Bio
Song Lin grew up in Tianjin, China. After obtaining B.S. from Peking University in 2008, he pursued graduate studies at Harvard University working with Eric Jacobsen. He then carried out postdoctoral studies with Chris Chang at UC Berkeley. He started his independent career at Cornell University in 2016 and was promoted to Associate Professor in 2021 and Tisch University Professor in 2023. He then joined Stanford University as a Professor of Chemistry in 2026. Song has received several early-career awards, including the Sloan Fellowship, ACS Cope Scholar, National Fresenius Award, Tetrahedron Young Investigator Award, Thieme–IUPAC Prize, Cottrell Scholar Award, Camille Dreyfus Teacher-Scholar Award, NSF CAREER Award, MIT Technology Review Innovators Under 35, BMS Unrestricted Grant, Lilly Research Award, and EPA Green Chemistry Challenge. His dedication to education has been recognized with a Stephen and Margery Russell Distinguished Teaching Award from Cornell University and a Nobel Laureate Signature Award for Graduate Education in Chemistry from the American Chemical Society. He is currently an Associate Editor at Organic Letters, and he serves on the Editorial Advisory Board of Chem, Synlett, Tetrahedron, and Tetrahedron Letters as well as the Scientific Advisory Board of OWiC Technologies.
https://orcid.org/0000-0002-8880-6476All Publications
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Electrochemical cross-electrophile coupling for carbon-heteroatom and heteroatom-heteroatom bond formation
NATURE SYNTHESIS
2026
View details for DOI 10.1038/s44160-026-01112-6
View details for Web of Science ID 001828646300001
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Site-Divergent Oxidations within Venerable Macrolide Antibiotic Scaffolds Unveil Compounds with Broad Spectrum and Anti-MRSA Activities
ACS CENTRAL SCIENCE
2026; 12 (3): 375-382
Abstract
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.
View details for DOI 10.1021/acscentsci.5c02343
View details for Web of Science ID 001716920400001
View details for PubMedID 41907500
View details for PubMedCentralID PMC13022725
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Desymmetrization of <i>meso</i>-Pyrrolidines via Oxoammonium-Catalyzed Enantioselective Hydride Transfer
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
2026; 148 (9): 9650-9658
Abstract
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.
View details for DOI 10.1021/jacs.5c20639
View details for Web of Science ID 001701877300001
View details for PubMedID 41747759
View details for PubMedCentralID PMC12983322
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Ni(DQ)<sub>2</sub>: A Useful Gateway to Zero-Valent Nickel Complexes
ORGANOMETALLICS
2026; 45 (4): 385-390
Abstract
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).
View details for DOI 10.1021/acs.organomet.5c00450
View details for Web of Science ID 001688907600001
View details for PubMedID 42312076
View details for PubMedCentralID PMC13271661
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Electrochemical Activation of α-Carbonyl Alkoxyamines for Direct Nucleophilic Substitution
ORGANIC LETTERS
2026; 28 (6): 1941-1946
Abstract
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.
View details for DOI 10.1021/acs.orglett.5c04873
View details for Web of Science ID 001679117800001
View details for PubMedID 41632699
View details for PubMedCentralID PMC12910718
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Cutting the cord for high-throughput electrochemistry
NATURE CHEMICAL ENGINEERING
2026; 3 (2): 140
View details for DOI 10.1038/s44286-026-00358-3
View details for Web of Science ID 001698946100001
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Experimental Lineage and Computational Analysis of a General Aminoxyl-Based Oxidation Catalyst: Generality from Substrate-Specific Interactions
ACS CATALYSIS
2025; 15 (20): 17548-17557
Abstract
Traditionally, catalyst optimization in asymmetric catalysis is approached as an iterative, heuristic-based process, where point modifications of a hit catalyst are tested against one (or a small number of) model substrate(s). While optimization to high levels of selectivity is sometimes successful, catalyst generality with respect to substrate scope (i.e., its ability to deliver a diverse set of target products with consistently high levels of selectivity) is more elusive. This work describes and models computationally a successful peptide catalyst optimization campaign carried out on a verifiably diverse set of substrates, which delivered a highly selective and general chiral catalyst. The success of every generational improvement of the catalyst design is now rationalized with atomistic resolution by ab initio modeling of the individual substrate that mostly benefits from that generational improvement. Structural and topological insights about the noncovalent interaction networks orchestrating both the catalyst conformation and the substrate-catalyst interactions were dissected, culminating on the underpinnings of the optimized catalyst's generality. Surprisingly and significantly, the generality of high selectivity for many substrates was found to be consistent with alternative, and indeed substrate-specific, interactions, suggesting that functional generality need not be a result of mechanistic homology.
View details for DOI 10.1021/acscatal.5c05893
View details for Web of Science ID 001588903700001
View details for PubMedID 41127635
View details for PubMedCentralID PMC12539552
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Deoxygenative Cyanofunctionalization of Aldehydes and Ketones Enabled by Electrochemical Reduction
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
2025; 147 (41): 36992-36998
Abstract
The deoxygenative difunctionalization of carbonyls converts readily available carbonyl compounds into value-added gem-difunctionalized building blocks. We report an electrochemical carbonyl umpolung approach for the deoxygenative cyanofunctionalization of aldehydes and ketones, affording various α-functionalized nitriles. Further derivatization of these products provides a versatile and modular platform for geminal disubstitution of carbonyl oxygens.
View details for DOI 10.1021/jacs.5c13173
View details for Web of Science ID 001588947900001
View details for PubMedID 41055545
View details for PubMedCentralID PMC12673927
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Main-Chain Ketone Installation in Polyethylene Chains: A Metal-Free Strategy toward Photodegradable Plastics
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
2025; 147 (41): 37204-37210
Abstract
Polyethylene with in-chain isolated ketones is an attractive target for achieving photodegradability while maintaining polyolefin material properties. This work reports a method to functionalize post-consumer polyethylene through radical C-H activation to install TEMPO functionalities and subsequent oxidation to obtain in-chain isolated ketones without compromising the polymer molecular weights. This process does not require metals, catalysts, or expensive reagents and allows tunable ketone incorporation up to 3 mol %. The thermal and mechanical properties were investigated to demonstrate that the ketone-containing polyethylene could potentially work as a photodegradable alternative of existing polyethylene. Photodegradation of the ketone-containing polyethylene reveals a clear decrease in molecular weights and suggests random installation of functionalities. This approach enables the conversion of post-consumer polyethylene into ketone functionalized materials through simple chemical transformations.
View details for DOI 10.1021/jacs.5c09943
View details for Web of Science ID 001585988700001
View details for PubMedID 41036739
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Electrochemical α-C―H Functionalization of Nitramines for Accessing Bifunctional Energetic Heterocycles
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
2025; 64 (47): e202515252
Abstract
The synthesis of energetic materials (EMs) often involves hazardous reagents and harsh conditions, raising safety and environmental concerns. We herein present an electrochemical method for the ⍺-C─H azolation of nitramines, enabling the integration of nitramines and various nitrogen-rich azoles as dual energetic components within the same molecule. To enhance the practicality of the overall synthesis, we developed a tandem two-step process that transforms free amines into nitramines using stable and readily available reagents, which was complemented by subsequent electrochemical azolation to complete a streamlined, scalable preparation of bifunctional energetic compounds. Finally, a continuous flow system was employed to further improve the practicality of the electrosynthetic method, which substantially reduced electrolyte usage and increased productivity. Computational and experimental data revealed that the introduction of azoles, particularly those with additional nitro substituents, improves the energy density and thermal stability of nitramines. This work provides a proof of concept that the reported electrochemical azolation reaction may not only offer a safer and more sustainable alternative to traditional approaches for energetic material synthesis, but it will also provide a platform for the discovery of novel compounds with favorable energetic properties.
View details for DOI 10.1002/anie.202515252
View details for Web of Science ID 001581817000001
View details for PubMedID 41013974
View details for PubMedCentralID PMC12624331
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Stereoselective Synthesis of Cyclic P(V) Compounds via Stereoconvergent Nucleophilic Substitution
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
2025; 64 (44): e202516385
Abstract
We report a simple, scalable, and stereoselective synthesis of chiral oxazaphosphoramides using phosphoryl chloride, an L-serine derivative, and various primary and secondary amines. Excellent stereoselectivities (typically >99:1 dr) were achieved via an unexpected, stereoconvergent nucleophilic substitution process, wherein two diastereomers of an oxazaphosphorochloridate intermediate were converted to a single diastereomer of an oxazaphosphoramide via distinct pathways. Electrochemical decarboxylative transformations allowed the products to be further diversified to afford three types of chiral oxazaphosphoramides with different ring substitutions.
View details for DOI 10.1002/anie.202516385
View details for Web of Science ID 001570531800001
View details for PubMedID 40932101
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Considerations in Pursuing Reaction Scope Generality
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
2025; 64 (41): e202511091
Abstract
The term "generality" has recently been popularized in synthetic chemistry, owing largely to the increasing use of high-throughput technology for producing vast quantities of data and the emergence of data science tools to plan and interpret these experiments. Despite this, the term has not been clearly defined, and there is no standardized approach toward developing a method with a diverse (general) scope. This minireview will examine different emerging strategies toward achieving generality using selected examples and aims to give the reader an overview of modern workflows that have been used to expedite this pursuit.
View details for DOI 10.1002/anie.202511091
View details for Web of Science ID 001566361500001
View details for PubMedID 40923451
View details for PubMedCentralID PMC12501685
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Regioselective Electrochemical Borylation of Oxygenated Allylic Electrophiles: Method Development and Synthetic Applications
ACS CENTRAL SCIENCE
2025; 11 (10): 1959-1968
Abstract
Allylboronic esters are highly versatile intermediates in organic synthesis. In this work, we report a general and scalable strategy for the regioselective deoxygenative borylation of allylic alcohols, enals, enones, and acrylates, upgrading these abundant functional groups in feedstock chemicals and natural products into value-added borylated synthetic handles. This method achieves efficient C-O bond activation under mild electroreductive conditions, and the effective control of regioselectivity was made possible by optimizing the borylating agent and supporting electrolyte. The utility of this approach was further demonstrated in a series of telescoped synthetic sequences, enabling alcohol and carbonyl transposition, formal cross-coupling of alcohols and aldehydes, allylic amination, and vinylogous homologation. This electrosynthetic protocol offers a broadly applicable, modular route to complex allylboron compounds from simple and readily available starting materials, including terpenoid natural products.
View details for DOI 10.1021/acscentsci.5c01074
View details for Web of Science ID 001562287600001
View details for PubMedID 41142340
View details for PubMedCentralID PMC12550627
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Deoxygenative Functionalization of Alcohols and Carbonyl Compounds via Electrochemical Reduction
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
2025; 64 (39): e202510069
Abstract
Oxygen-containing functional groups are prevalent motifs in natural products and feedstock chemicals, but direct methods for their deoxygenative transformation remain rare due to the difficult cleavage of the strong C-O bond. Here, we develop a general activation strategy that employs hydrosilanes as activating reagents for alcohols, carbonyls, and esters to afford a common silyl ether intermediate. Electrochemical reduction of the in situ generated silyl ether results in C-O cleavage to afford a carbanion, which reacts with a number of electrophiles for the construction of C-Si, C-B, C-Ge, and C-Sn bonds.
View details for DOI 10.1002/anie.202510069
View details for Web of Science ID 001549352100001
View details for PubMedID 40808503
View details for PubMedCentralID PMC12663921
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Dynamic kinetic resolution of phosphines with chiral supporting electrolytes
NATURE
2025; 643 (8074): 1288-1296
Abstract
The synthesis of enantiopure compounds is a central focus in organic chemistry owing to the prevalence of chiral centres in biological systems and the impact of homochirality on molecular properties. With growing recognition of electrochemistry as a powerful tool to improve the scope and sustainability of organic synthesis1, increasing efforts have been directed towards developing asymmetric electrocatalytic reactions to access challenging chiral molecules2-4. However, many useful electrochemical reactions rely on direct electrolysis without a catalyst, making them inherently difficult to render enantioselective. Supporting electrolytes are integral to electrochemical systems and, in addition to ensuring sufficient solution conductivity, they can influence the rate and selectivity of electrochemical transformations5. Chiral supporting electrolytes can mediate asymmetric reactions via direct electrolysis, but their use in organic electrosynthesis remains largely unexplored6,7. Here we describe the use of substoichiometric chiral phosphate salts as supporting electrolytes to facilitate the oxidation of racemic trivalent phosphines to afford enantioenriched phosphine oxides. Our approach relies on a dynamic-kinetic-resolution strategy that exploits the rapid pyramidal inversion of an anodically generated phosphoniumyl radical cation8, while a high concentration of chiral phosphate at the electrode-electrolyte interface9,10 enhances enantioselective control during rate-limiting nucleophilic addition. Our results highlight the promise of chiral supporting electrolytes for promoting radical-ion-mediated asymmetric transformations.
View details for DOI 10.1038/s41586-025-09238-x
View details for Web of Science ID 001530156800001
View details for PubMedID 40670793
View details for PubMedCentralID PMC12506892
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Chemoselective Electrochemical Coupling of Thioethers and Primary Amines for Accessing Sulfilimines and Sulfoximines
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
2025; 147 (25): 21290-21296
Abstract
We report the electrooxidative coupling of thioethers with primary alkylamines, furnishing structurally diverse sulfilimines and sulfoximines including unconventional isopeptides. Cyclic voltammetry and control experiments revealed that modulating the protonation states of reactants and products is key to achieving chemoselective oxidation.
View details for DOI 10.1021/jacs.5c04012
View details for Web of Science ID 001511012200001
View details for PubMedID 40506413
View details for PubMedCentralID PMC12305499
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Catalyst-Controlled Regiodivergent Oxidation of Unsymmetrical Diols
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
2025; 147 (10): 8118-8124
Abstract
In this work we use aminoxyl-peptide conjugates to catalyze the regiodivergent oxidation of unsymmetrical diols. Through structural tuning of both the aminoxyl catalytic core and the chiral peptide backbone, we achieved catalyst control that either reinforces or overrides the intrinsic steric bias, leading to oxidation of either the less hindered or the more hindered alcohol in high selectivity.
View details for DOI 10.1021/jacs.5c00330
View details for Web of Science ID 001435163400001
View details for PubMedID 40019207
View details for PubMedCentralID PMC11918261
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Light-activated hypervalent iodine agents enable diverse aliphatic C-H functionalization
NATURE CHEMISTRY
2025; 17 (3): 365-372
Abstract
The functionalization of aliphatic C-H bonds is a crucial step in the synthesis and transformation of complex molecules relevant to medicinal, agricultural and materials chemistry. As such, there is substantial interest in the development of general synthetic platforms that enable the efficient diversification of aliphatic C-H bonds. Here we report a hypervalent iodine reagent that releases a potent hydrogen atom abstractor for C-H activation under mild photochemical conditions. Using this reagent, we demonstrate selective (N-phenyltetrazole)thiolation of aliphatic C-H bonds for a broad scope of substrates. The synthetic utility of the thiolated products is showcased through various derivatizations. Simply by altering the radical trapping agent, our method can directly transform C-H bonds into diverse functionalities, including C-S, C-Cl, C-Br, C-I, C-O, C-N, C-C and C=C bonds.
View details for DOI 10.1038/s41557-025-01749-4
View details for Web of Science ID 001431825200001
View details for PubMedID 39994489
View details for PubMedCentralID PMC11972117
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Light-harvesting microelectronic devices for wireless electrosynthesis
NATURE
2025; 637 (8045): 354-+
Abstract
High-throughput experimentation (HTE) has accelerated academic and industrial chemical research in reaction development and drug discovery and has been broadly applied in many domains of organic chemistry1,2. However, application of HTE in electrosynthesis-an enabling tool for chemical synthesis-has been limited by a dearth of suitable standardized reactors3-7. Here we report the development of microelectronic devices, which are produced using standard nanofabrication techniques, to enable wireless electrosynthesis on the microlitre scale. These robust and inexpensive devices are powered by visible light and convert any traditional 96-well or 384-well plate into an electrochemical reactor. We validate the devices in oxidative, reductive and paired electrolysis and further apply them to achieve the library synthesis of biologically active compounds and accelerate the development of two electrosynthetic methodologies. We anticipate that, by simplifying the way electrochemical reactions are set up, this user-friendly solution will not only enhance the experience and efficiency of current practitioners but also substantially reduce the barrier for nonspecialists to enter the field of electrosynthesis, thus allowing the broader community of synthetic chemists to explore and benefit from new reactivities and synthetic strategies enabled by electrochemistry8-12.
View details for DOI 10.1038/s41586-024-08373-1
View details for Web of Science ID 001410545800023
View details for PubMedID 39780010
View details for PubMedCentralID PMC11972118
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Interview with the 2025 Tetrahedron young investigator award for organic synthesis
TETRAHEDRON CHEM
2025; 15
View details for DOI 10.1016/j.tchem.2025.100140
View details for Web of Science ID 001640294900003
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Oxoammonium-Catalyzed Ether Oxidation via Hydride Abstraction: Methodology Development and Mechanistic Investigation Using Paramagnetic Relaxation Enhancement NMR
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
2024; 146 (46): 31420-31432
Abstract
Hydride abstraction represents a promising yet underexplored approach in the functionalization of C-H bonds. In this work, we report the oxidation of α-C-H bonds of ethers via oxoammonium catalysis using 3-chloroperbenzoic acid (mCPBA) as the terminal chemical oxidant or by means of electrochemistry. Mechanistic studies revealed intricate equilibria and interconversion events between various catalytic intermediates in the presence of mCPBA, which alone however was incompetent to drive catalytic turnover. The addition of a small amount of strong acid HNTf2 or weakly coordinating salt NaSbF6 turned on catalytic turnover and promoted ether oxidation with excellent efficiency. NMR experiments leveraging paramagnetic relaxation enhancement effect allowed for quantification of open-shell catalytic intermediates in real time during the reaction course, which aided the identification of catalyst resting states and elucidation of reaction mechanisms.
View details for DOI 10.1021/jacs.4c11760
View details for Web of Science ID 001352470900001
View details for PubMedID 39527468
View details for PubMedCentralID PMC12005942
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Oxoammonium-Catalyzed Oxidation of <i>N</i>-Substituted Amines
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
2024; 146 (46): 31412-31419
Abstract
We report the development of oxoammonium-catalyzed oxidation of N-substituted amines via a hydride transfer mechanism. Steric and electronic tuning of catalyst led to complementary sets of conditions that can oxidize a broad scope of carbamates, sulfonamides, ureas, and amides into the corresponding imides. The reaction was further demonstrated on a 100-g scale using a continuous flow setup.
View details for DOI 10.1021/jacs.4c11758
View details for Web of Science ID 001352395600001
View details for PubMedID 39527490
View details for PubMedCentralID PMC11912027
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Optimizing Cu electrocatalysis using programmed alternating current
NATIONAL SCIENCE REVIEW
2024; 11 (9): nwae298
View details for DOI 10.1093/nsr/nwae298
View details for Web of Science ID 001322195200001
View details for PubMedID 39345333
View details for PubMedCentralID PMC11438234
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<i>α,β</i>-Desaturation and Formal <i>β</i>-C(sp<SUP>3</SUP>)-H Fluorination of <i>N</i>-Substituted Amines: A Late-Stage Functionalization Strategy Enabled by Electrochemistry
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
2024; 146 (33): 22982-22992
Abstract
Incorporation of C(sp3)-F bonds in biologically active compounds is a common strategy employed in medicinal and agricultural chemistry to tune pharmacokinetic and pharmacodynamic properties. Due to the limited number of robust strategies for C(sp3)-H fluorination of complex molecules, time-consuming de novo syntheses of such fluorinated analogs are typically required, representing a major bottleneck in the drug discovery process. In this work, we present a general and operationally simple strategy for site-specific β-C(sp3)-H fluorination of amine derivatives including carbamates, amides, and sulfonamides, which is compatible with a wide range of functional groups including N-heteroarenes. In this approach, an improved electrochemical Shono oxidation is used to set the site of functionalization via net α,β-desaturation to access enamine derivatives. We further developed a series of new transformations of these enamine intermediates to synthesize a variety of β-fluoro-α-functionalized structures, allowing efficient access to pertinent targets to accelerate drug discovery campaigns.
View details for DOI 10.1021/jacs.4c02548
View details for Web of Science ID 001289886200001
View details for PubMedID 39132893
View details for PubMedCentralID PMC11366977
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Accessing Alkoxy Radicals via Frustrated Radical Pairs: Diverse Oxidative Functionalizations of Tertiary Alcohols
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
2024; 146 (29): 19696-19703
Abstract
Alkoxy radicals are versatile reactive intermediates in organic synthesis. Here, we leverage the principle of frustrated radical pair to provide convenient access to these highly reactive species directly from tertiary alcohols via oxoammonium-mediated oxidation of the corresponding alkoxides. This approach enabled various synthetically useful transformations including β-scission, radical cyclization, and remote C-H functionalization, giving rise to versatile alkoxyamines that can be further elaborated to various functionalities.
View details for DOI 10.1021/jacs.4c07125
View details for Web of Science ID 001270054800001
View details for PubMedID 39012345
View details for PubMedCentralID PMC11366976
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A guide to troubleshooting metal sacrificial anodes for organic electrosynthesis
CHEMICAL SCIENCE
2024; 15 (16): 5814-5831
Abstract
The development of reductive electrosynthetic reactions is often enabled by the oxidation of a sacrificial metal anode, which charge-balances the reductive reaction of interest occurring at the cathode. The metal oxidation is frequently assumed to be straightforward and innocent relative to the chemistry of interest, but several processes can interfere with ideal sacrificial anode behavior, thereby limiting the success of reductive electrosynthetic reactions. These issues are compounded by a lack of reported observations and characterization of the anodes themselves, even when a failure at the anode is observed. Here, we weave lessons from electrochemistry, interfacial characterization, and organic synthesis to share strategies for overcoming issues related to sacrificial anodes in electrosynthesis. We highlight common but underexplored challenges with sacrificial anodes that cause reactions to fail, including detrimental side reactions between the anode or its cations and the components of the organic reaction, passivation of the anode surface by an insulating native surface film, accumulation of insulating byproducts at the anode surface during the reaction, and competitive reduction of sacrificial metal cations at the cathode. For each case, we propose experiments to diagnose and characterize the anode and explore troubleshooting strategies to overcome the challenge. We conclude by highlighting open questions in the field of sacrificial-anode-driven electrosynthesis and by indicating alternatives to traditional sacrificial anodes that could streamline reaction optimization.
View details for DOI 10.1039/d3sc06885d
View details for Web of Science ID 001182518900001
View details for PubMedID 38665512
View details for PubMedCentralID PMC11041367
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Co-Catalyzed Hydrofluorination of Alkenes: Photocatalytic Method Development and Electroanalytical Mechanistic Investigation
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
2024; 146 (7): 4380-4392
Abstract
The hydrofluorination of alkenes represents an attractive strategy for the synthesis of aliphatic fluorides. This approach provides a direct means to form C(sp3)-F bonds selectively from readily available alkenes. Nonetheless, conducting hydrofluorination using nucleophilic fluorine sources poses significant challenges due to the low acidity and high toxicity associated with HF and the poor nucleophilicity of fluoride. In this study, we present a new Co(salen)-catalyzed hydrofluorination of simple alkenes utilizing Et3N·3HF as the sole source of both hydrogen and fluorine. This process operates via a photoredox-mediated polar-radical-polar crossover mechanism. We also demonstrated the versatility of this method by effectively converting a diverse array of simple and activated alkenes with varying degrees of substitution into hydrofluorinated products. Furthermore, we successfully applied this methodology to 18F-hydrofluorination reactions, enabling the introduction of 18F into potential radiopharmaceuticals. Our mechanistic investigations, conducted using rotating disk electrode voltammetry and DFT calculations, unveiled the involvement of both carbocation and CoIV-alkyl species as viable intermediates during the fluorination step, and the contribution of each pathway depends on the structure of the starting alkene.
View details for DOI 10.1021/jacs.3c10989
View details for Web of Science ID 001160874900001
View details for PubMedID 38300825
View details for PubMedCentralID PMC11219133
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Anodic Cyclizations, Densely Functionalized Synthetic Building Blocks, and the Importance of Recent Mechanistic Observations
JOURNAL OF ORGANIC CHEMISTRY
2024; 89 (3): 1927-1940
Abstract
Anodic cyclization reactions can provide a versatile method for converting newly obtained chiral lactols to densely functionalized cyclic building blocks. The method works by first converting the lactol into an electron-rich olefin and then oxidatively generating a radical cation that is trapped by a nucleophile. Historically, such reactions have benefited from the use of less polar radical cations when the trapping nucleophile is a heteroatom and more polar radical cations when the reaction forms C-C bonds. This forced one to optimize underperforming reactions by resynthesizing the substrate. Here, we show that by taking advantage of methods that serve to drive a reversible initial cyclization reaction toward the product, this dichotomy and need to manipulate the substrate can be avoided. Two such methods were utilized: a faster second oxidation step and a mediated electrolysis. Both led to successful cyclizations using a polar radical cation and heteroatom nucleophiles.
View details for DOI 10.1021/acs.joc.3c02659
View details for Web of Science ID 001157564400001
View details for PubMedID 38231008
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A tutorial on asymmetric electrocatalysis (vol 52, pg 8106, 2023)
CHEMICAL SOCIETY REVIEWS
2024; 53 (1): 545
Abstract
Correction for 'A tutorial on asymmetric electrocatalysis' by Jonas Rein et al., Chem. Soc. Rev., 2023, https://doi.org/10.1039/D3CS00511A.
View details for DOI 10.1039/d3cs90096g
View details for Web of Science ID 001682395000001
View details for PubMedID 38050457
View details for PubMedCentralID PMC10759793
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Electroreductive Radical Addition-Polar Cyclization Cascade to Access Cycloalkanes
ORGANIC LETTERS
2023; 26 (1): 116-121
Abstract
Compared with flat aromatic scaffolds, three-dimensional aliphatic ring systems feature high structural complexity and topological diversity and, thus, have received increasing attention in drug discovery. Herein, we describe a mild and general electrochemical method for the modular synthesis of structurally distinct cyclic compounds, including monocyclic alkanes, benzo-fused ring systems, and spirocycles, from readily available alkenes and alkyl halides via a radical-polar crossover mechanism.
View details for DOI 10.1021/acs.orglett.3c03722
View details for Web of Science ID 001143322800001
View details for PubMedID 38157449
View details for PubMedCentralID PMC11192528
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Enabling Al sacrificial anodes in tetrahydrofuran electrolytes for reductive electrosynthesis
CHEMICAL SCIENCE
2023; 14 (45): 13108-13118
Abstract
Al0 is widely used as a sacrificial anode in organic electrosynthesis. However, there remains a notable knowledge gap in the understanding of Al anode interface chemistry under electrolysis conditions. We hypothesize that Al interfacial chemistry plays a pivotal role in the discernible bias observed in solvent selections for reductive electrosynthesis. The majority of existing methodologies that employ an Al sacrificial anode use N,N-dimethylformamide (DMF) as the preferred solvent, with only isolated examples of ethereal solvents such as tetrahydrofuran (THF). Given the crucial role of the solvent in determining the efficiency and selectivity of an organic reaction, limitations on solvent choice could significantly hinder substrate reactivity and impede the desired transformations. In this study, we aim to understand the Al metal interfaces and manipulate them to improve the performance of an Al sacrificial anode in THF-based electrolytes. We have discovered that the presence of halide ions (Cl-, Br-, I-) in the electrolyte is crucial for efficient Al stripping. By incorporating halide additive, we achieve bulk Al stripping in THF-based electrolytes and successfully improve the cell potentials of electrochemically driven reductive methodologies. This study will encourage the use of ethereal solvents in systems using Al sacrificial anodes and guide future endeavors in optimizing electrolytes for reductive electrosynthesis.
View details for DOI 10.1039/d3sc04725c
View details for Web of Science ID 001095822100001
View details for PubMedID 38023497
View details for PubMedCentralID PMC10664456
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A tutorial on asymmetric electrocatalysis
CHEMICAL SOCIETY REVIEWS
2023; 52 (23): 8106-8125
Abstract
Electrochemistry has emerged as a powerful means to enable redox transformations in modern chemical synthesis. This tutorial review delves into the unique advantages of electrochemistry in the context of asymmetric catalysis. While electrochemistry has historically been used as a green and mild alternative for established enantioselective transformations, in recent years asymmetric electrocatalysis has been increasingly employed in the discovery of novel asymmetric methodologies based on reaction mechanisms unique to electrochemistry. This tutorial review first provides a brief tutorial introduction to electrosynthesis, then explores case studies on homogenous small molecule asymmetric electrocatalysis. Each case study serves to highlight a key advance in the field, starting with the historic electrification of known asymmetric transformations and culminating with modern methods relying on unique electrochemical mechanistic sequences. Finally, we highlight case studies in the emerging reasearch areas at the interface of asymmetric electrocatalysis with biocatalysis and heterogeneous catalysis.
View details for DOI 10.1039/d3cs00511a
View details for Web of Science ID 001091084900001
View details for PubMedID 37910160
View details for PubMedCentralID PMC10842033
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Three-Component Cross-Electrophile Coupling: Regioselective Electrochemical Dialkylation of Alkenes
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
2023; 145 (41): 22298-22304
Abstract
The cross-electrophile dialkylation of alkenes enables the formation of two C(sp3)-C(sp3) bonds from readily available starting materials in a single transformation, thereby providing a modular and expedient approach to building structural complexity in organic synthesis. Herein, we exploit the disparate electronic and steric properties of alkyl halides with varying degrees of substitution to accomplish their selective activation and addition to alkenes under electrochemical conditions. This method enables regioselective dialkylation of alkenes without the use of a transition-metal catalyst and provides access to a diverse range of synthetically useful compounds.
View details for DOI 10.1021/jacs.3c06794
View details for Web of Science ID 001086389900001
View details for PubMedID 37801465
View details for PubMedCentralID PMC10625357
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Frustrated Radical Pairs in Organic Synthesis
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
2023; 145 (36): 19478-19489
Abstract
Frustrated radical pairs (FRPs) describe the phenomenon that two distinct radicals─which would otherwise annihilate each other to form a closed-shell covalent adduct─can coexist in solution, owing to steric repulsion or weak bonding association. FRPs are typically formed via spontaneous single-electron transfer between two sterically encumbered precursors─an oxidant and a reductant─under ambient conditions. The two components of a FRP exhibit orthogonal chemical properties and can often act in cooperativity to achieve interesting radical reactivities. Initially observed in the study of traditional frustrated Lewis pairs, FRPs have recently been shown to be capable of homolytically activating various chemical bonds. In this Perspective, we will discuss the discovery of FRPs, their fundamental reactivity in chemical bond activation, and recent developments of their use in synthetic organic chemistry, including in C-H bond functionalization. We anticipate that FRPs will provide new reaction strategies for solving challenging problems in modern organic synthesis.
View details for DOI 10.1021/jacs.3c07070
View details for Web of Science ID 001061239900001
View details for PubMedID 37656899
View details for PubMedCentralID PMC10625356
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Unraveling Hydrogen Atom Transfer Mechanisms with Voltammetry: Oxidative Formation and Reactivity of Cobalt Hydride
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
2023; 145 (32): 17665-17677
Abstract
The utility of transition metal hydride catalyzed hydrogen atom transfer (MHAT) has been widely demonstrated in organic transformations such as alkene isomerization and hydrofunctionalization reactions. However, the highly reactive nature of the hydride and radical intermediates has hindered mechanistic insight into this pivotal reaction. Recent advances in electrochemical MHAT have opened up the possibility for new analytical approaches for mechanistic diagnosis. Here, we report a voltammetric interrogation of Co-based MHAT reactivity, describing in detail the oxidative formation and reactivity of the key Co-H intermediate and its reaction with aryl alkenes. Insights from cyclic voltammetry and finite element simulations help elucidate the rate-limiting step as metal hydride formation, which we show to be widely tunable based on ligand design. Voltammetry is also suggestive of the formation of Co-alkyl intermediates and a dynamic equilibrium with the reactive neutral radical. These mechanistic studies provide information for the design of future hydrofunctionalization reactions, such as catalyst and silane choice, the relative stability of metal-alkyl species, and how hydrofunctionalization reactions utilize Co-alkyl intermediates. In summary, these studies establish an important template for studying MHAT reactions from the perspective of electrochemical kinetic frameworks.
View details for DOI 10.1021/jacs.3c03815
View details for Web of Science ID 001041582600001
View details for PubMedID 37530748
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Improving the Mg Sacrificial Anode in Tetrahydrofuran for Synthetic Electrochemistry by Tailoring Electrolyte Composition
JACS AU
2023: 2280-2290
Abstract
Mg0 is commonly used as a sacrificial anode in reductive electrosynthesis. While numerous methodologies using a Mg sacrificial anode have been successfully developed, the optimization of the electrochemistry at the anode, i.e., Mg stripping, remains empirical. In practice, electrolytes and organic substrates often passivate the Mg electrode surface, which leads to high overall cell potential causing poor energy efficiency and limiting reaction scale-up. In this study, we seek to understand and manipulate the Mg metal interfaces for a more effective counter electrode in tetrahydrofuran. Our results suggest that the ionic interactions between the cation and the anion of a supporting electrolyte can influence the electrical double layer, which impacts the Mg stripping efficiency. We find halide salt additives can prevent passivation on the Mg electrode by influencing the composition of the solid electrolyte interphase. This study demonstrates that, by tailoring the electrolyte composition, we can modify the Mg stripping process and enable a streamlined optimization process for the development of new electrosynthetic methodologies.
View details for DOI 10.1021/jacsau.3c00305
View details for Web of Science ID 001039661600001
View details for PubMedID 37654576
View details for PubMedCentralID PMC10466324
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Electrochemically Driven Deoxygenative Borylation of Alcohols and Carbonyl Compounds
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
2023; 145 (31): 16966-16972
Abstract
We present a new, unified approach for the transformation of benzylic and allylic alcohols, aldehydes, and ketones into boronic esters under electroreductive conditions. Key to our strategy is the use of readily available pinacolborane, which serves both as an activator and an electrophile by first generating a redox-active trialkylborate species and then delivering the desired deoxygenatively borylated product. This strategy is applicable to a variety of substrates and can be employed for the late-stage functionalization of complex molecules.
View details for DOI 10.1021/jacs.3c03418
View details for Web of Science ID 001037630300001
View details for PubMedID 37499221
View details for PubMedCentralID PMC10624253
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Regioselective aliphatic C-H functionalization using frustrated radical pairs
NATURE
2023; 619 (7970): 514-+
Abstract
Frustrated Lewis pairs (FLPs) are well documented for the activation of small molecules such as dihydrogen and carbon dioxide1-4. Although canonical FLP chemistry is heterolytic in nature, recent work has shown that certain FLPs can undergo single-electron transfer to afford radical pairs5. Owing to steric encumbrance and/or weak bonding association, these radicals do not annihilate one another, and they have thus been named frustrated radical pairs (FRPs). Notable preliminary results suggest that FRPs may be useful reagents in chemical synthesis6-8, although their applications remain limited. Here we demonstrate that the functionalization of C(sp3)-H bonds can be accomplished using a class of FRPs generated from disilazide donors and an N-oxoammonium acceptor. Together, these species undergo single-electron transfer to generate a transient and persistent radical pair capable of cleaving unactivated C-H bonds to furnish aminoxylated products. By tuning the structure of the donor, it is possible to control regioselectivity and tailor reactivity towards tertiary, secondary or primary C-H bonds. Mechanistic studies lend strong support for the formation and involvement of radical pairs in the target reaction.
View details for DOI 10.1038/s41586-023-06131-3
View details for Web of Science ID 001024096100012
View details for PubMedID 37407819
View details for PubMedCentralID PMC10530363
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Enantioselective radical cascade cyclization via Ti-catalyzed redox relay
TETRAHEDRON LETTERS
2023; 125
Abstract
Radical cascade cyclization reactions provide an efficient method for the construction of polycyclic architectures with multiple stereogenic centers. However, achieving enantioselectivity control of this type of reaction is a challenging task. Here, we report an enantioselective cyclization of polyfunctional aryl cyclopropyl ketone and alkyne units, wherein the stereochemical outcome is directed by a chiral Ti(salen) catalyst. This transformation was proposed to proceed via a radical cascade process involving the reductive ring-opening of the cyclopropyl ketone followed by two annulation events entailing cyclization of the ensuing alkyl radical onto the alkyne and subsequent addition of the incipient vinyl radical to the Ti(IV)-enolate.
View details for DOI 10.1016/j.tetlet.2023.154617
View details for Web of Science ID 001028885100001
View details for PubMedID 37449084
View details for PubMedCentralID PMC10338015
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Deep Electroreductive Chemistry: Harnessing Carbon- and Silicon-Based Reactive Intermediates in Organic Synthesis
ACS CATALYSIS
2023; 13 (12): 8038-8048
Abstract
This Viewpoint outlines our recent contribution in electroreductive synthesis. Specifically, we leveraged deeply reducing potentials provided by electrochemistry to generate radical and anionic intermediates from readily available alkyl halides and chlorosilanes. Harnessing the distinct reactivities of radicals and anions, we have achieved several challenging transformations to construct C-C, C-Si, and Si-Si bonds. We highlight the mechanistic design principle that underpinned the development of each transformation and provide a view forward on future opportunities in growing area of reductive electrosynthesis.
View details for DOI 10.1021/acscatal.3c01174
View details for Web of Science ID 001012032700001
View details for PubMedID 38707967
View details for PubMedCentralID PMC11067979
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Generality-oriented optimization of enantioselective aminoxyl radical catalysis
SCIENCE
2023; 380 (6646): 706-712
Abstract
Catalytic enantioselective methods that are generally applicable to a broad range of substrates are rare. We report a strategy for the oxidative desymmetrization of meso-diols predicated on a nontraditional catalyst optimization protocol by using a panel of screening substrates rather than a singular model substrate. Critical to this approach was rational modulation of a peptide sequence in the catalyst incorporating a distinct aminoxyl-based active residue. A general catalyst emerged, providing high selectivity in the delivery of enantioenriched lactones across a broad range of diols, while also achieving up to ~100,000 turnovers.
View details for DOI 10.1126/science.adf6177
View details for Web of Science ID 001010746400024
View details for PubMedID 37200427
View details for PubMedCentralID PMC10277815
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An Electrochemical Strategy to Synthesize Disilanes and Oligosilanes from Chlorosilanes
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
2023; 62 (26): e202303592
Abstract
Silanes are important compounds in industrial and synthetic chemistry. Here, we develop a general approach for the synthesis of disilanes as well as linear and cyclic oligosilanes via the reductive activation of readily available chlorosilanes. The efficient and selective generation of silyl anion intermediates, which are arduous to achieve by other means, allows for the synthesis of various novel oligosilanes by heterocoupling. In particular, this work presents a modular synthesis for a variety of functionalized cyclosilanes, which may give rise to materials with distinct properties from linear silanes but remain challenging synthetic targets. In comparison to the traditional Wurtz coupling, our method features milder conditions and improved chemoselectivity, broadening the functional groups that are compatible in oligosilane preparation. Computational studies support a mechanism whereby differential activation of sterically and electronically distinct chlorosilanes are achieved in an electrochemically driven radical-polar crossover mechanism.
View details for DOI 10.1002/anie.202303592
View details for Web of Science ID 000987900300001
View details for PubMedID 37084266
View details for PubMedCentralID PMC10310474
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Special Collection on Organic Electrocatalysis
EUROPEAN JOURNAL OF ORGANIC CHEMISTRY
2023; 26 (17)
View details for DOI 10.1002/ejoc.202300214
View details for Web of Science ID 000962185600001
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New Guidelines for Presenting Electrochemical Data in All ACS Journals
ACS CATALYSIS
2023; 13 (7): 4468-4469
View details for DOI 10.1021/acscatal.3c00995
View details for Web of Science ID 000957791400001
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A Physical Organic Approach towards Statistical Modeling of Tetrazole and Azide Decomposition
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
2023; 62 (17): e202218213
Abstract
Nitrogen atom-rich heterocycles and organic azides have found extensive use in many sectors of modern chemistry from drug discovery to energetic materials. The prediction and understanding of their energetic properties are thus key to the safe and effective application of these compounds. In this work, we disclose the use of multivariate linear regression modeling for the prediction of the decomposition temperature and impact sensitivity of structurally diverse tetrazoles and organic azides. We report a data-driven approach for property prediction featuring a collection of quantum mechanical parameters and computational workflows. The statistical models reported herein carry predictive accuracy as well as chemical interpretability. Model validation was successfully accomplished via tetrazole test sets with parameters generated exclusively in silico. Mechanistic analysis of the statistical models indicated distinct divergent pathways of thermal and impact-initiated decomposition.
View details for DOI 10.1002/anie.202218213
View details for Web of Science ID 000952198000001
View details for PubMedID 36823344
View details for PubMedCentralID PMC10079611
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Deuterodehalogenation Under Net Reductive or Redox-Neutral Conditions Enabled by Paired Electrolysis
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
2023; 62 (15): e202218858
Abstract
Interest in deuterated active pharmaceutical ingredients (APIs) is increasing as deuteration holds promise for kinetic isotope effect (KIE) regulated fine-tuning of API performance. Moreover, deuterium isotope labeling is frequently carried out to study organic and bioorganic reaction mechanisms and to facilitate complex target synthesis. As such, methods for highly selective deuteration of organic molecules are highly desirable. Herein, we present an electrochemical method for the selective deuterodehalogenation of benzylic halides via a radical-polar crossover mechanism, using inexpensive deuterium oxide (D2 O) as the deuterium source. We demonstrate broad functional group compatibility across a range of aryl and heteroaryl benzylic halides. Furthermore, we uncover a sequential paired electrolysis regime, which permits switching between net reductive and overall redox-neutral reactions of sulfur-containing substrates simply by changing the identity of the sacrificial reductant employed.
View details for DOI 10.1002/anie.202218858
View details for Web of Science ID 000941263000001
View details for PubMedID 36738472
View details for PubMedCentralID PMC10050105
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Structurally Diverse Bench-Stable Nickel(0) Pre-Catalysts: A Practical Toolkit for In Situ Ligation Protocols
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
2023; 62 (9): e202211794
Abstract
A flurry of recent research has centered on harnessing the power of nickel catalysis in organic synthesis. These efforts have been bolstered by contemporaneous development of well-defined nickel (pre)catalysts with diverse structure and reactivity. In this report, we present ten different bench-stable, 18-electron, formally zero-valent nickel-olefin complexes that are competent pre-catalysts in various reactions. Our investigation includes preparations of novel, bench-stable Ni(COD)(L) complexes (COD=1,5-cyclooctadiene), in which L=quinone, cyclopentadienone, thiophene-S-oxide, and fulvene. Characterization by NMR, IR, single-crystal X-ray diffraction, cyclic voltammetry, thermogravimetric analysis, and natural bond orbital analysis sheds light on the structure, bonding, and properties of these complexes. Applications in an assortment of nickel-catalyzed reactions underscore the complementary nature of the different pre-catalysts within this toolkit.
View details for DOI 10.1002/anie.202211794
View details for Web of Science ID 000916522000001
View details for PubMedID 36524997
View details for PubMedCentralID PMC9987410
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Electrochemical reactor dictates site selectivity in <i>N</i>-heteroarene carboxylations
NATURE
2023; 615 (7950): 67-+
Abstract
Pyridines and related N-heteroarenes are commonly found in pharmaceuticals, agrochemicals and other biologically active compounds1,2. Site-selective C-H functionalization would provide a direct way of making these medicinally active products3-5. For example, nicotinic acid derivatives could be made by C-H carboxylation, but this remains an elusive transformation6-8. Here we describe the development of an electrochemical strategy for the direct carboxylation of pyridines using CO2. The choice of the electrolysis setup gives rise to divergent site selectivity: a divided electrochemical cell leads to C5 carboxylation, whereas an undivided cell promotes C4 carboxylation. The undivided-cell reaction is proposed to operate through a paired-electrolysis mechanism9,10, in which both cathodic and anodic events play critical roles in altering the site selectivity. Specifically, anodically generated iodine preferentially reacts with a key radical anion intermediate in the C4-carboxylation pathway through hydrogen-atom transfer, thus diverting the reaction selectivity by means of the Curtin-Hammett principle11. The scope of the transformation was expanded to a wide range of N-heteroarenes, including bipyridines and terpyridines, pyrimidines, pyrazines and quinolines.
View details for DOI 10.1038/s41586-022-05667-0
View details for Web of Science ID 000937120600001
View details for PubMedID 36603811
View details for PubMedCentralID PMC10036166
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Electrochemical Diazidation of Alkenes Catalyzed by Manganese Porphyrin Complexes with Second-Sphere Hydrogen-Bond Donors
ACS CATALYSIS
2022; 12 (22): 14106-14112
View details for DOI 10.1021/acscatal.2c05186
View details for Web of Science ID 000898471900001
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Intercepting Hydrogen Evolution with Hydrogen-Atom Transfer: Electron-Initiated Hydrofunctionalization of Alkenes
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
2022; 144 (39): 17783-17791
Abstract
Hydrogen-atom transfer mediated by earth-abundant transition-metal hydrides (M-Hs) has emerged as a powerful tool in organic synthesis. Current methods to generate M-Hs most frequently rely on oxidatively initiated hydride transfer. Herein, we report a reductive approach to generate Co-H, which allows for canonical hydrogen evolution reactions to be intercepted by hydrogen-atom transfer to an alkene. Electroanalytical and spectroscopic studies provided mechanistic insights into the formation and reactivity of Co-H, which enabled the development of two new alkene hydrofunctionalization reactions.
View details for DOI 10.1021/jacs.2c08278
View details for Web of Science ID 000861500800001
View details for PubMedID 36137298
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Titanium radical redox catalysis: Recent innovations in catalysts, reactions, and modes of activation
CHEM
2022; 8 (7): 1805-1821
Abstract
Radical chemistry has emerged as a cornerstone in modern organic synthesis, providing chemists with numerous new tools to rapidly expand reactivity and chemical space in academic and industrial research. In this regard, titanium complexes have been recognized as an attractive class of catalysts owing to their rich redox activities in addition to the abundance and low toxicity of this early transition metal. Traditionally employed for the activation of epoxides and carbonyl compounds, Ti radical redox catalysis has broken into new grounds in recent years, giving rise to a diverse repertoire of useful transformations. In this Perspective, we highlight recent developments in the area of TiIII/IV catalysis with respect to the activation of different types of chemical bonds. Furthermore, we discuss future opportunities in integrating Ti radical chemistry with other catalytic systems as well as with emerging new technologies such as photochemistry and electrochemistry.
View details for DOI 10.1016/j.chempr.2022.06.005
View details for Web of Science ID 000841999200006
View details for PubMedID 36213842
View details for PubMedCentralID PMC9543366
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Eight-Fold Intensification of Electrochemical Azidooxygenation with a Flow-Through Electrode
ACS SUSTAINABLE CHEMISTRY & ENGINEERING
2022; 10 (23): 7648-7657
View details for DOI 10.1021/acssuschemeng.2c01525
View details for Web of Science ID 000813784800001
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Working at the interfaces of data science and synthetic electrochemistry
TETRAHEDRON CHEM
2022; 1
Abstract
Electrochemistry is quickly entering the mainstream of synthetic organic chemistry. The diversity of new transformations enabled by electrochemistry is to a large extent a consequence of the unique features and reaction parameters in electrochemical systems including redox mediators, applied potential, electrode material, and cell construction. While offering chemists new means to control reactivity and selectivity, these additional features also increase the dimensionalities of a reaction system and complicate its optimization. This challenge, however, has spawned increasing adoption of data science tools to aid reaction discovery as well as development of high-throughput screening platforms that facilitate the generation of high quality datasets. In this Perspective, we provide an overview of recent advances in data-science driven electrochemistry with an emphasis on the opportunities and challenges facing this growing subdiscipline.
View details for DOI 10.1016/j.tchem.2022.100012
View details for Web of Science ID 001640294300013
View details for PubMedID 35441154
View details for PubMedCentralID PMC9014485
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Electrochemically driven cross-electrophile coupling of alkyl halides
NATURE
2022; 604 (7905): 292-+
Abstract
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 objective3-5. 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.
View details for DOI 10.1038/s41586-022-04540-4
View details for Web of Science ID 000779281500001
View details for PubMedID 35189623
View details for PubMedCentralID PMC9016776
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Exploring Electrochemical C(sp<SUP>3</SUP>)-H Oxidation for the Late-Stage Methylation of Complex Molecules
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
2022; 144 (3): 1187-1197
Abstract
The "magic methyl" effect, a dramatic boost in the potency of biologically active compounds from the incorporation of a single methyl group, provides a simple yet powerful strategy employed by medicinal chemists in the drug discovery process. Despite significant advances, methodologies that enable the selective C(sp3)-H methylation of structurally complex medicinal agents remain very limited. In this work, we disclose a modular, efficient, and selective strategy for the α-methylation of protected amines (i.e., amides, carbamates, and sulfonamides) by means of electrochemical oxidation. Mechanistic analysis guided our development of an improved electrochemical protocol on the basis of the classic Shono oxidation reaction, which features broad reaction scope, high functional group compatibility, and operational simplicity. Importantly, this reaction system is amenable to the late-stage functionalization of complex targets containing basic nitrogen groups that are prevalent in medicinally active agents. When combined with organozinc-mediated C-C bond formation, our protocol enabled the direct methylation of a myriad of amine derivatives including those that have previously been explored for the "magic methyl" effect. This synthesis strategy thus circumvents multistep de novo synthesis that is currently necessary to access such compounds and has the potential to accelerate drug discovery efforts.
View details for DOI 10.1021/jacs.1c09412
View details for Web of Science ID 000745244300001
View details for PubMedID 35015533
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Unlocking the Potential of High-Throughput Experimentation for Electrochemistry with a Standardized Microscale Reactor
ACS CENTRAL SCIENCE
2021; 7 (8): 1347-1355
Abstract
Organic electrochemistry has emerged as an enabling and sustainable technology in modern organic synthesis. Despite the recent renaissance of electrosynthesis, the broad adoption of electrochemistry in the synthetic community, and especially in industrial settings, has been hindered by the lack of general, standardized platforms for high-throughput experimentation (HTE). Herein, we disclose the design of the HTe - Chem, a high-throughput microscale electrochemical reactor that is compatible with existing HTE infrastructure and enables the rapid evaluation of a broad array of electrochemical reaction parameters. Utilizing the HTe - Chem to accelerate reaction optimization, reaction discovery, and chemical library synthesis is illustrated using a suite of oxidative and reductive transformations under constant current, constant voltage, and electrophotochemical conditions.
View details for DOI 10.1021/acscentsci.1c00328
View details for Web of Science ID 000691796000012
View details for PubMedID 34471679
View details for PubMedCentralID PMC8393209
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Titanium and Cobalt Bimetallic Radical Redox Relay for the Isomerization of <i>N</i> -Bz Aziridines to Allylic Amides
SYNTHESIS-STUTTGART
2021; 53 (22): 4213-4220
Abstract
Herein a bimetallic radical redox-relay strategy is employed to generate alkyl radicals under mild conditions with titanium(III) catalysis and terminated via hydrogen atom transfer with cobalt(II) catalysis to enact base-free isomerizations of N-Bz aziridines to N-Bz allylic amides. This reaction provides an alternative strategy for the synthesis of allylic amides from alkenes via a three-step sequence to accomplish a formal transpositional allylic amination.
View details for DOI 10.1055/s-0037-1610779
View details for Web of Science ID 000679235400001
View details for PubMedID 34764520
View details for PubMedCentralID PMC8579959
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Electrocatalysis as an enabling technology for organic synthesis
CHEMICAL SOCIETY REVIEWS
2021; 50 (14): 7941-+
Abstract
Electrochemistry has recently gained increased attention as a versatile strategy for achieving challenging transformations at the forefront of synthetic organic chemistry. Electrochemistry's unique ability to generate highly reactive radical and radical ion intermediates in a controlled fashion under mild conditions has inspired the development of a number of new electrochemical methodologies for the preparation of valuable chemical motifs. Particularly, recent developments in electrosynthesis have featured an increased use of redox-active electrocatalysts to further enhance control over the selective formation and downstream reactivity of these reactive intermediates. Furthermore, electrocatalytic mediators enable synthetic transformations to proceed in a manner that is mechanistically distinct from purely chemical methods, allowing for the subversion of kinetic and thermodynamic obstacles encountered in conventional organic synthesis. This review highlights key innovations within the past decade in the area of synthetic electrocatalysis, with emphasis on the mechanisms and catalyst design principles underpinning these advancements. A host of oxidative and reductive electrocatalytic methodologies are discussed and are grouped according to the classification of the synthetic transformation and the nature of the electrocatalyst.
View details for DOI 10.1039/d1cs00223f
View details for Web of Science ID 000656623100001
View details for PubMedID 34060564
View details for PubMedCentralID PMC8294342
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Isolation and X-ray Crystal Structure of an Electrogenerated TEMPO-N<sub>3</sub> Charge-Transfer Complex
ORGANIC LETTERS
2021; 23 (2): 454-458
Abstract
Advances in radical-based catalytic reactions have created a demand for understanding their mechanistic underpinnings. Here, we present the isolation, structural elucidation, and theoretical analysis of a catalytically relevant charge-transfer species formed between the azidyl radical and (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO). The unusual bond angles and pancake bonding between these two fragments highlight the weak bonding interactions present in this complex. This X-ray structure validates computational predictions as well as mechanistic proposals of TEMPO-mediated radical azidation reactions.
View details for DOI 10.1021/acs.orglett.0c03966
View details for Web of Science ID 000643163800037
View details for PubMedID 33406362
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Reductive Electrosynthesis: A New Dawn
ALDRICHIMICA ACTA
2021; 54 (1): 17-27
View details for Web of Science ID 000686221700003
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An Electroreductive Approach to Radical Silylation via the Activation of Strong Si-Cl Bond
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
2020; 142 (51): 21272-21278
Abstract
The construction of C(sp3)-Si bonds is important in synthetic, medicinal, and materials chemistry. In this context, reactions mediated by silyl radicals have become increasingly attractive but methods for accessing these intermediates remain limited. We present a new strategy for silyl radical generation via electroreduction of readily available chlorosilanes. At highly biased potentials, electrochemistry grants access to silyl radicals through energetically uphill reductive cleavage of strong Si-Cl bonds. This strategy proved to be general in various alkene silylation reactions including disilylation, hydrosilylation, and allylic silylation under simple and transition-metal-free conditions.
View details for DOI 10.1021/jacs.0c10899
View details for Web of Science ID 000603395100007
View details for PubMedID 33290654
View details for PubMedCentralID PMC7951502
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Electroreductive Carbofunctionalization of Alkenes with Alkyl Bromides via a Radical-Polar Crossover Mechanism
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
2020; 142 (49): 20661-20670
Abstract
Electrochemistry grants direct access to reactive intermediates (radicals and ions) in a controlled fashion toward selective organic transformations. This feature has been demonstrated in a variety of alkene functionalization reactions, most of which proceed via an anodic oxidation pathway. In this report, we further expand the scope of electrochemistry to the reductive functionalization of alkenes. In particular, the strategic choice of reagents and reaction conditions enabled a radical-polar crossover pathway wherein two distinct electrophiles can be added across an alkene in a highly chemo- and regioselective fashion. Specifically, we used this strategy in the intermolecular carboformylation, anti-Markovnikov hydroalkylation, and carbocarboxylation of alkenes-reactions with rare precedents in the literature-by means of the electroreductive generation of alkyl radical and carbanion intermediates. These reactions employ readily available starting materials (alkyl halides, alkenes, etc.) and simple, transition-metal-free conditions and display broad substrate scope and good tolerance of functional groups. A uniform protocol can be used to achieve all three transformations by simply altering the reaction medium. This development provides a new avenue for constructing Csp3-Csp3 bonds.
View details for DOI 10.1021/jacs.0c08532
View details for Web of Science ID 000599506900024
View details for PubMedID 33231074
View details for PubMedCentralID PMC7951757
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Mechanistic Studies Inform Design of Improved Ti(salen) Catalysts for Enantioselective [3+2] Cycloaddition
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
2020; 142 (43): 18471-18482
Abstract
Ti(salen) complexes catalyze the asymmetric [3 + 2] cycloaddition of cyclopropyl ketones with alkenes. While high enantioselectivities are achieved with electron-rich alkenes, electron-deficient alkenes are less selective. Herein, we describe mechanistic studies to understand the origins of catalyst and substrate trends in an effort to identify a more general catalyst. Density functional theory (DFT) calculations of the selectivity determining transition state revealed the origin of stereochemical control to be catalyst distortion, which is largely influenced by the chiral backbone and adamantyl groups on the salicylaldehyde moieties. While substitution of the adamantyl groups was detrimental to the enantioselectivity, mechanistic information guided the development of a set of eight new Ti(salen) catalysts with modified diamine backbones. These catalysts were evaluated with four electron-deficient alkenes to develop a three-parameter statistical model relating enantioselectivity to physical organic parameters. This statistical model is capable of quantitative prediction of enantioselectivity with structurally diverse alkenes. These mechanistic insights assisted the discovery of a new Ti(salen) catalyst, which substantially expanded the reaction scope and significantly improved the enantioselectivity of synthetically interesting building blocks.
View details for DOI 10.1021/jacs.0c07128
View details for Web of Science ID 000582673500021
View details for PubMedID 33064948
View details for PubMedCentralID PMC7951186
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New Redox Strategies in Organic Synthesis by Means of Electrochemistry and Photochemistry
ACS CENTRAL SCIENCE
2020; 6 (8): 1317-1340
Abstract
As the breadth of radical chemistry grows, new means to promote and regulate single-electron redox activities play increasingly important roles in driving modern synthetic innovation. In this regard, photochemistry and electrochemistry-both considered as niche fields for decades-have seen an explosive renewal of interest in recent years and gradually have become a cornerstone of organic chemistry. In this Outlook article, we examine the current state-of-the-art in the areas of electrochemistry and photochemistry, as well as the nascent area of electrophotochemistry. These techniques employ external stimuli to activate organic molecules and imbue privileged control of reaction progress and selectivity that is challenging to traditional chemical methods. Thus, they provide alternative entries to known and new reactive intermediates and enable distinct synthetic strategies that were previously unimaginable. Of the many hallmarks, electro- and photochemistry are often classified as "green" technologies, promoting organic reactions under mild conditions without the necessity for potent and wasteful oxidants and reductants. This Outlook reviews the most recent growth of these fields with special emphasis on conceptual advances that have given rise to enhanced accessibility to the tools of the modern chemical trade.
View details for DOI 10.1021/acscentsci.0c00549
View details for Web of Science ID 000566668400012
View details for PubMedID 32875074
View details for PubMedCentralID PMC7453421
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Dual electrocatalysis enables enantioselective hydrocyanation of conjugated alkenes
NATURE CHEMISTRY
2020; 12 (8): 747-754
Abstract
Chiral nitriles and their derivatives are prevalent in pharmaceuticals and bioactive compounds. Enantioselective alkene hydrocyanation represents a convenient and efficient approach for synthesizing these molecules. However, a generally applicable method featuring a broad substrate scope and high functional group tolerance remains elusive. Here, we address this long-standing synthetic problem using dual electrocatalysis. Using this strategy, we leverage electrochemistry to seamlessly combine two canonical radical reactions-cobalt-mediated hydrogen-atom transfer and copper-promoted radical cyanation-to accomplish highly enantioselective hydrocyanation without the need for stoichiometric oxidants. We also harness electrochemistry's unique feature of precise potential control to optimize the chemoselectivity of challenging substrates. Computational analysis uncovers the origin of enantio-induction, for which the chiral catalyst imparts a combination of attractive and repulsive non-covalent interactions to direct the enantio-determining C-CN bond formation. This work demonstrates the power of electrochemistry in accessing new chemical space and providing solutions to pertinent challenges in synthetic chemistry.
View details for DOI 10.1038/s41557-020-0469-5
View details for Web of Science ID 000545163700003
View details for PubMedID 32601407
View details for PubMedCentralID PMC7390704
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Catalyzing Electrosynthesis: A Homogeneous Electrocatalytic Approach to Reaction Discovery
ACCOUNTS OF CHEMICAL RESEARCH
2020; 53 (3): 547-560
Abstract
Electrochemistry has been used as a tool to drive chemical reactions for over two centuries. With the help of an electrode and a power source, chemists are bestowed with an imaginary reagent whose potential can be precisely dialed in. The theoretically infinite redox range renders electrochemistry capable of oxidizing or reducing some of the most tenacious compounds (e.g., F- to F2 and Li+ to Li0). Meanwhile, a granular level of control over the electrode potential allows for the chemoselective differentiation of functional groups with minute differences in potential. These features make electrochemistry an attractive technique for the discovery of new modes of reactivity and transformations that are not readily accessible with chemical reagents alone. Furthermore, the use of an electrical current in place of chemical redox agents improves the cost-efficiency of chemical processes and reduces byproduct generation. Therefore, electrochemistry represents an attractive approach to meet the prevailing trends in organic synthesis and has seen increasingly broad use in the synthetic community over the past several years.While electrochemical oxidation or reduction can provide access to reactive intermediates, redox-active molecular catalysts (i.e., electrocatalysts) can also enable the generation of these intermediates at reduced potentials with improved chemoselectivity. Moreover, electrocatalysts can impart control over the chemo-, regio-, and stereoselectivities of the chemical processes that take place after electron transfer at electrode surfaces. Thus, electrocatalysis has the potential to significantly broaden the scope of organic electrochemistry and enable a wide range of new transformations. Our initial foray into electrocatalytic synthesis led to the development of two generations of alkene diazidation reactions, using transition-metal and organic catalysis, respectively. In these reactions, the electrocatalysts play two critical roles; they promote the single-electron oxidation of N3- at a reduced potential and complex with the resultant transient N3• to form persistent reactive intermediates. The catalysts facilitate the sequential addition of 2 equiv of azide across the alkene substrates, leading to a diverse array of synthetically useful vicinally diaminated products.We further applied this electrocatalytic radical mechanism to the heterodifunctionalization of alkenes. Anodically coupled electrolysis enables the simultaneous anodic generation of two distinct radical intermediates, and the appropriate choice of catalyst allowed the subsequent alkene addition to occur in a chemo- and regioselective fashion. Using this strategy, a variety of difunctionalization reactions, including halotrifluoromethylation, haloalkylation, and azidophosphinoylation, were successfully developed. Importantly, we also demonstrated enantioselective electrocatalysis in the context of Cu-promoted cyanofunctionalization reactions by employing a chiral bisoxazoline ligand. Finally, by introducing a second electrocatalyst that mediates oxidatively induced hydrogen atom transfer, we expanded scope of electrocatalysis to hydrofunctionalization reactions, achieving hydrocyanation of conjugated alkenes in high enantioselectivity. These developments showcase the generality of our electrocatalytic strategy in the context of alkene functionalization reactions. We anticipate that electrocatalysis will play an increasingly important role in the ongoing renaissance of synthetic organic electrochemistry.
View details for DOI 10.1021/acs.accounts.9b00529
View details for Web of Science ID 000526398000002
View details for PubMedID 32077681
View details for PubMedCentralID PMC7245362
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Reductive Electrophotocatalysis: Merging Electricity and Light To Achieve Extreme Reduction Potentials
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
2020; 142 (5): 2087-2092
Abstract
We describe a new electrophotocatalytic strategy that harnesses the power of light and electricity to generate an excited radical anion with a reducing potential of -3.2 V vs SCE, which can be used to activate substrates with very high reduction potentials (Ered ≈ -1.9 to -2.9 V). The resultant aryl radicals can be engaged in various synthetically useful transformations to furnish arylboronate, arylstannane, and biaryl products.
View details for DOI 10.1021/jacs.9b10678
View details for Web of Science ID 000512222700001
View details for PubMedID 31951390
View details for PubMedCentralID PMC7023851
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Electrocatalytic Diazidation of Alkenes
TRENDS IN CHEMISTRY
2020; 2 (1): 84-85
View details for DOI 10.1016/j.trechm.2019.10.005
View details for Web of Science ID 000521130800008
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Electrochemistry Broadens the Scope of Flavin Photocatalysis: Photoelectrocatalytic Oxidation of Unactivated Alcohols
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
2020; 59 (1): 409-417
Abstract
Riboflavin-derived photocatalysts have been extensively studied in the context of alcohol oxidation. However, to date, the scope of this catalytic methodology has been limited to benzyl alcohols. In this work, mechanistic understanding of flavin-catalyzed oxidation reactions, in either the absence or presence of thiourea as a cocatalyst, was obtained. The mechanistic insights enabled development of an electrochemically driven photochemical oxidation of primary and secondary aliphatic alcohols using a pair of flavin and dialkylthiourea catalysts. Electrochemistry makes it possible to avoid using O2 and an oxidant and generating H2 O2 as a byproduct, both of which oxidatively degrade thiourea under the reaction conditions. This modification unlocks a new mechanistic pathway in which the oxidation of unactivated alcohols is achieved by thiyl radical mediated hydrogen-atom abstraction.
View details for DOI 10.1002/anie.201910300
View details for Web of Science ID 000496868300001
View details for PubMedID 31617271
View details for PubMedCentralID PMC6923568
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Recent Advances in Titanium Radical Redox Catalysis
JOURNAL OF ORGANIC CHEMISTRY
2019; 84 (22): 14369-14380
Abstract
New catalytic strategies that leverage single-electron redox events have provided chemists with useful tools for solving synthetic problems. In this context, Ti offers opportunities that are complementary to late transition metals for reaction discovery. Following foundational work on epoxide reductive functionalization, recent methodological advances have significantly expanded the repertoire of Ti radical chemistry. This Synopsis summarizes recent developments in the burgeoning area of Ti radical catalysis with a focus on innovative catalytic strategies such as radical redox-relay and dual catalysis.
View details for DOI 10.1021/acs.joc.9b02465
View details for Web of Science ID 000497259900001
View details for PubMedID 31647872
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New Bisoxazoline Ligands Enable Enantioselective Electrocatalytic Cyanofunctionalization of Vinylarenes
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
2019; 141 (37): 14480-14485
Abstract
In contrast to the rapid growth of synthetic electrochemistry in recent years, enantioselective catalytic methods powered by electricity remain rare. In this work, we report the development of a highly enantioselective method for the electrochemical cyanophosphinoylation of vinylarenes. A new family of serine-derived chiral bisoxazolines with ancillary coordination sites were identified as optimal ligands.
View details for DOI 10.1021/jacs.9b03296
View details for Web of Science ID 000487180200002
View details for PubMedID 31498595
View details for PubMedCentralID PMC7023682
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Bimetallic Radical Redox-Relay Catalysis for the Isomerization of Epoxides to Allylic Alcohols
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
2019; 141 (24): 9548-9554
View details for DOI 10.1021/jacs.9b04993
View details for Web of Science ID 000471835600022
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Three-Component Chlorophosphinoylation of Alkenes via Anodically Coupled Electrolysis
SYNLETT
2019; 30 (10): 1199-1203
View details for DOI 10.1055/s-0039-1689934
View details for Web of Science ID 000471234600012
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Aminoxyl-Catalyzed Electrochemical Diazidation of Alkenes Mediated by a Metastable Charge-Transfer Complex
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
2019; 141 (7): 2825-2831
Abstract
We report the development of a new aminoxyl radical catalyst, CHAMPO, for the electrochemical diazidation of alkenes. Mediated by an anodically generated charge-transfer complex in the form of CHAMPO-N3, radical diazidation was achieved across a broad scope of alkenes without the need for a transition metal catalyst or a chemical oxidant. Mechanistic data support a dual catalytic role for the aminoxyl serving as both a single-electron oxidant and a radical group transfer agent.
View details for DOI 10.1021/jacs.8b13192
View details for Web of Science ID 000459642000007
View details for PubMedID 30673216
View details for PubMedCentralID PMC6405340
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Mn-Catalyzed Electrochemical Chloroalkylation of Alkenes
ACS CATALYSIS
2019; 9 (1): 746-754
Abstract
The heterodifunctionalization of alkenes is an efficient method for synthesizing highly functionalized organic molecules. In this report, we describe the use of anodically coupled electrolysis for the catalytic chloroalkylation of alkenes-a reaction that constructs vicinal C-C and C-Cl bonds in a single synthetic operation-from malononitriles or cyanoacetates and NaCl. Knowledge of the persistent radical effect guided the reaction design and development. A series of controlled experiments, including divided-cell electrolysis that compartmentalized the anodic and cathodic events, allowed us to identify the key radical intermediates and the pathway to their electrocatalytic formation. Cyclic voltammetry data further support the proposed mechanism entailing the parallel, Mn-mediated generation of two radical intermediates in an anodically coupled electrolysis followed by their selective addition to the alkene.
View details for DOI 10.1021/acscatal.8b03209
View details for Web of Science ID 000455286600076
View details for PubMedID 31304049
View details for PubMedCentralID PMC6625787
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Ti-Catalyzed Radical Alkylation of Secondary and Tertiary Alkyl Chlorides Using Michael Acceptors
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
2018; 140 (44): 14836-14843
Abstract
Alkyl chlorides are common functional groups in synthetic organic chemistry. However, the engagement of unactivated alkyl chlorides, especially tertiary alkyl chlorides, in transition-metal-catalyzed C-C bond formation remains challenging. Herein, we describe the development of a TiIII-catalyzed radical addition of 2° and 3° alkyl chlorides to electron-deficient alkenes. Mechanistic data are consistent with inner-sphere activation of the C-Cl bond featuring TiIII-mediated Cl atom abstraction. Evidence suggests that the active TiIII catalyst is generated from the TiIV precursor in a Lewis-acid-assisted electron transfer process.
View details for DOI 10.1021/jacs.8b08605
View details for Web of Science ID 000449887800043
View details for PubMedID 30303379
View details for PubMedCentralID PMC6530901
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Electrochemical Azidooxygenation of Alkenes Mediated by a TEMPO-N<sub>3</sub> Charge-Transfer Complex
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
2018; 140 (39): 12511-12520
Abstract
We report a mild and efficient electrochemical protocol to access a variety of vicinally C-O and C-N difunctionalized compounds from simple alkenes. Detailed mechanistic studies revealed a distinct reaction pathway from those previously reported for TEMPO-mediated reactions. In this mechanism, electrochemically generated oxoammonium ion facilitates the formation of azidyl radical via a charge-transfer complex with azide, TEMPO-N3. DFT calculations together with spectroscopic characterization provided a tentative structural assignment of this charge-transfer complex. Kinetic and kinetic isotopic effect studies revealed that reversible dissociation of TEMPO-N3 into TEMPO• and azidyl precedes the addition of these radicals across the alkene in the rate-determining step. The resulting azidooxygenated product could then be easily manipulated for further synthetic elaborations. The discovery of this new reaction pathway mediated by the TEMPO+/TEMPO• redox couple may expand the scope of aminoxyl radical chemistry in synthetic contexts.
View details for DOI 10.1021/jacs.8b06744
View details for Web of Science ID 000446920100033
View details for PubMedID 30160949
View details for PubMedCentralID PMC6212300
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Synthesis of Chlorotrifluoromethylated Pyrrolidines by Electrocatalytic Radical Ene-Yne Cyclization
CHEMISTRY-A EUROPEAN JOURNAL
2018; 24 (47): 12274-12279
Abstract
The stereoselective synthesis of chlorotrifluoromethylated pyrrolidines was achieved using anodically coupled electrolysis, an electrochemical process that combines two parallel oxidative events in a convergent and productive manner. The bench-stable and commercially available solids CF3 SO2 Na and MgCl2 were used as the functional group sources to generate CF3. and Cl. , respectively, via electrochemical oxidation, and the subsequent reaction of these radicals with the 1,6-enyne substrate was controlled with an earth-abundant Mn catalyst. In particular, the introduction of a chelating ligand allowed for the ene-yne cyclization to take place with high stereochemical control over the geometry of the alkene group in the pyrrolidine product.
View details for DOI 10.1002/chem.201802167
View details for Web of Science ID 000442491000020
View details for PubMedID 29766588
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A general, electrocatalytic approach to the synthesis of vicinal diamines
NATURE PROTOCOLS
2018; 13 (8): 1725-1743
Abstract
This protocol describes an electrochemical synthesis of 1,2-diazides from alkenes. Organic azides are highly versatile intermediates for synthetic chemistry, materials, and biological applications. 1,2-Diazides are commonly reduced to form 1,2-diamines, which are prevalent structural motifs in bioactive natural products, therapeutic agents, and molecular catalysts. The electrochemical formation of 1,2-diazides involves the anodic generation of an azidyl radical from sodium azide, followed by two successive additions of this N-centered radical to the alkene, and is assisted by a Mn catalyst. The electrosynthesis of 1,2-diazides can be carried out using various experimental setups comprising custom-made or commercially available reaction vessels and a direct-current power supply. Readily accessible electrode materials can be used, including carbon (made from reticulated vitreous carbon and pencil lead), nickel foam, and platinum foil. This protocol is also demonstrated using ElectraSyn, a standardized electrochemistry kit. Compared with conventional synthetic approaches, electrochemistry allows for the precise control of the anodic potential input, eliminates the need for stoichiometric and often indiscriminate oxidants, and minimizes the generation of wasteful byproducts. As such, our electrocatalytic synthesis exhibits various advantages over existing methods for alkene diamination, including sustainability, operational simplicity, substrate generality, and exceptional functional-group compatibility. The resultant 1,2-diazides can be smoothly reduced to 1,2-diamines in a single step with high chemoselectivity. To exemplify this, we include a procedure for catalytic hydrogenation using palladium on carbon. This protocol, therefore, constitutes a general approach to accessing 1,2-diazides and 1,2-diamines from alkenes.
View details for DOI 10.1038/s41596-018-0010-0
View details for Web of Science ID 000442299300001
View details for PubMedID 30072721
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An Electrocatalytic Approach to the Radical Difunctionalization of Alkenes
ACS CATALYSIS
2018; 8 (6): 5175-5187
View details for DOI 10.1021/acscatal.8b01069
View details for Web of Science ID 000434369600041
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Diastereo- and Enantioselective Formal [3+2] Cycloaddition of Cyclopropyl Ketones and Alkenes via Ti-Catalyzed Radical Redox Relay
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
2018; 140 (10): 3514-3517
Abstract
We report a stereoselective formal [3 + 2] cycloaddition of cyclopropyl ketones and radical-acceptor alkenes to form polysubstituted cyclopentane derivatives. Catalyzed by a chiral Ti(salen) complex, the cycloaddition occurs via a radical redox-relay mechanism and constructs two C-C bonds and two contiguous stereogenic centers with generally excellent diastereo- and enantioselectivity.
View details for DOI 10.1021/jacs.7b13710
View details for Web of Science ID 000427910700008
View details for PubMedID 29465998
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Anodically Coupled Electrolysis for the Heterodifunctionalization of Alkenes
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
2018; 140 (7): 2438-2441
Abstract
The emergence of new catalytic strategies that cleverly adopt concepts and techniques frequently used in areas such as photochemistry and electrochemistry has yielded a myriad of new organic reactions that would be challenging to achieve using orthodox methods. Herein, we discuss the strategic use of anodically coupled electrolysis, an electrochemical process that combines two parallel oxidative events, as a complementary approach to existing methods for redox organic transformations. Specifically, we demonstrate anodically coupled electrolysis in the regio- and chemoselective chlorotrifluoromethylation of alkenes.
View details for DOI 10.1021/jacs.7b13387
View details for Web of Science ID 000426143800012
View details for PubMedID 29406758
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Electrochemically Controlled Cationic Polymerization of Vinyl Ethers
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
2018; 140 (6): 2076-2079
Abstract
Control of polymer initiation, propagation and termination is important in the development of complex polymer structures and advanced materials. Typically, this has been achieved chemically, electrochemically, photochemically or mechanochemically. Electrochemical control has been demonstrated in radical polymerizations; however, regulation of a cationic polymerization has yet to be achieved. Through the reversible oxidation of a polymer chain end with an electrochemical mediator, temporal control over polymer chain growth in cationic polymerizations was realized. By subjecting a stable organic nitroxyl radical mediator and chain transfer agent to an oxidizing current, control over polymer molecular weight and dispersity is demonstrated and excellent chain end fidelity allows for the synthesis of block copolymers.
View details for DOI 10.1021/jacs.8b00173
View details for Web of Science ID 000425475300023
View details for PubMedID 29385348
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Electrocatalytic Difunctionalization of Olefins as a General Approach to the Synthesis of Vicinal Diamines
SYNLETT
2018; 29 (3): 257-265
View details for DOI 10.1055/s-0036-1591749
View details for Web of Science ID 000423997400006
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Electrocatalytic Radical Dichlorination of Alkenes with Nucleophilic Chlorine Sources
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
2017; 139 (43): 15548-15553
Abstract
We report a Mn-catalyzed electrochemical dichlorination of alkenes with MgCl2 as the chlorine source. This method provides operationally simple, sustainable, and efficient access to a variety of vicinally dichlorinated compounds. In particular, alkenes with oxidatively labile functional groups, such as alcohols, aldehydes, sulfides, and amines, were transformed into the desired vicinal dichlorides with high chemoselectivity. Mechanistic data are consistent with metal-mediated Cl atom transfer as the predominant pathway enabling dual C-Cl bond formation and contradict an alternative pathway involving electrochemical evolution of chlorine gas followed by Cl2-mediated electrophilic dichlorination.
View details for DOI 10.1021/jacs.7b09388
View details for Web of Science ID 000414506400041
View details for PubMedID 28988482
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Radical Redox-Relay Catalysis: Formal [3+2] Cycloaddition of <i>N</i>-Acylaziridines and Alkenes
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
2017; 139 (35): 12141-12144
Abstract
We report Ti-catalyzed radical formal [3+2] cycloadditions of N-acylaziridines and alkenes. This method provides an efficient approach to the synthesis of pyrrolidines, structural units prevalent in bioactive compounds and organocatalysts, from readily available starting materials. The overall redox-neutral reaction was achieved via a redox-relay mechanism, which harnesses radical intermediates for selective C-N bond cleavage and formation.
View details for DOI 10.1021/jacs.7b06723
View details for Web of Science ID 000410255600010
View details for PubMedID 28825816
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Metal-catalyzed electrochemical diazidation of alkenes
SCIENCE
2017; 357 (6351): 575-579
Abstract
Vicinal diamines are a common structural motif in bioactive natural products, therapeutic agents, and molecular catalysts, motivating the continuing development of efficient, selective, and sustainable technologies for their preparation. We report an operationally simple and environmentally friendly protocol that converts alkenes and sodium azide-both readily available feedstocks-to 1,2-diazides. Powered by electricity and catalyzed by Earth-abundant manganese, this transformation proceeds under mild conditions and exhibits exceptional substrate generality and functional group compatibility. Using standard protocols, the resultant 1,2-diazides can be smoothly reduced to vicinal diamines in a single step, with high chemoselectivity. Mechanistic studies are consistent with metal-mediated azidyl radical transfer as the predominant pathway, enabling dual carbon-nitrogen bond formation.
View details for DOI 10.1126/science.aan6206
View details for Web of Science ID 000407324800037
View details for PubMedID 28798126