Electrochemical Hydrogen Isotope Exchange of Amines Controlled by Alternating Current Frequency

Here, we report an electrochemical protocol for hydrogen isotope exchange (HIE) at -C(sp3)-H amine sites. Tetrahydroisoquinoline and pyrrolidine are selected as two model substrates because of their different proton transfer (PT) and hydrogen atom transfer (HAT) kinetics at the -C(sp3)-H amine sites, which are utilized to control the HIE reaction outcome at different applied alternating current (AC) frequencies. We found the highest deuterium incorporation for tetrahydroisoquinolines at 0 Hz (i.e., direct current (DC) electrolysis condition) and pyrrolidines at 0.5 Hz. Analysis of the product distribution and D incorporation at different frequencies reveals that HIE of tetrahydroisoquinolines is limited by its slow HAT, whereas HIE of pyrrolidines is limited by the overoxidation of its -amino radical intermediates. The AC-frequency-dependent HIE of amines can be potentially used to achieve elective labeling of -amine sites in one drug molecule, which will significantly impact the pharmaceutical industry.