Electrochemistry research in the Lin Laboratory
Song Lin, associate professor in the Department of Chemistry and Chemical Biology at Cornell University, has been focused for several years on developing new electrochemical processes that address important needs in organic synthesis. “Harnessing electrochemistry to solve the challenging transformations in organic synthesis is one of the most important research interests in our group,” he observes.
One of those areas relates to cross-electrophile coupling (XEC) of organic halides for C–C bond formation. Despite great advances in this area, Lin notes that the selective XEC of two alkyl halides for C(sp3)–C(sp3) bond formation remains elusive using traditional chemical approaches.
Inspired by the generation of C(sp3)–C(sp3) bonds via SN2 displacement, his research group, in collaboration with scientists at Caltech and Merck, envisioned a new approach to cross-coupling of two (one tertiary and one primary) alkyl halides by exploiting the disparate electronic and steric properties (1).
“This electrochemical approach enables XEC of a diverse range of unactivated and functionalized alkyl halides, including α-haloboronic esters, α-halosilanes, benzylic chlorides, and allylic/propargylic halides, under transition-metal-free conditions with excellent selectivity,” Lin states. It also operates by a mechanism different from that previously reported for cross-coupling reactions catalyzed by nickel complexes. “This new strategy circumvents the generation of Ni-alkyl intermediates that could often lead to unselective electrophile activation and various side reactions,” he explains.
As a result, the e-XEC reaction shows improved selectivity compared to known methods for C(sp3)–C(sp3) XEC. “This new reaction provides a robust and selective method for constructing C(sp3)-C(sp3) bonds, which remains a critical problem in modern organic chemistry. It will be particularly beneficial for drug discovery given that recent research in medicinal chemistry has demonstrated a correlation between higher fractions of sp3 carbons in drug candidates with improved success rates in clinical trials,” Lin says.
To date, the reaction has been scaled up to 20 mmol, providing multigram quantities of desired products in excellent yield. Lin hopes to further scale up the method to create a wide range of molecules for drug discovery. He does caution, however, that a wide gap remains between the current optimal laboratory conditions and GMP requirements for commercial pharmaceutical manufacturing. “We need to overcome several issues before further scale up the reaction, including using less of a safer electrolyte than the currently used tetrabutylammonium perchlorate and avoiding the use of a sacrificial magnesium anode.”
In addition to the e-XEC reaction, the Lin group has used an electrocatalysis strategy for the oxidative difunctionalization of alkenes (2). He and his colleagues are also working to further scale up the electrochemical diazidation of alkenes, another transformation developed by his group (3). This reaction provides an efficient and robust approach to the synthesis of precursors of vicinal diamines, a functional moiety that is widely prevalent in many natural products and a large number of bioactive compounds.
- S. Lin et al., “Electrochemically Driven Cross-Electrophile Coupling of Alkyl Halides,” ChenRxiv, Dec. 13, 2021. DOI: 10.26434/chemrxiv-2021-c2hd6-v2.
- Juno C. Siu, Niankai Fu, and Song Lin, Acc. Chem. Res., 53, 547-560 (2020). DOI: 10.1021/acs.accounts.9b00529 .
- N. Fu, et al., Science, 357, 575-579 (2017). DOI: 10.1126/science.aan6206.