Arylcarbamoylated allylcarbamido-β-cyclodextrin: synthesis and immobilization on nonfunctionalized silica gel as a chiral stationary phase

Four new chiral stationary phases based on mono-(6^A-allylcarbamido-6^A-deoxy)-arylcarbamoylated β-cyclodextrin were synthesized. The chiral stationary phase of phenylcarbamoylated β-cyclodextrin exhibited excellent separation capability for a variety of chiral compounds. Compared with the previous work, it was found that the spacer remained on the surface of the silica gel and decreased the enantioseparation capability.     

Surface-up click access to allylimidazolium bridged cyclodextrin dimer phase for efficient enantioseparation

In this work, a novel allylimidazolium-bridged bis(β-cyclodextrin) chiral stationary phase was fabricated via a surface-up thiol-ene click chemistry reaction between 7-SH-β-cyclodextrin and 1-allylimidazole-β-cyclodextrin bonded on a silica surface. The structure of the allylimidazolium-bridged bis(β-cyclodextrin) chiral stationary phase was characterized by Fourier transform infrared spectra, ¹³C nuclear magnetic resonance, thermogravimetric analysis, and elemental analysis. Its chiral chromatographic performances were systematically evaluated by separating 35 racemic analytes including isoxazolines, dansyl-amino acids, and flavanones under reversed-phase high-performance liquid chromatography. Compared with the corresponding bottom and top layer of the β-cyclodextrin stationary phase, the allylimidazolium-bridged bis(β-cyclodextrin) chiral stationary phase afforded significantly accentuated chiral recognition ability due to its abundant hydrogen bond sites, electrostatic interactions, and synergistic inclusion. Furthermore, the allylimidazolium-bridged bis(β-cyclodextrin) chiral stationary phase showed better enantioseparation ability compared to other reported bridged cyclodextrin stationary phases. In particular, Ar-Phs and dansyl-amino acid could be completely separated by allylimidazolium-bridged bis(β-mono-6^A-deoxy-6-allylimidazolium-β-cyclodextrin chiral stationary phase) chiral stationary phase with high resolutions of 1.14–7.20 and 3.16–5.82, respectively. Molecular docking reveals that good enantioseparation ability arises from the different interaction modes and the synergistic effect of allylimidazolium-bridged bis(β-cyclodextrin) chiral stationary phase.     

Effect of Single-walled Carbon Nanotubes on Cellulose Phenylcarbamate Chiral Stationary Phases

Single-walled carbon nanotubes(SWNTs)have a high adsorption ability and nanoscale interactions.Cellulose trisphenylcarbamates possess high enantioseparation ability in high-performance liquid chromatography(HPLC).Single-walled carbon nanotubes mixed with cellulose trisphenylcarbamate are coated on the silica gel as chiral stationary phases and higher enantioseparation factors are obtained.After a single-walled carbon nanotube is linked to the 6-position of cellulose 2,3-bisphenylcarbamate,its enantioseparation resolution increases compared to that of the cellulose trisphenylcarbamate.It is the first time that SWNTs have been applied to enantioseparation.The results indicate that the single-walled carbon nanotubes are good promoters of chiral recognition.This method can be used to improve the enantioseparation efficiency of the polysaccharide chiral stationary phases.     

Novel cyclodextrin chiral stationary phases for high performance liquid chromatography enantioseparation: Effect of cyclodextrin type

Three novel chiral stationary phases (CSPs) were prepared by regioselective chemical immobilization of mono(6^A-N-allylamino-6^A-deoxy)perphenylcarbamoylated (PICD) α-, β-, and γ-cyclodextrins (CDs) onto silica support via hydrosilylation. Their enantioseparation properties in high performance liquid chromatography (HPLC) were evaluated with a large spectrum of racemates including flavanone compounds, β-adrenergic blockers, amines and non-protolytic compounds. The effect of CD's cavity size on enantioseparation abilities was studied and discussed. The results indicated that CD's surface loading at silica support played an important role in the enantioseparation on these CSPs under normal-phase conditions while inclusion phenomena contributed the major driving force under reverse-phase conditions. As expected, α-PICD demonstrated the best resolutions towards flavonone and most aromatic alcohols under normal-phase conditions with the highest surface loading; while Fujimura's competitive inclusion model can be applied to explain the better enantioseparations towards β-adrenergic blockers, amines and non-protolytic compounds with α- and β-PICD CSPs. γ-PICD CSP showed superior enantioseparation ability for sterically encumbered analytes like flavanone compounds under both normal-phase and reversed phase conditions.     

Effect of Chiral Additives in the Preparation of Cellulose-Based Chiral Stationary Phases in HPLC, and Effect on Enantiomer Resolution

Chiral stationary phases (CSPs) for high-performance liquid chromatographic (HPLC) have been prepared by coating silica gel with cellulose tribenzoate or cellulose trisphenylcarbamate. The effect of chiral additives on preparation of the CSPs was studied with (+)-l-mandelic acid, (−)-2-phenyl-1-propanol, (+)-1-phenyl-1,2-ethanediol and (−)-1-(1-naphthyl)ethanol as chiral additives for cellulose tribenzoate and (−)-2-phenyl-1-propanol and (+)-phenylsuccinic acid as chiral additives for cellulose trisphenylcarbamate. The results showed that chiral recognition by these stationary phases was increased in comparison with the original CSPs, especially the resolution (R _S) obtained. The method can be used to improve the efficiency of enantiomer separation by silica gel stationary phases coated with polymers.     

Enantioseparation characteristics of the chiral stationary phases based on natural and regenerated chitins

Natural and regenerated chitins were derivatized with 3,5‐dimethyphenyl isocyanate. The corresponding chiral stationary phases were prepared by coating the resulting chitin derivatives on 3‐aminopropyl silica gel. The swelling capacity of the chitin derivatives, enantioseparation capability, as well as eluents tolerance of the chiral stationary phases were evaluated. The results demonstrated no remarkable difference in enantioseparation capability between natural and regenerated chitins based chiral stationary phases. The similar enantioseparation characteristics of two chiral stationary phases could be understood by comparing the IR spectra of related chitin derivatives. The one of the two chiral stationary phases prepared by coating the chitin derivative with a lower molecular weight generally provided better enantioseparations. All chiral stationary phases can work in 100% chloroform, 100% ethyl acetate, 100% acetone, and the mobile phases containing a certain amount of tetrahydrofuran. The chiral stationary phase prepared from the chitin derivative with the highest swelling capacity exhibited better enantioseparations than others. This chiral stationary phase was damaged by flushing with 100% tetrahydrofuran, however, the enantioseparation capability was recovered again after the column was allowed to stand for 1 month. Furthermore, the recovered chiral stationary phase provided better enantioseparations for some chiral analytes than before.     

Synthesis and characterization of novel chiral calix[4]arene bearing (R)-(+)-1-phenylethylamine bonded silica particles

Two novel chiral di- and tri-amide derivatives of p-tert-butylcalix[4]arene were synthesized by (R)-(+)-1-Phenylethylamine via convenient reactions and then immobilized on aminopropyl functionalized silica particles. The prepared chiral calix[4]arenes and their silica polymers (Calix-SP1 and Calix-SP2) were characterized using ¹H NMR, ¹³C NMR, FT-IR, and thermal and elemental analysis techniques.     

Comparison of D,L-Mandelic Acid Resolution on Zeolite and Silica Supported Pirkle-Type Chiral Stationary Phases

 Zeolite A, a material of crystalline character, and Hypersil silica have been used as support for the preparation of chiral stationary phases. On the amorphous silica support surface the silanol groups are randomly dispersed. The crystalline zeolite secondary building units consisting primarily of SiO₄, AlO₄ ⁻ tetrahedra determine the regularity of surface silanol groups. Owing to the crystal lattice structure, the location of silanols is well determined and hence the dispersion of chiral selector molecules chemically bonded onto the zeolite surface silanol groups is fundamentally arranged. Amides of DNB-L-Leu, DNB-L-Phe, B-L-Leu chiral selector molecules were anchored onto the zeolite silanols and B-L-Leu onto the silica support silanols. Lipophilic buffer in RP conditions has dynamically modified the residual silanols of each support. The enantioseparation of ion paired D,L-mandelic acid from aqueous solution on the zeolite and silica supported chiral stationary phases prove a superior enantioseparation on the zeolite supported phases. Revision February 18, 2000.     

Preparation and Enantioseparation Property of Chiral Stationary Phases Based on Cellulose Tris(3,5-dimethylbenzoate)——A New Way to Prepare Polysaccharide-coating Type Chiral Stationary Phases

A new method to prepare polysaccharide-coating type chiral stationary phases （CSPs） was developed in this work. As a typical example, naked silica gel was coated by cellulose, which was then derivatized with 3,5-dimethylbenzoyl chloride to afford cellulose tris（3,5-dimethylbenzoate）-silica gel （CTDBS） complex. The silanols on CTDBS were end-capped with 3- aminopropyltriethoxysilane to obtain CSP 1. The amino groups on CSP 1 were further end-capped with 3,5-dimethylbenzoyl chloride to give CSP 2. The silanols on CTDBS were end-capped with methyltrimethoxysilane to yield CSP 3. CSPs 1-3 were characterized by FTIR, solid-state 13C-NMR and elemental analysis. The enantioseparation abilities of CSPs 1-3 were evaluated with structurally various chiral analytes. The enantioseparation results demonstrated that the end-capping moieties on CSPs 1 and 2 significantly affected enantioseparation. In addition, the effect of the structures of chiral analytes and end- capping moieties on the retention factors and the resolutions was discussed.     

COVALENTLY BONDING CHIRAL POLYURETHANE ON AMINATED SILICA GEL： A NEW STRATEGY TO PREPARE CHIRAL STATIONARY PHASE FOR HIGH PERFORMANCE LIQUID CHROMATOGRAPHY

Two polyurethanes of different molecular weights were prepared by the copolymerization of phenyl diisocyanate and diisopropyl tartrate. The polyurethanes having terminal isocyanate groups were reacted with 3-aminopropyl silica gel to afford two chiral stationary phases. The Mn of the two polyurethanes were 4057 g/mol and 6442 g/mol. The polyurethanes and the corresponding chiral stationary phases were characterized by FT-IR, 1H NMR and elemental analysis. The loading capacities of the polyurethanes on silica gel were 0.68 mmol units/g and 0.61 mmol units/g, respectively. The separation performance and the influence of additives, triethylamine and trichloroacetic acid, on the separation of chiral compounds were investigated by HPLC. The chiral stationary phase prepared from polyurethane with Mn of 4057 g/mol demonstrated better enantioseparation capability than that with Mn of 6442 g/mol. Additionally, it was found that the addition of triethylamine and trichloroacetic acid in the mobile phases significantly improved the enantioseparation for these two chiral stationary phases.     

A new single‐urea‐bound 3,5‐dimethylphenylcarbamoylated β‐cyclodextrin chiral stationary phase and its enhanced separation performance in normal‐phase liquid chromatography

A new single‐urea‐bound chiral stationary phase based on 3,5‐dimethylphenylcarbamoylated β‐cyclodextrin was prepared through the Staudinger reaction of mono (6^A‐azido‐6^A‐deoxy)‐per(3,5‐dimethylphenylcarbamoylated) β‐cyclodextrin and 3‐aminopropyl silica gel under CO₂ atmosphere. The new phase exhibited good enantioseparation performance for 33 analytes using normal‐phase HPLC conditions; 19 of them were baseline separated. Effects of structure of analytes, alcoholic modifiers, and acidic/basic additives on separation performances of this new cyclodextrin chiral stationary phase have been studied in detail. The results showed that the retention and resolution of acidic and basic analytes on the CSP were greatly affected by the additives. Peak symmetry for some analytes could be improved by simultaneously adding acidic and basic additives to the mobile phase. This work expands the potential applications of the cyclodextrin‐based chiral stationary phases in the normal‐phase HPLC.     

HPLC Enantioseparation of Novel Spirobrassinin Analogs on the Cyclofructan Chiral Stationary Phases

A novel series of nine chiral analogs of spirobrassinin, which have potential biological activity, was separated for the first time on three different derivatized cyclofructan chiral stationary phases in the normal phase mode. The effects of mobile phase composition, the type and concentration of polar modifier, additives, and the analyte structure on the retention and enantioseparation were studied. The results proved that for cyclofructan-based chiral stationary phases, the R-naphthylethyl carbamate cyclofructan 6 provides the best separation efficiency for the analyzed compounds. The effect of temperature on the separation was also investigated and the corresponding thermodynamic parameters were evaluated from linear Van’t Hoff plots (lnk or lnα versus 1/T). It was found that the enantioseparation was enthalpy controlled. In addition, the elution order of the enantiomers was determined in all the cases.     

Mono(6-N-allylamino-6-deoxy)perphenylcarbamoylated β-cyclodextrin: synthesis and application as a chiral stationary phase for HPLC

A novel cyclodextrin derivative: mono(6^A-N-allylamino-6^A-deoxy)perphenylcarbamoylated β-cyclodextrin was synthesized. Hydrosilylation with (EtO)₃SiH and then reaction of the reactive siloxane with pristine silica gel afforded a facile entry into a durable, structurally well-defined chiral stationary phase capable of enantioseparation of a variety of racemic drugs.     

Cationic cyclodextrins chemically-bonded chiral stationary phases for high-performance liquid chromatography

Two covalently bonded cationic β-CD chiral stationary phases (CSPs) prepared by graft polymerization of 6^A-(3-vinylimidazolium)-6-deoxyperphenylcarbamate-β-cyclodextrin chloride or 6^A-(N,N-allylmethylammonium)-6-deoxyperphenylcarbamoyl-β-cyclodextrin chloride onto silica gel were successfully applied in high-performance liquid chromatography (HPLC). Their enantioseparation capability was examined with 12 racemic pharmaceuticals and 6 carboxylic acids. The results indicated that imidazolium-containing β-CD CSP afforded more favorable enantioseparations than that containing ammonium moiety under normal-phase HPLC. The cationic moiety on β-CD CSPs could form strong hydrogen bonding with analytes in normal-phase liquid chromatography (NPLC) to enhance the analytes’ retention and enantioseparations. In reversed-phase liquid chromatography (RPLC), the analytes exhibited their maximum retention when the pH of mobile phase was close to their pK_a value. Inclusion complexation with CD cavity and columbic/ionic interactions with cationic substituent on the CD rim would afford accentuated retention and enantioseparations of the analytes.     

Enantiomeric separation in high-performance liquid chromatography using novel β-cyclodextrin derivatives modified by R-configuration groups as chiral stationary phases

Two new chiral stationary phases (CSP) were successfully prepared through bonding β-cyclodextrin (CD) derivatives modified by R-configuration groups (R-CPGCD, R-HMPGCD) to silica gel. Nineteen chiral nitro aromatic alcohol derivatives were separated under the polar organic and the reversed phase modes. Better enantioseparation was obtained in the reversed phase mode. The resolution values of the analytes ranged from 1.98 to 7.57 and from 2.19 to 8.14 on R-CPGCD and R-HMPGCD CSPs, respectively, using a mobile phase composed of methanol/water (v/v, 40/60). Better enantioseparation was obtained on R-HMPGCD CSP than on R-CPGCD CSP because of stronger hydrogen bonding and π-π interactions between the substituents on the cyclodextrin derivatives and the analytes. For different analytes, the increasing electronic density of the benzene ring was found to be favorable to the enantioseparation of the test analytes. The thermodynamic parameters showed that the enantioseparation of analytes was enthalpy-controlled and a lower temperature aided the enantiomeric separation of the solutes on the two CSPs. MD simulations were used to investigate the recognition mechanism between the chiral selectors and the analyte using R-, S-2-naphthalenemethanol and R-CPGCD and R-HMPGCD complexes as examples. S-2-naphthalenemethanol had the stronger interactions with R-CPGCD and R-HMPGCD than the R-isomer. The substituent derivatized on R-CPGCD and the cyclodextrin cavity contributed to the discrimination of the S-isomer, but only the derivatized group on R-HMPGCD was found to play a major role in separating prosess. In addition, the larger free energy deviation of the R- and S-isomers in the R-HMPGCD system brought about a higher resolution value (R_s = 8.14).     

Preparation of a new chiral acridino-18-crown-6 ether-based stationary phase for enantioseparation of racemic protonated primary aralkyl amines

Starting from commercially available and relatively cheap chemicals first enantiopure dimethyl-substituted monoaza-18-crown-6 ether (R,R)-21 containing a diphenylamine unit was prepared, which was then transformed to dimethyl-substituted acridino-18-crown-6 ligand (R,R)-19 having an N-allyl-carbamoyl linker by several steps. The terminal double bond of the latter made possible to attach (R,R)-19 to γ-mercaptopropyl-functionalized spherical HPLC quality silica gel obtaining a new chiral stationary phase (R,R)-CSP-37. Based on electronic circular dichroism (ECD) studies the N-allyl-carbamoyl group attached to the acridine ring of the chiral host (R,R)-19 does weaken exciton interaction between the host and guest molecules, but does not destroy the discriminating power of the chiral host. An HPLC column filled with (R,R)-CSP-37 was tested for the enantioseparation of racemic 1-(1-naphthyl)- and 1-(2-naphthyl)ethylamine hydrogenperchlorates using isocratic conditions.     

Click chemistry for facile immobilization of cyclodextrin derivatives onto silica as chiral stationary phases

Click chemistry was applied to immobilize mono-azido-β-cyclodextrin derivatives onto the surface of silica to give novel chiral stationary phases (CSPs). The desired CSPs showed high stability and excellent enantioseparation effects in capillary electrochromatography (CEC).     

Synthesis and application of mono-6-(3-methylimidazolium)-6-deoxyperphenylcarbamoyl-beta-cyclodextrin chloride as chiral stationary phases for high-performance liquid chromatography and supercritical fluid chromatography

The synthesis of mono-6-(3-methylimidazolium)-6-deoxyperphenylcarbamoyl-beta-cyclodextrin chloride (MPCCD) and its application in chiral stationary phases (CSPs) for high-performance liquid chromatography (HPLC) and supercritical fluid chromatography (SFC) are being reported. This chiral selector is coated onto silica gel in different weight percentages (15, 20 and 35%, w/w) to obtain CSPs having different loading content. These new chiral stationary phases are tested using normal-phase HPLC for enantioseparation of racemic aromatic alcohols. Indeed, the enantiodiscrimination abilities of these CSPs are found to be influenced by the loading content of the chiral selector. Among the three columns (MPCCD-C15, MPCCD-C20 and MPCCD-C35), the best enantioseparation results are obtained using a column containing 20% (w/w) of MPCCD (MPCCD-C20). The resolution (R(s)) obtained for p-fluorophenylethanol, p-chlorophenylethanol, p-bromophenylethanol, p-iodophenylethanol and p-fluorophenyl-3-buten-1-ol using MPCCD-C20 ranges from 3.83 to 5.65. Good enantioseparation results are obtained for these analytes under SFC separation conditions using the MPCCD-C20 column.     

Enantioseparation of 1-Phenyl-1,2,3,4-tetrahydroisoquinoline on Polysaccharide-Based Chiral Stationary Phases

The enantiomers of 1-phenyl-1,2,3,4-tetrahydroisoquinoline have been directly separated on polysaccharide-based chiral stationary phases (CSPs). The normal phase separation of (S)- and (R)-1-phenyl-1,2,3,4-tetrahydroisoquinoline was accomplished by screening of the immobilized Chiralpak IC column with different eluents. The effect of mobile phase type on retention, selectivity and resolution was studied. 2-Propanol or ethanol/n-hexane/ethanolamine mixtures were applied as mobile phases by screening of following polysaccharide-based immobilized (Chiralpak IA, Chiralpak IC) and coated (Lux Cellulose-1, Lux Cellulose-2, Lux Amylose-2) CSPs. Polar organic and reversed-phase conditions were also tested for direct enantioseparation of 1-phenyl-1,2,3,4-tetrahydroisoquinoline.     

Monolithic silica columns functionalized with substituted polyproline‐derived chiral selectors as chiral stationary phases for high‐performance liquid chromatography

In this study, two polyproline‐derived chiral selectors are bonded to monolithic silica gel columns. In spite of high chiral selector coverage, the derivatization was found to have only a slight effect on the hydrodynamics of the mobile phase through the column. The enantioseparation ability of the resulting chiral monolithic columns was evaluated with a series of structurally diverse racemic test compounds. When compared to analogous bead‐based chiral stationary phases, higher enantioseparation and broader application domain were observed for monolithic columns. Moreover, the increase in flow rate produces a minor reduction of resolution, which permits to shorten analysis time. Additionally, increased loadability defines chiral polyproline derived monoliths as adequate for preparative chromatography.