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.