On‐DNA Nitro Reduction for Use in DNA‐Encoded Library Synthesis: Methods, Applications, and Challenges

ABSTRACT

Deoxyribonucleic acid (DNA)‐encoded library (DEL) technology is an established platform used in small‐molecule discovery, but its scope depends on reactions that remain efficient and selective when the substrates are tethered to DNA. Aryl nitro reductions are particularly valuable because nitroarenes are low‐cost, stable, structurally diverse building blocks, and the resulting anilines, including 1,2‐diaminobenzenes, provide access to amides, ureas, benzimidazoles, and other N‐containing scaffolds. Over the past decade, on‐DNA nitro reduction methods have been reported across several mechanistic classes, including heterogeneous transfer hydrogenation, Na ₂ S ₂ O ₄ ‐based electron transfer, metal‐free diboron‐mediated reduction, and Fe(II)‐ and Pd/borohydride‐mediated reductions. This review organizes these methods according to their mechanisms and compares their efficiencies, chemoselectivities, DNA compatibilities, and operational practicalities, focusing on their characteristic side reactions, and it also examines the DNA‐tag length, which is a crucial but often overlooked variable. Most protocols have been validated for short DNA headpieces, but nitro reduction may occur after at least one encoding cycle during DEL construction. A recent comparative study revealed that tag elongation could alter the efficiency, chemoselectivity, and formation of side products. Therefore, we provide practical criteria for use in method selection and identify priorities for further development.