Host–Guest Mismatch Enables Selective Hydrogen Atom Transfer

Endogenous binding of molecular guests inside cavities of their hosts has been routinely utilized in enzymatic and supramolecular catalysis. In contrast, exogenous binding‐where a guest selectively associates with the exterior surface, rather than the cavity, of its host owing to their size mismatch‐remains a largely unexplored paradigm for controlling the selectivity of chemical reactions. Here, we report that the exogenous binding between natural cyclodextrins (CDs) and a polyoxometalate catalyst leads to high site‐selectivity in hydrogen atom transfer between them. The decatungstate anion (W 10 O 32 4– ), a photoactive polyoxometalate capable of abstracting hydrogen atoms from C–H bonds on organic molecules, was found to associate noncovalently with CDs in aqueous solution. The large size of W 10 O 32 4– , however, precludes the formation of deep inclusion complexes and confines its interactions with the narrow rim of CDs, as evidenced by 1 H NMR titration and x‐ray crystallography. This exogenous association increases the effective local concentration of W 10 O 32 4– near the C6–H bonds, accelerating HAT at these positions upon photoexcitation and rendering C6 functionalization kinetically dominant over slower, less selective background pathways. The host‐guest mismatch approach offers a general platform for the selective, one‐step ligations of CDs onto natural products, drugs, fluorescent probes as well as “click” compatible molecular scaffolds.