Imino-thiolate-templated synthesis of a chloride-selective neutral macrocyclic host with a specific “turn-off–on” fluorescence response for hypochlorite (ClO−)

A precise replacement of one oxygen atom with sulfur in the intra-annular amide-1-methylene-pyrene substituent allowed us to efficiently synthesize a novel macrocyclic host 2 for selective recognition of chloride ions. The high yield of the macrocyclization process (64%) between sterically demanding substrates was attributed to a combination of external and internal templating effects of chloride and – previously unrecognized in the literature – thioimidate anions –C(N–)S− (generated in situ by deprotonation of thioamide by sodium methoxide), respectively. Both templating agents help to adopt a favorable folded conformation of the open-chain intermediate leading to a sterically crowded structure of 2. The host was characterized by single crystal X-ray analysis and its anion recognition properties were determined by 1H-NMR titration experiments in a demanding (DMSO-d6 + 0.5% H2O) solvent mixture. The host exhibits one of the highest reported selectivities toward chloride among systems binding anions by hydrogen bonding interactions (Ka,Cl− = 1130 M−1, Ka,Cl−/Ka,anion up to 35.3). Host 2 is essentially nonfluorescent due to the quenching effect of a thioamide group, however, the selective oxidation of the CS moiety by the hypochlorite (ClO−) anion was found to fully restore the fluorescence (λem = 377 nm). This demonstrates the first example of metal-free macrocyclic sensors for the selective detection of this biologically important analyte.