Electrostatic and Allosteric Cooperativity in Ion-Pair Binding: A Quantitative and Coupled Experiment–Theory Study with Aryl–Triazole–Ether Macrocycles

Cooperative binding of ion pairs
to receptors is crucial for the
manipulation of salts, but a comprehensive understanding of cooperativity
has been elusive. To this end, we combine experiment and theory to
quantify ion-pair binding and to separate allostery from electrostatics
to understand their relative contributions. We designed aryl–triazole–ether
macrocycles (MC) to be semiflexible, which allows ion
pairs (NaX; X = anion) to make contact, and to be monocyclic to simplify
analyses. A multiequilibrium model allows us to quantify, for the
first time, the experimental cooperativity, α, for the equilibrium MC·Na+ + MC·X– ⇌ MC·NaX + MC, which is associated
with contact ion-pair binding of NaI (α = 1300, ΔGα = −18 kJ mol–1) and NaClO4 (α = 400, ΔGα = −15 kJ mol–1) in 4:1
dichloromethane–acetonitrile. We used accurate energies from
density functional theory to deconvolute how the electrostatic effects
and the allosteric changes in receptor geometry individually contribute
to cooperativity. Computations, using a continuum solvation model
(dichloromethane), show that allostery contributes ∼30% to
overall positive cooperativity. The calculated trend of electrostatic
cooperativity using pairs of spherical ions (NaCl > NaBr > NaI)
correlates
to experimental observations (NaI > NaClO4). We show
that
intrinsic ionic size, which dictates charge separation distance in
contact ion pairs, controls electrostatic cooperativity. This finding
supports the design principle that semiflexible receptors can facilitate
optimal electrostatic cooperativity. While Coulomb’s law predicts
the size-dependent trend, it overestimates electrostatic cooperativity;
we suggest that binding of the individual anion and cation to their
respective binding sites dilutes their effective charge. This comprehensive
understanding is critical for rational designs of ion-pair receptors
for the manipulation of salts.