Exploring the formation of medium-sized cyclic amines within self-assembled yoctoliter inner-spaces

Medium-sized (7-11-membered) rings are difficult to cyclize for both enthalpic and entropic reasons. Moreover, S_N2 cyclizations to such products in the greenest of solvent (H₂O) are complicated by competing substrate hydrolysis. Here we explore the utility of the yoctoliter (10^-24 L) inner-space of a dimeric container - assembled via the hydrophobic effect - to catalyze the formation of strained, 7-11-membered cyclic amines. Specifically, we examine the ability of the dimeric capsule of deep-cavity cavitand octa-acid 1 to promote cyclization processes, by leveraging relatively large pseudo-halide sulfonate leaving groups to minimize product inhibition and engender catalysis. We find that strained 7-membered azepane can be formed catalytically, with reaction rates dependent on the conformation or motif of the bound guest. We also find that the hydrolysis rate of a bound guest can be up to four orders of magnitude slower than the free state, and in such watertight complexes strained 11-membered aza-cycloundecane can also be formed. More generally, our results provide the first examples of S_N2 cyclizations to medium-sized cyclic amines in water, and provide benchmarks in quantifying the degree of water tightness of water-based container molecules.