weiter 5. Cyclodextrin Derivatives

Due to the large number of hydroxyl groups in the cyclodextrin molecule (18, 21 and 24 hydroxyl groups in α-cyclodextrin, β-cyclodextrin and γ-cyclodextrin respectively), the number of possible derivatives of natural cyclodextrins is very high. The hydroxyl groups can be converted to different functional groups in a variety of ways. Therefore it is not especially surprising that in 2003, 1500 derivatives were already known from publications. A vast number of the known derivatives are destined to remain permanent objects of research, since it is too complicated and labor-intensive to synthesize them industrially.
However, around 100 derivatives are manufactured on an industrial scale and sold as specialty chemicals. In addition to methylated and hydroxypropylated cyclodextrins, the reactive monochlorotriazinyl cyclodextrin in particular is manufactured on a large scale and used for textile finishing. Figure 1.28 shows the molecular structures of the cyclodextrin derivatives manufactured by Wacker Chemie AG.
Fig. 1.28: Molecular structures of the cyclodextrin derivatives manufactured by Wacker Chemie AG

Anfangweiter In the production of methylated cyclodextrins, the degree of substitution can be controlled via the choice of reaction conditions. The scientific name heptakis(2,6-di-O-methyl) β-cyclodextrin describes the cyclodextrin derivative in which the hydroxyl groups at carbon atoms 2 and 6 have been replaced by methoxy groups. The name of this derivative can be abbreviated to dimethyl-β-cyclodextrin. Similarly, heptakis(2,3,6-tri-O-methyl) β-cyclodextrin is the fully methylated cyclodextrin derivative otherwise known as trimethyl-β-cyclodextrin. The alkylating agents methyl iodide or dimethyl sulfate are used to produce these ether derivatives. The ethers are formed in alkaline milieu under the following conditions:
Fig. 1.29: Different reaction conditions yield tri- or dimethylated cyclodextrin
Anfangweiter In the presence of the more extreme sodium hydride, the fully methylated derivative is obtained in almost 100% yield, while the yield of dimethyl ß-cyclodextrin is only 78%.
Partially methylated cyclodextrins can be synthesized due to the different reactivities of the hydroxyl groups at carbon atoms 2, 3 and 6. The hydroxyl group at carbon atom 2 is the most reactive, whilst that at carbon atom 3 is the least reactive. However, in extreme reaction conditions the differences are too slight to allow selective methylation. Derivatization principally modifies water solubility, in addition to the height and the diameter of the lower opening of the cyclodextrin molecule. The introduction of the methyl groups increases water solubility until 2/3rds of the hydroxyl groups have been substituted. If the methylation continues, the product then becomes less water-soluble again. However, even trimethyl-β-cyclodextrin is more soluble than natural β-cyclodextrin.

Substance

β-Cyclodextrin

Dimethyl-β-Cyclodextrin

Trimethyl-β-Cyclodextrin

Solubility at 25° C

18.5 g/L

570 g/L

31 g/L
Table 1.7: Solubility of β-cyclodextrin, dimethyl-β-cyclodextrin and trimethyl β cyclodextrin in water

Anfangweiter This observation is surprising at first sight, since the polar hydroxyl groups are replaced by non-polar methyl groups. But closer examination of the molecular structure can explain the change in this physical property. The extremely poor solubility of β-cyclodextrin in water can be attributed to the formation of intramolecular hydrogen bonds between the hydroxyl group at carbon atom 2 and the hydroxyl group at carbon atom 3 of the adjacent glucose unit in the cyclodextrin molecule (see Fig. 1.30).
Fig. 1.30: Comparison of the molecular structure of β-cyclodextrin and dimethyl-β-cyclodextrin
Anfangweiter This intramolecular hydrogen bond can no longer form in the derivative, and so the hydroxyl group at carbon atom 3 can interact with the water molecules in the surrounding environment. This produces a thirty-fold increase in solubility.
The reason for the improved water solubility of the fully methylated β-cyclodextrin compared with natural β-cyclodextrin cannot be fully explained. The exterior actually becomes considerably more hydrophobic due to the substitution of all hydroxyl groups. But the methyl groups, which are bulkier than the hydrogen atoms, cause steric hindrance on the upper edge of the cyclodextrin molecule that is reduced by tilting the glucose units. In addition, twisting occurs in individual glucose units. These factors lead to increased solubility in water.
Derivatization affects not only solubility in water but also solubility in organic solvents. Methylated derivatives are highly soluble in methanol, ethanol and dimethyl sulfoxide due to the hydrophobic exterior, whilst natural β-cyclodextrin is virtually insoluble in these solvents.

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