Toward Improving the Selectivity of Organic Halide Electrocarboxylation with Mechanistically Informed Solvent Selection

Abstract

The use of a liquid electrolyte is nearly ubiquitous in electrosynthetic systems and can have a significant impact on the selectivity and efficiency of electrochemical reactions. Solvent selection is thus a key step during optimization, yet this selection process usually involves trial-and-error. As a step toward more rational solvent selection, this work examines how the electrolyte solvent impacts the selectivity of electrocarboxylation of organic halides. For the carboxylation of a model alkyl bromide, hydrogenolysis is the primary side reaction. Isotope-labeling studies indicate the hydrogen atom in the hydrogenolysis product comes solely from the aprotic electrolyte solvent. Further mechanistic studies reveal that under synthetically relevant electrocarboxylation conditions, the hydrogenolysis product is formed via deprotonation of the solvent. Guided by these mechanistic findings, a simple computational descriptor based on the free energy to deprotonate a solvent molecule was shown to correlate strongly with carboxylation selectivity, overcoming limitations of traditional solvent descriptors such as pK a . Through careful mechanistic analysis surrounding the role of the solvent, this work furthers the development of selective electrocarboxylation systems and more broadly highlights the benefits of such analysis to electrosynthetic reactions.

Electroreductive Deoxygenative C−H and C−C Bond Formation from Non‐Derivatized Alcohols Fueled by Anodic Borohydride Oxidation

“…A series of experiments were conducted to investigate the source of the proton in the hydrodeoxygenation products (Figure 4C). The use of d 7 ‐DMF did not result in deuterium incorporation in the alkane product 2 a , confirming that this solvent is a poor proton‐donor [97] . Thus, the tetrabutylammonium cation of the supporting electrolyte and/or borohydride counterion appeared as a plausible source of protons via Hofmann elimination [98,99] .…”

“…The use of d 7 -DMF did not result in deuterium incorporation in the alkane product 2 a, confirming that this solvent is a poor proton-donor. [97] Thus, the tetrabutylammonium cation of the supporting electrolyte and/or borohydride counterion appeared as a plausible source of protons via Hofmann elimination. [98,99] To probe this hypothesis, reactions were carried out using a supporting electrolyte unable of undergoing such elimination: KPF 6 .…”

Electroreductive Desulfurative Transformations with Thioethers as Alkyl Radical Precursors**

“…Subsequent reduction of the resulting α‐radical to the corresponding enolate, followed by protonation, affords the conjugate addition product. In reactions using THF as solvent, protons are presumably originating from the HFIP additive or the tetrabutylammonium ion of the supporting electrolyte via Hofmann elimination [34] due to the poor proton‐donating properties of THF [33] . While the C(sp 3 )−C(sp 3 ) bond formation is assumed to primarily occur via radical intermediates, [26] contributions from conjugate addition of carbanionic intermediates cannot be ruled out [35] .…”

Fine tuning of electrosynthesis pathways by modulation of the electrolyte solvation structure

“…34 The solvent deprotonation free energy is also known to control the selectivity in organic halide electrocarboxylation, where solvents with high deprotonation energies limit the competing hydrogenolysis reaction. 35 Also revealing are the anodic phenol/arene C-C crosscoupling reactions using 1,1,1,3,3,3-hexauoropropan-2-ol (HFIP) as solvent (structure given in Fig. 3a), for which the addition of water or methanol was shown to dramatically improve the yield and selectivity of the targeted reaction.…”