The intramolecular hydrogen bonded-halogen bond: A new strategy for preorganization and enhanced binding

Abstract

Natural and synthetic molecules use weak noncovalent forces to preorganize structure and enable remarkable function. Herein, we introduce the intramolecular hydrogen bonded-halogen bond (HB-XB) as a novel method to preorganize halogen bonding (XBing) molecules, while generating a polarization-enhanced XB. Positioning a fluoroaniline between two iodopyridinium XB donors engendered intramolecular hydrogen bonding (HBing) to the electron-rich belt of both XB donors. NMR solution studies established the efficacy of the HB-XB. The receptor with HB-XBs (G2XB) displayed a nearly 9-fold increase in halide binding over control receptors. Gas-phase density functional theory conformational analysis indicated that the amine stabilizes the bidentate conformation. Furthermore, gas-phase interaction energies showed that the bidentate HB-XBs of G2XBme2+ are more than 3.2 kcal mol-1 stronger than the XBs in a control without the intramolecular HB. Additionally, crystal structures confirm that HB-XBs form tighter contacts with I- and Br- and produce receptors that are more planar. Collectively the results establish the intramolecular HB-XB as a tractable strategy to preorganize XB molecules and regulate XB strength.