Orthosteric Control of Acidity Through Sulfate Binding in a Neutral Cyclo[8]pyrrole

Abstract

ABSTRACT Acid–base equilibria can be shifted when binding events alter the local electrostatic and hydrogen‐bonding environment of an ionizable site. Implementing such binding‐linked acidity changes in a discrete synthetic system would enable regulation of proton activity without changing molecular composition or solvent. Here we describe a new naphthalimide‐fused analogue of cyclo[8]pyrrole in which anion recognition dramatically shifts protonation equilibria. Whereas established cyclo[8]pyrroles preferentially form globally aromatic dications, the electron‐deficient macrocycle shows an unusual preference for a persistent neutral redox state, while simultaneously revealing exceptionally high Brønsted acidity in organic solvents. The neutral macrocycle retains key anion‐recognition characteristics of dicationic cyclo[8]pyrroles, including strong sulfate affinity. Sulfate binding increases the effective first p K a in DMSO by roughly four units, providing an orthosteric, anion‐actuated acid switch and expanding the design space of switchable acidity beyond host–guest p K a shifts and light‐addressable photoacids.