H <b> ⁺ </b> /Ag <b> ⁺ </b> Switch of Enantioselectivity in i-Motif DNA-Based Friedel–Crafts Reactions

DNA-metal complexes represent a growing class of artificial metalloenzymes for enantioselective catalysis. Unlike protein pockets, the structural tunability of DNA scaffolds, such as the G-quadruplex, enables dynamic control over enantioselectivity. However, these catalysts often exhibit low catalytic efficiency and limited enantioselectivity switching, underscoring a high demand for rational design strategies to advance this field. Capitalizing on the programmable cytosine-cytosine base pairing in i-motif DNA (imDNA), we develop a tetrad-capping strategy to construct a copper(II) hybrid catalyst (imDNA(H⁺)/Cu²⁺) featuring hemiprotonated cytosine-cytosine base pairs (C-H⁺-C). This catalyst achieves quantitative conversions and up to 98% enantiomeric excess (ee) in Friedel-Crafts reactions. Remarkably, Ag⁺ ions reconfigure imDNA(H⁺) into a distinct imDNA(Ag⁺) conformation, realizing inversion of enantioselectivity (up to -93% ee) with the 4,4'-dimethyl-2,2'-bipyridine copper(II) complex (Cu²⁺(dmbpy)). The chiral inversion originates from distinct H⁺- and Ag⁺-regulated i-motif topologies. Comprehensive spectroscopic, electrophoretic, and thermodynamic analyses reveal that imDNA(Ag⁺) adopts an antiparallel strand orientation stabilized by four C-Ag⁺-C and two G-Ag⁺-G base pairs, in contrast to the capped imDNA(H⁺). The plausible binding sites of catalytic copper(II) species are proposed through binding assays and mutagenesis, where three Cu²⁺ ions are located within three loop regions of imDNA(H⁺), and two Cu²⁺(dmbpy) complexes might primarily interact with imDNA(Ag⁺) via end-stacking. This work establishes a general paradigm for designing tunable DNA hybrid catalysts via programmable base pairing, opening avenues for diverse enantioselective transformations.