Selectands

It is system-intrinsic for highly selective chiral recognition events that the enantiore-cognition capability of a chemical receptor or selector system is somehow restricted to a certain group of target selectands. While universal applicability of a CSP may certainly be a desired, frequently postulated property for a powerful chiral phase, it is for sure that it eventually remains a wish because of the contradictive and mutually exclusive nature of specificity and universal applicability. To get around... 

For comparison, the corresponding tfb values for the nonchiral selectand DNB-Gly obtained by ITC are included. A relative error, AK /K, estimated on the basis of the chi-square fitting in which an error of 5% of the measured quantity was assigned for each titration point is about 30% (ITC) and 50% (CD, UV). 

Another, yet completely different access to macroscopic binding strengths of selectands on CSPs has been described by Hellriegel et al. [65] employing suspended-state NMR spectroscopy. Thus, HR-MAS 2D transfer-nuclear Overhauser effect spectroscopy (NOESY) was utilized to distinguish solutes strongly binding to the... 

Various endeavors have been undertaken to get insight into the 3D selector-selectand complex structures and to elucidate chiral recognition mechanisms of cinchonan carbamate selectors for a few model selectands (in particular, DNB-Leu). Such studies comprised NMR [92-94], ET-IR [94-96], X-ray diffraction [33,59,92,94], and molecular modeling investigations (the latter focusing on molecular dynamics [92,93,97], and 3D-QSAR CoMFA studies [98]). 

Although the various cinchonan carbamate selectors that were investigated had distinct substituents and were in complex with different selectands, common... 

As much as the quinoline ring is concerned useful information on the existence or absence of ir-K-interactions with corresponding aromatic moieties in the selectands could indeed be derived by help of CIS of aromatic protons. Substantial upheld CIS in the range of AS = -0.24 to —0.37 ppm have been detected in the S -complex of DNB-Leu with the 0-9-tert-butylcarbamoyl-6 -neopentoxy-cinchonidine selector for the quinoline protons and the proton in para-position of the DNB group, while the corresponding / -complex was devoid of this effect [92], Essentially the same observation was made for the DNB-Ala-Ala selectand, but not for DNB-Ala-Ala-Ala,... 

This interpretation was also supported by the spectra of the corresponding N-methyl-leucine derivative in which the H-donor of the selectand was substituted by a methyl group and therefore not available for hydrogen bonding. Both complexes showed a similar spectral behavior as the weak 5-complex of DNB-Leu The C=0 stretch was always shifted from 1725 (uncomplexed autoassociated selector) to 1739 cm (indicative for disrupted H-bonds) in the 5-complex and R-complex as well. These FT-IR data may be regarded as an unequivocal proof for the existence of a stereoselective H-bond between the NH of DNB-Leu and the selector s carbonyl group (Figures 1.10 and 1.11). 

The same set of measurements for DNP-Leu as selectand and 0-9-allylcarbamoyl-10,11-dihydroquinidine as selector displayed a considerably different picture. While no indication for H-bond formation between the aromatic a-amino group and the carbamate of the selector could be deduced, the IR spectra of free and respective complexed forms suggested the occurrence of K-K-interactions of the DNP group as evidenced by a shifted C=C stretching vibration from 1594 to 1588 cm in the stronger bound 5-complex (force constant weakened due to delocalized electrons). This type of shift was not found in the weak TJ-complex, but in the corresponding 5-complex of DNP-N-methyl-Leu as well. The spectral data nicely reflect the binding relationships in HPLC where both DNP-Leu and DNP-N-methyl-Leu are well separated with comparable separation factors, but with an elution order that is opposite compared to DNB-Leu. 

FIGURE 1.19 X-ray crystal structures of selector-selectand complexes (ion-pairs) (a) O-9-(P-chloro-fert-butylcarbamoyl)quinine with iV-(3,5-dinitrobenzoyl)-(5)-leucine, (b) tbe pseudoenantiomeric complex of 0-9-( 3-cbloro-tert-butylcarbamoyl)quinidine with N-(3,5-dinitrobenzoyl)-(i )-leucine, (c) 0-9-( 3-cbloro-terf-butylcarbamoyl)quinine with N-(3,5-dinitrobenzoyl)-(5)-alanyl-(5)-alanine, and (d) comparison of tbe complexes of (a) and (c). Most hydrogens have been omitted for the purpose of clarity. (Reprinted from C. Czerwenka et al., Anal. Chem., 74 5658 (2002). With permission.)... 

In simple experiments, particulate silica-supported CSPs having various cin-chonan carbamate selectors immobilized to the surface were employed in an enantioselective liquid-solid batch extraction process for the enantioselective enrichment of the weak binding enantiomer of amino acid derivatives in the liquid phase (methanol-0.1M ammonium acetate buffer pH 6) and the stronger binding enantiomer in the solid phase [64]. For example, when a CSP with the 6>-9-(tcrt-butylcarbamoyl)-6 -neopentoxy-cinchonidine selector was employed at an about 10-fold molar excess as related to the DNB-Leu selectand which was dissolved as a racemate in the liquid phase specified earlier, an enantiomeric excess of 89% could be measured in the supernatant after a single extraction step (i.e., a single equilibration step). This corresponds to an enantioselectivity factor of 17.7 (a-value in HPLC amounted to 31.7). Such a batch extraction method could serve as enrichment technique in hybrid processes such as in combination with, for example, crystallization. In the presented study, it was however used for screening of the enantiomer separation power of a series of CSPs. 

FIGURE 1.35 SLM process using O-9-(l-adamantylcarbamoyl)-10,ll-dihydro-ll-octadecylsulfinylquinme and corresponding quinidine derivative as chiral carriers for the preparative separation of enantiomers of Al-derivatized amino acids (e.g., DNB-Leu). (a) ftinciple of the carrier SLM process with carrier-mediated transport (top) and (nonstereoselective) nonspecific transport processes (bottom), (b) General experimental setup of the SLM production unit with two membrane modules, (c) Multistage SLM purification process. P, permeate QD/QN, membrane modnles snpported with quinidine-derived and quinine-derived chiral carriers. R, S, D, L refers to the respective enantiomers of the selectand (DNB-Leu). (Reproduced from A. Maximini et al., J. Membr. ScL, 276 221 (2006). With permission.)... 

Chankvetadze, B., and Blaschke, G. (1999). Selector-selectand interactions in chiral capillary electrophoresis. Electrophoresis 20, 2592—2604. 

Bowser and Chen developed a mathematical treatment that takes into account both 1 1 and 1 2 binding stoichiometry between the selector and the selectand (42). The deviations from 1 1 binding stoichiometry were more easily seen with the -reciprocal plot. The diagnostic power of the y-recip-rocal plot was the weakest among all linear plots. The same authors compared linear and nonlinear regression methods for binding constant calcu-... 

The main disadvantage of CE for the investigation of interactions between chiral drugs and cyclodextrins is that CE does not provide any direct information on the structure of selector-selectand complexes. In the next section, some complementary techniques for the investigation of chiral drug-cyclodextrin interactions are discussed and parallels are drawn between these techniques and CE. 

Information about the stoichiometry of selector-selectand complex is difficult to gain from CE. However, this knowledge is useful in order to characterize the structure of intermolecular complexes as well as for the calculation of the binding constants. Previous research and review papers (3, 4,62,65) summarize the application of this technique to the problems related to chiral CE. As shown in Fig. 4, despite the involvement of different parts of the CL molecule in complex formation, the stoichiometry of CL complexes most likely is the same (1 1) with /3-CD and HDAS-/3-CD (65). 

Together with ESI MS, other soft ionization MS techniques, such as matrix-assisted laser desorption/ionization time of flight (MALDI TOF) and fast atom bombardment (FAB) MS, may be used for the determination of the stoichiometry of selector-selectand complexes. 

ID-ROESY studies performed on the complex between (+)-BrPh and /3-CD in solution did not allow one to explain the NOE effect observed on the protons of the maleate counteranion (70). X-ray crystallographic studies performed on the monocrystals obtained from a 1 1 aqueous solution of (+)-BrPh maleate and /3-CD (Fig. 8) provide a plausible explanation for the contradiction maintained in Ref. 70. In particular, as shown in Fig. 8, (+)-BrPh forms with /3-CD, at least in the solid state, not a 1 1 complex but a complex with 1 2 stoichiometry. In this complex the (+)-BrPh molecule is sandwiched between two molecules of /3-CD. The 4-bromophenyl moiety of (+)-BrPh enters the cavity of one of the /3-CD molecules, whereas the cavity of another /3-CD molecule is occupied by the maleate counteranion. Thus, X-ray crystallography may provide useful information on the supra-molecular structure of the selector-selectand complexes and in this way complement well ID-ROESY data. However, the aforementioned possible differences between the structure of the complexes in solution and in the solid phase must be considered. 

In the early 1990s, several studies were published on the computation of selector-selectand interactions in chiral CE. This relates basically to the interactions between CDs and their chiral guests, which seem to be caused by the fact that CDs are rather rigid molecules of medium size and therefore calculations for these molecules are easier and faster and may be rather precise. In addition, many CDs are well studied by alternative techniques for structure elucidation. Among these, X-ray crystallographic data are of the highest interest. 

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