Nitrooxylation in Organic Synthesis: From Classical Nitrate Ester Formation to Modern Catalytic Strategies

Organic nitrate esters (R-ONO₂) are structurally and electronically distinct from nitro compounds, featuring a polarized C-O-NO₂ linkage with an intrinsically weak O-N bond. This characteristic imparts unique reactivity, enabling controlled bond cleavage and rendering nitrate esters valuable in energetic materials, pharmaceuticals (as nitric oxide (NO) donors), and as synthetic intermediates. Nitrooxylation, the installation of the -ONO₂ group, has historically relied on harsh mixed-acid systems (e.g., nitric acid/sulfuric acid), which suffer from poor selectivity, limited functional-group tolerance, and significant safety concerns. Recent advances have shifted the field toward milder and more controlled approaches. Catalytic systems, bench-stable nitrooxy transfer reagents, and alternative activation modes have improved selectivity and operational safety. In particular, photochemical, electrochemical, and mechanochemical strategies enable the in situ generation of reactive nitrogen oxide species (e.g., NO₂•, NO₃•) under controlled conditions, expanding the scope to include alkene difunctionalization, C(sp³)-H functionalization, and selective O-nitration of alcohols. This review provides a comprehensive overview of the evolution of nitrooxylation chemistry, from classical methods to modern synthetic platforms. Emphasis is placed on mechanistic understanding, reagent design, and the interplay between electronic structure and reactivity, with the aim of guiding future developments toward safe, selective, and sustainable nitrate ester synthesis.