A DFT Study on Sc-Catalyzed Diastereoselective Cyclization of 2-Picoline with 1,5-Hexadiene: Mechanism and Origins of Regio- and Stereoselectivity

Density functional theory (DFT) calculations elucidate the mechanism of diastereoselective cyclization of 2-picoline with 1,5-hexadiene catalyzed by a cationic half-sandwich scandium complex. The catalytic cycle proceeds through four key stages: formation of active species, initial alkene insertion, cis-selective cyclization, and protonation. Central to the mechanism is the dual role of 2-picoline, which initially coordinates as a supporting ligand to facilitate C–H activation and regioselective 1,2-insertion but must dissociate to enable stereocontrol. The mono(2-picoline)-coordinated complex C3 is identified as the thermodynamically favored active species. C–H activation reactivity follows the trend: ortho-C(sp2)–H (2-picoline-free) > ortho-C(sp2)–H (2-picoline-coordinated) > benzylic C(sp3)–H (2-picoline-free) > benzylic C(sp3)–H (2-picoline-coordinated), a preference governed by a wider Cα–Sc–Cα′ angle and shorter Sc···X (X = Cα, Cα′, H) distances that enhance scandium–substrate interaction. Subsequent 1,5-hexadiene insertion proceeds with high 1,2-regioselectivity through a picoline-assisted pathway. The stereoselectivity-determining step reveals a mechanistic dichotomy: while picoline coordination is essential for initial activation, its dissociation is required for intramolecular cyclization. This ligand displacement avoids prohibitive steric repulsion in the transition state, directing the reaction exclusively toward the cis-cyclized product. The cycle concludes with a sterically accessible mono-coordinated protonation. This work establishes a “ligand-enabled then ligand-displaced” mechanism, highlighting dynamic substrate coordination as a critical design principle for achieving high selectivity in rare-earth-catalyzed C–H functionalization.