Chiral ion-pairing reagents

Two other strategies for producing separations of enantiomers involve the addition of chiral modifiers to the mobile phase (e.g. chiral ion-pairing reagents), which can bring about separation on for instance an ordinary ODS column and the formation of derivatives with chirally pure reagents that produce different diastereoisomers when reacted with opposite enantiomers of a particular compound (see GC example, Ch. II p. 219). 

The enantioseparation by CE using cinchona derivatives as chiral ion-pairing reagents has been the subject of in-depth reviews [120],... 

Figure 22.2 Separation of /V-(1-phenylethyl)phthalamic acid enantiomers with a chiral ion-pair reagent [reproduced with permission from C. Pettersson, J. Chromatogr., 316, 553 (1984)]. Conditions stationary phase, LiChrosorb S1100,5 pm mobile phase, dichloromethane-butane-1,2-diol (99 1) containing 0.35 mM each of quinine and acetic acid UV detector. The negative peak at ca. 19 min is a system peak.

If a chiral reagent capable of forming a complex (in the strictest sense), an ion pair or any other adduct with the enantiomers in the sample is added to the mobile phase, there is a chance that the distribution coefficients of the dia-stereomers formed between the mobile and stationary phases will be different and, therefore, these can be separated on an HPLC column. An example is the separation of A-(l-phenylethyl)phthalamic acid enantiomers using quinine as a chiral ion-pair reagent (Fig. 21.2). 

The indirect and direct approaches are discussed below. Indirect chiral separations are less common and, thus, only are described briefly. In the direct approach section, different CSs are discussed such as cyclodex-trins, crown ethers, linear oUgo- and polysaccharides, macrocyclic antibiotics, proteins, Ugand exchange type selectors, chiral ion-pairing reagents, and chiral surfactants. In every section, a theoretical explanation of the... 

Finally, we mention here the work by Ning [56] on salting effects in reversed mobile phases for chiral separation of both cis and trans benzonaphthazepine enantiomers on a cellulose tris(3,5-dimethylphenylcarbamate) CSP. The salting-in effect of sodium perchlorate was noted to make the analytes more soluble in the mobile phase so that the CSP can selectively retain the four stereoisomers. The salting-out effect of sodium chloride induces hydrophobic self association and, accordingly, the author proposed that sodium chloride works differently than conventional ion-pair reagents used in nonchiral reverse-phased chromatography. 

The most important applications of chiral mobile phase additives in liquid ehromatogra-phy are ehiral ion-pair chromatography (section 4.3.3) and inclusion complex formation with cyclodextrins and similar chiral selectors. Other ehiral mobile phase additives have been used only oeeasionally, and with modest sueeess [ 1,3,32,153]. Multifunctional ion-pair reagents, such as 10-camphorsulfonic acid [154], derivatives of tartatie acid (e.g. di-n-butyltartrate) [155,156], peptides (e.g. N-carbobenzoxyglyeine-L-proline) [157-161],... 

There are a number of variables in FSCE that can be used in the optimization of FSCE methods. These include the operating pH, electrolyte type and concentration, capillary dimensions, temperature, and injection volume. Electrolyte additives such as ion-pair reagents and chiral substances can also be employed in order to manipulate selectivity. 

DUAL CYCLODEXTRIN SYSTEMS Applying Only One CD in CE occasionally is insufficient to completely resolve chiral compounds as can be seen above. Therefore, either another CD or a combination of two CDs in dual systems can be tested to enhance both enantioselectivity and resolution. The second CD then provides enantioselectivity itself, competes with the other CD, or provides a differential migration rate. A dual system usually combines a neutral and a charged CD, or more rarely either two charged or two neutral CDs. CDs might also be combined with carbohydrates, ion-pairing reagents, surfactants, crown ethers,... 

Oxindoles are the structural motifs frequently found in many natural products and biologically active molecules. Many of them feature a chiral quaternary stereocenter at the C3 position of the heterocycHc ring. In the presence of suitable phase-transfer catalysts (Q X ), 3-substituted oxindoles could proceed to form the intermediary chiral ion pair, which was trapped by electrophihc substrates (E) such as alkylating reagents [91, 123], molecular oxygen [124], imines [95], and Michael acceptors [76, 125] to give the corresponding products (Scheme 12.17). 

Catalytic asymmetric methylation of 6,7-dichloro-5-methoxy-2-phenyl-l-indanone with methyl chloride in 50% sodium hydroxide/toluene using M-(p-trifluoro-methylbenzyDcinchoninium bromide as chiral phase transfer catalyst produces (S)-(+)-6,7-dichloro-5-methoxy-2-methyl-2--phenyl-l-indanone in 94% ee and 95% yield. Under similar conditions, via an asymmetric modification of the Robinson annulation enqploying 1,3-dichloro-2-butene (Wichterle reagent) as a methyl vinyl ketone surrogate, 6,7 dichloro-5-methoxy 2-propyl-l-indanone is alkylated to (S)-(+)-6,7-dichloro-2-(3-chloro-2-butenyl)-2,3 dihydroxy-5-methoxy-2-propyl-l-inden-l-one in 92% ee and 99% yield. Kinetic and mechanistic studies provide evidence for an intermediate dimeric catalyst species and subsequent formation of a tight ion pair between catalyst and substrate. 

An extensive review appeared on the configurational stability of enantiomeric organolithium reagents and the transfer of the steric information in their reactions. From the point of view of the present chapter an important factor that can be evaluated is the ease by which an inversion of configuration takes place at the metallation site. It happens that H, Li, C and P NMR spectra of diastereotopic species have been central to our understanding of the epimerization mechanism depicted in equation 26, where C and epi-C represent the solvated complex of one chiral species and its epimer, respectively. It has been postulated that inversion of configuration at the Li attachment site takes place when a solvent-separated ion pair is formed. This leads to planarization of the carbanion, its rotation and recombination to form the C—Li bond, as shown in equation 27, where Li+-L is the solvated lithium cation. An alternative route for epimerization is a series of... 

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