DFT study of nickel-catalyzed regio- and enantioselective hydroalkoxylation of 1,3-dienes with methanol: inner-sphere versus outer-sphere mechanisms†

We present a density functional theory (DFT) study on a remarkable nickel-catalyzed regio- and enantioselective hydroalkoxylation and C–O bond formation reaction of 1,3-dienes with methanol (a common yet underutilized oxygen nucleophile). An in-depth computational analysis, aided by the Curtin–Hammett principle, unravels this complex reaction and provides novel mechanistic insights. The catalytically active species, a π complex with the diene substrate, undergoes a regioselective proton transfer from methanol to the diene. This ligand-to-ligand hydrogen transfer (LLHT) proceeds via an outer-sphere mechanism, critically facilitated by additional H-bonded methanol molecules, rather than the originally proposed inner-sphere mechanism without hydrogen-bonding assistance. The regioselectivity of the LLHT step is governed by the electronic effects and hydrogen bonding interactions. Subsequently, the resulting nickel η³-allyl intermediate initiates an enantioselective outer-sphere nucleophilic attack by the methoxide anion on the allyl ligand, yielding the chiral product. The origins of the enantioselectivity include stronger noncovalent C(sp³)–H/π interactions and the absence of steric hindrance in the key transition state that leads to the (S)-enantiomer. The mechanistic insights uncovered in this study can guide the further development of nickel-catalyzed C–O bond-forming reactions utilizing alkenes and alcohols as substrates.