Brush-type selectors

Fig. 6-9. Imprintable brush-type selectors. (From Welch [70].)...

The majority of the original chiral selectors for brush-type CSPs were derived from natural chiral compounds. Selectors prepared from amino acids, such as phenyl... 

The brush-type (Pirkle-type) CSPs have been used predominantly under normal phase conditions in LC. The chiral selector typically incorporates tt-acidic and/or n-basic functionality, and the chiral interactions between the analyte and the CSP include dipole-dipole interactions, n-n interactions, hydrogen bonding, and steric hindrance. The concept of reciprocity has been used to facilitate the rational design of chiral selectors having the desired selectivity [45]. 

A new brush-type CSP, the Whelk-0 1, was used by Blum et al. for the analytical and preparative-scale separations of racemic pharmaceutical compounds, including verapamil and ketoprofen. A comparison of LC and SFC revealed the superiority of SFC in terms of efficiency and speed of method development [50]. The Whelk-0 1 selector and its homologues have also been incorporated into polysiloxanes. The resulting polymers were coated on silica and thermally immobilized. Higher efficiencies were observed when these CSPs were used with sub- and supercritical fluids as eluents, and a greater number of compounds were resolved in SFC compared to LC. Compounds such as flurbiprofen, warfarin, and benzoin were enantioresolved with a modified CO, eluent [37]. 

New brush-type phases (donor-acceptor interactions) are appearing all the time. " Examples are stationary phases comprising quinine derivatives and trichloro-dicyanophenyl-L-a-amino acids as chiral selectors. Quinine carbamates, which are suitable for the separation of acidic molecules through an ionic interaction with the basic quinine group, are also commonly used but in general they are classified with the anion-exchange type of chiral selectors (see further) because of their interaction mechanism, even though r-donor, r-acceptor properties occur. (Some separations on Pirkle-type CSPs are shown in Table 2.)... 

Brush-type, proteins, CDs, natural molecular imprint-based polymers (MIP), and macrocyclic antibiotics have been immobilized as chiral selectors on packed-CEC columns. Zheng and Shamsi demonstrated the possibility of using chiral CEC—ESI/MS with a commercially packed column for the determination of warfarin enantiomers in human plasma using coumachlor as an internal standard (IS). Robustness of this chiral CEC capillary was recently improved by a novel procedure and applied for the simultaneous enantiosepara-tion of height /1-blockers with multimodal CSP using different combinations of vancomycin and teicoplanin, as presented in Figure 5. ... 

Figure 13. Schematic view of brush-type CSPs showing the chiral selector substituents oriented towards the liquid phase. Solvent molecules and the respective solvation are not shown. Stereoselective [SO-SA] interactions, attractive or repulsive, are located invariably within the heterogeneously structured chiral stationary phase.

Mechanistic considerations (e.g., the extensive work published on brush-type phases) or the practitioner s experience might help to select a chiral stationary phase (CSP) for initial work. Scouting for the best CSP/mobile phase combination can be automated by using automated solvent and column switching. More than 100 different CSPs have been reported in the literature to date. Stationary phases for chiral pSFC have been prepared from the chiral pool by modifying small molecules, like amino acids or alkaloids, by the deriva-tization of polymers such as carbohydrates, or by bonding of macrocycles. Also, synthetic selectors such as the brush-type ( Pirkle ) phases, helical poly(meth) acrylates, polysiloxanes and polysiloxane copolymers, and chiral selectors physically coated onto graphite surfaces have been used as stationary phases. 

With chromatographic production processes the elution order of the enantiomers is of importance. In SMB processes the raffinate enantiomer can often be obtained with better economics as it is recovered at higher purities and concentrations. If the CSP offers the possibility of choosing one of the two optically active forms of the selector, the adsorbent on which the desired enantiomer elutes first should be chosen. This option can be used especially with the brush-type phases with monomolec-ular chiral selectors. Even if the CSP is not available in both forms, the elution order should be checked carefully as the elution order might be reversed on two very similar adsorbents or with two similar mobile phase combinations. Okamoto (1991) and Dingenen (1994) have shown that by changing only from 1-propanol to 2-propanol, respectively with 1-butanol, the elution order on a cellulose-based CSP might reverse. 

The brush-type of CSP was introduced by Pirkle who was one of the pioneers of modern enantioselective liquid chromatography [55]. The most frequently used 7i-acceptor phases are derived from the amino acids phenylglycine (DNBPG) (Fig. 6.8) or leucine (DNBLeu) covalently or ionically bonded to 3-aminopropyl silica gel [56, 57]. These CSPs are commercially available for analytical or preparative separation of enantiomers. Further CSPs based on amino acid or amine chiral selectors such as valine, phenylalanine, tyrosine [58] and l,2-tr s-diaminocyclohexane (DACH-DNB phase) [59] and 1,2-traus-diphenylethylene diamine (ULMO phase) [60] were also developed (Fig. 6.8). These CSPs have been applied for the preparative separation of the enantiomers of a few racemic compounds, but the number of reported preparative applications has remained very limited over the last 10 years. 

Laemmerhofer, M., Lindner,W. Quinine and quinidine derivatives as chiral selectors. I. Brush type chiral stationary phases for high-performance liquid chromatography based on cinchonan carbamates and their application as chiral anion exchangers, J. Chromatogr. A, 1996, 741, 33-48. 

A special subclass of brush-type chiral stationary phases are the ion-exchange CSPs developed by Lammerhofer and Lindner (1996). By introducing an additional ionic moiety, a strong interaction between the selector and the selectand can be achieved. The first commercial available phases are based on the Cinchona alkaloids Quinine and Quinidine with an additional weak anion-exchange function offering good separation possibilities for chiral acids. A strong dependence of the capacity from the counter ion of the mobile phase could be demonstrated by Arnell (2009). 

Chiral stationary phases can exist in different forms [10] (see Fig. 8). Some selectors can be used as particulate phase materials, such as polymeric cellulose triacetate. Polymeric cellulose and amylose derivatives are often coated onto silica carrier particles so that only 20% of the CSP consists of the chiral selector. This combination of stationary phase and chiral polymer combines good chromatographic properties (due to the homogeneous particle size distribution) with a high density of chiral adsorption sites in the polysaccharide derivatives. Another approach is selected for the so-called brush-type CSPs. In these, the chiral selector is covalently bound to the surface of the silica particles. These phases show high chemical inertness and allow the use of a multitude of different mobile phases. 

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