Understanding the Mechanisms of Cobalt-Catalyzed Hydrogenation and Dehydrogenation Reactions

Cobalt­(II) alkyl complexes of aliphatic PNP pincer ligands have been synthesized and characterized. The cationic cobalt­(II) alkyl complex [(PNHP^Cy)­Co­(CH₂SiMe₃)]­BAr^F₄ (<b>4</b>) (PNHP^Cy = bis­[(2-dicyclohexylphosphino)­ethyl]­amine) is an active precatalyst for the hydrogenation of olefins and ketones and the acceptorless dehydrogenation of alcohols. To elucidate the possible involvement of the N–H group on the pincer ligand in the catalysis via a metal–ligand cooperative interaction, the reactivities of <b>4</b> and [(PNMeP^Cy)­Co­(CH₂SiMe₃)]­BAr^F₄ (<b>7</b>) were compared. Complex <b>7</b> was found to be an active precatalyst for the hydrogenation of olefins. In contrast, no catalytic activity was observed using <b>7</b> as a precatalyst for the hydrogenation of acetophenone under mild conditions. For the acceptorless dehydrogenation of 1-phenylethanol, complex <b>7</b> displayed similar activity to complex <b>4</b>, affording acetophenone in high yield. When the acceptorless dehydrogenation of 1-phenylethanol with precatalyst <b>4</b> was monitored by NMR spectroscopy, the formation of the cobalt­(III) acetylphenyl hydride complex [(PNHP^Cy)­Co^III(κ²-O,C-C₆H₄C­(O)­CH₃)­(H)]­BAr^F₄ (<b>13</b>) was detected. Isolated complex <b>13</b> was found to be an effective catalyst for the acceptorless dehydrogenation of alcohols, implicating <b>13</b> as a catalyst resting state during the alcohol dehydrogenation reaction. Complex <b>13</b> catalyzed the hydrogenation of styrene but showed no catalytic activity for the room temperature hydrogenation of acetophenone. These results support the involvement of metal–ligand cooperativity in the room temperature hydrogenation of ketones but not the hydrogenation of olefins or the acceptorless dehydrogenation of alcohols. Mechanisms consistent with these observations are presented for the cobalt-catalyzed hydrogenation of olefins and ketones and the acceptorless dehydrogenation of alcohols

Understanding the Mechanisms of Cobalt-Catalyzed Hydrogenation and Dehydrogenation Reactions

Cobalt­(II) alkyl complexes of aliphatic PNP pincer ligands have been synthesized and characterized. The cationic cobalt­(II) alkyl complex [(PNHP^Cy)­Co­(CH₂SiMe₃)]­BAr^F₄ (<b>4</b>) (PNHP^Cy = bis­[(2-dicyclohexylphosphino)­ethyl]­amine) is an active precatalyst for the hydrogenation of olefins and ketones and the acceptorless dehydrogenation of alcohols. To elucidate the possible involvement of the N–H group on the pincer ligand in the catalysis via a metal–ligand cooperative interaction, the reactivities of <b>4</b> and [(PNMeP^Cy)­Co­(CH₂SiMe₃)]­BAr^F₄ (<b>7</b>) were compared. Complex <b>7</b> was found to be an active precatalyst for the hydrogenation of olefins. In contrast, no catalytic activity was observed using <b>7</b> as a precatalyst for the hydrogenation of acetophenone under mild conditions. For the acceptorless dehydrogenation of 1-phenylethanol, complex <b>7</b> displayed similar activity to complex <b>4</b>, affording acetophenone in high yield. When the acceptorless dehydrogenation of 1-phenylethanol with precatalyst <b>4</b> was monitored by NMR spectroscopy, the formation of the cobalt­(III) acetylphenyl hydride complex [(PNHP^Cy)­Co^III(κ²-O,C-C₆H₄C­(O)­CH₃)­(H)]­BAr^F₄ (<b>13</b>) was detected. Isolated complex <b>13</b> was found to be an effective catalyst for the acceptorless dehydrogenation of alcohols, implicating <b>13</b> as a catalyst resting state during the alcohol dehydrogenation reaction. Complex <b>13</b> catalyzed the hydrogenation of styrene but showed no catalytic activity for the room temperature hydrogenation of acetophenone. These results support the involvement of metal–ligand cooperativity in the room temperature hydrogenation of ketones but not the hydrogenation of olefins or the acceptorless dehydrogenation of alcohols. Mechanisms consistent with these observations are presented for the cobalt-catalyzed hydrogenation of olefins and ketones and the acceptorless dehydrogenation of alcohols

Crystallization of a Metastable Solvate and Impact of the Isolation Method on the Material Properties of the Anhydrous Product

We report the crystallization of a metastable small-molecule solvate and the effect of the isolation method on the physical and material properties of the resulting anhydrous material. The anhydrous crystalline products obtained from two different isolation routes using either a temperature-driven form change or a solvent-wash-mediated form change were analyzed by a suite of material-sparing characterization methods probing both physical form and material properties such as particle size distribution and powder flow behavior. The temperature-driven desolvation method was found to be time-consuming and undesirable. A relatively rapid desolvation approach was obtained using an ethyl acetate wash-mediated process. However, this method leads to powder with a broader particle size distribution, poorer flowability, higher interparticulate friction, and lower bulk density compared with the powder obtained by the temperature-driven desolvation process. The direct impact of the method of isolation on the material properties of the drug substance highlights the importance of not only understanding the crystallization process and form landscape but also the ability to implement systematic characterization to identify key powder properties of drug candidates early in the drug development process