Steric Control of Cooperative Anion Transport Mediated by β- and δ‑Hexachlorocyclohexane Multivalent Carriers

The β- and δ-hexachlorocyclohexane (HCH) diastereoisomers display triaxial C-H donor sites, favorably oriented for anion binding via weak hydrogen bonding (HB), prompting us to investigate their transmembrane anion transport properties. Notably, we found that only δ-HCH facilitates efficient Cl^- translocation via a cooperative carrier mechanism (EC₅₀ = 1.78 mol % (8.25 μM)), while β-HCH shows no measurable activity under the same conditions. Although both isomers exhibit comparable binding affinities in solution, the steric hindrance in β-HCH likely prevents formation of the cooperative HB interactions required to offset the chloride dehydration penalty during translocation across the membrane, rendering β-HCH inactive toward Cl^- transport. Both β- and δ-HCH display high Br^- and NO₃ ^- transport activity, with δ-HCH showing higher efficiency, consistent with a cooperative binding mode. Notably, δ-HCH also induces membrane depolarization in liposome models by mediating voltage-responsive Cl^- transport down its electrochemical gradient. Together, our experimental and theoretical results illustrate how steric accessibility can control cooperativity of multivalent weak HB C-H donor carriers, resulting in an efficient anion transport.