biostudies-literatureZhang WNIGMS NIH HHS292-297https://www.ebi.ac.uk/biostudies/studies/S-EPMC9016776biostudies-literatureUnknown604(7905)Recent research in medicinal chemistry has suggested that there is a correlation between an increase in the fraction of sp³ carbons-those bonded to four other atoms-in drug candidates and their improved success rate in clinical trials¹. As such, the development of robust and selective methods for the construction of carbon(sp³)-carbon(sp³) bonds remains a critical problem in modern organic chemistry². Owing to the broad availability of alkyl halides, their direct cross-coupling-commonly known as cross-electrophile coupling-provides a promising route towards this objective^3-5. Such transformations circumvent the preparation of carbon nucleophiles used in traditional cross-coupling reactions, as well as stability and functional-group-tolerance issues that are usually associated with these reagents. However, achieving high selectivity in carbon(sp³)-carbon(sp³) cross-electrophile coupling remains a largely unmet challenge. Here we use electrochemistry to achieve the differential activation of alkyl halides by exploiting their disparate electronic and steric properties. Specifically, the selective cathodic reduction of a more substituted alkyl halide gives rise to a carbanion, which undergoes preferential coupling with a less substituted alkyl halide via bimolecular nucleophilic substitution to forge a new carbon-carbon bond. This protocol enables efficient cross-electrophile coupling of a variety of functionalized and unactivated alkyl electrophiles in the absence of a transition metal catalyst, and shows improved chemoselectivity compared with existing methods.NatureElectrochemically driven cross-electrophile coupling of alkyl halides.PMC9016776R01 GM134088Zhang WLu LLehnherr DMondragon JLin SStrotman NWang YRein JSee KAWare SDfalseElectrochemically driven cross-electrophile coupling of alkyl halides.Recent research in medicinal chemistry has suggested that there is a correlation between an increase in the fraction of sp³ carbons-those bonded to four other atoms-in drug candidates and their improved success rate in clinical trials¹. As such, the development of robust and selective methods for the construction of carbon(sp³)-carbon(sp³) bonds remains a critical problem in modern organic chemistry². Owing to the broad availability of alkyl halides, their direct cross-coupling-commonly known as cross-electrophile coupling-provides a promising route towards this objective^3-5. Such transformations circumvent the preparation of carbon nucleophiles used in traditional cross-coupling reactions, as well as stability and functional-group-tolerance issues that are usually associated with these reagents. However, achieving high selectivity in carbon(sp³)-carbon(sp³) cross-electrophile coupling remains a largely unmet challenge. Here we use electrochemistry to achieve the differential activation of alkyl halides by exploiting their disparate electronic and steric properties. Specifically, the selective cathodic reduction of a more substituted alkyl halide gives rise to a carbanion, which undergoes preferential coupling with a less substituted alkyl halide via bimolecular nucleophilic substitution to forge a new carbon-carbon bond. This protocol enables efficient cross-electrophile coupling of a variety of functionalized and unactivated alkyl electrophiles in the absence of a transition metal catalyst, and shows improved chemoselectivity compared with existing methods.2022-01-01T00:00:00Z2022 Apr2025-04-03T22:45:06.394Z2024-10-16T10:48:56.295ZS-EPMC90167763518962310.1038/s41586-022-04540-4