Competition-Derived Relative Reactivity and 3D Electronic-State Analysis of Site- and Facial Selectivity in NaBH₄/MeOH Ketone Reductions

In this study, competition experiments, in which two substrates react simultaneously with the same reagent, were used to build a unified kinetic scale for the reduction of ketones by sodium borohydride (NaBH₄) in methanol, expressed as activation free energy differences (ΔΔ<i>G</i>^‡).

Kinetic data for 89 structurally diverse ketone reaction faces tracked substituent electronic effects and steric congestion, and transition-state calculations identified methanolysis as the step that determines the identity of the active reductant. A Lasso model trained on 83 of these reaction faces with three-dimensional electron-density, electrostatic-potential, and carbonyl-centered projected CO π* descriptors achieved <i>R</i>² = 0.804 under strict nested outer leave-one-out cross-validation.