Application of NMR to Cyclodextrins and Their Complexes

NMR Parameters and the Complexing Ability of Cyclodextrins and Their Derivatives 

The unequivocal assignment of as many signals in NMR spectra as possible is a prerequisite of a successful structural and/or conformational analysis. Therefore, a knowledge of and chemical shifts of cyclodextrin molecules is crucial in any study of their complexes. Besides the data for the smallest, most often used a-, j8-, and y-CyDs [3], resonance assignments were obtained for the larger CyDs composed of more than eight a-glucose units discussed in Chapter 13 [29-32]. 

For CyD complexes a number of stoichiometric ratios has been observed [2]. The most commonly reported ratios are H G = 1 1 and H G = 2 1. However, other stoichiometries as well as ternary CyD-containing complexes [47] are known. An example of 2 1 stoichiometry is the camphor-a-CyD complex in which the guest molecule is embedded inside a capsule formed by two host molecules [48]. Fenbu-fen (y-oxo-[l,l -biphenyl]-4-butanoic acid) is an interesting example of a compound which shows stoichiometry dependence on the CyD cavity size. It does not form an inclusion complex with a-CyD, but displays H G = 1 1 stoichiometry with f-CyD and H G = 1 2 stoichiometry with y-CyD [49, 50]. Metoprolol is another such compound which forms 1 1 complexes with a-CyD and f-CyD but with y-CyD it forms an H G = 1 2 complex [51]. A similar phenomenon detected using HPLC for a complex with a first-generation dendrimer is presented in Chapter 5 [52]. On the other hand, 1-adamantanecarboxylic acid and f-CyD form a complex with temperature-dependent stoichiometry, H G = 1 1 at 25 °C and H G = 1 2 at 0 °C [28]. For the complexation of dodecyltrimethylammonium bromide with a-CyD two competing associations with stoichiometries of H G = 1 1 and H G = 2 1 have been reported [53]. Use of the method of continuous variations in such situations becomes questionable and information about the complex stoichiometry is revealed directly from the titration measurement described in Section 9.2.3. 

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Nuclear magnetic resonance (NMR) spectroscopy is one of the most powerful and versatile methods for the elucidation of molecular structure and dynamics. It is also very well suited to study molecular complexes and their properties [1]. Therefore, it has been widely used for studying inclusion complexes formed by cyclodextrins (CyD) [2-4]. Some examples of the applications of NMR in conjunction with other techniques are presented in other chapters, in particular in Chapter 6. The success of NMR spectroscopy in this field is due to its ability to study complex chemical systems and to determine stoichiometry, association constants, and conformations of molecular complexes, as well as to provide information on their symmetry and dynamics. Furthermore, compared to other techniques, NMR spectroscopy provides a superior method to study complexation phenomena, because guest and host molecules are simultaneously observed at the atomic level. 

Smith et have prepared 11 chiral calix[4]arenes, calix[4]resorcarenes, and anionic cyclodextrin derivatives and investigated the properties of their lanthanide (Yb, Dy +) complexes as chiral lanthanide shift reagents (LSR). Baldovini et alP report an application of a camphor-derived chiral complex, Yb(hfc)3 (hfc = tris[3-(heptafluoropropylhydroxymethylene)-(- -)-camphorate]) to differentiate the C NMR spectra of enantiomers of bornyl acetate. 

Let us compare the methods applied by Pedersen for establishing the complex formation with a modern approach. Today tedious solubility studies are carried out almost exclusively with practical applications in mind, but they are not performed to prove the complex formation. For instance, one ofthe main reasons for the use of cyclodextrin complexes in the pharmaceutical industry is their solubilizing effect on drugs [8]. There, and almost only there, solubility studies are a must. As concerns spectroscopic methods, at present the NMR technique is one ofthe main tools enabling one to prove the formation of inclusion complex, carry out structural studies (for instance, making use of the NOE effect [9a]), determine the complex stability [9b, c] and mobility of its constituent parts [9d]. However, at the time when Pedersen performed his work, the NMR method was in the early stage of development, and thus inaccurate, and its results proved inconclusive. UV spectra retained their significance in supramolecular chemistry, whilst at present the IR method is used to prove the complex formation only in very special cases. 

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