Dual chiral separation system

Combination of chiral selectors is a well-known approach in chiral EKC [2, 3, 43, 45-56], A chiral separation in CE may be decoupled in two basic steps (a) chiral recognition which occurs at the molecular level and (b) transformation of chiral recognition to a chiral separation [2], In order to design a dual chiral separation system, it is useful to analyze both of the above-mentioned steps separately. When two chiral selectors cooperate in the first (recognition) step, for instance, when a mixed complex of one analyte and two selector molecules are formed, a design of the dual system becomes almost impossible without involving additional techniques and cannot be optimized according to the below-described simplified approach [45,47]. 

In selected cases the application of a dual chiral separation system allows to observe extremely high selectivities of enantioseparations [49], This technique also bears a certain potential for a better understanding of the fine mechanisms of chiral separations which are sometimes difficult to be observed in a single selector system [50-52]. 

Extending the scope of combined chiral selector systems beyond CDs, one may note that this mode has been used in CE for a rather long time [53-56], The very first example of combined chiral selectors in CE seems to be the report by Fanali et al. [53] in 1989 when 15 mM L-(+)-tartaric acid buffer was used in combination with 15 mM P-CD in order to resolve the enantiomers of chiral cobalt complexes. CDs have also been combined with chiral surfactants such as cholic acids [54, 55] and synthetic micelle-forming agents [56], In recent years, several studies were published on the combination of CDs with chiral [57, 58] and achiral [51, 59-61] crown ethers. The latter studies [59-62] where the achiral crown ether cannot contribute to enantioseparations independently clearly illustrate that the simplified approach described in [12, 47] may not be universally applied to all dual chiral separation systems in CE. 

Often dual chiral recognition systems ]462,463] involving mixtures of chiral SOs have been shown to enhance enantioselectivity. With dual systems of cyclodextrins (CDs), cationic mono(6-amino-6-deoxy)-p CD and a neutral CD (trimethyl-p-CD or dimethyl-p CD), it could be illustrated that arylpropionic acid enantiomers were baseline resolved, while with a single SO, no or insufficient separation of the enantiomers could be achieved [462J. 

Lin et al. [95] used capillary electrophoresis with dual cyclodextrin systems for the enantiomer separation of miconazole. A cyclodextrin-modified micellar capillary electrophoretic method was developed using mixture of /i-cyclodextrins and mono-3-0-phenylcarbamoyl-/j-cyclodextrin as chiral additives for the chiral separation of miconazole with the dual cyclodextrins systems. The enantiomers were resolved using a running buffer of 50 mmol/L borate pH 9.5 containing 15 mmol/L jS-cyclodextrin and 15 mmol/L mono-3-<9-phcnylcarbamoyl-/j-cyclodextrin containing 50 mmol/L sodium dodecyl sulfate and 1 mol/L urea. A study of the respective influence of the /i-cyclodcxtrin and the mono-3-(9-phenylcarbamoyl-/i-cyclodextrin concentration was performed to determine the optical conditions with respect to the resolution. Good repeatability of the method was obtained. 

F Lelievre, P Gareil, Y Bahaddi, H Galons. Intrinsic selectivity in capillary electrophoresis for chiral separations with dual cyclodextrin systems. Anal Chem 69 393-401, 1997. 

Dual cyclodextrin systems can be developed to provide impressive selectivity of separation [30—32], A typical recipe uses 0.5-1 mM of a charged CD and 5-10 mM of a neutral CD. The development of a dual-CD system chiral separation of secondary amine drug substances is illustrated in Figure 4 using various blends of CDs. A complete separation is only found in run (d), where the buffer contained 5 mM of a neutral and 1 mM of a charged CD. 

Recently, multidimensional GC has been employed in enantioselective analysis by placing a chiral stationary phase such as a cyclodextrin in the second column. Typically, switching valves are used to heart-cut the appropriate portion of the separation from a non-chiral column into a chiral column. Heil et al. used a dual column system consisting of a non-chiral pre-column (30 m X 0.25 mm X 0.38 p.m, PS-268) and a chiral (30 m X 0.32 mm X 0.64 p.m, heptakis(2,3-di-(9-methyl-6-(9-tert-butyldimethylsilyl)-(3-cyclodextrin) (TBDM-CD) analytical column to separate derivatized urinary organic acids that are indicative of metabolic diseases such as short bowel syndrome, phenylketonuria, tyrosinaemia, and others. They used a FID following the pre-column and an ion trap mass-selective detector following the... 

Matthijs, N., Van Hemehyck, S., Maftouh, M., Massart, D.L., Vander Heyden, Y. Electrophoretic separation strategy for chiral pharmaceuticals using highly-snlfated and neutral cyclodextrins based dual selector systems. An. Chim. Acta 2004, 525, 247-263. 

When using PFT with a neutral selector, it is quite difficult to avoid any entrance of the chiral selector into the ionization source, particularly at a high pH, where EOF is important. The use of BGE at low pH and/or coated capillary to minimize EOF is therefore mandatory. However, the coaxial sheath gas, which generally assists the ionization process, leads to an aspirating phenomenon of the chiral selector in the MS direction. Javerfalk et al. were the first to apply PFT with a neutral methyl-/i-CD for the separation of racemic bupivacaine and ropivacaine with a polyacrylamide-coated capillary and an acidic pH buffer (pH 3). Cherkaoui et al. employed another neutral CD (HP-/1-CD) with a PVA-coated capillary for the analysis of amphetamines and their derivatives. To prevent a detrimental aspiration effect, analyses were carried out without nebulization pressure. Numerous other studies presented excellent results such as the enantioselective separation of adrenoreceptor antagonist drugs using tandem mass spectrometry (MS/MS) the separation of clenbuterol enantiomers after solid-phase extraction (SPE) of plasma samples or the use of CD dual system for the simultaneous chiral determination of amphetamine, methamphetamine, dimethamphetamine, and p-hydroxymethamphetamine in urine. 

Apart from ATRP, the concept of dual initiation was also applied to other (controlled) polymerization techniques. Nitroxide-mediated living free radical polymerization (LFRP) is one example reported by van As et al. and has the advantage that no further metal catalyst is required [43], Employing initiator NMP-1, a PCL macroinitiator was obtained and subsequent polymerization of styrene produced a block copolymer (Scheme 4). With this system, it was for the first time possible to successfully conduct a one-pot chemoenzymatic cascade polymerization from a mixture containing NMP-1, CL, and styrene. Since the activation temperature of NMP is around 100 °C, no radical polymerization will occur at the reaction temperature of the enzymatic ROP. The two reactions could thus be thermally separated by first carrying out the enzymatic polymerization at low temperature and then raising the temperature to around 100 °C to initiate the NMP. Moreover, it was shown that this approach is compatible with the stereoselective polymerization of 4-MeCL for the synthesis of chiral block copolymers. 

Synergistic effects in terms of efficiency of CE enantioseparation have been observed when a second (not necessarily chiral) selector is added in the same buffer system. It has been demonstrated that a combination of 18-crown-6 and )-cyclodextrin can achieve or enhance enantioselective separations of nonpolar amines, which are rarely observed with cyclodextrins alone <1997JCH(781)129, 1997JCH(695)157>. The formation of a ternary sandwich complex (dual complex) is postulated to be responsible for such a beneficial effect. 

Because of its rapid and high separation efficiency, the multilayer coil CPC has been extensively used for separation and purification of variety of compounds using suitable organic/aqueous solvent systems. The application also covers special CCC techniques such as peak-focusing CCC and pH-zone-refining CCC (see pH-Peak-Focusing and pH-Zone-Refining CCC, p. 1808) chiral and affinity CCC (see Chiral CCC, p. 413) foam CCC (see Foam CCC, p. 905), liquid-liquid dual CCC and CCC/MS (see CCC/MS, p. 323). 

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