Deuterogenation of unsaturated organic compounds is an attractive route for installing C(sp3)−D bonds, but the existing methods typically use expensive D2 and introduce only two deuterium atoms per unsaturation. Herein we report the hydrogenative perdeuteration of alkenes using readily available H2 and D2O instead of D2, catalysed by an acridanide-based ruthenium pincer complex and resulting in the incorporation of up to 4.9 D atoms per C=C double bond in a single synthetic step. Importantly, adding a catalytic amount of thiol, which serves as a transient cooperative ligand, ensures the incorporation of deuterium rather than protium by balancing the rates of two sequential deuteration processes. The current method opens an avenue for installing perdeuteroalkyl groups at specific sites from widely available alkenes under mild conditions.
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J.L. thanks the Feinberg Graduate School (FGS) of the Weizmann Institute of Science for a Senior Postdoctoral Fellowship. L.L. thanks the FGS for a Dean Excellence Postdoctoral Fellowship. We thank M. Rauch for help with the computational work.
The authors declare no competing interests.
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Based on our previous work (ref. 22), the catalytically active form of Ru-1 (species I) most likely exhibits a facially-coordinated pincer ligand (fac). For each of the above reactions, reactants and products are only shown for the forward direction, to enhance clarity.
Progress of the deuterium labeling reaction in the presence of varying amounts of thiol, as represented by the amount of protium incorporated into D2O.
a,b, Deuteration attempts in the absence of H2 (see Supplementary Fig. 97); the incomplete deuteration in D-1a may be due to consumption of the ruthenium-hydride complex without regeneration. c,d, Deuterogenation with D2 in a 30 mL (c) and 220 mL (d) reactor; the improvement in the deuterium content of D-2a indicates that the reaction is affected by the amount of D2, which can be explained by the theoretical D content of the system (considering 1.5 mmol of H atoms in 1a; see Supplementary Note 3). e, Deuterogenation with D2 in a 220 mL reactor in the absence of thiol; the results indicate direct exchange between D2 and Ru-1. f, Hydrogenative perdeuteration of 1a; although only 0.6 mmol of H2 was employed, the thiol ensured fast and continuous transfer of deuterium from D2O (55 mmol) to both H2 and the alkene C − H bonds.
a, Screening of different thiols. Various thiol TCLs exert different effects on the H/D exchange between D2O and H2, as well as alkene perdeuteration, due to differences in their electronic and steric properties. Consequently, different thiols lead to varying deuteration results, with cyHexSH providing the best result of all examined thiols. b, Compatibility of the catalytic system with different functional groups that are frequently found in bioactive molecules and pharmaceuticals (active protons were not taken into consideration in evaluating additive recovery). Some strongly-coordinating N-donors, that is, benzylamine, pyridine and phenylpropionitrile, showed detrimental effects, but even in these cases good product yields were obtained (71%–83%), and deuterium incorporation remained high. Among the studied additives, only benzoic acid completely halted the catalytic activity. This may be due to deactivation of the catalyst by formation of a stable ruthenium-carboxylate species, as has been previously observed (ref. 25). c, Optimization of catalytic conditions.
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Luo, J., Lu, L., Montag, M. et al. Hydrogenative alkene perdeuteration aided by a transient cooperative ligand. Nat. Chem. 15, 1384–1390 (2023). https://doi.org/10.1038/s41557-023-01313-y
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