DFT and AFIR Study on the Mechanism and the Origin of Enantioselectivity in Iron-Catalyzed Cross-Coupling Reactions

The mechanism of the full catalytic cycle for Fe-chiral-bisphosphine-catalyzed cross-coupling reaction between alkyl halides and Grignard reagents (Nakamura and co-workers, J. Am. Chem. Soc. 2015, 137, 7128) was rationalized by using density functional theory (DFT) and multicomponent artificial force-induced reaction (MC-AFIR) methods. The computed mechanism consists of (a) C–Cl activation, (b) transmetalation, (c) C–Fe bond formation, and (d) C–C bond formation through reductive elimination. Our survey on the prereactant complexes suggested that formation of FeII(BenzP*)­Ph2 and FeI(BenzP*)­Ph complexes are thermodynamically feasible. FeI(BenzP*)­Cl complex is the active intermediate for C–Cl activation. FeII(BenzP*)­Ph2 complex can be formed if the concentration of Grignard reagent is high. However, it leads to biphenyl (byproduct) instead of the cross-coupling product. This explains why slow addition of Grignard reagent is critical for the cross-coupling reaction. The MC-AFIR method was used for systematic determination of transition states for C–Fe bond formation and C–C bond formation starting from the key intermediate FeII(BenzP*)­PhCl. According to our detailed analysis, C–C bond formation is the selectivity-determining step. The computed enantiomeric ratio of 95:5 is in good agreement with the experimental ratio (90:10). Energy decomposition analysis suggested that the origin of the enantioselectivity is the deformation of Ph-ligand in Fe-complex, which is induced by the bulky tert-butyl group of BenzP* ligand. Our study provides important mechanistic insights for the cross-coupling reaction between alkyl halides and Grignard reagents and guides the design of efficient Fe-based catalysts for cross-coupling reactions.