DFT calculations have been carried out to study the mechanism of Cu­(AcO)2-catalyzed N-alkylation of amino derivatives with primary alcohols. The calculations indicate that tBuOK is necessary for the generation of the active catalyst from Cu­(AcO)2 and that the catalytic cycle involves three sequential steps: (1) Cu-catalyzed alcohol oxidation to give the corresponding aldehyde and copper hydride, (2) aldehyde-amine condensation to generate an imine, (3) imine reduction to yield the expected N-alkylation secondary amine product and to regenerate the active catalyst. Based on the comparison of different reaction pathways, we conclude that the outer-sphere hydrogen transfer in a stepwise manner is the most favorable pathway for both alcohol oxidation and imine reduction. Thermodynamically, alcohol oxidation and imine formation are all uphill, but imine reduction is downhill significantly, which is the driving force for the catalytic transformation. Using the energetic span model, we find that the turnover frequency-determining transition state (TDTS) and the turnover frequency-determining intermediate (TDI) are the hydride transfer transition state for imine reduction and the active catalyst, respectively. The calculated turnover frequency (TOF) roughly agrees with the experimental observation and, therefore, further supports the validity of the proposed hydrogen transfer mechanism.