Energy Decomposition Analyses Reveal the Origins of Catalyst and Nucleophile Effects on Regioselectivity in Nucleopalladation of Alkenes

Abstract

Nucleopalladation is one of the most common mechanisms for Pd-catalyzed hydro- and oxidative functionalization of alkenes. Due to the electronic bias of the π-alkene-palladium complexes, nucleopalladations with terminal aliphatic alkenes typically deliver the nucleophile to the more substituted sp2 carbon to form the Markovnikov-selective products. The selective formation of the anti-Markovnikov nucleopalladation products requires the inherent electronic effects to be overridden, which is still a significant challenge for reactions with simple aliphatic alkenes. Because the interactions between the nucleophile and the alkene substrate are influenced by a complex combination of multiple types of steric and electronic effects, a thorough understanding of the interplay of these underlying interactions is needed to rationalize and predict the regioselectivity. Here, we employ an energy decomposition approach to quantitatively separate the different types of nucleophile-substrate interactions, including steric, electrostatic, orbital interactions, and dispersion effects, and to predict the impacts of each factor on regioselectivity. We demonstrate the use of this approach on the origins of catalyst-controlled anti-Markovnikov-selectivity in Hull’s Pd-catalyzed oxidative amination reactions. In addition, we evaluated the regioselectivity in a series of nucleopalladation reactions with different neutral and anionic Pd catalysts and N- and O-nucleophiles with different steric and electronic properties. Based on these computational analyses, a generalized scheme is established to identify the dominant nucleophile-substrate interaction affecting the regioselectivity of nucleopalladations with different Pd catalysts and nucleophiles.

Reactivity and Selectivity Controlling Factors in the Pd/Dialkylbiarylphosphine-Catalyzed C–C Cleavage/Cross-Coupling of an N-Fused Bicyclo α-Hydroxy-β-Lactam

“…In addition, there is also a weak H-bonding interaction (H 1 –O 1 distance of 2.563 and 2.633 Å, in TS-6p and TS-6d , respectively, Figure ) between the Pd-coordinated Ph and O-center of the OR-substituent. To provide additional support for the analysis presented above and identify other factors that possibly impact the interaction between the sub and ligand fragments in TS-6p and TS-6d , we also performed natural energy decomposition analysis (NEDA) calculations . These studies (see the Supporting Information for more details) have identified that weak interactions (e.g., van der Waals, dipole–dipole, and dipole–(induced dipole)), combined under the electrical interaction (EL) term, do not contribute significantly to the calculated energy difference between TS-6p and TS-6d , and a charge transfer (CT) interaction between the ligand and sub fragments contributes significantly to the calculated total electronic energies of TS-6p and TS-6d : it is 8.1 kcal/mol larger in TS-6p than in TS-6d . …”

Chiral phosphoric acid-catalyzed stereodivergent synthesis of trisubstituted allenes and computational mechanistic studies

“…Due to the relatively rigid conformation of (R)-SPINOL-C1 catalyst, stacking-type model is favored for the TSs of proton transfer step to fit the cavity of catalyst with certain entropy loss, leading to S-axial chirality configuration. That is consistent with less steric repulsion between catalyst and substrate in the stackingtype model, which is the dominant effect by Energy Decomposition Analysis (EDA) calculations 68 as shown in Fig. 5b.…”

Palladium/Copper‐catalyzed Oxidation of Aliphatic Terminal Alkenes to Aldehydes Assisted by p‐Benzoquinone

“…The α,β‐unsaturated aldehyde 3 a was formed via the dehydrogenation of 2 a catalyzed by palladium in the presence of BQ as a hydrogen acceptor (vide infra) . Some bulky secondary and tertiary alcohols were examined as the reaction solvent because steric hindrance was expected to control the regioselectivity of the reaction to preferentially form the anti‐Markovnikov product . t ‐BuOH was found to be the optimal solvent (Table S2).…”