This review presents a survey of new high specific activity tritium labeling reagents and methodologies developed in recent years and their applications to tritium labeling chemistry. The review is organized on the basis of reagent type, its development and applications. Emphasis is placed on the synthetic applications of the reagents and techniques that have an exceptionally high capability to produce high specific activity tritium labeled compounds. The focus of this review is on chemical labeling syntheses and does not include heterogeneous/homogeneous metal-catalyzed hydrogentritium exchange and biochemical reactions. 6 Conclusion

The essential nature of rapid radiotracer synthesis very early in drug discovery programs has driven the need for better and more varied tritium incorporation methods. This review presents a summary of recent advances for tritium introduction via tritiated water, tritium gas, complex tritides, and a range of recently improved tritiation reagents. Access to a wider range of tritiated reagents (for tritioacetylation, tritioformylation, methylation, etc.) and commercial manifolds for the transfer and use of tritium gas is also discussed.

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The first application of tritium NMR spectroscopy to the direct observation of proton‐exchange kinetics is described; this technique allows the study of milligram amounts of substrates and for substrates with multiple exchangeable positions. The examples include benzene and the ring and methyl positions of p‐xylene reacting with cesium cyclohexylamide in cyclohexylamine, and the enolate positions of cyclohexanone and methyl 7,12‐dihydroxy‐3‐ketocholan‐24‐oate reacting with heptafluorobutyric acid in dioxane.

Small discrepancies between 3H and 1H chemical shifts in organic compounds led to the finding that the ratio of Larmor frequencies ωT/ωH depends on the carbon‐hydrogen bond hybridisation. The ‘best’ ratio for ghost referencing of 3H NMR spectra was then determined from measurements on purified partially tritiated TMS as 1.066639738±2 × 10−9. Some 3H isotope effects on chemical shifts are listed and the 3H isotope effect on the methylene geminal coupling constant in benzyl methyl sulphoxide is measured. Use of 2H in the measurement of 2J(HH) coupling constants has inherent disadvantages, overcome by use of 3H substitution.