Hydrogen Bond Microenvironment Regulation by Trifluoroethanol in 1,1-Dimethylguanidine-Catalyzed α-Hydroxylation

Solventeffects exert a profound influence on reaction rates, selectivity, and reaction pathways. In reactions involving hydrogen bonding, the solvent can directly affect the formation, stabilization, and transformation of key intermediates. We report a 1,1-dimethylguanidine (DMG)-catalyzed aerobic α-hydroxylation of 2-methyl-1-tetralone (MTet) and investigate the microenvironmental regulation of this reaction using trifluoroethanol (TFE) as a model addition. The results demonstrate that the catalytic efficiency of the DMG system is significantly enhanced by TFE, indicating that the reaction is highly sensitive to the local hydrogen-bonding microenvironment. Combined analyses using 1 H NMR, NOE spectroscopy, density functional theory (DFT) calculations, and molecular dynamics (MD) simulations reveal that TFE does not directly interact with MTet. Instead, it reorganizes the solvent microenvironment around the catalytic center through hydrogen bonding. In contrast, although hexafluoroisopropanol (HFIP) is capable of forming stronger hydrogen bonds, its excessive binding strength and steric congestion restrict access to the catalytic site, thereby inhibiting the reaction. Ethanol (EtOH), on the other hand, lacks sufficient hydrogen-bonding ability to effectively modulate the reaction pathway. This study elucidates the role of hydrogen-bond-mediated solvent effects in aerobic α-hydroxylation and provides a molecular-level mechanistic basis for regulating multicomponent catalytic reactions through local hydrogen-bonding microenvironments.