Abstract
Electroreductive cyclization (ERC) occurs when an electron-deficient alkene is bound to an acceptor molecule, and cyclization is carried out by electrochemical reduction, directing creation of a new σ bond between the acceptor molecule and β-carbon of the alkene. Electrochemistry is vital for these difficult reactions where two electrophiles are reacted. ERC reactions have been used in the total synthesis of many complex natural products and pharmaceutical applications, such as in syntheses of the Corey lactone derivative and the anticancer compound quadrone. Reduced metal-salens can be used as electrocatalysts for ERC reactions. In prior computational and experimental studies comparing multiple metal centers, reduced Ni(II)- and Zn(II)-salen were found to best promote inner sphere electron transfer to ERC substrates. In this computational study, the mechanism and stereoselectivity for substrate cyclization using both achiral and chiral Ni(II)- and Zn(II)-salen electrocatalysts are examined. Two ERC substrates are used, both an α, β-unsaturated ester and aldehyde. Two pathways are studied for each metal-salen catalyzed ERC. In the concerted pathway, substrate cyclization and separation from the metal-salen occur simultaneously. This is the necessary pathway for achieving stereoselectivity (cis vs. trans stereoisomers across the new σ-bond in the cyclized product) in the ERC reaction, which is important for synthetic applications. In the stepwise pathway, substrate separation from the metal-salen occurs first, generating an intermediate radical carbanion that cyclizes in a second step. Density functional theory (DFT) calculations are performed, yielding thermodynamic and kinetic data for each ERC reaction salen/substrate combination, allowing pathway preference to be determined. Electron transfer and energy transfer processes, such as those seen in UV-Vis excitation spectra, can be used in photoactivated chemotherapy and photodynamic therapy, where the varied photophysical and photochemical properties of transition metal complexes can be utilized. In the second arm of this computational study, TD-DFT (time-dependent density functional theory), the main computational technique for computing electronic transition energies, is used to predict UV-Vis excitation spectra for a variety of substituted and unsubstituted metal-salens with different metal centers (Ni, Zn, Co, Cu) using three different density functionals (B97-1, B3LYP, CAM-B3LYP). The spectra are analyzed to identify both the longest absorption wavelength and most intense wavelength absorption for each metal-salen compound studied with the ultimate goal of seeing whether any correlation exists between these wavelengths and the Hammett sigma parameter (σp) for the substituents of the substituted metal-salens. For a smaller selection of the substituted metal-salen data, results for the different functionals are compared and electronic transitions are visualized and categorized.