Computational Design of Thiourea-based Cyclophane Sensors for Small Anions

Abstract

The host–guest binding properties of a tri-thiourea cyclophane receptor (1) with several common anions have been investigated using density functional theory (DFT) and molecular dynamics calculations. Receptor 1 is predicted to be an effective receptor for binding small halogen and Y-shaped (NO3– and AcO–) anions in the gas phase, cyclohexane and chloroform. The calculated order of anion binding affinity for the receptor 1 in chloroform is F– > Cl– > AcO– > NO3– >Br– > H2PO4– > HSO4–. The binding free energies are strongly influenced by a dielectric solvent medium. The structures of the receptor–anion complexes are characterized by multiple (typically 6) hydrogen bonds in all cases. The overall binding affinity of various anions is determined by the basicity of anion, size and shape of the binding site, and solvent medium. Explicit chloroform solvent molecular dynamics simulations of selected receptor–anion complexes reveal that the anions are strongly bound within the binding pocket via hydrogen-bonding interactions to all the receptor protons throughout the simulation. A sulfur analogue of receptor 1 (2), with a larger central cavity, is shown to be a more effective sensor than 1 for small anions. Two different approaches to develop the thiourea-based cyclophane receptor into a chromogenic sensor were examined.