CHAPTER 1
Chemistry and Physicochemistry of Cyclodextrins
The main products of photosynthesis are two glucose polymers: cellulose and starch. These two carbohydrate polymers represent a considerable part of the renewable energy source of the Earth. While cellulose is the resistant and structure-forming component in the cells, starch is the mobilisable, convertible energy depot. Starch consists of two glucose polymers: amylose and amylopectin. Dextrins, the products of partial hydrolysis of starch, can give cyclic dextrins under the action of glucosyltransferase enzyme. Cyclodextrins (CDs) are cyclic, non-reducing oligosaccharides consisting of D-glucopyranose units bonded through α-1,4 linkages.
The three major cyclodextrins are the following; the smallest is the α-CD (Schardinger's α-dextrin, cyclomaltohexose, cyclohexaglucan, cyclohexaamylose or C6A) with six glucose units, followed by β-CD (Schardinger's β-dextrin, cyclomaltoheptose, cycloheptaglucan, cycloheptaamylose or C7A) with seven glucose units and γ-CD (Schardinger's γ-dextrin, cyclomaltooctose, cyclooctoglucan, cyclooctaamylose or C8A) with eight glucose units. Unsubstituted native CDs are crystalline, non-hygroscopic, homogeneous substances, which are torus-like macrocycles built up from glucopyranose (glucose) units (Figure 1.1). In CDs, the sugars adopt a 4C1 chair conformation and orient themselves so that the molecule forms a toroidal truncated cone structure. The cavity is lined by the hydrogen atoms and the glycosidic oxygen bridges. The non-bonding electron pairs of the glycosidic oxygen bridges are directed towards the inside of the cavity to produce a high electron density and lend it some Lewis base character.
The C-2 hydroxyl group of one glycopyranose unit can form a hydrogen bond with the C-3 hydroxyl group of the neighbouring glucopyranose unit. In the β-CD molecule a complete secondary belt is formed by these hydrogen bonds, so that β-CD is a rather rigid structure. This arrangement of hydrogen bonds can explain the observation that β-CD has the lowest solubility of all native CDs. The lower solubility of β-CD in water relative to α-and γ-CDs may also be due to the marked structure of water arising from water–β-CD interactions.
The hydrogen belt is incomplete in the α-CD molecule because one of the glycopyranose units is in a distorted position; therefore, instead of the six possible hydrogen bonds, only four can be formed. The γ-CD molecule has a more flexible structure and consequently is the most soluble of the three native CDs. The equilibrium constants for hydrogen-deuterium exchange in the secondary hydroxyl groups of α-, β- and γ-CDs also indicate that the strongest hydrogen bond system is formed in the β-CD molecule. The most important physical and chemical characteristics of native CDs can be compared (Table 1.1).
Because of their torus-like geometry, relatively hydrophobic surface of the internal cavity and the hydrophilic character of external hydroxyl groups (Figure 1.2), CD molecules easily form inclusion complexes with a wide variety of organic and inorganic molecules. This complex-forming capacity is the reason for their widespread application in chemistry and in separation science (Table 1.2).
CDs can be created with larger cavity diameters; however, these products are interesting only from a synthetic point of view, because they can contain too many water molecules, so that the driving force of complex formation is negligible.
1 Selector Properties
As has been frequently demonstrated cyclodextrins are capable of forming inclusion complexes with compounds having a size compatible with the dimensions of the cavity. Inclusion complexes are entities comprising two or more molecules; the 'host' includes a 'guest' molecule, totally or in part, by only physical forces, that is, without covalent bonding. CDs are typical host molecules and may include a great variety of molecules having the size of one or two benzene rings, or even larger compounds, which have a side chain of comparable size, to form crystalline inclusion complexes. Complexation occurs when there is a steric compatibility between the CD cavity and the guest molecule and the affinity of the guest molecule for the CD cavity is higher than for the other components present (i.e. solvent). It has been established that, besides steric compatibility, hydrophobic interactions, van der Waals interactive forces and hydrogen bonding independently or in combination play a considerable role in the determination of the strength of inclusion complexes. The stoichiometry of inclusion compounds is usually 1:1; however, complexes can be made of two or more guests (especially with the large γ-CD cavity) or with several CD molecules by the inclusion of different parts of a large guest molecule.
Many physicochemical methods have been used for the study of the formation of inclusion complexes. Thus calorimetry, spectrophotometry and various liquid chromatographic methods, such as reversed-phase thin-layer and high-performance liquid chromatography, have been successfully used for the assessment of the various aspects of host–guest interaction.
Inclusion complex formation is stereoselective; thus it affords a possibility of resolving enantiomers. A reasonable, simple three-point interaction model has been adopted for explanation of the enantiomer separations of CDs in liquid chromatography. This model is based on the assumption that one part of the host molecule, preferably an aromatic group, must interact with the cavity of the CD and the other parts of the molecule can interact with the primary and the secondary OH groups of the CD rim. As the steric matching and consequently the energy of interaction between the two enantiomers and the three points of attachment can be different, it may result in the separation of the corresponding enantiomer pair yielding enantiodifferentiation. Molecular mechanistic investigations have also been used to explain the behaviour of CDs and CD derivatives as chiral phases or chiral stationary phase additives in GC. The calculations indicated a marked opening of the rim of the primary OH groups in the cyclodextrin's cavity and of the secondary OH groups being tilted inwards to the cavity (presumably to enhance the network of secondary hydrogen bonding). It has also been deduced that the remarkable flexibility of the CD ring can be responsible for the adaptation of molecules to a wide range of shapes.
CDs have been effectively employed for chiral separations and for the improvement of a large number of separation processes in many chromatographic techniques, either as mobile-phase additives (dissolved in the mobile phase, as modifiers) or as stationary phases or stationary-phase additives. CDs offer numerous advantages. They are thermostable to a reasonable temperature which is important in GC; furthermore, they are...
