Computational Electrosynthesis Study of Anodic Intramolecular Olefin Coupling: Elucidating the Role of the Electrical Double Layer

Electrosynthesis can lead to new strategies for synthesizing complex molecules through selective oxidation and reduction of functional groups. Because the initiating electron transfer to/from the electrode typically occurs within the electrical double layer region near the electrode surface, it is often possible to optimize reaction yields and selectivity by tuning the composition of the electrical double layer. In this work, we focus on anodic intramolecular olefin coupling reactions, which have been extensively utilized by others in synthesis applications. We present a computational electrosynthesis study for a prototypical reaction to elucidate the electrochemical reaction mechanism and effect of the electrochemical environment. The reaction involves intramolecular cyclization of a diene to form either a five- or six membered ring, and both regioselectivity and yield may be modulated by the electrical double layer. Utilizing both classical molecular dynamics and quantum mechanics/molecular mechanics (QM/MM) methods, we calculate free energies for several steps in the electrochemical reaction, including “work” terms for bringing reactants/intermediates to the electrode surface, reaction free energies for cyclization in both +1 and +2 oxidation states of the diene, and absolute first and second oxidation potentials. Importantly, all free energy calculations incorporate an atomistic description of the electrical double layer under the relevant applied voltage. Our simulations elucidate general double layer effects for this class of reactions, including solvophobic attraction of the organic reactant to the carbon electrode surface as modulated by electrolyte composition and stabilization of the oxidized intermediate at the anode due to electrostatic interactions with surrounding counterions. We show that different choices of electrolyte can substantially alter the stability of cyclization intermediates by changing the double layer composition and substrate-counterion interactions, implying consequences for both regioselectivity and yield. Overall, our study highlights the utility of density functional theory (DFT)-based QM/MM as an important tool within computational electrosynthesis protocols.