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 + )/Cu 2+ ) 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 (Cu 2+ (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 Cu 2+ ions are located within three loop regions of imDNA(H + ), and two Cu 2+ (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.