Song Lin

Conspectus: Electrochemical reduction is a powerful means of generating reactive radical and anionic species with a degree of modularity and versatility that rivals other traditional chemical and photochemical reduction approaches. Our group has been motivated by the goal of using electrolysis as an enabling tool to develop reactivity and selectivity that are inaccessible using traditional reductants. In particular, we have leveraged the characteristics of direct electrolysis to promote sequential electron-transfer events that enable net-reductive radical-polar crossover, generating nucleophilic anionic intermediates from electrophilic reactants that undergo umpolung reactions with additional electrophiles. Guided further by physical organic principles, we identified systems that selectively activate a variety of common electrophiles to engage in a diverse array of formal cross-electrophile coupling (XEC) reactions. In this Account, we first describe the development of electroreductive cross-coupling of alkyl halides and its extension to silicon–silicon bond formation. This mechanistic framework was then applied to three-component dialkylation of alkenes using two distinct alkyl halides with high site- and chemoselectivity. Beyond alkyl halides, we further expanded the scope of electroreductive XEC to the deoxygenative functionalization of alcohols with a collection of heteroatom-based electrophiles. These transformations were enabled by in situ activation strategies that convert alcohols into reductively active intermediates, allowing them to behave analogously to alkyl halides and undergo borylation, silylation, and related coupling reactions. Finally, we recognized that an analogous activation logic could also enable the reductive functionalization of carbonyl compounds including ketones, aldehydes, and esters, which remains a major synthetic challenge that cannot be readily resolved by direct cathodic reduction. The continued evolution of activation methods ultimately enabled the formal geminal difunctionalization of electronically unbiased aldehydes and ketones that would otherwise require strongly reducing potentials to activate. These methods provided efficient access to densely functionalized sp3-carbon centers while demonstrating that product selectivity can be regulated through Faradaic control, a unique feature of electrochemistry.

Oxoammonium-mediated hydride transfer is an important yet relatively underexplored elementary step in C–H functionalization. In this work, we employed cyclic voltammetry (CV) to measure the rates of hydride transfer between electrochemically generated oxoammonium catalysts and 42 substrates including ethers, carbamates, amides, and sulfonamides. Through quantum mechanical (QM) calculations, we uncovered a new transition-state model for hydride transfer in which the N atom of the catalyst resides near a heteroatom (X = N or O) of the substrate to allow alignment of the oxoammonium’s O═N+ motif and the substrate’s forming C═X+ bond. Energy decomposition analysis was subsequently performed to elucidate the key factors that govern the kinetics of oxoammonium-mediated hydride transfer. Beyond conventional electronic and steric considerations, we identified substrate distortion, secondary orbital interactions, and noncovalent interactions as critical factors that influence hydride transfer reactivity. We anticipate that these kinetic data along with the mechanistic insights they provide will inform future catalyst development and synthetic applications to broaden the scope of oxoammonium catalysis.

In this work, we identify dithioacetals as synthetically accessible, redox-active, and traceless activating groups that enable the electroreductive transformation of aliphatic ketones and aldehydes. This strategy effectively converts these carbonyl compounds into dianion equivalents to undergo deoxygenative gem-difunctionalization with various electrophiles. Faradaic control was achieved over reaction chemoselectivity, allowing for the combinatorial construction of densely functionalized silanes, boronates, and germanes.

Real-time monitoring of chemical reactions is often achieved using specialized instrumentation along with custom-designed reactors or intrusive sample withdrawal. Here, we 15 introduce reaction telemetry, a wireless analytical strategy that enables remote, nonintrusive monitoring directly within operating reaction vessels. This approach employs light-powered microelectronic devices that communicate optically and function as autonomous sensing elements. We demonstrate continuous thermometric and calorimetric measurements across diverse chemical systems, providing real-time access to reaction dynamics under native operating conditions with 20 sub-second temporal resolution. The resulting measurements will support catalyst evaluation, safety assessment, mechanistic investigation, and data-driven reaction discovery. By embedding analytical functionality directly within reaction vessels, reaction telemetry establishes a general framework for information-rich observation of chemical processes across research, development, and education.

The synthesis of bioactive compounds with differential, and ideally enhanced, activities presents persistent and growing challenges for the field of organic synthesis. By leveraging Nature’s ability to build complex, stereochemically rich, and biologically active molecular scaffolds, site-selective modification of natural products can deliver analogs without the need for lengthy de novo syntheses. Yet, achieving selective reactivity at a single desired position is complicated by the presence of multiple iterations of similar reactive functional groups, thus precluding widespread adoption of catalyst-controlled site-selective modification. Herein we describe the development of complementary systems for the oxidation of secondary alcohols on erythromycin A, clarithromycin, and azithromycin using a newly designed azaadamantyl oxoammonium catalyst, wherein different hydroxyl groups show disparate reactivities under the same conditions. The application of this methodology has enabled the generation of a suite of oxidized macrolide antibiotics and derivatives that take advantage of the newly installed carbonyls. Antimicrobial activity testing revealed that multiple compounds retain activity against a broad range of pathogens consistent with erythromycin A coverage. Additionally, three of the compounds reported herein display antibiotic activity against CA-MRSA and MRSA­(mph(C)), for which the clinical analogs erythromycin A, clarithromycin, and azithromycin exhibit no activity at tested concentrations.

We report the oxidative desymmetrization of urea-protected pyrrolidines via site-selective hydride transfer from enantiotopic C–H bonds. The optimal oxoammonium–peptide conjugate catalyst provided over 90% ee across all tested pyrrolidines, providing products that can readily undergo subsequent N-deprotection and other derivatization reactions to form medicinally relevant compounds. We isolated key on-cycle catalytic intermediates, which allowed us to elucidate both the mechanism of catalytic activation and the origin of stereochemical induction in detail. In particular, a stereochemical model for asymmetric induction emerged from analyzing a covalent catalyst–substrate adduct, which served as an isolable analog of the enantiodetermining transition state. In this model, a tight hydrogen bond between the urea protecting group and the peptide directs the asymmetric hydride transfer.

We report the convenient synthesis of Ni(DQ)₂ (DQ = duroquinone) from readily available Ni(II) and Ni(0) precursors, guided by DFT calculations. By virtue of its π-accepting homoleptic ligand environment, Ni(DQ)₂ undergoes facile ligand exchange with phosphine, bis-nitrogen, and diene ligands and thus represents a convenient Ni(0) source in synthetic organometallic chemistry. As a precatalyst, Ni(DQ)₂ is found be a competent air-stable precursor for emerging methodology where Ni(COD)(DQ) is ineffective (COD = 1,5-cyclooctadiene).

The reactivity and synthetic utility of TEMPO-derived alkoxyamines as functional handles remains insufficiently explored. This report interrogates the factors governing the stereospecific substitution of electroactivated TEMPO-derived α-carbonyl alkoxyamines. Concurrent with direct electrolysis, electroanalytical studies and theoretical calculations provided a complementary platform by which one could predict the efficacy for substrates to undergo desired substitution using benzoic acid or N-sulfonyl carbamate nucleophiles.