Acceptor-type CSPs

Donor-acceptor-type CSPs capitalize on synthetic or semi-synthetic chiral low-mo-lecular-weight SOs capable of enantioselectively recognizing analytes by complementary arrays of nonionic attractive interactions [67]. The repertoire of fhese nonionic interactions generally comprises hydrogen bonding, jt-k-s lack ing, di-pole-dipole-slacking and steric interactions. 

The majority of donor-acceptor-type SOs has been designed to exploit jt-jc-stacking interactions between electron-rich and electron-deficient aromatic systems as the primary attractive interaction force. The chemical structures of several popular 71-donor-acceptor-type CSPs are given in Fig. 7.20. 

Other useful n-donor-acceptor-type CSPs have been advanced from C2-sym- 

Disadvantages of donor-acceptor type CSPs are their rather limited scope of application and incompatibility with polar-organic and reversed-phase mobile phase conditions. Thus, the spatially well-defined, but restricted functional group repertoires of donor-acceptor-type SOs can satisfy the chiral recognition requirements of a few classes of analytes only. In addition, to produce useful levels of enantioselectivity with donor-acceptor-type CSPs, analytes may frequently require dedicated (achiral) derivatization to attenuate basicity/acidity and/or to complement 

Recent studies indicate that cinchona carbamate-type CSPs may also present an interesting option to address enantiomer separation problems involving nonacidic analytes. Thus, the enantiomers of a set of quinazolone-based drug candidates have been successfully resolved [266], employing acetonitrile and methanol-containing hydro-organic mobile phases. The enantiomer separation of various types of arlyalcohol derivatives under normal-phase conditions has also been achieved on cinchona-type carbamate CSPs [267-269]. 

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Fig. 7.20 Chemical structures of selected commercial re-donor—acceptor-type CSPs.

More recent developments in the field of the Pirkle-type CSPs are the mixed r-donor/ r-acceptor phases such as the Whelk-Of and the Whelk-02 phases.The Whelk-Of is useful for the separation of underiva-tized enantiomers from a number of families, including amides, epoxides, esters, ureas, carbamates, ethers, aziridines, phosphonates, aldehydes, ketones, carboxylic acids, alcohols and non-steroidal anti-inflammatory drugs.It has been used for the separation of warfarin, aryl-amides,aryl-epoxides and aryl-sulphoxides. The phase has broader applicability than the original Pirkle phases. The broad versatility observed on this phase compares with the polysaccharide-derived CSPs... 

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.)... 

Pirkle type CSPs contain a chiral moiety having phenyl ring and, therefore, the formation of a it-it charge-transfer diastereoisomeric complex of the enantiomers (with the phenyl group) with CSP is supposed to be essential. In view of this, the re-acidic CSPs are suitable for the chiral resolution of re-donor solutes and vice versa. However, the newly developed CSPs containing both re-acidic and re-basic groups are suitable for the chiral resolution of both types of solute (i.e., re-donor and re-acceptor analytes). 

Pirkle-type phases are amino acid derivatives possessing an aromatic entity which can undergo n-n interactions with the solute. The aromatic entity can be either a n donor or n acceptor. The CSP and the solute form a n donor/acceptor pair. This complex is then stabilized by additional interactions such as hydrogen bonding, dipole interactions, or steric repulsion [8]. The Pirkle-type phases are most commonly used in normal-phase mode in order to enhance the n-n and hydrogen bond interactions. Hexane with an alcoholic modifier, such as isopropanol, is the mobile phase of choice. These phases have... 

Such polyacrylamide type CSPs are best operated under normal-phase conditions (usually u-hexane with a polar modifier like alcohols, dioxane, THF, etc.). The spectrum of applicability includes a wide variety of drug substances with hydrogen donor-acceptor and aromatic groups. Other groups also prepared CSPs from chiral (meth)acrylamide monomers with various chiral amino components. An extensive review on this topic was published by Kinkel 47j. 

Parallel to the n-donor-acceptor CSPs related to Pirkle s pioneering work for the understanding of chiral recognition phenomena and for gaining insight into SO-SA complexation principles on the molecular level, the protein type CSPs can claim a major credit for the rapid development of chiral technology in pharmaceutical and life sciences. 

The application of the reciprocality concept has led to the design of various phases of the Ji-donor/acceptor type [61, 62]. One successful phase is the Whelk-O 1 CSP developed by Pirkle and Welch [63-65]. 

The enantiophore query used in the search is derived from the CSP and directly built from a 3D structure model of the target CSP molecule, as it can be used today for the determination of new lead compounds [20, 21]. This procedure does not need an important modeling expertise. One can easily recognize the different center types in the receptor in question. These can be hydrogen-bond donors and acceptors, charged... 

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