Site-selective deuteration of C–H bonds increases the lifetime and efficacy of drug molecules. Although effective methods to form C(sp2)–D bonds are known, processes for making C(sp3)–D bonds often have low site selectivity, require expensive and unrecoverable D2 gas, or use stoichiometric reagents. Here we report cost-efficient and site-selective reductive deuteration using a tandem electrochemical chemical palladium membrane reactor. This architecture mediates the chemical reaction of deuterium atoms (derived from reusable D2O in an electrochemical compartment) with alkynes, aldehydes and imines. The formation of C(sp3)–D and C(sp2)–D bonds in the isolated chemical compartment is made possible by the deuterium-selective permeability of the membrane that partitions the electrochemical compartment from the chemical compartment. We have utilized the reactor for the deuteration step in the construction of a common drug, cinacalcet, to demonstrate that this method can be used to incorporate deuterium atoms in a pharmaceutical.
Subscribe to Journal
Get full journal access for 1 year
only $8.25 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
The data supporting the findings in this study are available either within the paper or its Supplementary Information, or from the corresponding author on reasonable request.
Wiberg, K. B. The deuterium isotope effect. Chem. Rev. 55, 713–743 (1955).
Belleau, B., Burba, J., Pindell, M. & Reiffenstein, J. Effect of deuterium substitution in sympathomimetic amines on adrenergic responses. Science 133, 102–104 (1961).
Schmidt, C. First deuterated drug approved. Nat. Biotechnol. 35, 493–494 (2017).
Mullard, A. FDA approves first deuterated drug. Nat. Rev. Drug Discov. 16, 305 (2017).
DeWitt, S. H. & Maryanoff, B. E. Deuterated drug molecules: focus on FDA-approved deutetrabenazine. Biochemistry 57, 472–473 (2018).
Atzrodt, J., Derdau, V., Kerr, W. J. & Reid, M. C−H Functionalisation for hydrogen isotope exchange. Angew. Chem. Int. Ed. 57, 3022–3047 (2018).
Junk, T. & James Catallo, W. Hydrogen isotope exchange reactions involving C–H (D, T) bonds. Chem. Soc. Rev. 26, 401–406 (1997).
Koniarczyk, J. L., Hesk, D., Overgard, A., Davies, I. W. & McNally, A. A general strategy for site-selective incorporation of deuterium and tritium into pyridines, diazines, and pharmaceuticals. J. Am. Chem. Soc. 140, 1990–1993 (2018).
Ma, S., Villa, G., Thuy-Boun, P. S., Homs, A. & Yu, J.-Q. Palladium-catalyzed ortho-selective C–H deuteration of arenes: evidence for superior reactivity of weakly coordinated palladacycles. Angew. Chem. Int. Ed. 53, 734–737 (2014).
Yu, R. P., Hesk, D., Rivera, N., Pelczer, I. & Chirik, P. J. Iron-catalysed tritiation of pharmaceuticals. Nature 529, 195–199 (2016).
Pieters, G. et al. Regioselective and stereospecific deuteration of bioactive aza compounds by the use of ruthenium nanoparticles. Angew. Chem. Int. Ed. 53, 230–234 (2014).
Yang, H. et al. Site-selective nickel-catalyzed hydrogen isotope exchange in N-heterocycles and its application to the tritiation of pharmaceuticals. ACS Catal. 8, 10210–10218 (2018).
Valero, M. et al. C–H-Functionalization—prediction of selectivity in iridium(i) catalyzed hydrogen isotope exchange competition reactions. Angew. Chem. Int. Ed. 59, 5626–5631 (2020).
Zarate, C., Yang, H., Bezdek, M. J., Hesk, D. & Chirik, P. J. Ni(i)–X Complexes bearing a bulky α-diimine ligand: synthesis, structure, and superior catalytic performance in the hydrogen isotope exchange in pharmaceuticals. J. Am. Chem. Soc. 141, 5034–5044 (2019).
Valero, M. et al. NHC‐stabilized iridium nanoparticles as catalysts in hydrogen isotope exchange reactions of anilines. Angew. Chem. Int. Ed. 132, 3545–3550 (2020).
Hale, L. V. A. & Szymczak, N. K. Stereoretentive deuteration of α-chiral amines with D2O. J. Am. Chem. Soc. 138, 13489–13492 (2016).
Palmer, W. N. & Chirik, P. J. Cobalt-catalyzed stereoretentive hydrogen isotope exchange of C(sp3)–H bonds. ACS Catal. 7, 5674–5678 (2017).
Valero, M., Weck, R., Güssregen, S., Atzrodt, J. & Derdau, V. Highly selective directed iridium-catalyzed hydrogen isotope exchange reactions of aliphatic amides. Angew. Chem. Int. Ed. 57, 8159–8163 (2018).
Kerr, W. J., Mudd, R. J., Reid, M., Atzrodt, J. & Derdau, V. Iridium-catalyzed Csp3–H activation for mild and selective hydrogen isotope exchange. ACS Catal. 8, 10895–10900 (2018).
Klei, S. R., Golden, J. T., Tilley, T. D. & Bergman, R. G. Iridium-catalyzed H/D exchange into organic compounds in water. J. Am. Chem. Soc. 124, 2092–2093 (2002).
Khaskin, E. & Milstein, D. Simple and efficient catalytic reaction for the selective deuteration of alcohols. ACS Catal. 3, 448–452 (2013).
Neubert, L. et al. Ruthenium-catalyzed selective α,β-deuteration of bioactive amines. J. Am. Chem. Soc. 134, 12239–12244 (2012).
Zhang, X. et al. Carbene-catalyzed α,γ-deuteration of enals under oxidative conditions. ACS Catal. 10, 5475–5482 (2020).
Loh, Y. Y. et al. Photoredox-catalyzed deuteration and tritiation of pharmaceutical compounds. Science 358, 1182–1187 (2017).
Michelotti, A. & Roche, M. 40 Years of hydrogen–deuterium exchange adjacent to heteroatoms: a survey. Synthesis 51, 1319–1328 (2019).
Nishimura, S. Handbook of Heterogeneous Catalytic Hydrogenation for Organic Synthesis (Wiley, 2001).
Yang, J. Deuterium: Discovery and Applications in Organic Chemistry (Elsevier, 2016).
Liu, J. & Liu, X. Deuteride Materials (Springer, 2019).
Than, C., Morimoto, H., Andres, H. & Williams, P. G. Tritium and deuterium labelling studies of alkali metal borohydrides and their application to simple reductions. J. Label. Comp. Radiopharm. 38, 693–711 (1996).
Erb, W. T., Jones, J. R. & Lu, S.-Y. Microwave enhanced deuteriations in the solid state using alumina doped sodium borodeuteride. J. Chem. Res. 23, 728–729 (1999).
Li, H. et al. A selective and cost-effective method for the reductive deuteration of activated alkenes. Tetrahedron Lett. 58, 2757–2760 (2017).
Li, H. et al. Pentafluorophenyl esters: highly chemoselective ketyl precursors for the synthesis of α,α-dideuterio alcohols using SmI2 and D2O as a deuterium source. Org. Lett. 22, 1249–1253 (2020).
Szostak, M., Spain, M. & Procter, D. J. Selective synthesis of α,α-dideuterio alcohols by the reduction of carboxylic acids using SmI2 and D2O as deuterium source under SET conditions. Org. Lett. 16, 5052–5055 (2014).
Sajiki, H. et al. Complete replacement of H2 by D2 via Pd/C-catalyzed H/D exchange reaction. Org. Lett. 6, 3521–3523 (2004).
Chandrasekhar, S., Vijaykumar, B. V. D., Mahesh Chandra, B., Raji Reddy, C. & Naresh, P. Flow chemistry approach for partial deuteration of alkynes: synthesis of deuterated taxol side chain. Tetrahedron Lett. 52, 3865–3867 (2011).
Mándity, I. M., Martinek, T. A., Darvas, F. & Fülöp, F. A simple, efficient, and selective deuteration via a flow chemistry approach. Tetrahedron Lett. 50, 4372–4374 (2009).
Valero, M. & Derdau, V. Highlights of aliphatic C(sp3)–H hydrogen isotope exchange reactions. J. Labelled Comp. Radiopharm. 63, 266–280 (2019).
Tomioka, K., Shioiri, T. & Sajiki, H. New Horizons of Process Chemistry:Scalable Reactions and Technologies (Springer, 2017).
Qiu, C. et al. Highly crystalline K-intercalated polymeric carbon nitride for visible-light photocatalytic alkenes and alkynes deuterations. Adv. Sci. 6, 1801403 (2019).
Fuchs, P. L., Charette, A. B., Rovis, T. & Bode, J. W. Essential Reagents for Organic Synthesis (John Wiley & Sons, 2016).
Inoue, H., Abe, T. & Iwakura, C. Successive hydrogenation of styrene at a palladium sheet electrode combined with electrochemical supply of hydrogen. Chem. Commun. 55–56 (1996).
Iwakura, C., Yoshida, Y. & Inoue, H. A new hydrogenation system of 4-methylstyrene using a palladinized palladium sheet electrode. J. Electroanal. Chem. 431, 43–45 (1997).
Sherbo, R. S., Delima, R. S., Chiykowski, V. A., MacLeod, B. P. & Berlinguette, C. P. Complete electron economy by pairing electrolysis with hydrogenation. Nat. Catal. 1, 501–507 (2018).
Sherbo, R. S., Kurimoto, A., Brown, C. M. & Berlinguette, C. P. Efficient electrocatalytic hydrogenation with a palladium membrane reactor. J. Am. Chem. Soc. 141, 7815–7821 (2019).
Delima, R. S., Sherbo, R. S., Dvorak, D. J., Kurimoto, A. & Berlinguette, C. P. Supported palladium membrane reactor architecture for electrocatalytic hydrogenation. J. Mater. Chem. A. 7, 26586–26595 (2019).
Jansonius, R. P. et al. Hydrogenation without H2 using a palladium membrane flow cell. Cell Rep. Phys. Sci. 1, 100105–100114 (2020).
Wicke, E., Brodowsky, H. & Züchner, H. in Hydrogen in Metals II 73–155 (Springer, 1978).
Lihn, C. J., Wan, C. C. & Perng, T. P. In situ comparison of diffusivities for hydrogen and deuterium in palladium. J. Appl. Electrochem. 25, 61–67 (1995).
Bhatia, S. et al. Stereoretentive H/D exchange via an electroactivated heterogeneous catalyst at sp3 C–H sites bearing amines or alcohols. Eur. J. Org. Chem. 4230–4235 (2016).
Liu, X., Liu, R., Qiu, J., Cheng, X. & Li, G. Chemical-reductant-free electrochemical deuteration reaction using deuterium oxide. Angew. Chem. Int. Ed. https://doi.org/10.1002/anie.202005765 (2020).
Maxted, E. B. The poisoning of metallic catalysts. Adv. Catal. 3, 129–178 (1951).
Englisch, M., Jentys, A. & Lercher, J. A. Structure sensitivity of the hydrogenation of crotonaldehyde over Pt/SiO2 and Pt/TiO2. J. Catal. 166, 25–35 (1997).
Hattori, K., Sajiki, H. & Hirota, K. Chemoselective control of hydrogenation among aromatic carbonyl and benzyl alcohol derivatives using Pd/C(en) catalyst. Tetrahedron 57, 4817–4824 (2001).
Puleo, T. R., Strong, A. J. & Bandar, J. S. Catalytic α-selective deuteration of styrene derivatives. J. Am. Chem. Soc. 141, 1467–1472 (2019).
Q3D(R1) Elemental Impurities: Guidance for Industry 41 (US Department of Health and Human Services, 2015).
Roessler, F. Catalysis in the industrial production of pharmaceuticals and fine chemicals. CHIMIA 50, 106–109 (1996).
Silverman, R. B. & Holladay, M. W. The Organic Chemistry of Drug Design and Drug Action (Academic Press, 2014).
Zhang, Z. & Tang, W. Drug metabolism in drug discovery and development. Acta Pharm. Sin. B 8, 721–732 (2018).
Guengerich, F. P. Common and uncommon cytochrome P450 reactions related to metabolism and chemical toxicity. Chem. Res. Toxicol. 14, 611–650 (2001).
We thank Y. Ling and J. Zhu at the UBC Mass Spectrometry Centre for assistance with gas chromatography–mass spectrometry and liquid-chromatography–mass spectrometry, M. Ezhova at the nuclear magnetic resonance laboratory and M. Soon at the Pacific Centre for Isotopic and Geochemical Research for ICP–OES experiments. We are grateful to the Canadian Natural Science and Engineering Council (RGPIN-2018-06748), Canadian Foundation for Innovation (229288), Canadian Institute for Advanced Research (BSE-BERL-162173) and Canada Research Chairs for financial support. This research was undertaken thanks in part to funding from Canada First Research Excellence Fund, Quantum Materials and Future Technologies Program.
The authors declare no competing interests.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Kurimoto, A., Sherbo, R.S., Cao, Y. et al. Electrolytic deuteration of unsaturated bonds without using D2. Nat Catal 3, 719–726 (2020). https://doi.org/10.1038/s41929-020-0488-z