Cyclodextrins (CD) are cyclic oligosaccharides, comprising six (α-CD), seven (β-CD) or eight (ɣ-CD) glucose monomers in the shape of a hollow, truncated cone (Figure ). Their C6 primary hydroxyls rim the narrower face of the cone, while their C2 and C3 secondary hydroxyls are located on the wider face (Figure ). The hydroxyls make the exterior of cyclodextrin hydrophilic and contribute to its aqueous solubility, while the internal cavity remains hydrophobic, allowing for noncovalent association with lipophilic and amphiphilic molecules. The cyclodextrins have found practical applications, such as solubilization of small, lipophilic, drug molecules , and encapsulation of volatile compounds . Cyclodextrins also have been adopted as test cases for computational methods of predicting noncovalent binding affinities. In this context, they represent simple models for the association of proteins with drug molecules , and are being used to test and enhance the accuracy of the potential functions used in molecular simulations . Although many experimental cyclodextrin-guest affinity data are available , most are for unmodified cyclodextrins and hence probe only the interactions of guest molecules with the glucose monomers of the native host. Expanding the diversity of chemical interactions is of great interest in the computational chemistry community, because it would open new possibilities for using host-guest binding data to test and improve potential functions Applications in other fields, such as chemical separations and pharmaceutical formulations, are also likely. Cyclodextrins can be diversified through the addition of functional groups at either the primary or secondary hydroxyls, leading to changes in size, shape and physical properties. For example, although native β-CD is not particularly water-soluble (18 mg/mL), randomly-methylated-β-cyclodextrin and 2hydroxypropyl-β-cyclodextrin have aqueous solubilities of over 500 mg/mL . Derivatization can also modulate the binding affinities of these hosts for guest molecules that bind in the hydrophobic cavity of CD . When modifying affinity and specificity is the goal, it is preferable to derivatize the secondary hydroxyl groups of the host, rather than the primary ones, as derivatizing the secondary hydroxyls typically has a greater effect on binding affinity . This makes intuitive sense, because bound guest molecules are more likely to protrude through the wider secondary opening, where they can interact with the added substituents, than through the narrower primary opening . It is also of interest to create monosubstituted derivatives, rather than adding multiple substituents, to avoid crowding of this entryway and/or a combinatorial explosion of variants in the reaction products . Despite important advances , the selective addition of substituents at the secondary face has long posed challenges in synthesis and purification . Many modification strategies lead to a complex mixture of products, such as randomly-methylated-β-CD. In addition, modified CDs may aggregate or become insoluble, reducing their effectiveness as host molecules . Furthermore, selective modification of the secondary face of β-CD has involved arduous, low-yielding, reaction procedures, and existing approaches typically require access to purification equipment, such as lyophilizers and centrifuges , not available to all groups interested in synthesizing such derivatives. Mechanosynthetic methods, which may overcome tedious work ups and time consuming purifications, have still afforded only modest reaction yields . Thus, the literature has focused mainly on substituting the primary face of β-CD, which is easier to functionalize due to the greater nucleophilicity and reduced steric hindrance of its hydroxyls. However, the resulting products are, arguably, less interesting from the standpoint of generating diversity in binding affinity and specificity.