Alternating Current Electrolysis For Trifluoromethylation Of (hetero)arenes And Alkenes

Author

Sachini Dilrukshi Rodrigo Dasanayaka, Wayne State University

Access Type

WSU Access

Date of Award

January 2023

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Chemistry

First Advisor

Long Luo

Second Advisor

Hien Nguyen

Abstract

Developing new and improved methods for synthesizing drug candidates from petrochemical feedstocks has been a long-standing interest for chemists. Driven by the increased demand for green chemistry, electrochemical organic synthesis has recently received much attention from synthetic chemists. Conventional electrosynthesis uses either constant current or constant potential, known as direct current (DC) electrolysis. Much less attention has been paid to the unconventional electrolysis mode called alternating current (AC) electrolysis. In contrast to DC, where the electric current only flows in one direction, charge flow changes its direction periodically under AC. In particular, both oxidation and reduction can be performed on the surface of a single electrode with alternating voltage (±V). The recent resurgence of electroorganic synthesis has spiked the curiosity of researchers to revisit this unconventional electrolysis mode. This dissertation explores the unique reactivities of AC electrolysis and its application to organic synthesis.The first part of this dissertation focuses on how AC electrolysis can facilitate the effective reaction of electrogenerated intermediates in the diffusion layer with oscillating polarity. One inherent limitation in paired electrolysis is that the slow mass transfer of intermediates between two electrodes requires stable intermediates. For reactions involving short-lived intermediates, paired electrolysis generally leads to low yields due to the loss of the intermediates during mass transfer. During AC electrolysis, an alternating voltage is applied to drive the redox transformations of the substrates sequentially at the same electrode. In this new protocol, intermediates are no longer required to migrate between the two electrodes but rather react at the same electrode upon switching the potential enabling short-lived intermediates to react immediately upon the electrode polarity reversal, which was previously unobtainable. Our study examined the trifluoromethylation of aryl C-H bonds that afford aryl trifluoromethylene targets, a common motif found in a range of pharmaceutical drug candidates. Because the radical intermediates formed by CF3 radical addition to (hetero)arenes lost the aromaticity, they are unstable and can cause low yields of trifluoromethylated products using the paired electrolysis setup. However, under AC electrolysis conditions, we achieved a higher product yield of 84% than its counterpart DC electrolysis (13%), highlighting the unique application of AC for organic synthesis. Our innovative ACE approach allows the frequency to be tuned; hence, the time between the redox events is controlled for individual target compounds. This unique property of ACE provides superior control over the reaction conditions than conventional paired electrolysis. The second part of the dissertation describes another unique application of AC electrolysis for organic synthesis. Functional group tolerance is one of the important phenomena in organic synthesis. The functional group compatibility of an electrosynthetic method is typically limited by its reaction potential window. We demonstrated that alternating current (AC) electrolysis can overcome such potential window-limited functional group compatibility. Using alkene heterodifunctionalization as a model system, we design and demonstrate a series of AC-driven reactions that add two functional groups sequentially and separately under the cathodic and anodic pulses, including chloro/bromotrilfuoromethylation and chlorosulfonylation. We discovered that the oscillating redox environment during AC electrolysis allows the regeneration of the redox-active functional groups after their oxidation or reduction in the preceding step. As a result, even though redox labile functional groups such as pyrrole, quinone, and aryl thioether fall in the reaction potential window, they are tolerated by AC electrolysis, leading to synthetically useful yields. The cyclic voltammetric study has confirmed that the product yield is limited by the extent of starting material regeneration during the redox potential cycling. Our findings open a new avenue for improving functional group compatibility in electrosynthesis and show the possibility of predicting the product yield under AC electrolysis from voltammogram features.

Recommended Citation

Dasanayaka, Sachini Dilrukshi Rodrigo, "Alternating Current Electrolysis For Trifluoromethylation Of (hetero)arenes And Alkenes" (2023). Wayne State University Dissertations. 3920.
https://digitalcommons.wayne.edu/oa_dissertations/3920