Ligand Effect in Alkali‐Metal‐Catalyzed Transfer Hydrogenation of Ketones

This work unveils the reactivity patterns, as well as ligand and additive effect on alkali‐metal‐base‐catalyzed transfer hydrogenation of ketones. Crucially to this reactivity is the presence of a Lewis acid (alkali cation), as opposed to a simple base effect. With aryl ketones, the observed reactivity order is Na + >Li + >K + , whereas for aliphatic substrates it follows the expected Lewis acidity, Li + >Na + >K + . Importantly, the reactivity pattern can be drastically changed by adding ligands and additives. Kinetic, labelling, and competition experiments as well as DFT calculations suggested that the reaction proceeds through a concerted direct hydride‐transfer mechanism, originally suggested by Woodward. The lithium cation was found to be intrinsically more active than heavier congeners, but in the case of aryl ketones a decrease in reaction rate was observed at ≈40 % conversion with lithium cations. Noncovalent‐interaction analysis revealed that this deceleration effect originated from specific noncovalent interactions between the aryl moiety of 1‐phenylethanol and the carbonyl group of acetophenone, which stabilize the product in the coordination sphere of lithium and thus poison the catalyst. The ligand/additive effect is a complicated phenomenon that includes a combination of several factors, such as the decrease of activation energy by ligation (confirmed by distortion/interaction calculations of N , N , N ’, N ’‐tetramethylethylenediamine, TMEDA) and the change in relative stabilization of reagents and substrates in the solution and the coordination sphere of the metal. Finally, we observed that lithium‐base‐catalyzed transfer hydrogenation can be further facilitated by the addition of an inexpensive and benign reagent, LiCl, which likely operates by re‐initiating the reaction on a new lithium center.