Computational investigation of palladium-catalyzed allene–allene cross-coupling

Abstract

The construction of [4]dendralenes poses a significant synthetic challenge. Palladium-catalyzed oxidative allene–allene cross-coupling offers high selectivity, but its mechanistic basis, competing pathways, and rate-determining step remain unclear. Herein, we investigate a palladium-catalyzed oxidative allene–allene cross-coupling mechanism using density functional theory (DFT) methods. Two competing pathways (Pathway 1 and Pathway 2) for R groups on the trisubstituted allene reactant, bearing either a –CH₂-EWG (electron-withdrawing group) or –CH₂-aryl substituent, were systematically evaluated. Computational results show that Pathway 2, involving selective allenic α-C–H bond cleavage in the β-H elimination step, is kinetically favored (ΔΔG^‡ = 7.3 kcal mol⁻¹), strongly correlating with experimental observations. Carbopalladation (ΔG^‡ = 22.8 kcal mol⁻¹) is identified as the rate-determining step (RDS) for both Pathway 1 and Pathway 2. Mechanistic analysis rationalizes the remarkable selectivities of this strategy, including (i) regioselective C–H activation, (ii) cross-selective carbocyclization–carbopalladation, and (iii) stereoselective cis/trans isomerism. The literature gap—specifically, the lack of mechanistic understanding of selectivity in palladium-catalyzed oxidative allene–allene cross-coupling, including unresolved questions about competing pathways and rate-determining steps—has been clearly explained. Furthermore, we reveal the pivotal role of the allylic directing group, which facilitates C–H activation through a synergistic Pd–π interaction. Distortion–interaction (D/I) analysis revealed that higher distortion energy is responsible for this regioselectivity. This work provides atomic-level insights into the design of dendralene architectures and broadens the scope of stereocontrolled polyene synthesis.