NMR of Cyclodextrins and Their Complexes

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. 

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NMR Parameters and the Complexing Ability of Cyclodextrins and Their Derivatives... 

X-Ray diffractogram of the precipitate was compared with those of coumarin, 3-cyclodextrin and their mixtrue, as shown in Fig. 3. The diffractogram of the mixture could be described with those of coumarin and the cyclodextrin, while the latter can not explain the spectrum of the precipitate, which should have a different crystal structure from those of coumarin and the cyclodextrin. The elemental analysis and NMR spectrum show the precipitate is composed of 1 mole of coumarin and 1 mole of 3-cyclodextrin. This and the data shown in Figs. 1-3 indicate that coumarin is fairly strongly bonded to the cyclodextrin to form an inclusion complex at the solid state. 

Suzuki, M., Y. Sasaki, J. Szejtll emd E. Fenyvesl -13C NMR spectra of cyclodextrin monomers, derivatives and their complexes with methyl orange... 

Recently, NMR spectroscopy has been used to study the effect of substituents in structural PBN (402) and 5,5-dimethylpyrroline A-oxide (DMPO) (403) analogs on their complexing ability with natural (j-cyclodextrin (402, 403). 

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. 

Bakkour Y, Vermeersch G, Morcellet M, Boschin F, Martel B, Azaroual N. 2006. Formation of cyclodextrin inclusion complexes with doxycyclin-hyclate NMR investigation of their characterisation and stability. Journal of Inclusion Phenomena and Macrocyclic Chemistry 54(1-2) 109-114. 

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]. 

Historically, nuclear magnetic resonance (NMR) spectroscopy was the instrumental technique that provided the first experimental evidence for inclusion complex formation of cyclodextrins (CD) and guest molecules in the liquid phase [1]. Since that time NMR spectroscopy remains one of the key techniques for studying CD complexes with their ligands [2],... 

The solution reactions were carried out with or without cyclodextrins in (CH3)2S0, (CH3)2SO-d0 or carbon tetrachloride. The typical experimental procedure was as follows. tra/7S-Cinnamic acid (11 mg, 0.08 mmol), powdered cx-cyclodextrin complex (162 mg, contained 0.08 mmol of the acid), and 3-cyclodextrin complex (100 mg, contained 0.08 mmol of the acid) were dissolved in 0.4 ml of (CH3)2S0-d6, to which 0.1 ml of the same solvent containing bromine (0.08 mmol) was added at 25°C. At 2 h intervals, the conversion of the acid was determined by NMR spectra. Then the reaction mixtures were poured into 20 ml of 15 wt % aqueous sodium chloride soluticn, followed by extraction with diethyl ether. The products were obtained as white solid by evaporation of the ether layer and their optical rotations were measured in ethanol on a polarimeter. 

The solid inclusion complexes were obtained as precipitates from aqueous solutions of ethyl trans-cinnamate and a- and B-cyclodextrins in 80 and 95% yields, respectively. The ester in the complexes was determined by NMR in deuterodimethyl sulfoxide, and the molar ratios of the ester to the cyclodextrins were observed as 0.5 for the a-cyclodextrin complex and 1,0 for the 3-cyclodextrin complex. The X-ray diffraction patterns of these complexes showed that they were highly crystalline as shown in Figure 1, and could not be described with those of the ester and the cyclodextrin the precipitates should have different crystal structures from those of the guest and the hosts. These inclusion complexes have been prepared, and their dissolution and thermal behavior were examined by Uekama, et al. [9], Hursthouse, et al. determined [10] the crystal structure of 3-cyclodextrin complex with ethyl trans-cinnamate and showed that the complex was composed of 1 mole of the guest and 1 mole of the host. 

High resolution carbon-13 NMR spectroscopy is one of the most useful methods in the analysis of the structure and molecular dynamics of cyclodextrin inelusion-complexes both in aqueous solution[1,2] and in the solid state[3]. Earlier cariDon-13 NMR studies of a-CD inclusion complexes with benzoic acid, p-nitrophenol, and p-nitrophenolate in aqueous solution have shown that the included lead(head see Fig.lA) carbons show high-field shifts compared to low-field shifts of corresponding para(tail Fig.lA) carbons[4,5]. Similar distinctive patterns of carbon-13 displacement s have been also observed for p-hydroxybenzoic acid and it has been concluded that the carboxyl group of p-hydroxybenzoic acid is directed into the a-CD cavity [4]. A variety of substituted benzenes are known to show quite similar carbon-13 high (head) and low (tail) field shifts, irrespective of the kinds of substituents if their size are matched to the a-CD cavity [4,5]. These characteristic carbon-13 displacements induced by complexation with a-CD... 

New applications of ID and 2D solid-state NMR spectroscopy in structural studies of inclusion complexes formed by organic host lattices (cyclodextrins, calixarenes, cyclophosphazenes, and fullerenes) have been described by Potrzebowski and Kazmierski. This review article gives short characteristics of host molecules and their solid-state NMR studies. Less common systems, which are mainly interesting as model systems for the solid-state NMR studies, are also considered. 

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