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

Abstract

Medium-sized (7-11-membered) rings are difficult to cyclize for both enthalpic and entropic reasons. Moreover, SN2 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 SN2 cyclizations to medium-sized cyclic amines in water, and provide benchmarks in quantifying the degree of watertightness of water-based container molecules.