Proximity‐Induced Ligation of Noncomplementary Oligonucleotides Triggered by Charge‐Transfer Interactions

While DNA‐templated ligations typically rely on the sequence‐specific hybridization of complementary strands to bring reactive groups into close proximity, charge‐transfer assisted ligation (CTAL) is proposed as a fundamentally different strategy. Rather than depending on a DNA template for spatial organization, CTAL exploits charge‐transfer interactions between reactants to promote bond formation between two noncomplementary DNA strands. The strategic placement of donor and acceptor units at the termini of DNA strands drives the colocalization of reactive functional groups, enabling efficient reactions at sub‐micromolar concentrations. The versatility of the CTAL is demonstrated on CuAAC and SPAAC click reactions, allowing the formation of conjugates with 3′‐5′, 3′‐3′, or 5′‐5′ junctions, with outstanding apparent rate constants in the 10 4 –10 5 M −1 s −1 range, while the nonassisted reactions are inoperative in such dilute conditions (0.5 µM). Furthermore, the potential of the CTAL is extended to RNA–RNA and siRNA–DNA aptamer ligations. Finally, a traceless strategy based on a cleavable linker is developed, which allows the removal of aromatic units after ligation under basic conditions.