Tuning the Sign and Magnitude of Complexation-Induced pKa Shifts in Cucurbit[7]uril Host-Guest Complexes by Molecular Engineering

Cucurbiturils are popular macrocyclic receptors that bind complementary guest molecules with high affinity in aqueous environments. They are recognized for their ability to selectively bind positively charged guest molecules, including ionizable ammonium cations which frequently display much higher affinity than their neutral counterparts. This selectivity for the protonated species is translated into an increase in the basicity of encapsulated guests (i. e. into complexation-induced positive pK_a shifts). However, despite being very rare, negative pK_a shifts can be observed for specific guests. Following a previous work from our group reporting slightly negative pK_a shifts for flavylium and chalcone dyes featuring N-diethylamino substituents (ΔpK_a=− 0.2), herein we report a systematic study on the complexation of N-dialkylaminochalcones with CB7. The results show that the pK_a shifts of these host-guest complexes can be rationally tuned by the nature of the N-dialkylamino groups and as well by target substitutions on the skeleton of the dye, allowing the design of a CB7 1 : 1 host-guest complex with a ΔpK_a=− 0.6.