We report an intermolecular, cross-selective [2 + 2] cycloaddition between cyclic styrenes and olefin acceptors proceeding via visible-light irradiation, enabled by the extended triplet lifetime of cyclic styrenes. A broad range of olefins, including electron-deficient and simple alkenes, (hetero)styrenes, arylimines, vinyl boronate esters, among others, underwent efficient cycloaddition with cyclic styrenes constrained by four-, five-, and rigidified six-membered rings, providing rapid access to sp3-rich fused cyclobutane scaffolds. Notably, the [2 + 2] cycloaddition between two electronically similar styrenes, which typically gives statistical mixtures of homo- and heterodimers, proceeded with excellent chemoselectivity and yield between cyclic and acyclic styrenes without requiring a large excess of one reactant, facilitated by the significant difference in triplet lifetime between the reacting partners. Mechanistic studies and DFT calculations support a Dexter energy transfer mechanism of substrate activation and underscore the critical role of triplet lifetime extension in enabling the observed reactivity. The utility of this method is demonstrated in the total synthesis of lindleyanin, requiring only two steps.

ConspectusMethods that enable the selective functionalization of C-C bonds offer unique opportunities for the skeletal diversification of complex molecules and provide access to unique structures without the need for de novo synthesis. While considerable advances have been made in transition-metal-based approaches, much recent work has focused on alternative strategies for C-C bond cleavage enabled by transient free radicals. In particular, alkoxy radicals derived from simple alcohols are known to significantly destabilize adjacent C-C bonds, enabling spontaneous cleavage to eject a carbon-centered radical and afford carbonyl products via β-fragmentation. While this reactivity has long been recognized, its applications in synthesis have been limited, in part, by the challenges associated with generating the key alkoxy radical intermediates. The high bond dissociation free energies (BDFEs) of aliphatic alcohol O-H bonds (∼105 kcal/mol) preclude direct homolytic activation by hydrogen atom transfer, and most established strategies rely instead on stoichiometric prefunctionalization of the O-H bond. These approaches often further limit the scope of amenable chemistries that can be applied for postcleavage alkyl radical functionalization. Methods that could overcome these constraints have considerable synthetic potential, enabling straightforward access to reconfigured carbon frameworks from an abundant class of starting materials, as well as modular opportunities for radical functionalization. In this Account, we present our efforts toward the development of proton-coupled electron transfer (PCET) as a general mechanism for alkoxy radical generation from simple alcohols. In turn, this advance enabled us to develop a suite of novel methods for editing complex carbon frameworks via the cleavage and functionalization of C(sp3)-C(sp3) bonds. We first discuss the development of catalytic ring-opening isomerization reactions of cyclic benzylic carbinols to access linear aryl ketone products through a redox-relay approach. In these reactions, single electron oxidation of the substrate arene by an excited-state Ir(III) photocatalyst generates an arene radical cation that serves as an internal oxidant for an intramolecular PCET event, furnishing the alkoxy radical intermediate. This intermediate then undergoes C-C β-scission to provide the isomerized linear ketone products. We next present the discovery of an improved catalytic system for the direct activation of simple aliphatic alcohols. We then apply these chemistries for the light-driven depolymerization of lignin biopolymers, commercial phenoxy resins, hydroxylated polymers, and thiol epoxy thermosets. Notably, many of these redox isomerization reactions are thermodynamically unfavorable, providing isomerization products that are thermodynamically less stable than their corresponding starting materials. We then discuss the application of O-H PCET for the reconfiguration of saturated carbocyclic frameworks to provide expanded and contracted carbocyclic products. Applications of this reconfiguration strategy toward the 1,3-alkyl rearrangement of linear alcohols are also presented. Lastly, we discuss a method for the peripheral-to-core transposition of amine groups of saturated cyclic amino alcohols to access nitrogen-containing heterocyclic products. Taken together, these examples highlight how excited-state PCET can be leveraged for the catalytic generation of high energy O-centered radicals for regioselective C-C bond cleavage and enables the direct reconfiguration of complex carbon frameworks.

We report a method for the dynamic resolution of racemic amines enabled by catalytic photoredox-mediated racemization coupled to in situ diastereomeric crystallization. In this design, an excited-state iridium chromophore and an achiral thiol cocatalyst mediate the racemization of α-chiral amines under mild, redox-neutral conditions. In the presence of commercially available chiral resolving acids, the desired amine enantiomer is continually precipitated from solution as an insoluble diastereomeric salt. We demonstrate the utility of this method across several structurally distinct families of secondary and tertiary amines with high yields and high levels of enantioselectivity. Given the widespread importance of α-stereogenic amines in the synthesis of fine chemicals, we anticipate that this approach may find further applications that streamline the preparation of these valuable chiral compounds.

The design of catalysts capable of functionalizing unactivated C(sp3)-H bonds remains a significant goal in synthetic organic chemistry. Herein, we present a novel set of iridium polypyridyl complexes bearing pendent Brønsted basic carboxylates that become potent hydrogen atom abstraction catalysts upon visible light irradiation. Thermochemical and spectroscopic characterization reveal that these excited-state complexes exhibit bond dissociation free energies (BDFEs) of up to 105 kcal mol-1 with long excited-state lifetimes. We demonstrate that these complexes can catalyze C-H alkylation reactions in which the Ir carboxylate mediates both C-H abstraction and formation steps. Mechanistic, spectroscopic, and computational studies are consistent with C-H abstraction proceeding through an excited-state proton-coupled electron transfer (PCET) step. The modular nature of these Ir polypyridyl complexes establishes a foundation for designing tunable and efficient C-H functionalization catalysts based on covalent tethering of excited-state oxidants and bases.

We report the enantioselective hydrodifluoroalkylation of alkenes proceeding via an asymmetric hydrogen atom transfer (HAT) event catalyzed by thiol-containing tetrapeptides. Photocatalytic generation of a difluoroacetyl radical followed by carbon-carbon bond formation results in a prochiral carbon-centered radical that engages with the chiral catalyst. A trialkylamine reductant is proposed to turn over the catalyst in this net-reductive transformation. Notably, incorporating an (S)-β-methyl-substituted cysteine as the N-terminal residue improved selectivity relative to that of the native N-terminal cysteine (Cys) residue, and X-ray crystallographic analysis supports the conformational underpinning of this effect. A range of enantioenriched γ-substituted amides were synthesized in up to a 96:4 enantiomeric ratio, demonstrating the broad functional group tolerance of this method. Models accounting for asymmetric induction are proposed with supporting DFT calculations.

This study describes a method for the stereoselective synthesis of highly functionalized bicyclo[2.1.0]pentanes (housanes). The approach utilizes a two-step sequence, a silver- or gold-catalyzed cyclopropenation of alkynes followed by an intermolecular [2 + 2] photocycloaddition reaction with electron-deficient alkenes. The cyclopropenation is an established reaction of aryldiazoacetates. A regioselective [2 + 2] cycloaddition of the cyclopropane was developed using blue LED irradiation, a commercially available photocatalyst as a triplet-sensitizer, and low reaction temperature (-40 degrees C). The [2 + 2] cycloaddition is highly diastereoselective, and when enantioenriched cyclopropenes are used, it proceeds with enantioretention.

Hammett substituent constants (σ), which quantify the electronic effects of functional groups, are widely used for predicting the properties of organic compounds and investigating reaction mechanisms. While these values have been obtained for a wide range of closed-shell substituents, measurements of analogous values for open-shell substituents are rare due to challenges associated with their short lifetimes. In this report, we developed a combined experimental and computational approach for quantifying the electronic properties of open-shell substituents based on changes in nitrile vibrational frequencies (ν(C≡N)). By coupling pulse radiolysis and time-resolved infrared spectroscopy (PR-TRIR), we measured ν(C≡N) IR bands of 30 para- and meta-substituted benzonitriles bearing C-, N-, and S-centered radicals. A linear scaling relationship was obtained between these experimental values and values obtained from DFT calculations. Using these computed values, two different Hammett constants, σm, and σp+, were determined for a series of C-, N-, O-, S-, Si-, and B-centered radicals. The differences between σm and σp+ values enable the separate evaluation of inductive and resonance effects in these open-shell substituents. The results suggest that there are three classes of radicals: one is electron withdrawing (σm, σp+ > 0), one is electron donating (σm, σp+ < 0), and one is inductively withdrawing but resonance donating (σm > 0, σp+ < 0). Our study represents a general approach to the analysis of the electronic properties of open-shell species and has potential applications in a wide range of molecular processes involving free radical intermediates.

We report a photoredox-enabled deracemization of cyclic α-aryl ketones that occurs with high stereoselectivity and yield and proceeds by mechanistically distinct proton transfer reactions. This reaction is jointly mediated by a visible-light photocatalyst and a chiral phosphate base cocatalyst under blue light irradiation. Notably, the extent of deracemization for this reaction exhibits an unexpected dependence on the identity of the photocatalyst and the concentration of a chiral base cocatalyst, wherein the extent of deracemization can be increased by employing photocatalysts with more positive ground-state reduction potentials, raising the concentration of the chiral base cocatalyst, or by a combination of these factors. This effect is attributed to two competing processes, back-electron transfer and deprotonation, which consume the same reaction intermediate, and we propose a kinetic model that rationalizes this behavior. We also demonstrate that the redox properties of the photocatalyst impact the stereoselectivity of the product-forming step, which is the dominant stereoselective step in this transformation. Together, these mechanistic insights facilitate a deeper understanding of the complexity of light-driven deracemization reactions involving reversible electron transfer and suggest approaches by which the stereoselectivity of these processes may be increased.

Nucleophilic aromatic substitution (SNAr) reactions are widely employed in organic synthesis yet typically require the use of electron-deficient arenes for efficient reactivity. Herein, we report a photocatalytic protocol for formal SNAr of electron-rich 4-halophenols with azole nucleophiles under mild, redox-neutral conditions. The transformation proceeds via a two-stage mechanism consisting of initial halophenol oligomerization to produce a key oligo(phenylene oxide) intermediate and its subsequent breakdown through SNAr with the azole enabled by photoredox-catalyzed arene umpolung. Reaction monitoring, stoichiometric control experiments, and luminescence quenching data implicate phenoxyl radicals and Brønsted acid-activated oligo(phenylene oxide) radicals as the reactive species in the oligomerization and the SNAr stages, respectively. The synthetic utility of this method is demonstrated across 17 (pseudo)halophenols bearing a variety of leaving groups (F, Cl, Br, OMs, and OTs) and 22 azole examples.

Biologically active molecules are often comprised of ring structures that precisely position functional groups to enable target-specific interactions. The iterative permutation of these structural arrangements is central to the modern drug discovery process, necessitating de novo synthesis to access isomeric compounds with distinct biological properties. However, methods to interconvert saturated ring systems remains limited. We report a general method for the peripheral-to-core nitrogen internalization of amino cycloalkanols to access N-heterocycles of various oxidation states. In this process, an excited-state iridium chromophore and weak Brønsted base cooperatively promote the endergonic redox isomerization of cyclic amino alcohols to linear amine-containing products that undergo in situ cyclization. This strategy enables the expansion, contraction, and carbon-to-nitrogen substitution of cyclic amino alcohols, providing access to structurally distinct heterocyclic scaffolds.

We show that in low dielectric constant (εr) solvents, the prototypical cationic photoredox catalyst [Ir(III)(dFCF3ppy)2-(5,5'-dCF3bpy)]+ is capable of oxidizing its counterion in an unexpected photoinduced electron transfer (PET) process. Photoinduced oxidation of the tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (abbv. [BAr4F]-) anion leads to its irreversible decomposition and a buildup of the neutral Ir(III)(dFCF3ppy)3-(5,5'-dCF3 bpy·-) (abbv. [Ir(dCF3·-)]0) species. The rate constant of the PET reaction, krxn, between the two oppositely charged ions was determined by monitoring the growth of absorption features associated with the singly reduced product molecule, [Ir(dCF3·-)]0, in various solvents with a range of εr. The PET reaction between the ions of [Ir(dCF3) - BAr4F] is predicted to be nonspontaneous (ΔGPET ≥ 0) in high εr solvents, such as acetonitrile, and we observe that krxn ≃ 0 under these circumstances. However, krxn increases as εr decreases. We attribute this change in spontaneity to the electrostatic work described by the Born (ΔGS) and Coulomb (W) correction terms to the change in Gibbs free energy of a PET (ΔGPET). The electrostatic work associated with these often-neglected corrections can be utilized to design novel and surprising photoredox chemistry. Our facile preparation of [Ir(dCF3·-)]0 is one example of a general rule: ion-paired reactants can result in energetic neutral products that chemically store photon energy without an associated Coulomb binding between them.

Biologically active molecules are often composed of ring structures that precisely position functional groups to enable target-specific interactions. The iterative permutation of these structural arrangements is central to the modern drug discovery process, necessitating de novo synthesis to access isomeric compounds with distinct biological properties. However, methods to interconvert saturated ring systems remain limited. Here we report a general method for the peripheral-to-core nitrogen internalization of amino cycloalkanols to access N-heterocycles of various oxidation states. In this process, an excited-state iridium chromophore and weak Brønsted base cooperatively promote the endergonic redox isomerization of cyclic amino alcohols to linear amine-containing products that undergo in situ cyclization. This strategy enables the expansion, contraction, and carbon-to-nitrogen substitution of cyclic amino alcohols, providing access to structurally distinct heterocyclic scaffolds.

Catalytic intermolecular olefin hydroamination is an enabling synthetic strategy that offers direct and atom-economical access to a variety of nitrogen-containing compounds from abundant feedstocks. However, despite numerous advances in catalyst design and reaction development, hydroamination of N–H azoles with unactivated olefins remains an unsolved problem in synthesis. We report a dual phosphine and photoredox catalytic protocol for the hydroamination of numerous structurally diverse and medicinally relevant N–H azoles with unactivated olefins. Hydroamination proceeds with high anti-Markovnikov regioselectivity and N-site selectivity. The mild conditions and high functional group tolerance of the reaction permit the rapid construction of molecular complexity and late-stage functionalization of bioactive compounds. N–H bond activation is proposed to proceed via polar addition of the N–H heterocycle to a phosphine radical cation, followed by P–N α-scission from a phosphoranyl radical intermediate. Reac-tivity and N-site selectivity are classified by heterocycle N–H BDFE and nitrogen-centered radical (NCR) spin density, respectively, which can serve as a useful predictive aid in extending the reaction to unseen azoles.

Conspectus: Chemists have long been inspired by biological photosynthesis, wherein a series of excited-state electron transfer (ET) events facilitate the conversion of low energy starting materials such as H2O and CO2 into higher energy products in the form of carbohydrates and O-2. While this model for utilizing light-driven charge transfer to drive catalytic reactions thermodynamically "uphill" has been extensively adapted for small molecule activation, molecular machines, photoswitches, and solar fuel chemistry, its application in organic synthesis has been less systematically developed. However, the potential benefits of these approaches are significant, both in enabling transformations that cannot be readily achieved using conventional thermal chemistry and in accessing distinct selectivity regimes that are uniquely enabled by excited-state mechanisms. In this Account, we present work from our group that highlights the ability of visible light photoredox catalysis to drive useful organic transformations away from their equilibrium positions, addressing a number of long-standing synthetic challenges. We first discuss how excited-state ET enabled the first general methods for the catalytic anti-Markovnikov hydroamination of unactivated alkenes with alkyl amines. In these reactions, an excited-state iridium(III) photocatalyst reversibly oxidizes secondary amine substrates to their corresponding aminium radical cations (ARCs). These electrophilic N-centered radicals can then react with olefins to furnish valuable tertiary amine products with complete anti-Markovnikov regioselectivity. Notably, some of these products are less thermodynamically stable than their corresponding amine and alkene starting materials. We next present a strategy for light-driven C-C bond cleavage within various aliphatic alcohols mediated by homolytic activation of alcohol O-H bonds by excited-state proton-coupled electron transfer (PCET). The resulting alkoxy radical intermediates then undergo C-C beta-scission to ultimately provide isomeric linear carbonyl products that are often higher in energy than their cyclic alcohol precursors. Applications of this chemistry for the light-driven depolymerization of lignin biomass, commercial phenoxy resin, hydroxylated polyolefin derivatives, and thermoset polymers are presented as well. We then describe a method for the contrathermodynamic positional isomerization of highly substituted olefins by means of cooperative photoredox and chromium(II) catalysis. In this work, generation of an allylchromium(III) species that can undergo highly regioselective in situ protodemetalation enables access to a less substituted and thermodynamically less stable positional isomer. Product selectivity in this reaction is determined by the large differential in oxidation potentials between differently substituted olefin isomers. Lastly, we discuss a light-driven deracemization reaction developed in collaboration with the Miller group, wherein a racemic urea substrate undergoes spontaneous optical enrichment upon visible light irradiation in the presence of an iridium(III) chromophore, a chiral Br & oslash;nsted base, and a chiral peptide thiol. Excellent levels of enantioselectivity are achieved via sequential and synergistic proton transfer (PT) and H atom transfer (HAT) steps. Taken together, these examples highlight the ability of excited-state ET events to enable access to nonequilibrium product distributions across a wide range of catalytic, redox-neutral transformations in which photons are the only stoichiometric reagents.

A light-driven method for the generation of aryl radicals from triarylbismuth(III) and (V) reagents is described. Aryl radical generation is proposed to occur through the ligand-assisted mesolytic cleavage of an organobismuth(IV) intermediate generated from either oxidation of Bi-III or reduction of Bi-V. This mode of aryl radical generation is demonstrated to be compatible with a range of bimolecular radical arylations, including hydroarylation of electron-deficient olefins and arylation of diboronates, disulfides, sulfonyl cyanides, phosphites, and isocyanides. The intermediacy of an aryl radical is supported by radical trapping and radical clock experiments, and Bi-IV-aryl mesolysis is supported computationally.

Nitrogen-vacancy centers in diamond are a promising platform for nanoscale nuclear magnetic resonance sensing. Despite significant progress towards using NV centers to detect and localize nuclear spins down to the single spin level, NV-based spectroscopy of individual, intact, arbitrary target molecules remains elusive. NV molecular sensing requires that target molecules are immobilized within a few nanometers of NV centers with long spin coherence time. The inert nature of diamond typically requires harsh functionalization techniques such as thermal annealing or plasma processing, limiting the scope of functional groups that can be attached to the surface. Solution-phase chemical methods can be more readily generalized to install diverse functional groups, but they have not been widely explored for single-crystal diamond surfaces. Moreover, realizing shallow NV centers with long spin coherence times requires highly ordered single-crystal surfaces, and solution-phase functionalization has not yet been shown to be compatible with such demanding conditions. In this work, we report a versatile strategy to directly functionalize C-H bonds on single-crystal diamond surfaces under ambient conditions using visible light. This functionalization method is compatible with charge stable NV centers within 10 nm of the surface with spin coherence times comparable to the state of the art. As a proof of principle, we use shallow ensembles of NV centers to detect nuclear spins from functional groups attached to the surface. Our approach to surface functionalization based on visible light-driven C-H bond activation opens the door to deploying NV centers as a broad tool for chemical sensing and single-molecule spectroscopy.

A general method for the light-driven intermolecular anti-Markovnikov hydroamination of alkenes with primary sulfonamides, sulfamides, and sulfamates is presented. The reaction is mediated by a ternary catalyst system composed of an iridium(III) chromophore, a fluorinated alkoxide base, and a thiol H-atom donor. We hypothesize that the reactions proceed via a proton-coupled electron transfer (PCET) mechanism wherein implementation of the alkoxide base imparts additional thermochemical driving force for the homolytic activation of strong N-H bonds that were previously inaccessible using this methodology. This furnishes electrophilic N-centered radicals that subsequently interface with a wide range of unactivated alkenes for C-N bond formation. This protocol exhibits a broad substrate scope and great functional group tolerance, further highlighting the advantages of excited-state PCET as a platform for catalytic radical generation from common organic functional groups.

While heteroatom-centered radicals are understood to be highly electrophilic, their ability to serve as transient electron-withdrawing groups and facilitate polar reactions at distal sites has not been extensively developed. Here, we report a new strategy for the electronic activation of halophenols, wherein generation of a phenoxyl radical via formal homolysis of the aryl O-H bond enables direct nucleophilic aromatic substitution of the halide with carboxylate nucleophiles under mild conditions. Pulse radiolysis and transient absorption studies reveal that the neutral oxygen radical (O•) is indeed an extraordinarily strong electron-withdrawing group [σp-(O•) = 2.79 vs σp-(NO2) = 1.27]. Additional mechanistic and computational studies indicate that the key phenoxyl intermediate serves as an open-shell electron-withdrawing group in these reactions, lowering the barrier for nucleophilic substitution by more than 20 kcal/mol relative to the closed-shell phenol form of the substrate. By using radicals as transient activating groups, this homolysis-enabled electronic activation strategy provides a powerful platform to expand the scope of nucleophile-electrophile couplings and enable previously challenging transformations.

We report a highly enantioselective radical-based hydroamination of enol esters with sulfonamides jointly catalyzed by an Ir photocatalyst, Brønsted base, and tetrapeptide thiol. This method is demonstrated for the formation of 23 protected β-amino-alcohol products, achieving selectivities up to 97:3 er. The stereochemistry of the product is set through selective hydrogen atom transfer from the chiral thiol catalyst to a prochiral C-centered radical. Structure-selectivity relationships derived from structural variation of both the peptide catalyst and olefin substrate provide key insights into the development of an optimal catalyst. Experimental and computational mechanistic studies indicate that hydrogen-bonding, π-π stacking, and London dispersion interactions are contributing factors for substrate recognition and enantioinduction. These findings further the development of radical-based asymmetric catalysis and contribute to the understanding of the noncovalent interactions relevant to such transformations.