Access Type

Open Access Dissertation

Date of Award

January 2023

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Chemistry

First Advisor

Long Luo

Abstract

Electrochemical organic synthesis is experiencing a renaissance driven by the increasing demand for green chemistry and engineering in the pharmaceutical industry. Synthetic organic electrochemical methods can be divided into three types: anodic, cathodic, and paired electrolysis. Paired electrolysis, in which two desirable half-reactions are performedsimultaneously at the two electrodes, is mostly underdeveloped. However, paired electrolysis can be technologically significant because it not only improves energy efficiency by using both electrodes but also provides a unique reaction environment where two redox-opposite reactions of substrates take place in the same pot. A major challenge for paired electrolysis is that the difficulties associated with matching the generation and interelectrode transport rates of the different highly reactive intermediates pose substantial obstacles to achieving the selective transformation over undesired alternative pathways. To address this challenge for paired electrolysis, we proposed to use alternating current electrolysis (ACE). During ACE, an alternating current (AC) voltage (±V) is applied between two electrodes to drive the redox transformations of the substrates sequentially at the same electrode. This dissertation aims to develop a new electrosynthetic strategy to control the reaction kinetics of amine functionalization and hydrogen isotope exchange using ACE. The first part of this dissertation focuses on the method development for controlling oneor two-electron oxidation of selective amine functionalization using ACE. We present a mechanism by which adjusting AC frequency enables to control of the one- or two-electron oxidation for selective α-amine functionalization. Using this method, we successfully minimize the two-electron oxidation to iminium cation, providing easy access to the arylation product through one-electron oxidation by applying optimal frequency. Moreover, we found this happens by giving a negative potential environment for the deprotonation step, which can prevent the twoelectron oxidation of amino radicals to iminium cation. Importantly, we have established an accessible electroanalytical procedure to identify the optimal frequencies of various amine substrates within a few minutes, which maximizes the one-electron oxidation to generate an arylation product. With this method, we can eliminate the time-consuming trial and error approach in optimizing the reaction condition of AC electrolysis. We anticipate that this highly efficient and novel AC electrolysis approach can be used to achieve unique reactivities in the fields of synthetic and medicinal chemistry. The second part of the dissertation describes the development of an electrosynthetic method for Hydrogen isotope exchange (HIE) of α-amino C(sp3)-H bond. Here, we report an electrochemical protocol for hydrogen isotope exchange (HIE) at α-C(sp3)-H amine sites. Tetrahydroisoquinoline and pyrrolidine are selected as two model substrates because of their different proton transfer and hydrogen atom transfer kinetics at the α-C(sp3)-H amine sites, which are utilized to control the HIE reaction outcome at different applied alternating current frequencies. We found the highest D incorporation for tetrahydroisoquinolines at 0 Hz (i.e., DC electrolysis condition) and pyrrolidines at 0.5 Hz. Analysis of the product distribution and D incorporation at different frequencies reveals that the HIE of tetrahydroisoquinolines is limited by its slow HAT, whereas the HIE of pyrrolidines is limited by the overoxidation of its α-amino radical intermediates. The AC-frequency-dependent HIE of amines can be potentially used to achieve elective labeling of α-amine sites in one drug molecule, which will significantly impact the pharmaceutical industry.

Download

Share

COinS