Aqueous compatible post‐synthetic on‐column conjugation of nucleic acids using amino‐modifiers

Nucleic acid conjugation methodologies involve linking the nucleic acid sequence to other (bio)molecules covalently. This typically allows for nucleic acid property enhancement whether it be for therapeutic purposes, biosensing, etc. Here, we report a streamlined, aqueous compatible, on‐column conjugation methodology using nucleic acids containing a site‐specific amino‐modifier. Both monophosphates and carboxylates were amenable to the conjugation strategy, allowing for the introduction of a variety of useful handles including azide, aryl, and hydrophobic groups in DNA. We find that an on‐column approach is superior to post‐synthetic template‐directed synthesis, mainly with respect to product purification and recovery.