding amide derivatives, and high enantiomeric discrimination ability for the CHCH3 groups of the (R)- and (S)-urea derivatives.

Development of BINOL derived axially chiral molecular probe for electrochemical discrimination of tryptophan enantiomers

Nanopores are increasingly utilized as tools for single-molecule detection in biotechnology. Many nanopores are fabricated through procedures that require special materials, expensive facilities and experienced operators, which limit their usefulness on a wider scale. We have developed a simple method of fabricating a robust, low-noise nanopore by externally penetrating a nanocavity enclosed in the terminal of a capillary pipet. The nanocavity was shown to have a pore size on the scale of a single molecule, verified by translocation of molecules of known sizes, including double-stranded DNA (2 nm), gold nanoparticles (10 nm), and ring-shaped cyclodextrin (1.5 nm). The small pore size allows entrapment of a single cyclodextrin molecule. The glass nanopore with a trapped cyclodextrin proves useful in single-molecule discrimination of chiral enantiomers.

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 tertiary and quaternary amine solvating agents for NMR spectroscopy were synthesized from the wood resin derivative (+)-dehydroabietylamine (2). The resolution of enantiomers of model compounds [Mosher’s acid (3) and its n-Bu4N salt (4)] (guests) by (+)-dehydroabietyl-N,N-dimethylmethanamine (5) and its ten different ammonium salts (hosts) was studied. The best results with 3 were obtained using 5 while with 4 the best enantiomeric resolution was obtained using (+)-dehydroabietyl-N,N-dimethylmethanaminium bis(trifluoromethane-sulfonimide) (6). The compounds 5 and 6 showed a 1:1 complexation behaviour between the host and guest. The capability of 5 and 6 to recognize the enantiomers of various α-substituted carboxylic acids and their n-Bu4N salts in enantiomeric excess (ee) determinations was demonstrated. A modification of the RES-TOCSY NMR pulse sequence is described, allowing the enhancement of enantiomeric discrimination when the resolution of multiplets is insufficient.

Derivatives of the chiral selector N-(3,5-dinitrobenzoyl)leucine were prepared and used as chiral selectors for enantiomer discrimination in single-stage electrospray ionization mass spectrometric experiments. The chiral selectors were designed to remove the ionization site from the sites required for effective chiral recognition. Addition of a chiral analyte to a solution of the two pseudoenantiomeric chiral selectors, which differ in absolute stereochemistry and the length of the tether connecting the tertiary amine site used for ionization via protonation and the rest of the chiral selector, affords selector-analyte complexes in the electrospray ionization mass spectrum where the ratio of these complexes is dependent on the enantiomeric composition of the analyte. The relationship between the ratio of the selector-analyte complexes in the electrospray ionization mass spectrum and the enantiomeric composition of the analyte can be used to relate the extent of enantioselectivity that is being observed and for quantitative enantiomeric composition determinations. Investigations into the scope and limitations of this method, plus a comparison to the enantioselectivities observed by chiral HPLC using a N-(3,5-dinitrobenzoyl)leucine-derived chiral stationary phase, is presented.

Enantiomeric discrimination of chiral primary amines was performed by both reversed-phase HPLC and normal-phase HPLC after labeling with a chiral fluorescent derivatization reagent, (1R,2R)- and (1S,2S)-trans-2-(2,3-anthracenedicarboximido)cyclohexanecarbonyl chloride. Use of HPLC permits separation of diastereomeric derivatives of amines up to C30 which have a primary amino group at the middle of the alkyl chain. The derivatives of primary amines having an anteiso alkyl chain, which has a chiral branched-methyl at the n-3 position of the alkyl chain, were also separated by HPLC, and it was also possible to separate niphatesine D by reversed-phase HPLC after derivatization.

Study on the use of boromycin as a chiral selector in capillary electrophoresis

Utility of crown ethers derived from methyl β- d-galactopyranoside and their lanthanide couples as chiral NMR discriminating agents

An efficient and accurate enantiomeric differentiation strategy for amino alcohol (AA) is crucial in diverse arenas ranging from drug design to disease prevention. However, many approaches suffer from insufficient responsiveness for the discrimination of enantiomers in complexed matrices. Here, we reported hydrogen-bonding-regulated double-fingerprint strategy-based Janus microgels (JMG), PVA-encapsulated gold nanorods (GNRs) and MIL-101(Fe), for accurate and sensitive differentiation of phenylalaninol (Pha) enantiomers. Crucially, distinct SERS signals were witnessed for d- versus l-Pha enantiomers due to stereoselective interactions between the amino moiety of Pha and the carboxyl group of GNRs. Meanwhile, the hydroxyl group of d-/l-Pha interacts with the amide group of MIL-101(Fe) to generate a hydrogen-bonded complex, leading to different fluorescence signal intensities. The omnipotent dual-fingerprint tactic enables discrimination of six types of amino alcohol racemates. Compared with the results acquired by the traditional method, these acquired by JMG-based bimodal assay offer significant advancement in reliability and stability of stereoselective detection. Therefore, the JMG-based sensing platforms offer enormous potential for reliable discrimination of enantiomers and on-site fast screening.

Chiral discrimination of amino acid enantiomers based on different interactions with Cu2+