Mechanism of Cobalt-Catalyzed Direct Aminocarbonylation of Unactivated Alkyl Electrophiles: Outer-Sphere Amine Substitution to Form Amide Bond

Experimentalists have recently achieved the first chemoselective aminocarbonylation of unactivated alkyl electrophiles, using the common cobalt reagent Co₂(CO)₈ as a catalyst. Here, we present a detailed density functional theory (DFT) mechanistic study on this remarkable reaction. Induced by the Lewis base morpholine (or MOR, the amine substrate), Co₂(CO)₈ disproportionates to [Co(CO)₃(MOR)₂]⁺ and [Co(CO)₄]^-. The active catalyst [Co(CO)₄]^- undergoes an S_N2 reaction with the alkyl tosylate substrate to form an alkylcobalt(I) carbonyl intermediate with an inverted configuration at the α-carbon. The alkylcobalt(I) carbonyl complex favors CO migratory insertion over β-hydride elimination. The resulting acylcobalt(I) carbonyl intermediate, along with the MOR and CO substrates, could introduce several pathways for the amide C-N bond formation. The inner-sphere pathways involving Co(I)-bound MOR are ruled out. The outer-sphere pathway in which MOR attacks the Co(I)-bound acyl leads to the amide product and the regenerated [Co(CO)₄]^-. The S_N2 process is the rate-determining step with the largest energy span (ΔG^┼ = 22.8 kcal/mol). The side reaction of double CO insertion faces a higher selectivity-determining energy barrier and hence is less favorable. This DFT work provides deep mechanistic insights into the Co₂(CO)₈-promoted chemoselective aminocarbonylation of unactivated alkyl electrophiles, thereby having implications for organocobalt catalysis and transition-metal-catalyzed amide C-N bond-forming reactions.