Hydrogen isotopes are unique tools for identifying and understanding biological and chemical processes. Hydrogen isotope labelling allows for the traceless and direct incorporation of an additional mass or radioactive tag into an organic molecule with almost no changes in its chemical structure, physical properties, or biological activity. Using deuterium-labelled isotopologues to study the unique mass-spectrometric patterns generated from mixtures of biologically relevant molecules drastically simplifies analysis. Such methods are now providing unprecedented levels of insight in a wide and continuously growing range of applications in the life sciences and beyond. Tritium ( H), in particular, has seen an increase in utilization, especially in pharmaceutical drug discovery. The efforts and costs associated with the synthesis of labelled compounds are more than compensated for by the enhanced molecular sensitivity during analysis and the high reliability of the data obtained. In this Review, advances in the application of hydrogen isotopes in the life sciences are described.

The increasing demand for stable isotopically labeled compounds has led to an increased interest in H/D-exchange reactions at carbon centers. Today deuterium-labeled compounds are used as internal standards in mass spectrometry or to help elucidate mechanistic theories. Access to these deuterated compounds takes place significantly more efficiently and more cost effectively by exchange of hydrogen by deuterium in the target molecule than by classical synthesis. This Review will concentrate on the preparative application of the H/D-exchange reaction in the preparation of deuterium-labeled compounds. Advances over the last ten years are brought together and critically evaluated.

The various applications of hydrogen isotopes (deuterium, D, and tritium, T) in the physical and life sciences demand a range of methods for their installation in an array of molecular architectures. In this Review, we describe recent advances in synthetic C-H functionalisation for hydrogen isotope exchange.

A novel and convenient protocol for the catalytic hydrogen-deuterium exchange of biologically active tertiary amines utilizing the borrowing hydrogen methodology has been developed. In the presence of the readily available Shvo catalyst, excellent chemoselectivity toward α- and β-protons with respect to the nitrogen atom as well as high degree of deuterium incorporation and functional group tolerance is achieved. This allowed for the deuteration of complex pharmaceutically interesting substrates, including examples for actual marketed drug compounds. Notably, this method constitutes a powerful tool for the generation of valuable internal standard materials for LC-MS/MS analyses highly demanded for various life-science applications.

Organic chemistry Z 0200The Renaissance of H/D Exchange -[282 refs.]. -(ATZRODT, J.; DERDAU, V.; FEY, T.; ZIMMERMANN, J.; Angew. Chem., Int. Ed. 46 (2007) 41, 7744-7765; Isotope Chem. Metab. Synth., Sanofi-Aventis Dtschl. GmbH, D-65926 Frankfurt/M., Germany; Eng.) -Bartels 51-243

This review addresses method developments both homogeneous and heterogeneous Pd-and Pt-catalyzed exchange, including catalyst activation principles and recent practical applications together with example procedures. Specific requirements for isotopically labelled internal MS standard preparation are discussed from a Sanofi-Aventis perspective on recent examples.

Conventional thermal and microwave conditions were compared for hydrogen-deuterium (H/D) exchange reactions of aminobenzoic acids catalysed by NaBD(4)-activated Pd/C or RhCl(3) with D(2)O as the deuterium source. We also investigated different NaBD(4)-activated metal catalysts (including Pd/C, RhCl(3) and Pt/C) under microwave conditions for an efficient H/D exchange of aromatic and heterocyclic compounds. Even higher deuterium incorporations were obtained for Pd/C and Pt/C catalyst mixtures due to the previously observed synergistic effect. Finally, we have applied these optimised conditions for one-step syntheses of the MS standards of several pharmaceutically active compounds.

The preparation of N‐heterocyclic carbene‐stabilized iridium nanoparticles and their application in hydrogen isotope exchange reactions is reported. These air‐stable and easy‐to‐handle iridium nanoparticles showed a unique catalytic activity, allowing selective and efficient hydrogen isotope incorporation on anilines using D2 or T2 as isotopic source. The usefulness of this transformation has been demonstrated by the deuterium and tritium labeling of diverse complex pharmaceuticals.