Selective Catalytic Deuterium Labeling of Alcohols during a Transfer Hydrogenation Process of Ketones Using D₂O as the Only Deuterium Source. Theoretical and Experimental Demonstration of a Ru–H/D⁺ Exchange as the Key Step

Abstract

The new complex [(η 6 -p-cym)RuCl(κ 2 -N,N-dmbpy)](BF 4 ) (pcym = p-cymene; dmbpy = 4,4′-dimethyl-2,2′-bipyridine) is water-soluble and active in the catalytic transfer hydrogenation (TH) of different ketones (cyclohexanone, 2-cyclohexenone, and 3-pentanone) to the corresponding alcohols using aqueous HCOONa/HCOOH as the hydrogen source at pH 4.4. A higher activity was found for the TH of the imine N-benzylideneaniline under the same conditions. Excellent results have been obtained for catalyst recycling. Aqua, formato, and hydrido species were detected by 1 H NMR experiments in D 2 O. Importantly, when the catalytic reaction was carried out in D 2 O, selective deuteration at the C α of the alcohols was observed due to a rapid Ru−H/D + exchange, which was also deduced theoretically. This process involves a reversal of polarity of the D + ion, which is transformed into a Ru−D function ("umpolung"). Negligible deuterium labeling was observed for the imine, possibly due to the high activity in the TH process and also to the decrease in the hydrido complex concentration due to the stability of a hydrido-imine intermediate. Both facts should ensure that the TH reaction will compete favorably with the Ru−H/D + exchange. The basic nature of the imine hydrogenation product can also hinder the stated Ru−H/D + exchange. On the basis of DFT calculations, all these hypotheses are discussed. In addition, calculations at this level also support the participation of the stated aqua, formato, and hydrido intermediates in the catalytic reaction and provide a detailed microscopic description of the full catalytic cycle. In the case of the imine TH process, the formation of the hydrido complex (decarboxylation step) is clearly the limiting step of the cycle. On the contrary, in the hydrogenation of cyclohexanone, both decarboxylation and reduction steps exhibit similar barriers, and due to the limitations of the solvent model employed, a definitive conclusion on the rate-determining step cannot be inferred.

Ru(II)‐η6‐benzene Complexes of Dibenzosuberenyl Appended Aroyl/Acylthiourea Ligands: In vitro Biomolecular Interaction Studies and Catalytic Transfer Hydrogenation

“…[13][14][15][16][17][18] Since last decade, a variety of half-sandwich ruthenium complexes have been extensively investigated in TH. [19] The [Ru(h 6 -arene)(ligand)Cl]/[Ru(h 6 -arene)(ligand)Cl 2 ] type of "piano stool" complexes exhibit the structural features which favour the sequential reactions involved in catalysis. The slight modification of ligands led to striking changes in the properties of the resulting half-sandwich arene ruthenium complexes.…”

Simple 1,3-diamines and their application as ligands in ruthenium(ii) catalysts for asymmetric transfer hydrogenation of aryl ketones

“…With regard to solvents, water was revealed to be the best choice, as when iPrOH or MeOH was employed, the reaction conversion resulted significantly decreased. 5,38 In the same way the selection of hydrogen donors 39 Unexpectedly the presence of an additional chiral centre in position 2 of the ligands 3 and 4 did not improve the enantioselectivity but in contrast it negatively influenced the stereoselectivity of the catalysts along with a significant decrease in the reaction rate (entries 3 and 4 vs. 1 and 2). The results obtained by changing the position of the tosyl moiety confirmed the importance of the stereogenic centre to be in proximity of the amine involved in the catalytic cycle contributing to increase both the reaction conversion and enantioselectivity through a steric and/or an electronic effect (entries 1 vs. 2 and 3 vs. 4).…”

Ionic Liquids: Recent Advances and Applications in Boron Chemistry

“…Isotope labelling of chemicals has broad applications in the pharmaceutical and fine chemicals industries . For example, deuterium‐labeled compounds such as D 2 O, C 6 D 6 , and CDCl 3 can be used as solvents in NMR spectroscopy, in labeled drugs, and as probes in mass spectrometry .…”

“…Isotope labelling of chemicals has broad applications in the pharmaceutical and fine chemicals industries . For example, deuterium‐labeled compounds such as D 2 O, C 6 D 6 , and CDCl 3 can be used as solvents in NMR spectroscopy, in labeled drugs, and as probes in mass spectrometry . Isotope‐labeled chemicals can be synthesized either by using the appropriately labeled substrates or by a catalytic isotope exchange process .…”

“…For example, deuterium‐labeled compounds such as D 2 O, C 6 D 6 , and CDCl 3 can be used as solvents in NMR spectroscopy, in labeled drugs, and as probes in mass spectrometry . Isotope‐labeled chemicals can be synthesized either by using the appropriately labeled substrates or by a catalytic isotope exchange process . Deuterated alcohols can be prepared by reduction of the corresponding aldehydes or ketones with deuterated reagents such as NaBD 4 and LiAlD 4 , .…”