Open-shell Intermediates Research Articles

Transition-Metal-Catalyst-Free Electroreductive Hydroarylation of Alkenes with Aryl Halides

The radical hydroarylation of alkenes provides synthetically valuable linear alkylarenes with high anti-Markovnikov selectivity. Aryl halides are ideal radical precursors owing to their chemical stability and wide commercial availability. Over the past few decades, electrochemistry has proven to be an convenient approach for accessing open-shell intermediates through a single-electron transfer process, and the electroreduction of aryl halides has been demonstrated as a powerful method to generate aryl radical species.1 Despite recent progress in the development of aryl radical-involved electroreductive coupling reactions, the reported intermolecular radical hydroarylation of alkenes without transition-metal catalysts still has some drawbacks, such as the use of a Hg pool cathode and liquid NH3 solvent.2 Hearin, we report a transition-metal-catalyst-free elctroreductive hydroarylation of alkenes using aryl halides as radical precursors. The hydroarylation was performed in acetonitrile using an undivided cell equipped with an Al anode and a Pt cathode, and the use of 1,3-dicyanobenzene as a redox mediator under visible-light irradiation enabled the desired transformation to proceed with high efficiency. Electron-deficient (hetero)aryl chlorides and electron-rich aryl iodides successfully reacted with various Michael acceptors and styrene derivatives, providing a variety of linear alkylarenes in good to high yields. Mechanistic investigations indicated that this transformation would proceed through a reductive radical-polar crossover pathway.(1) Xiang, H.; He, J.; Qian, W.; Qiu, M.; Xu, H.; Duan, W.; Ouyang, Y.; Wang, Y.; Zhu, C. Molecules 2023, 28, 857.(2) Chami, Z.; Gareil, M.; Pinson, J.; Savéant, J.-M.; Thiébault, A. J. Org. Chem. 1991, 56, 586–595. Figure 1

Direct Observation of All Open-Shell Intermediates in a Photocatalytic Cycle.

Molecular photocatalysis has shown tremendous success in sustainable energy and chemical synthesis. However, visualizing the transient open-shell intermediates in photocatalysis is a significant and long-standing challenge. By employing our recently developed innovative time-resolved electron paramagnetic resonance technique, we directly observed all radicals and radical ions involved in the photocatalytic addition of pempidine to tert-butyl acrylate. The full picture of the photocatalytic cycle is vividly illustrated by the fine structures, chemical kinetics, and dynamic spin polarization of all open-shell intermediates directly observed in this prototypical system. Given the universality of this methodology, we believe it greatly empowers the research paradigm of direct observation in both photocatalysis and radical chemistry.

Boosting Energy-Transfer Processes via Dispersion Interactions.

The generation of open-shell intermediates under mild conditions has opened broad synthetic opportunities during this century. However, these reactive species often require a case specific and tailored tuning of experimental parameters in order to efficiently convert substrates into products. We report a general approach that can overcome these ubiquitous limitations for several visible-light promoted energy-transfer processes. The use of either naphthalene (5-20 equiv.) or simple binaphthyl derivatives (10-30 mol %) greatly increases their efficiency, giving rise to a new strategy for catalysis. The trend is consistent among different media, photocatalysts, light sources and substrates, allowing one to improve existing methods, to more easily optimize conditions for new ones, and, moreover, to disclose otherwise inaccessible reaction pathways.

(Invited) Electroreductive C-S and C-O Bond Cleavage in Thioethers and Alcohols

Alcohols and thioethers are highly prevalent in both natural and synthetic organic compounds but remain underexplored as starting materials in radical transformations. For this reason, new synthetic methods are highly desirable to unlock the potential of the compound classes. Here, electroreductive cleavage of C-S and C-O bonds in aryl alkyl thioethers and benzylic alcohols is described, along with mechanistic details. The reactions proceed via radical intermediates that, depending on the potential at which they form, may be trapped with electron deficient alkenes in Giese reactions. Alternatively, the open shell intermediates can undergo a radical-polar crossover to the corresponding anions with subsequent protonation or carboxylation to furnish alkanes or arylacetic acid products. Figure 1

(Invited) Electrocatalytic Radical-Polar Crossover Hydrofunctionalization of Alkenes

Due to the unique reactivity of open-shell intermediates, the development of catalytic transformations driven by single-electron transfer (SET) has been an area of intense research in organic chemistry. In particular, the employment of unconventional means of activation, including photoredox catalysis and electrocatalysis, has provided unique entry to single-electron reactivities and led to new solutions to challenging synthetic problems that are not readily addressed using existing tools.We disclose a general electrocatalytic hydrofunctionalization by utilizing a wide range of alkenes. The integration of the two involves an electrochemically instigated cobalt-hydride-catalyzed radical-polar crossover of alkenes that enable the generation of key cationic intermediates, which could readily be entrapped by challenging nucleophiles. We highlight the importance of precise control of the reaction potential by electrochemistry in conjunction with the decisive role of 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) as the co-solvent to obtain optimal and exclusive chemoselectivity.In addition, we develope an electrocatalytic method for intramolecular hydroamination of allylic sulfonamides to access azetidines. The merger of cobalt catalysis and electricity enables regioselective generation of key carbocationic intermediates, which could directly undergo intramolecular C-N bond formation. The mechanistic investigations including electrochemical kinetic analysis suggest that the catalyst regeneration by nucleophilic cyclization is involved in the rate-determining step (RDS) of our electrochemical protocol and highlight the ability of electrochemistry in providing ideal means to mediate catalyst oxidation.

Iodanyl Radical Catalysis.

ConspectusHypervalent iodine reagents find application as selective chemical oxidants in a diverse array of oxidative transformations. The utility of these reagents is often ascribed to (1) the proclivity to engage being selective two-electron redox transformations; (2) facile ligand exchange at the three-centered, four-electron (3c-4e) hypervalent iodine-ligand (I-X) bonds; and (3) the hypernucleofugacity of aryl iodides. One-electron redox and iodine radical chemistry is well-precedented in the context of inorganic hypervalent iodine chemistry─for example, in the iodide-triiodide couple that drives dye-sensitized solar cells. In contrast, organic hypervalent iodine chemistry has historically been dominated by the two-electron I(I)/I(III) and I(III)/I(V) redox couples, which results from intrinsic instability of the intervening odd-electron species. Transient iodanyl radicals (i.e., formally I(II) species), generated by reductive activation of hypervalent I-X bonds, have recently gained attention as potential intermediates in hypervalent iodine chemistry. Importantly, these open-shell intermediates are typically generated by activation of stoichiometric hypervalent iodine reagents, and the role of the iodanyl radical in substrate functionalization and catalysis is largely unknown.Our group has been interested in advancing the chemistry of iodanyl radicals as intermediates in the sustainable synthesis of hypervalent I(III) and I(V) compounds and as novel platforms for substrate activation at open-shell main-group intermediates. In 2018, we disclosed the first example of aerobic hypervalent iodine catalysis by intercepting reactive intermediates in aldehyde autoxidation chemistry. While we initially hypothesized that the observed oxidation was accomplished by aerobically generated peracids via a two-electron I(I)-to-I(III) oxidation reaction, detailed mechanistic studies revealed the critical role of acetate-stabilized iodanyl radical intermediates. We subsequently leveraged these mechanistic insights to develop hypervalent iodine electrocatalysis. Our studies resulted in the identification of new catalyst design principles that give rise to highly efficient organoiodide electrocatalysts that operate at modest applied potentials. These advances addressed classical challenges in hypervalent iodine electrocatalysis related to the need for high applied potentials and high catalyst loadings. In some cases, we were able to isolate the anodically generated iodanyl radical intermediates, which allowed direct interrogation of the elementary chemical reactions characteristic of iodanyl radicals. Both substrate activation via bidirectional proton-coupled electron transfer (PCET) reactions at I(II) intermediates and disproportionation reactions of I(II) species to generate I(III) compounds have been experimentally validated.This Account discusses the emerging synthetic and catalytic chemistry of iodanyl radicals. Results from our group have demonstrated that these open-shell species can play a critical role in sustainable synthesis of hypervalent iodine reagents and play a heretofore unappreciated role in catalysis. Realization of I(I)/I(II) catalytic cycles as a mechanistic alternative to canonical two-electron iodine redox chemistry promises to open new avenues to application of organoiodides in catalysis.

Photoinduced Electron Transfer from Xanthates to Acyl Azoliums: Divergent Ketone Synthesis via N-Heterocyclic Carbene Catalysis.

Considering the prevalence of alcohols and carboxylic acids, their fragment cross-coupling reactions could hold significant implications in organic synthesis. Herein, we report a versatile method for synthesizing a diverse range of ketones from alcohols and carboxylic acid derivatives via N-heterocyclic carbene (NHC) catalysis. Mechanistic investigations revealed that photoexcited xanthates and acyl azoliums undergo single electron transfer (SET) under photocatalyst-free conditions, generating NHC-derived ketyl radicals and alkyl radicals. These open-shell intermediates subsequently undergo the radical-radical cross-coupling reaction, yielding valuable ketones. Furthermore, this approach can be employed in three-component reactions involving alkenes and enynes, resulting in structurally diverse cross-coupled ketones. The unified strategy offers a unique opportunity for the fragment coupling of a diverse range of alcohols and carboxylic acid derivatives, accommodating diverse functional groups even in complex settings.

Photoredox-Catalysis-Enabled Ring-Opening Functionalization of Aryl Cyclopropanes

AbstractCyclopropanes have long been recognized as privileged synthons in organic synthesis, providing access to 1,3-difunctionalized scaffolds. However, the synthetic potential of aryl cyclopropanes, one of the most important subclasses of cyclopropanes, is far less explored. Recently, we uncovered a visible-light-promoted strategy for the ring-opening functionalization of a series of aryl cyclopropanes through open-shell intermediates. By leveraging the activation of an aryl radical cation derived from an oxidative single-electron transfer, the C–C bond of the cyclopropane is weakened and cleaves upon a regio- and stereoselective nucleophilic attack with an exogenous nucleophile to provide a benzyl radical that can be readily elaborated to diverse functionalities.1 Introduction2 Core Concept of Our Design3 Photoredox-Catalyzed Oxoamination of Aryl Cyclopropanes4 Photoredox-Catalyzed Hydroheterofunctionalization of Aryl Cyclopropanes5 Photoredox-Catalyzed Fluoroallylation of gem-Difluorocyclopropanes6 Conclusion

Asymmetric Photochemical [2 + 2]-Cycloaddition of Acyclic Vinylpyridines through Ternary Complex Formation and an Uncontrolled Sensitization Mechanism.

Stereochemical control of photochemical reactions that occur via triplet energy transfer remains a challenge. Suppressing off-catalyst stereorandom reactivity is difficult for highly reactive open-shell intermediates. Strategies for suppressing racemate-producing, off-catalyst pathways have long focused on formation of ground state, substrate-catalyst chiral complexes that are primed for triplet energy transfer via a photocatalyst in contrast to their off-catalyst counterparts. Herein, we describe a strategy where both a chiral catalyst-associated vinylpyridine and a nonassociated, free vinylpyridine substrate can be sensitized by an Ir(III) photocatalyst, yet high levels of diastereo- and enantioselectivity in a [2 + 2] photocycloaddition are achieved through a preferred, highly organized transition state. This mechanistic paradigm is distinct from, yet complementary to current approaches for achieving high levels of stereocontrol in photochemical transformations.

Noncovalent Stabilization of Radical Intermediates in the Enantioselective Hydroamination of Alkenes with Sulfonamides.

Noncovalent interactions (NCIs) are critical elements of molecular recognition in a wide variety of chemical contexts. While NCIs have been studied extensively for closed-shell molecules and ions, very little is understood about the structures and properties of NCIs involving free radical intermediates. In this report, we describe a detailed mechanistic study of the enantioselective radical hydroamination of alkenes with sulfonamides and present evidence suggesting that the basis for asymmetric induction in this process arises from attractive NCIs between a neutral sulfonamidyl radical intermediate and a chiral phosphoric acid (CPA). We describe experimental, computational, and data science-based evidence that identifies the specific radical NCIs that form the basis for the enantioselectivity. Kinetic studies support that C-N bond formation determines the enantioselectivity. Density functional theory investigations revealed the importance of both strong H-bonding between the CPA and the N-centered radical and a network of aryl-based NCIs that serve to stabilize the favored diastereomeric transition state. The contributions of these specific aryl-based NCIs to the selectivity were further confirmed through multivariate linear regression analysis by comparing the measured enantioselectivity to computed descriptors. These results highlight the power of NCIs to enable high levels of enantioselectivity in reactions involving uncharged open-shell intermediates and expand our understanding of radical-molecule interactions.

Geometrical and Electronic Structure of Cation Radical Species of Tetraarylanthraquinodimethane: An Intermediate for Unique Electrochromic Behavior.

Two tetraarylanthraquinodimethane (Ar4 AQD) derivatives having two different aryl groups (aminophenyl and methoxyphenyl) were prepared by sequential dibromomethylation and Suzuki-coupling reactions. X-ray analyses showed that they adopt a folded structure in the neutral state whereas the corresponding dications have a planar anthracene ring, to which diarylmethylium units are perpendicularly attached. Different from Ar4 AQD having the same substituents that undergoes facile two-electron transfer during interconversion with the dicationic state, the intermediary cation radical becomes long-lived in the newly prepared unsymmetric derivatives. The geometric and electronic structures of the open-shell intermediates were elucidated through electrochemical and theoretical investigation, with revealing that the cation radicals adopt the twisted geometry like dications. Upon electrolyses of the dications, the twisted cation radicals were involved in the electrochromism whereas their steady-state concentration is negligible in the oxidation process, thus realizing unique tricolor electrochromic behavior with a hysteretic pattern of color change (colorless -> purple -> blue -> colorless).

Engineered P450 Atom-Transfer Radical Cyclases are Bifunctional Biocatalysts: Reaction Mechanism and Origin of Enantioselectivity.

New-to-nature radical biocatalysis has recently emerged as a powerful strategy to tame fleeting open-shell intermediates for stereoselective transformations. In 2021, we introduced a novel metalloredox biocatalysis strategy that leverages the innate redox properties of the heme cofactor of P450 enzymes, furnishing new-to-nature atom-transfer radical cyclases (ATRCases) with excellent activity and stereoselectivity. Herein, we report a combined computational and experimental study to shed light on the mechanism and origins of enantioselectivity for this system. Molecular dynamics and quantum mechanics/molecular mechanics (QM/MM) calculations revealed an unexpected role of the key beneficial mutation I263Q. The glutamine residue serves as an essential hydrogen bond donor that engages with the carbonyl moiety of the substrate to promote bromine atom abstraction and enhance the enantioselectivity of radical cyclization. Therefore, the evolved ATRCase is a bifunctional biocatalyst, wherein the heme cofactor enables atom-transfer radical biocatalysis, while the hydrogen bond donor residue further enhances the activity and enantioselectivity. Unlike many enzymatic stereocontrol rationales based on a rigid substrate binding model, our computations demonstrate a high degree of rotational flexibility of the allyl moiety in an enzyme-substrate complex and succeeding intermediates. Therefore, the enantioselectivity is controlled by the radical cyclization transition states rather than the substrate orientation in ground-state complexes in the preceding steps. During radical cyclization, anchoring effects of the Q263 residue and steric interactions with the heme cofactor concurrently control the π-facial selectivity, allowing for highly enantioselective C-C bond formation. Our computational findings are corroborated by experiments with ATRCase mutants generated from site-directed mutagenesis.

Dihydroquinazolinones as adaptative C(sp3) handles in arylations and alkylations via dual catalytic C\u2013C bond-functionalization

C–C bond forming cross-couplings are convenient technologies for the construction of functional molecules. Consequently, there is continual interest in approaches that can render traditionally inert functionality as cross-coupling partners, included in this are ketones which are widely-available commodity chemicals and easy to install synthetic handles. Herein, we describe a dual catalytic strategy that utilizes dihydroquinazolinones derived from ketone congeners as adaptative one-electron handles for forging C(sp3) architectures via α C–C cleavage with aryl and alkyl bromides. Our approach is achieved by combining the flexibility and modularity of nickel catalysis with the propensity of photoredox events for generating open-shell reaction intermediates. This method is distinguished by its wide scope and broad application profile––including chemical diversification of advanced intermediates––, providing a catalytic technique complementary to existing C(sp3) cross-coupling reactions that operates within the C–C bond-functionalization arena.

Photobiocatalysis for Abiological Transformations.

Harnessing biocatalysts for novel abiological transformations is a longstanding goal of synthetic chemistry. Combining the merits of biocatalysis and photocatalysis allows for selective transformations fueled by visible light and offers many advantages including new reactivity, high enantioselectivity, greener syntheses, and high yields. Photoinduced electron or energy transfer enables synthetic methodologies that complement conventional two electron processes or offer orthogonal pathways for developing new reactions. Enzymes are well suited and can be tuned by directed evolution to exert control over open-shell intermediates, thereby suppressing undesirable reactions and delivering high chemo- and stereoselectivities. Within the past decade, the combination of biocatalysis and photocatalysis was mainly focused on exploiting light-regenerated cofactors to function native enzymatic activity. However, recent developments have demonstrated that the combination can unlock new-to-nature chemistry. Particularly, the discovery and application of new strategies are well poised to expand the applications of photobiocatalysis.In the past five years, our lab has been studying the combinations of photocatalysis and biocatalysis that can be applied to create new synthetic methodologies and solve challenges in synthetic organic chemistry. Our efforts have expanded the strategies for combining external photocatalysts with enzymes through the construction of a synergistic cooperative stereoconvergent reduction system consisting of photosensitized energy transfer and ene-reductase-catalyzed alkene reduction. Additionally, our efforts have also extended the capability of cofactor-dependent photoenzymatic systems to include enantioselective bimolecular radical hydroalkylations of alkenes by irradiating electron donor-acceptor complexes comprised of enzymatic redox active cofactors and unnatural substrates.In this Account, we highlight strategies developed by our group and others for combining biocatalysis and photocatalysis with the aim of introducing non-natural reactivity to enzymes. Presently, strategies applied to achieve this goal include the repurposing of natural photoenzymes, the elucidation of new photoreactivity within cofactor-dependent enzymes, the combination of external photocatalysts with enzymes, and the construction of artificial photoenzymes. By demonstrating the successful applications of these strategies for achieving selective new-to-nature transformations, we hope to spur interest in expanding the scope of photobiocatalytic systems through the use and extension of these strategies and creation of new strategies. Additionally, we hope to elucidate the intuition in synergizing the unique capabilities of biocatalysis and photocatalysis so that photobiocatalysis can be recognized as a potential solution to difficult challenges in synthetic organic chemistry.

Nontraditional Fragment Couplings of Alcohols and Carboxylic Acids: C(sp3)-C(sp3) Cross-Coupling via Radical Sorting.

Alcohols and carboxylic acids are among the most commercially abundant, synthetically versatile, and operationally convenient functional groups in organic chemistry. Under visible light photoredox catalysis, these native synthetic handles readily undergo radical activation, and the resulting open-shell intermediates can subsequently participate in transition metal catalysis. In this report, we describe the C(sp3)-C(sp3) cross-coupling of alcohols and carboxylic acids through the dual combination of N-heterocyclic carbene (NHC)-mediated deoxygenation and hypervalent iodine-mediated decarboxylation. This mild and practical Ni-catalyzed radical-coupling protocol was employed to prepare a wide array of alkyl-alkyl cross-coupled products, including highly congested quaternary carbon centers from the corresponding tertiary alcohols or tertiary carboxylic acids. We demonstrate the synthetic applications of this methodology to alcohol C1-alkylation and formal homologation, as well as to the late-stage functionalization of drugs, natural products, and biomolecules.

A General Organocatalytic System for Electron Donor–Acceptor Complex Photoactivation and Its Use in Radical Processes

We report herein a modular class of organic catalysts that, acting as donors, can readily form photoactive electron donor–acceptor (EDA) complexes with a variety of radical precursors. Excitation with visible light generates open-shell intermediates under mild conditions, including nonstabilized carbon radicals and nitrogen-centered radicals. The modular nature of the commercially available xanthogenate and dithiocarbamate anion organocatalysts offers a versatile EDA complex catalytic platform for developing mechanistically distinct radical reactions, encompassing redox-neutral and net-reductive processes. Mechanistic investigations, by means of quantum yield determination, established that a closed catalytic cycle is operational for all of the developed radical processes, highlighting the ability of the organic catalysts to turn over and iteratively drive every catalytic cycle. We also demonstrate how the catalysts’ stability and the method’s high functional group tolerance could be advantageous for the direct radical functionalization of abundant functional groups, including aliphatic carboxylic acids and amines, and for applications in the late-stage elaboration of biorelevant compounds and enantioselective radical catalysis.

Site-Selective Functionalization of Methionine Residues via Photoredox Catalysis.

Bioconjugation technologies have revolutionized the practice of biology and medicine by allowing access to novel biomolecular scaffolds. New methods for residue-selective bioconjugation are highly sought to expand the toolbox for a variety of bioconjugation applications. Herein we report a site-selective methionine bioconjugation protocol that uses photoexcited lumiflavin to generate open-shell intermediates. This reduction-potential-gated strategy enables access to residues unavailable with traditional nucleophilicity-based conjugation methods. To demonstrate the versatility and robustness of this new protocol, we have modified various proteins and further utilized this functional handle to append diverse biological payloads.

Fragment Coupling Reactions in Total Synthesis That Form Carbon-Carbon Bonds via Carbanionic or Free Radical Intermediates.

Fragment coupling reactions that form carbon-carbon bonds are valuable transformations in synthetic design. Advances in metal-catalyzed cross-coupling reactions in the early 2000s brought a high level of predictability and reliability to carbon-carbon bond constructions involving the union of unsaturated fragments. By comparison, recent years have witnessed an increase in fragment couplings proceeding via carbanionic and open-shell (free radical) intermediates. The latter has been driven by advances in methods to generate and utilize carbon-centered radicals under mild conditions. In this Review, we survey a selection of recent syntheses that have implemented carbanion- or radical-based fragment couplings to form carbon-carbon bonds. We aim to highlight the strategic value of these disconnections in their respective settings and to identify extensible lessons from each example that might be instructive to students.

A Photochemical Organocatalytic Strategy for the α-Alkylation of Ketones by using Radicals.

Reported herein is a visible‐light‐mediated radical approach to the α‐alkylation of ketones. This method exploits the ability of a nucleophilic organocatalyst to generate radicals upon SN2‐based activation of alkyl halides and blue light irradiation. The resulting open‐shell intermediates are then intercepted by weakly nucleophilic silyl enol ethers, which would be unable to directly attack the alkyl halides through a traditional two‐electron path. The mild reaction conditions allowed functionalization of the α position of ketones with functional groups that are not compatible with classical anionic strategies. In addition, the redox‐neutral nature of this process makes it compatible with a cinchona‐based primary amine catalyst, which was used to develop a rare example of enantioselective organocatalytic radical α‐alkylation of ketones.

Enantioselective Hydroamination of Alkenes with Sulfonamides Enabled by Proton-Coupled Electron Transfer.

An enantioselective, radical-based method for the intramolecular hydroamination of alkenes with sulfonamides is reported. These reactions are proposed to proceed via N-centered radicals formed by proton-coupled electron transfer (PCET) activation of sulfonamide N-H bonds. Noncovalent interactions between the neutral sulfonamidyl radical and a chiral phosphoric acid generated in the PCET event are hypothesized to serve as the basis for asymmetric induction in a subsequent C-N bond forming step, achieving selectivities of up to 98:2 er. These results offer further support for the ability of noncovalent interactions to enforce stereoselectivity in reactions of transient and highly reactive open-shell intermediates.