Synthesis of Randomly Substituted Anionic Cyclodextrins in Ball Milling

Abstract

A number of influencing factors mean that the random substitution of cyclodextrins (CD) in solution is difficult to reproduce. Reaction assembly in mechanochemistry reduces the number of these factors. However, lack of water can improve the reaction outcomes by minimizing the reagent's hydrolysis. High-energy ball milling is an efficient, green and simple method for one-step reactions and usually reduces degradation and byproduct formation. Anionic CD derivatives have successfully been synthesized in the solid state, using a planetary ball mill. Comparison with solution reactions, the solvent-free conditions strongly reduced the reagent hydrolysis and resulted in products of higher degree of substitution (DS) with more homogeneous DS distribution. The synthesis of anionic CD derivatives can be effectively performed under mechanochemical activation without significant changes to the substitution pattern but the DS distributions were considerably different from the products of solution syntheses.

Keywords: anionic cyclodextrin; high-energy ball milling; random substitution; solvent-free reactions.

Scheme 1

Synthesis of anionic βCD derivatives in solution.

Scheme 2

Synthesis of anionic βCD derivatives with high-energy ball milling (HEBM).

Figure 1

Capillary electropherograms of carboxymethylated βCD (a) synthesized in solution (compound 2, item 1 in Table 1); (b) synthesized in ball mill (compound 2′, item 3 in Table 1).

Figure 2

Capillary electropherograms of carboxyethylated βCD (a) synthesized in solution (compound 3, item 8 in Table 1); (b) synthesized in ball mill (compound 3′, item 6 in Table 1).

Figure 3

Capillary electropherograms of carboxyethylated βCD (a) synthesized from sodium acrylate (compound 3′′, item 7 in Table 1); and (b) carboxyethyl residue in carbamoylethyl βCD (compound 5, item 9 in Table 1).

Figure 4

Capillary electropherograms of sulfobutylated βCD (a) synthesized in solution (compound 4, item 7 in Table 1); (b) synthesized in ball mill (compound 4′, item 13 in Table 1).