Selector-selectand complex

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]). 

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.)... 

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. 

LebriUa has developed a chiral mass spectrometry method that has potential to determine enantiomeric excess of mixtures. The method involves an ion—molecule reaction between a neutral amine and a noncovalent charged complex (formed via ESI) consisting of a selector (cyclodextrin) and the desired selectand (chiral substrate, typically an amino acid). The protonated selector—selectand complex undergoes a guest—ligand exchange reaction with the amine. The rate of this reaction is sensitive to the chirality of the bound selectand and thus can be used to the quantify enantiomeric excess of other mixtures using suitable calibration curves. 

Technical aspects of stoichiometric determination of selector-selectand complexes based on NMR spectroscopy have been summarized in several works [132, 134, 137,139,141,206,208-215], The most convenient way seems to be a preparation of equimolar solutions of a selector and a selectand and mixing them in the ratio 10 0 9 1 8 2 .., 0 10 and the measurement of the NMR spectra of these samples. 

Thus, as this example shows, NMR specftometry, which is in general a very powerful technique, may not always be applicable in studies of selector-selectand complexes. One additional example of this kind is shown in Fig. 12 [114]. The data shown in this figure indicate that the continuous variation plot cannot be constructed due to multiple complexations between the DIM and the CM- -CD. Despite this failure, the data shown in [117] are very informative. Besides the aforementioned multiple complex formation, these data indicate that the complexes formed have a different stoichiometry and in addition, the chiral recognition pattern in the complexes with different stoichiometry is opposite to each other. The latter seems to be the unique and the most interesting result of this experiment. 

NMR Spectroscopic Studies of Structure of Selector-Selectand Complexes in Solution... 

The teicoplanin CSPs are recommended for the separation native amino acid enantiomers in reversed-phase mode [11]. It was established that the carbohydrate units on the teicoplanin selector (Fig. 3) were hindering the enantiomer approach making the transient selector-selectand complex more difficult to form [15]. This mechanistic point will be studied in detail later. 

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