DFT Study on the Origin of 1,2-Regioselectivity in Cu2O-Catalyzed Addition of Acetonitrile to Cinnamaldehyde

Abstract

The synthesis of unsaturated β-hydroxy nitriles is of significant importance in pharmaceutical and materials chemistry. However, traditional transition-metal-catalyzed reactions of α,β-unsaturated carbonyls often suffer from poor regioselectivity, favoring the thermodynamically controlled 1,4-addition over the desired 1,2-addition. To elucidate the origin of the high 1,2-regioselectivity observed experimentally in the Cu2O/t-BuOK catalytic system, comprehensive density functional theory (DFT) calculations were performed using the M06-L-D3 functional with the ma-def2-TZVP basis set in the SMD solvation model. The computational results reveal that the reaction proceeds via a multistep mechanism involving ligand coordination, C–H activation, and nucleophilic addition. The Hard–Soft Acid–Base (HSAB) theory and Dewar–Chatt–Duncanson (DCD) model confirm that the soft Cu(I) centers preferentially coordinate with the soft C═C double bond of the aldehyde rather than the hard carbonyl oxygen. This coordination mode effectively polarizes the substrate, enhancing the electrophilicity of the carbonyl carbon and suppressing the competing 1,4-addition pathway. Among the identified pathways, the route via compound 11 is the most energetically favorable. The proton transfer assisted by t-BuO– exhibits an energy barrier of 16.5 kcal/mol, leading to the formation of a nucleophilic cyanide anion. Subsequently, the energy barrier of 1,2-addition is 5.8 kcal/mol lower than that of 1,4-addition, a preference attributed to stronger noncovalent interactions (NCIs) and shorter bond-forming distances in the transition state. This study provides deep mechanistic insights into the copper-catalyzed cyanomethylation of α,β-unsaturated aldehydes, highlighting the critical role of metal-substrate coordination geometry in controlling regioselectivity.