Nitrogen Isotope Exchange (NIE): Opportunities and Challenges

Nitrogen atom extensively exists in pharmaceuticals, natural products, and functional materials. Nitrogen-14 is the most abundant isotope of nitrogen, while nitrogen-13 and nitrogen-15 are two other important isotopes. Compounds including nitrogen-13 or nitrogen-15 are widely applied in mechanism elucidation, SABRE-SHEATH technology, positron emission tomography (PET), and other scientific fields. Late-stage isotope exchange strategy has been proven to be an efficient solution in the preparation of hydrogen/carbon-labeled complex functional molecules. In recent years, a variety of nitrogen isotope exchange strategies have been developed for the isotope labeling of nitrogen-containing compounds such as amines, sulfonamides, cyanides, as well as nitrogen-containing heterocycles. These methods involve diverse chemical approaches such as transition-metal-catalysis, organocatalysis, ANORC (addition of nucleophile, ring opening, ring closing sequence), and so on. In this review, we summarized the works about nitrogen isotope exchange from 1994 to 2025, mainly including recent breakthroughs in the synthesis of nitrogen-isotope-labeled compounds. Moreover, the current limitations of nitrogen isotope exchange were also discussed.