PUBLICATIONS
Intermolecular Anti-Markovnikov Hydroamination of Alkenes with Sulfonamides, Sulfamides, and Sulfamates
Angela Lin, Mathis J. Karrasch, Qiaolin Yan, Jacob M. Ganley, Benjamin G. Hejna, Robert R. Knowles
ACS Catal.. 2024, 14, 13098–13104. DOI: 10.1021/acscatal.4c03960
Abstract: 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.
Cooperative Phosphine-Photoredox Catalysis Enables N–H Activation of Azoles for Intermolecular Olefin Hydroamination
Kassandra Sedillo, Flora Fan, Robert R. Knowles, Abigail G. Doyle
J. Am. Chem. Soc. 2024, 146, 20349–20356. DOI: 10.1021/jacs.4c05881
Abstract: 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 azole to a phosphine radical cation, followed by P–N α-scission from a phosphoranyl radical intermediate. Reactivity and N-site selectivity are classified by azole N–H BDFE and nitrogen-centered radical spin density, respectively, which can serve as a useful predictive aid in extending the reaction to unseen azoles.
Organic Synthesis Away from Equilibrium: Contrathermodynamic Transformations Enabled by Excited-State Electron Transfer
Angela Lin, Sumin Lee, and Robert R. Knowles
Acc. Chem. Res. 2024, 57, 1827–1838. DOI: 10.1021/acs.accounts.4c00227
Abstract:
(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 O2. 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.
Diamond Surface Functionalization via Visible Light–Driven C–H Activation for Nanoscale Quantum Sensing
Lila V. H. Rodgers, Suong T. Nguyen, James H. Cox, Kalliope Zervas, Zhiyang Yuan, Sorawis Sangtawesin, Alastair Stacey, Cherno Jaye, Conan Weiland, Anton Pershin, Adam Gali, Lars Thomsen, Simon A. Meynell, Lillian B. Hughes, Ania C. Bleszynski Jayich, Xin Gui, Robert J. Cava, Robert R. Knowles, and Nathalie P. de Leon
PNAS 2024, 121, e2316032121. DOI: 10.1073/pnas.2316032121
Abstract:
Nitrogen-vacancy (NV) centers in diamond are a promising platform for nanoscale NMR sensing. Despite significant progress toward 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. Such sensing requires that target molecules are immobilized within nanometers of NV centers with long spin coherence. 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 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 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, forming C–F, C–Cl, C–S, and C–N bonds at the surface. This method is compatible with NV centers within 10 nm of the surface with spin coherence times comparable to the state of the art. As a proof- of- principle demonstration, we use shallow ensembles of NV centers to detect nuclear spins from surface- bound functional groups. Our approach to surface functionalization opens the door to deploying NV centers as a tool for chemical sensing and single- molecule spectroscopy.
Organobismuth Compounds as Aryl Radical Precursors via Light-Driven Single-Electron Transfer
Nicholas D. Chiappini, Eric P. Geunes, Ethan T. Bodak, Robert R. Knowles
ACS Catal. 2024, 14, 2664–2670. DOI: 10.1021/acscatal.3c05598
Abstract: 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.
Photocatalytic Anti-Markovnikov Hydroamination of Alkenes with Primary Heteroaryl Amines
Eric P. Geunes, Jonathan M. Meinhardt, Emily J. Wu, and Robert R. Knowles
J. Am. Chem. Soc. 2023, 145, 21738–21744. DOI: 10.1021/jacs.3c08428
Abstract: We report a light-driven method for the intermolecular anti-Markovnikov hydroamination of alkenes with primary heteroaryl amines. In this protocol, electron transfer between an amine substrate and an excited-state iridium photocatalyst affords an aminium radical cation (ARC) intermediate that undergoes C–N bond formation with a nucleophilic alkene. Integral to reaction success is the electronic character of the amine, wherein increasingly electron-deficient heteroaryl amines generate increasingly reactive ARCs. Counteranion-dependent reactivity is observed, and iridium triflate photocatalysts are employed in place of conventional iridium hexafluorophosphate complexes. This method exhibits broad functional group tolerance across 55 examples of N-alkylated products derived from pharmaceutically relevant heteroaryl amines.
Catalytic Asymmetric Hydrogen Atom Transfer: Enantioselective Hydroamination of Alkenes
Benjamin G. Hejna, Jacob M. Ganley, Huiling Shao, Haowen Tian, Jonathan D. Ellefsen, Nicholas J. Fastuca, K. N. Houk, Scott J. Miller, Robert R. Knowles
J. Am. Chem. Soc. 2023, 145, 16118–16129. DOI: 10.1021/jacs.3c04591
Abstract: 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.
https://pubs.acs.org/doi/10.1021/jacs.3c04591
Isotopic Singly Reduced Iridium Chromophores: Synthesis, Characterization, and Photochemistry
Yunjung Baek, Adam Reinhold, Lei Tian, Philip D. Jeffrey, Gregory D. Scholes, and Robert R. Knowles
J. Am. Chem. Soc. 2023, 145, 12499–12508. DOI: 10.1021/jacs.2c13249
Abstract: One-electron reduced photosensitizers have been invoked as crucial intermediates in photoredox catalysis, including multiphoton excitation and electrophotocatalytic processes. However, such reduced chromophores have been less investigated, limiting mechanistic studies of their associated electron transfer processes. Here, we report a total of 11 different examples of isolable singly reduced iridium chromophores. Chemical reduction of a cyclometalated iridium complex with potassium graphite affords a 19-electron species. Structural and spectroscopic characterizations reveal a ligand-centered reduction product. The reduced chromophore absorbs a wide range of light from ultraviolet to near-infrared and exhibits photoinduced bimolecular electron transfer reactivity. These studies shed light on elusive reduced iridium chromophores in both ground and excited states, providing opportunities to investigate a commonly invoked intermediate in photoredox catalysis.
Isotopic Fractionation as a Mechanistic Probe in Light-Driven C–H Bond Exchange Reactions
Guanqi Qiu, Chi-Li Ni, and Robert R. Knowles
J. Am. Chem. Soc. 2023, 145 11537–11543. DOI: 10.1021/jacs.2c11212
Abstract: Here, we report a diagnostic framework for elucidating the mechanisms of photoredox-based hydrogen isotope exchange (HIE) reactions based on hydrogen/deuterium (H/D) fractionation. Traditional thermal HIE methods generally proceed by reversible bond cleavage and bond reformation steps that share a common transition state. However, bond cleavage and bond reformation in light-driven HIE reactions can proceed via multiple, non-degenerate sets of elementary steps, complicating both mechanistic analysis and attendant optimization efforts. Building on classical treatments of equilibrium isotope effects, the fractionation method presented here extracts information regarding the nature of the key bond-forming and bond-breaking steps by comparing the extent of deuterium incorporation into an exchangeable C–H bond in the substrate relative to the H/D isotopic ratio of a solvent reservoir. We show that the extent of fractionation is sensitive to the mechanism of the exchange process and provides a means to distinguish between degenerate and non-degenerate mechanisms for isotopic exchange. In model systems, the mechanisms implied by the fractionation method align with those predicted by thermochemical considerations. We then employed the method to study HIE reactions whose mechanisms are ambiguous on thermodynamic grounds.
Chemical Recycling of Thiol Epoxy Thermosets via Light-Driven C–C Bond Cleavage
Suong T. Nguyen, Lydia R. Fries, James H. Cox, Yuting Ma, Brett P. Fors, and Robert R. Knowles
J. Am. Chem. Soc. 2023, 145 11151–11160. DOI: 10.1021/jacs.3c00958
Abstract: Epoxy thermosets are high-volume materials that play a central role in a wide range of engineering applications; however, technologies to recycle these polymers remain rare. Here, we present a catalytic, light-driven method that enables chemical recycling of industrially relevant thiol epoxy thermosets to their original monomer at ambient temperature. This strategy relies on the proton-coupled electron transfer (PCET) activation of hydroxy groups within the polymer network to generate key alkoxy radicals that promote the fragmentation of the polymer through C–C bond β-scission. The method fully depolymerizes insoluble thiol epoxy thermosets into well-defined mixtures of small-molecule products, which can collectively be converted into the original monomer via a one-step dealkylation process. Notably, this process is selective and efficient even in the presence of other commodity plastics and additives commonly found in commercial applications. These results constitute an important step toward making epoxy thermosets recyclable and more generally exemplify the potential of PCET to offer a more sustainable end-of-life for a diverse array of commercial plastics.
Radicals as Exceptional Electron-Withdrawing Groups: Nucleophilic Aromatic Substitution of Halophenols Via Homolysis-Enabled Electronic Activation
Nick Y. Shin, Elaine Tsui, Adam Reinhold, Gregory D. Scholes, Matthew J. Bird, Robert R. Knowles
J. Am. Chem. Soc. 2022, 144, 21783–21790. DOI: 10.1021/jacs.2c10296
Abstract: 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.
Radical Redox Annulations: A General Light-Driven Method for the Synthesis of Saturated Heterocycles
Philip R. D. Murray, Isabelle Nathalie-Marie Leibler, Sandrine M. Hell, Eris Villalona, Abigail G. Doyle, Robert R. Knowles
ACS Catal. 2022, 12, 13732–13740. DOI: 10.1021/acscatal.2c04316
Abstract: We introduce here a two-component annulation strategy that provides access to a diverse collection of five- and six-membered saturated heterocycles from aryl alkenes and a family of redox-active radical precursors bearing tethered nucleophiles. This transformation is mediated by a combination of an Ir(III) photocatalyst and a Brønsted acid under visible-light irradiation. A reductive proton-coupled electron transfer generates a reactive radical which undergoes addition to an alkene. Then, an oxidative radical-polar crossover step leading to carbocation formation is followed by ring closure through cyclization of the tethered nucleophile. A wide range of heterocycles are easily accessible, including pyrrolidines, piperidines, tetrahydrofurans, morpholines, δ-valerolactones, and dioxanones. We demonstrate the scope of this approach through broad structural variation of both reaction components. This method is amenable to gram-scale preparation and to complex fragment coupling.
Interference of nuclear wavepackets in a pair of proton transfer reactions
Xinzi Zhang, Kyra N. Schwarz, Luhao Zhang, Francesca Fassioli, Bo Fu, Lucas Q. Nguyen, Robert R. Knowles, Gregory D. Scholes
Proc. Natl. Acad. Sci. U.S.A. 2022, 119, e2212114119 DOI: 10.1073/pnas.2212114119
Abstract: Quantum mechanics revolutionized chemists’ understanding of molecular structure. In contrast, the kinetics of molecular reactions in solution are well described by classical, statistical theories. To reveal how the dynamics of chemical systems transition from quantum to classical, we study femtosecond proton transfer in a symmetric molecule with two identical reactant sites that are spatially apart. With the reaction launched from a superposition of two local basis states, we hypothesize that the ensuing motions of the electrons and nuclei will proceed, conceptually, in lockstep as a superposition of probability amplitudes until decoherence collapses the system to a product. Using ultrafast spectroscopy, we observe that the initial superposition state affects the reaction kinetics by an interference mechanism. With the aid of a quantum dynamics model, we propose how the evolution of nuclear wavepackets manifests the unusual intersite quantum correlations during the reaction.
Noncovalent Stabilization of Radical Intermediates in the Enantioselective Hydroamination of Alkenes with Sulfonamides
Eve Y. Xu, Jacob Werth, Casey B. Roos, Andrew J. Bendelsmith, Matthew S. Sigman, Robert R. Knowles
J. Am. Chem. Soc. 2022, 144, 18948–18958. DOI: 10.1021/jacs.2c07099
Abstract: 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.
Reversible Homolysis of a Carbon–Carbon σ-Bond Enabled by Complexation-Induced Bond-Weakening
Suhong Kim, Pan-Pan Chen, K. N. Houk, Robert R. Knowles
J. Am. Chem. Soc. 2022, 144 15488–15496. DOI: 10.1021/jacs.2c01229
Abstract: A case study of catalytic carbon–carbon σ-bond homolysis is presented. The coordination of a redox-active Lewis acid catalyst reduces the bond-dissociation free energies of adjacent carbon–carbon σ-bonds, and this complexation-induced bond-weakening is used to effect reversible carbon–carbon bond homolysis. Stereochemical isomerization of 1,2-disubstituted cyclopropanes was investigated as a model reaction with a ruthenium (III/II) redox couple adopted for bond weakening. Results from our mechanistic investigation into the stereospecificity of the isomerization reaction are consistent with selective complexation-induced carbon–carbon bond homolysis. The ΔG‡ of catalyzed and uncatalyzed reactions were estimated to be 14.4 and 40.0 kcal/mol, respectively with the computational method, (U)PBE0-D3/def2-TZVPP-SMD(toluene)//(U)B3LYP-D3/def2-SVP. We report this work as the first catalytic example where the complexation-induced bond-weakening effect is quantified through transition state analysis.
Ion-pair reorganization regulates reactivity in photoredox catalysts
Justin D. Earley, Anna Zieleniewska, Hunter H. Ripberger, Nick Y. Shin, Megan S. Lazorski, Zachary J. Mast, Hannah J. Sayre, James K. McCusker, Gregory D. Scholes, Robert R. Knowles, Obadiah G. Reid, Garry Rumbles
Nat. Chem. 2022, 14, 746–753 DOI: 10.1038/s41557-022-00911-6
Abstract: Cyclometalated and polypyridyl complexes of d6 metals are promising photoredox catalysts, using light to drive reactions with high kinetic or thermodynamic barriers via the generation of reactive radical intermediates. However, while tuning of their redox potentials, absorption energy, excited-state lifetime and quantum yield are well-known criteria for modifying activity, other factors could be important. Here we show that dynamic ion-pair reorganization controls the reactivity of a photoredox catalyst, [Ir[dF(CF3)ppy]2(dtbpy)]X. Time-resolved dielectric-loss experiments show how counter-ion identity influences excited-state charge distribution, evincing large differences in both the ground- and excited-state dipole moment depending on whether X is a small associating anion (PF6−) that forms a contact-ion pair versus a large one that either dissociates or forms a solvent-separated pair (BArF4−). These differences correlate with the reactivity of the photocatalyst toward both reductive and oxidative electron transfer, amounting to a 4-fold change in selectivity toward oxidation versus reduction. These results suggest that ion pairing could be an underappreciated factor that modulates reactivity in ionic photoredox catalysts.
Contra-Thermodynamic Positional Isomerization of Olefins
Kuo Zhao, Robert R. Knowles
J. Am. Chem. Soc. 2022, 144, 137–144. DOI: 10.1021/jacs.1c11681
Abstract: A light-driven method for the contra-thermodynamic positional isomerization of olefins is described. In this work, stepwise PCET activation of a more substituted and more thermodynamically stable olefin substrate is mediated by an excited-state oxidant and a Brønsted base to afford an allylic radical that is captured by a Cr(II) cocatalyst to furnish an allylchromium(III) intermediate. In situ protodemetalation of this allylchromium complex by methanol is highly regioselective and affords an isomerized and less thermodynamically stable alkene product. The higher oxidation potential of the less substituted olefin isomer renders it inert to further oxidation by the excited-state oxidant, enabling it to accumulate in solution over the course of the reaction. A broad range of isopropylidene substrates are accommodated, including enol ethers, enamides, styrenes, 1,3-dienes, and tetrasubstituted alkyl olefins. Mechanistic investigations of the protodemetalation step are also presented.
Ir(III)-Naphthoquinone Complex as a Platform for Photocatalytic Activity
Walter D. Guerra, Hannah J. Sayre, Hunter H. Ripberger, Emmanuel Odella, Gregory D. Scholes, Thomas A. Moore, Robert R. Knowles, Ana L. Moore
J. Photochem. Photobiol. 2022, 9, 100098. DOI: 10.1016/j.jpap.2021.100098
Abstract: Inspired by the primary events that take place in Photosystem II (PSII), we designed and synthesized a heteroleptic Ir(III) complex featuring an attached naphthoquinone (NQ) as an electron transfer (ET) auxiliary reminiscent of the plastoquinone electron acceptor in PSII. In this design, NQ is covalently attached to the 2,2′-bipyridyl (bpy) ligand of [Ir(dF(CF3)ppy)2(bpy)][PF6], (dF(CF3)ppy = 2-(2,4-difluorophenyl)-5-(trifluoromethyl)pyridine). Following excitation of the photocatalyst ([Ir(dF(CF3)ppy)2(bpy-NQ)][PF6]), reduced NQ (NQ•‒) was observed in transient absorption spectroscopy. This novel catalyst has potential applications in oxidative and reductive photocatalytic processes.
https://www.sciencedirect.com/science/article/pii/S266646902100083X
Photochemical and Electrochemical Applications of Proton-Coupled Electron Transfer in Organic Synthesis
Philip R. D., James H. Cox, Nicolas D. Chiappini, Casey B. Roos, Elizabeth A. McLoughlin, Benjamin G. Hejna, Suong T. Nguyen, Hunter H. Ripberger, Jacob M. Ganley, Elaine Tsui, Nick Y. Shin, Brian Koronkiewicz, Guanqi Qiu, Robert R. Knowles
Chem. Rev. 2022, 122, 2017−2291. DOI: 10.1021/acs.chemrev.1c00374
Abstract: We present here a review of the photochemical and electrochemical applications of multi-site proton-coupled electron transfer (MS-PCET) in organic synthesis. MS-PCETs are redox mechanisms in which both an electron and a proton are exchanged together, often in a concerted elementary step. As such, MS-PCET can function as a non-classical mechanism for homolytic bond activation, providing opportunities to generate synthetically useful free radical intermediates directly from a wide variety of common organic functional groups. We present an introduction to MS-PCET and a practitioner’s guide to reaction design, with an emphasis on the unique energetic and selectivity features that are characteristic of this reaction class. We then present chapters on oxidative N–H, O–H, S–H, and C–H bond homolysis methods, for the generation of the corresponding neutral radical species. Then, chapters for reductive PCET activations involving carbonyl, imine, other X═Y π-systems, and heteroarenes, where neutral ketyl, α-amino, and heteroarene-derived radicals can be generated. Finally, we present chapters on the applications of MS-PCET in asymmetric catalysis and in materials and device applications. Within each chapter, we subdivide by the functional group undergoing homolysis, and thereafter by the type of transformation being promoted. Methods published prior to the end of December 2020 are presented.
PCET-Based Ligand Limits Charge Recombination with an Ir(III) Photoredox Catalyst
Hannah Sayre, Hunter H. Ripberger, Emmanuel Odella, Anna Zieleniewska, Daniel A. Heredia, Garry Rumbles, Gregory D. Scholes, Thomas A. Moore, Ana L. Moore, Robert R. Knowles
J. Am. Chem. Soc. 2021, 143, 13034–13043. DOI: 10.1021/jacs.1c01701
Abstract: Upon photoinitiated electron transfer, charge recombination limits the quantum yield of photoredox reactions for which the rates for the forward reaction and back electron transfer are competitive. Taking inspiration from a proton-coupled electron transfer (PCET) process in Photosystem II, a benzimidazole-phenol (BIP) has been covalently attached to the 2,2′-bipyridyl ligand of [Ir(dF(CF3)ppy)2(bpy)][PF6] (dF(CF3)ppy = 2-(2,4-difluorophenyl)-5-(trifluoromethyl)pyridine; bpy = 2,2′-bipyridyl). Excitation of the [Ir(dF(CF3)ppy)2(BIP-bpy)][PF6] photocatalyst results in intramolecular PCET to form a charge-separated state with oxidized BIP. Subsequent reduction of methyl viologen dication (MV2+), a substrate surrogate, by the reducing moiety of the charge separated species demonstrates that the inclusion of BIP significantly slows the charge recombination rate. The effect of ∼24-fold slower charge recombination in a photocatalytic phthalimide ester reduction resulted in a greater than 2-fold increase in reaction quantum efficiency.
Depolymerization of Hydroxylated Polymers via Light-Driven C–C Bond Cleavage
Suong T. Nguyen, Elizabeth A. McLoughlin, James H. Cox, Brett P. Fors, Robert R. Knowles
J. Am. Chem. Soc. 2021, 143, 12268−12277. DOI: 10.1021/jacs.1c05330
Abstract: The accumulation of persistent plastic waste in the environment is widely recognized as an ecological crisis. New chemical technologies are necessary both to recycle existing plastic waste streams into high-value chemical feedstocks and to develop next-generation materials that are degradable by design. Here, we report a catalytic methodology for the depolymerization of a commercial phenoxy resin and high molecular weight hydroxylated polyolefin derivatives upon visible light irradiation near ambient temperature. Proton-coupled electron transfer (PCET) activation of hydroxyl groups periodically spaced along the polymer backbone furnishes reactive alkoxy radicals that promote chain fragmentation through C–C bond β-scission. The depolymerization produces well-defined and isolable product mixtures that are readily diversified to polycondensation monomers. In addition to controlling depolymerization, the hydroxyl group modulates the thermomechanical properties of these polyolefin derivatives, yielding materials with diverse properties. These results demonstrate a new approach to polymer recycling based on light-driven C–C bond cleavage that has the potential to establish new links within a circular polymer economy and influence the development of new degradable-by-design polyolefin materials.
Mechanistic Investigation and Optimization of Photoredox Anti-Markovnikov Hydroamination
Yangzhong Qin, Qilei Zhu, Rui Sun, Jacob M. Ganley, Robert R. Knowles, Daniel G. Nocera
J. Am. Chem. Soc. 2021, 143, 10232–10242. DOI: 10.1021/jacs.1c03644
Abstract: The reaction mechanism and the origin of the selectivity for the photocatalytic intermolecular anti-Markovnikov hydroamination of unactivated alkenes with primary amines to furnish secondary amines have been revealed by time-resolved laser kinetics measurements of the key reaction intermediates. We show that back-electron transfer (BET) between the photogenerated aminium radical cation (ARC) and reduced photocatalyst complex (Ir(II)) is nearly absent due to rapid deprotonation of the ARC on the sub-100 ns time scale. The selectivity for primary amine alkylation is derived from the faster addition of the primary ARCs (as compared to secondary ARCs) to alkenes. The turnover of the photocatalyst occurs via the reaction between Ir(II) and a thiyl radical; the in situ formation of an off-cycle disulfide from thiyl radicals suppresses this turnover, diminishing the efficiency of the reaction. With these detailed mechanistic insights, the turnover of the photocatalyst has been optimized, resulting in a >10-fold improvement in the quantum yield. These improvements enabled the development of a scalable flow protocol, demonstrating a potential strategy for practical applications with improved energy efficiency and cost-effectiveness.
1,3-Alkyl Transposition in Allylic Alcohols Enabled by Proton-Coupled Electron Transfer
Kuo Zhao, Gesa Seidler, Robert R. Knowles
Angew. Chem. Int. Ed. 2021, 60, 20190–20195. DOI: 10.1021/ja404342j
Abstract: A method is described for the isomerization of acyclic allylic alcohols into β-functionalized ketones via 1,3-alkyl transposition. This reaction proceeds via light-driven proton-coupled electron transfer (PCET) activation of the O–H bond in the allylic alcohol substrate, followed by C–C β-scission of the resulting alkoxy radical. The transient alkyl radical and enone acceptor generated in the scission event subsequently recombine via radical conjugate addition to deliver β-functionalized ketone products. A variety of allylic alcohol substrates bearing alkyl and acyl migratory groups were successfully accommodated. Insights from mechanistic studies led to a modified reaction protocol that improves reaction performance for challenging substrates.
Intermolecular Crossed [2 + 2] Cycloaddition Promoted by Visible-Light Triplet Photosensitization: Expedient Access to Polysubstituted 2-Oxaspiro[3.3]heptanes
Philip R. D. Murray, Willem M. M. Bussink, Geraint H. M. Davies, Farid W. van der Mei, Alyssa H. Antropow, Jacob T. Edwards, Laura Akullian D’Agostino, J. Michael Ellis, Lawrence G. Hamann, Fedor Romanov-Michailidis, Robert R. Knowles
J. Am. Chem. Soc 2021, 143, 4055–4063. DOI: 10.1021/jacs.1c01173
Abstract: This paper describes an intermolecular cross-selective [2 + 2] photocycloaddition reaction of exocyclic arylidene oxetanes, azetidines, and cyclobutanes with simple electron-deficient alkenes. The reaction takes place under mild conditions using a commercially available Ir(III) photosensitizer upon blue light irradiation. This transformation provides access to a range of polysubstituted 2-oxaspiro[3.3]heptane, 2-azaspiro[3.3]heptane, and spiro[3.3]heptane motifs, which are of prime interest in medicinal chemistry as gem-dimethyl and carbonyl bioisosteres. A variety of further transformations of the initial cycloadducts are demonstrated to highlight the versatility of the products and enable selective access to either of a syn– or an anti-diastereoisomer through kinetic or thermodynamic epimerization, respectively. Mechanistic experiments and DFT calculations suggest that this reaction proceeds through a sensitized energy transfer pathway.
Expeditious synthesis of aromatic-free piperidinium-functionalized polyethylene as alkaline anion exchange membranes
Wei You, Jacob M. Ganley, Brian G. Ernst, Cheyenne R. Peltier, Hsin-Yu Ko, Robert A. DiStasio Jr., Robert R. Knowles, Geoffrey W. Coates
Chem. Sci. 2021, 12, 3898–3910. DOI: 10.1039/D0SC05789D
Abstract: Alkaline anion exchange membranes (AAEMs) with high hydroxide conductivity and good alkaline stability are essential for the development of anion exchange membrane fuel cells to generate clean energy by converting renewable fuels to electricity. Polyethylene-based AAEMs with excellent properties can be prepared via sequential ring-opening metathesis polymerization (ROMP) and hydrogenation of cyclooctene derivatives. However, one of the major limitations of this approach is the complicated multi-step synthesis of functionalized cyclooctene monomers. Herein, we report that piperidinium-functionalized cyclooctene monomers can be easily prepared via the photocatalytic hydroamination of cyclooctadiene with piperidine in a one-pot, two-step process to produce high-performance AAEMs. Possible alkaline-degradation pathways of the resultant polymers were analyzed using spectroscopic analysis and dispersion-inclusive hybrid density functional theory (DFT) calculations. Quite interestingly, our theoretical calculations indicate that local backbone morphology—which can potentially change the Hofmann elimination reaction rate constant by more than four orders of magnitude—is another important consideration in the rational design of stable high-performance AAEMs.
https://pubs.rsc.org/en/content/articlelanding/2021/SC/D0SC05789D
Photocatalytic Generation of Aminium Radical Cations for C–N Bond Formation
Jacob M. Ganley, Philip R. D. Murray, Robert R. Knowles
ACS Catal. 2020, 10, 11712–11738. DOI: 10.1021/acscatal.0c03567
Abstract: Aminium radical cations have been extensively studied as electrophilic aminating species that readily participate in C–N bond forming processes with alkenes and arenes. However, their utility in synthesis has been limited, as their generation required unstable, reactive starting materials and harsh reaction conditions. Visible-light photoredox catalysis has emerged as a platform for the mild production of aminium radical cations from either unfunctionalized or N-functionalized amines. This Perspective covers recent synthetic methods that rely on the photocatalytic generation of aminium radical cations for C–N bond formation, specifically in the context of alkene hydroamination, arene C–H bond amination, and the mesolytic bond cleavage of alkoxyamines.
Catalytic Generation of Alkoxy Radicals from Unfunctionalized Alcohols
Elaine Tsui, Huaiju Wang, Robert R. Knowles
Chem. Sci. 2020, 11, 11124-11141. DOI: 10.1039/D0SC04542J
Abstract: Alkoxy radicals have long been recognized as powerful synthetic intermediates with well-established reactivity patterns. Due to the high bond dissociation free energy of aliphatic alcohol O–H bonds, these radicals are difficult to access through direct homolysis, and conventional methods have instead relied on activation of O-functionalized precursors. Over the past decade, however, numerous catalytic methods for the direct generation of alkoxy radicals from simple alcohol starting materials have emerged and created opportunities for the development of new transformations. This minireview discusses recent advances in catalytic alkoxy radical generation, with particular emphasis on progress toward the direct activation of unfunctionalized alcohols enabled by transition metal and photoredox catalysis.
https://pubs.rsc.org/en/content/articlelanding/2020/sc/d0sc04542j
Catalytic Hydroetherification of Unactivated Alkenes Enabled by Proton‐Coupled Electron Transfer
Elaine Tsui, Anthony J. Metrano, Yuto Tsuchiya, Robert R. Knowles
Angew. Chem., Int. Ed. 2020, 59, 11845–11849. DOI: 10.1002/anie.202003959
Abstract: We report a catalytic, light‐driven protocol for the intramolecular hydroetherification of unactivated alkenols to furnish cyclic ether products. These reactions occur under visible light irradiation in the presence of an Ir(III)‐based photoredox catalyst, a Brønsted base catalyst, and a hydrogen atom transfer co‐catalyst. Reactive alkoxy radicals are proposed as key intermediates, generated via the direct homolytic activation of alcohol O–H bonds through a proton‐coupled electron transfer mechanism. This method exhibits a broad substrate scope and high functional group tolerance, and it accommodates a diverse range of alkene substitution patterns. Results demonstrating the extension of this catalytic system to carboetherification reactions are also presented.
Enantioselective Hydroamination of Alkenes with Sulfonamides Enabled by Proton-Coupled Electron Transfer
Casey B. Roos, Joachim Demaerel, David E. Graff, Robert R. Knowles
J. Am. Chem. Soc. 2020, 142, 5974–5979. DOI: 10.1021/jacs.0c01332
Abstract: 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. Non-covalent 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 non-covalent interactions to enforce stereoselectivity in reactions of transient and highly reactive open-shell intermediates.
Light-Driven Depolymerization of Native Lignin Enabled by Proton-Coupled Electron Transfer
Suong T. Nguyen, Philip R. D. Murray, Robert R. Knowles
ACS Catal. 2020, 10, 800–805. DOI: 10.1021/acscatal.9b04813
Abstract: Here we report a catalytic, light-driven method for the redox-neutral depolymerization of native lignin biomass at ambient temperature. This transformation proceeds via a proton-coupled electron-transfer (PCET) activation of an alcohol O–H bond to generate a key alkoxy radical intermediate, which then facilitates the β-scission of a vicinal C–C bond. Notably, this single-step depolymerization is driven solely by visible-light irradiation, requires no stoichiometric chemical reagents and produces no stoichiometric waste. This method exhibits good efficiency and excellent selectivity for the activation and fragmentation of the β-O-4 linkage in the polymer backbone, even in the presence of numerous other PCET-active functional groups. The feasibility of this protocol in enabling the cleavage of the β-1 linkage in model lignin dimers was also demonstrated. These results provide further evidence that visible-light photocatalysis can serve as a viable method for the direct conversion of lignin biomass into valuable arene feedstocks.
Light-driven deracemization enabled by excited-state electron transfer
Nick Y. Shin, Jonathan M. Ryss, Xin Zhang, Scott J. Miller, Robert R. Knowles
Science 2019, 366, 364–369. DOI: 10.1126/science.aay2204
Abstract: Deracemization is an attractive strategy for asymmetric synthesis, but intrinsic energetic challenges have limited its development. Here, we report a deracemization method in which amine derivatives undergo spontaneous optical enrichment upon exposure to visible light in the presence of three distinct molecular catalysts. Initiated by an excited-state iridium chromophore, this reaction proceeds through a sequence of favorable electron, proton, and hydrogen-atom transfer steps that serve to break and reform a stereogenic C–H bond. The enantioselectivity in these reactions is jointly determined by two independent stereoselective steps that occur in sequence within the catalytic cycle, giving rise to a composite selectivity that is higher than that of either step individually. These reactions represent a distinct approach to creating out-of-equilibrium product distributions between substrate enantiomers using excited-state redox events.
Anti-Markovnikov Hydroamination of Unactivated Alkenes with Primary Alkyl Amines
David C. Miller, Jacob M. Ganley, Andrew J. Musacchio, Trevor C. Sherwood, William R. Ewing, Robert R. Knowles
J. Am. Chem. Soc. 2019, 141, 16590–16594. DOI: 10.1021/jacs.9b08746
Abstract: We report here a photocatalytic method for the intermolecular anti-Markovnikov hydroamination of unactivated olefins with primary alkyl amines to selectively furnish secondary amine products. These reactions proceed through aminium radical cation (ARC) intermediates and occur at room temperature under visible light irradiation in the presence of an iridium photocatalyst and an aryl thiol hydrogen atom donor. Despite the presence of excess olefin, high selectivities are observed for secondary over tertiary amine products, even though the secondary amines are established substrates for ARC-based olefin amination under similar conditions.
Understanding Chemoselectivity in Proton-Coupled Electron Transfer: A Kinetic Study of Amide and Thiol Activation
Guanqi Qiu, Robert R. Knowles
J. Am. Chem. Soc. 2019, 141, 16575–16578. DOI: 10.1021/jacs.9b08398
Abstract: While the mechanistic understanding of proton-coupled electron transfer (PCET) has advanced significantly, few reports have sought to elucidate the factors that control chemoselectivity in these reactions. Here we present a kinetic study that provides a quantitative basis for understanding the chemoselectivity in competitive PCET activations of amides and thiols relevant to catalytic olefin hydroamidation reactions. These results demonstrate how the interplay between PCET rate constants, hydrogen-bonding equilibria, and rate-driving force relationships jointly determine PCET chemoselectivity under a given set of conditions. In turn, these findings predict reactivity trends in a model hydroamidation reaction, rationalize the selective activation of amide N–H bonds in the presence of much weaker thiol S–H bonds, and deliver strategies to improve the efficiencies of PCET reactions employing thiol co-catalysts.
C–H Alkylation via Multisite-Proton-Coupled Electron Transfer of an Aliphatic C–H Bond
Carla M. Morton, Qilei Zhu, Hunter Ripberger, Ludovic Troian-Gautier, Zi S. D. Toa, Robert R. Knowles, Erik J. Alexanian
J. Am. Chem. Soc. 2019, 141, 13253–13260. DOI: 10.1021/jacs.9b06834
Abstract: The direct, site-selective alkylation of unactivated C(sp3)–H bonds in organic substrates is a long-standing goal in synthetic chemistry. General approaches to the activation of strong C–H bonds include radical-mediated processes involving highly reactive intermediates, such as heteroatom-centered radicals. Herein, we describe a catalytic, intermolecular C–H alkylation that circumvents such reactive species via a new elementary step for C–H cleavage involving multisite-proton-coupled electron transfer (multisite-PCET). Mechanistic studies indicate that the reaction is catalyzed by a noncovalent complex formed between an iridium(III) photocatalyst and a monobasic phosphate base. The C–H alkylation proceeds efficiently using diverse hydrocarbons and complex molecules as the limiting reagent and represents a new approach to the catalytic functionalization of unactivated C(sp3)–H bonds.
Catalytic Ring Expansions of Cyclic Alcohols Enabled by Proton-Coupled Electron Transfer
Kuo Zhao, Kenji Yamashita, Joseph E. Carpenter, Trevor C. Sherwood, William R. Ewing, Peter T. W. Cheng, Robert R. Knowles
J. Am. Chem. Soc. 2019, 141, 8752–8757. DOI: 10.1021/jacs.9b03973
Abstract: We report here a catalytic method for the modular ring expansion of cyclic aliphatic alcohols. In this work, proton-coupled electron transfer activation of an allylic alcohol substrate affords an alkoxy radical intermediate that undergoes subsequent C–C bond cleavage to furnish an enone and a tethered alkyl radical. Recombination of this alkyl radical with the revealed olefin acceptor in turn produces a ring-expanded ketone product. The regioselectivity of this C–C bond-forming event can be reliably controlled via substituents on the olefin substrate, providing a means to convert a simple n-membered ring substrate to either n+1 or n+2 ring adducts in a selective fashion.
PCET-Enabled Olefin Hydroamidation Reactions with N-Alkyl Amides
Suong T. Nguyen, Qilei Zhu, Robert R. Knowles
ACS Catal. 2019, 9, 4502–4507. DOI: 10.1021/acscatal.9b00966
Abstract: Olefin aminations are important synthetic technologies for the construction of aliphatic C–N bonds. Here we report a catalytic protocol for olefin hydroamidation that proceeds through transient amidyl radical intermediates that are formed via proton-coupled electron transfer (PCET) activation of the strong N–H bonds in N-alkyl amides by an excited-state iridium photocatalyst and a dialkyl phosphate base. This method exhibits a broad substrate scope, high functional group tolerance, and amenability to use in cascade polycyclization reactions. The feasibility of this PCET protocol in enabling the intermolecular anti-Markovnikov hydroamidation reactions of unactivated olefins is also demonstrated.
Decarboxylative Intramolecular Arene Alkylation Using N-(Acyloxy)phthalimides, an Organic Photocatalyst, and Visible Light
Trevor C. Sherwood, Hai-Yun Xiao, Roshan G. Bhaskar, Eric M. Simmons, Serge Zaretsky, Martin P. Rauch, Robert R. Knowles, T. G. Murali Dhar
J. Org. Chem. 2019, 84, 8630–8379. DOI: 10.1021/acs.joc.9b00432
Abstract: An intramolecular arene alkylation reaction has been developed using the organic photocatalyst 4CzIPN, visible light, and N-(acyloxy)phthalimides as radical precursors. Reaction conditions were optimized via high-throughput experimentation, and electron-rich and electron-deficient arenes and heteroarenes are viable reaction substrates. This reaction enables access to a diverse set of fused, partially saturated cores which are of high interest in synthetic and medicinal chemistry.
Evaluation of excited state bond weakening for ammonia synthesis from a manganese nitride: stepwise proton coupled electron transfer is preferred over hydrogen atom transfer
Florian Loose, Dian Wang, Lei Tian, Gregory D. Scholes, Robert R. Knowles, Paul J. Chirik
Chem. Commun. 2019, 55, 5595–5598. DOI: 10.1039/C9CC01046G
Abstract: Concepts for the thermodynamically challenging synthesis of weak N–H bonds by photoinduced proton coupled electron transfer are explored. Upon irradiation with blue light, ammonia synthesis was achieved from the manganese nitride (tBuSalen)MnN (tBuSalen = (S,S)-(+)-N,N′-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediamine) in the presence of 9,10-dihydroacridine and a ruthenium photocatalyst in iPrOH solution. Although in one case the ruthenium complex bears a remote N–H bond that weakens to 41 kcal mol−1 upon irradiation, control experiments with the N-methylated analog demonstrate the ruthenium complex serves as a photoreductant rather than hydrogen-atom transfer catalyst in aprotic solvents. Luminescence quenching experiments support a ruthenium(II)/(III) cycle rather than a ruthenium(I)/(II) alternative. Identification of the manganese complex following ammonia synthesis was also accomplished.
https://pubs.rsc.org/en/content/articlelanding/2019/cc/c9cc01046g
N–H Bond Formation in a Manganese(V) Nitride Yields Ammonia by Light-Driven Proton-Coupled Electron Transfer
Dian Wang, Florian Loose, Paul J. Chirik, Robert R. Knowles
J. Am. Chem. Soc. 2019, 141, 4795–4799. DOI: 10.1021/jacs.8b12957
Abstract: A method for the reduction of a manganese nitride to ammonia is reported, where light-driven proton-coupled electron transfer enables the formation of weak N–H bonds. Photoreduction of (saltBu)MnVN to ammonia and a Mn(II) complex has been accomplished using 9,10-dihydroacridine and a combination of an appropriately matched photoredox catalyst and weak Brønsted acid. Acid-reductant pairs with effective bond dissociation free energies between 35 and 46 kcal/mol exhibited high efficiencies. This light-driven method may provide a blueprint for new approaches to catalytic homogeneous ammonia synthesis under ambient conditions.
Rate–Driving Force Relationships in the Multisite Proton-Coupled Electron Transfer Activation of Ketones
Guanqi Qiu, Robert R. Knowles
J. Am. Chem. Soc. 2019, 141, 2721–2730. DOI: 10.1021/jacs.8b13451
Abstract: Here we present a detailed kinetic study of the multisite proton-coupled electron transfer (MS-PCET) activations of aryl ketones using a variety of Brønsted acids and excited-state Ir(III)-based electron donors. A simple method is described for simultaneously extracting both the hydrogen-bonding equilibrium constants and the rate constants for the PCET event from deconvolution of the luminescence quenching data. These experiments confirm that these activations occur in a concerted fashion, wherein the proton and electron are transferred to the ketone substrate in a single elementary step. The rates constants for the PCET events were linearly correlated with their driving forces over a range of nearly 19 kcal/mol. However, the slope of the rate–driving force relationship deviated significantly from expectations based on Marcus theory. A rationalization for this observation is proposed based on the principle of non-perfect synchronization, wherein factors that serve to stabilize the product are only partially realized at the transition state. A discussion of the relevance of these findings to the applications of MS-PCET in organic synthesis is also presented.
A Redox Strategy for Light-Driven, Out-of-Equilibrium Isomerizations and Application to Catalytic C–C Bond Cleavage Reactions
Eisuke Ota, Huaiju Wang, Nils Lennart Frye, Robert R. Knowles
J. Am. Chem. Soc. 2019, 141, 1457–1462. DOI: 10.1021/jacs.8b12552
Abstract: We report a general protocol for the light-driven isomerization of cyclic aliphatic alcohols to linear carbonyl compounds. These reactions proceed via proton-coupled electron-transfer activation of alcohol O–H bonds followed by subsequent C–C β-scission of the resulting alkoxy radical intermediates. In many cases, these redox-neutral isomerizations proceed in opposition to a significant energetic gradient, yielding products that are less thermodynamically stable than the starting materials. A mechanism is presented to rationalize this out-of-equilibrium behavior that may serve as a model for the design of other contrathermodynamic transformations driven by excited-state redox events.
Applications and Prospects for Triplet–Triplet Annihilation Photon Upconversion
Martin P. Rauch, Robert R. Knowles
Chimia. 2018, 72, 501–507. DOI: 10.2533/chimia.2018.501
Abstract: Triplet–triplet annihilation photon upconversion (TTA-UC) is a photophysical process in which the energy of two photons are combined into a single photon of higher energy. While this strategy has been recognized in applications ranging from bioimaging to solar energy conversion, its uses in synthetic organic chemistry have not been extensively developed. Here, we present a short tutorial on the theoretical underpinnings and the design principles of TTA-UC systems. Selected applications are then discussed to highlight key features of the TTA mechanism, along with a prospective discussion of the potential of these mechanisms to enable innovation in photocatalysis, methods development, and synthetic organic chemistry.
https://www.ingentaconnect.com/content/scs/chimia/2018/00000072/f0020007/art00006
Enantioselective Synthesis of Pyrroloindolines via Noncovalent Stabilization of Indole Radical Cations and Applications to the Synthesis of Alkaloid Natural Products
Emily C. Gentry, Lydia J. Rono, Martina E. Hale, Rei Matsuura, Robert R. Knowles
J. Am. Chem. Soc. 2018, 140, 3394–3402. DOI: 10.1021/jacs.7b13616
Abstract: While interest in the synthetic chemistry of radical cations continues to grow, controlling enantioselectivity in the reactions of these intermediates remains a challenge. Based on recent insights into the oxidation of tryptophan in enzymatic systems, we report a photocatalytic method for the generation of indole radical cations as hydrogen-bonded adducts with chiral phosphate anions. These noncovalent open-shell complexes can be intercepted by the stable nitroxyl radical TEMPO· to form alkoxyamine-substituted pyrroloindolines with high levels of enantioselectivity. Further elaboration of these optically enriched adducts can be achieved via a catalytic single-electron oxidation/mesolytic cleavage sequence to furnish transient carbocation intermediates that may be intercepted by a wide range of nucleophiles. Taken together, this two-step sequence provides a simple catalytic method to access a wide range of substituted pyrroloindolines in enantioenriched form via a standard experimental protocol from a common synthetic intermediate. The design, development, mechanistic study, and scope of this process are presented, as are applications of this method to the synthesis of several dimeric pyrroloindoline natural products.
Intermolecular Anti-Markovnikov Hydroamination of Unactivated Alkenes with Sulfonamides Enabled by Proton-Coupled Electron Transfer
Qilei Zhu, David E. Graff, Robert R. Knowles
J. Am. Chem. Soc. 2018, 140, 741–747. DOI: 10.1021/jacs.7b11144
Abstract: Here we report a catalytic method for the intermolecular anti-Markovnikov hydroamination of unactivated alkenes using primary and secondary sulfonamides. These reactions occur at room temperature under visible light irradiation and are jointly catalyzed by an iridium(III) photocatalyst, a dialkyl phosphate base, and a thiol hydrogen atom donor. Reaction outcomes are consistent with the intermediacy of an N-centered sulfonamidyl radical generated via proton-coupled electron transfer activation of the sulfonamide N–H bond. Studies outlining the synthetic scope (>60 examples) and mechanistic features of the reaction are presented.
Catalytic intermolecular hydroaminations of unactivated olefins with secondary alkyl amines
Andrew J. Musacchio, Brendan C. Lainhart, Xin Zhang, Saeed G. Naguib, Trevor C. Sherwood, Robert R. Knowles
Science. 2017, 355, 727–730. DOI: 10.1126/science.aal3010
Abstract: The intermolecular hydroamination of unactivated alkenes with simple dialkyl amines remains an unsolved problem in organic synthesis. We report a catalytic protocol for efficient additions of cyclic and acyclic secondary alkyl amines to a wide range of alkyl olefins with complete anti-Markovnikov regioselectivity. In this process, carbon-nitrogen bond formation proceeds through a key aminium radical cation intermediate that is generated via electron transfer between an excited-state iridium photocatalyst and an amine substrate. These reactions are redox-neutral and completely atom-economical, exhibit broad functional group tolerance, and occur readily at room temperature under visible light irradiation. Certain tertiary amine products generated through this method are formally endergonic relative to their constituent olefin and amine starting materials and thus are not accessible via direct coupling with conventional ground-state catalysts.
Catalytic alkylation of remote C–H bonds enabled by proton-coupled electron transfer
Gilbert J. Choi, Qilei Zhu, David C. Miller, Carol J. Gu, Robert R. Knowles
Nature. 2016, 539, 268–271. DOI: 10.1038/nature19811
Abstract: Despite advances in hydrogen atom transfer (HAT) catalysis, there are currently no molecular HAT catalysts that are capable of homolysing the strong nitrogen–hydrogen (N–H) bonds of N-alkyl amides. The motivation to develop amide homolysis protocols stems from the utility of the resultant amidyl radicals, which are involved in various synthetically useful transformations, including olefin amination and directed carbon–hydrogen (C–H) bond functionalization. In the latter process—a subset of the classical Hofmann–Löffler–Freytag reaction—amidyl radicals remove hydrogen atoms from unactivated aliphatic C–H bonds. Although powerful, these transformations typically require oxidative N-prefunctionalization of the amide starting materials to achieve efficient amidyl generation. Moreover, because these N-activating groups are often incorporated into the final products, these methods are generally not amenable to the direct construction of carbon–carbon (C–C) bonds. Here we report an approach that overcomes these limitations by homolysing the N–H bonds of N-alkyl amides via proton-coupled electron transfer. In this protocol, an excited-state iridium photocatalyst and a weak phosphate base cooperatively serve to remove both a proton and an electron from an amide substrate in a concerted elementary step. The resultant amidyl radical intermediates are shown to promote subsequent C–H abstraction and radical alkylation steps. This C–H alkylation represents a catalytic variant of the Hofmann–Löffler–Freytag reaction, using simple, unfunctionalized amides to direct the formation of new C–C bonds. Given the prevalence of amides in pharmaceuticals and natural products, we anticipate that this method will simplify the synthesis and structural elaboration of amine-containing targets. Moreover, this study demonstrates that concerted proton-coupled electron transfer can enable homolytic activation of common organic functional groups that are energetically inaccessible using traditional HAT-based approaches.
Catalytic Ring-Opening of Cyclic Alcohols Enabled by PCET Activation of Strong O–H Bonds
Hatice G. Yayla, Huaiju Wang, Kyle T. Tarantino, Hudson S. Orbe, Robert R. Knowles
J. Am. Chem. Soc. 2016, 138, 10794–10797. DOI: 10.1021/jacs.6b06517
Abstract: We report a new photocatalytic protocol for the redox-neutral isomerization of cyclic alcohols to linear ketones via C–C bond scission. Mechanistic studies demonstrate that key alkoxy radical intermediates in this reaction are generated via the direct homolytic activation of alcohol O–H bonds in an unusual intramolecular PCET process, wherein the electron travels to a proximal radical cation in concert with proton transfer to a weak Brønsted base. Effective bond strength considerations are shown to accurately forecast the feasibility of alkoxy radical generation with a given oxidant/base pair.
Synthetic Applications of Proton-Coupled Electron Transfer
Emily C. Gentry, Robert R. Knowles
Acc. Chem. Res. 2016, 49, 1546–1556. DOI: 10.1021/acs.accounts.6b00272
Abstract: Redox events in which an electron and proton are exchanged in a concerted elementary step are commonly referred to as proton-coupled electron transfers (PCETs). PCETs are known to operate in numerous important biological redox processes, as well as recent inorganic technologies for small molecule activation. These studies suggest that PCET catalysis might also function as a general mode of substrate activation in organic synthesis. Over the past three years, our group has worked to advance this hypothesis and to demonstrate the synthetic utility of PCET through the development of novel catalytic radical chemistries. The central aim of these efforts has been to demonstrate the ability of PCET to homolytically activate a wide variety of common organic functional groups that are energetically inaccessible using known molecular H atom transfer catalysts.
Catalytic Carbocation Generation Enabled by the Mesolytic Cleavage of Alkoxyamine Radical Cations
Qilei Zhu, Emily C. Gentry, Robert R. Knowles
Angew. Chem., Int. Ed. 2016, 55, 9969–9973. DOI: 10.1002/anie.201604619
Abstract: A new catalytic method is described to access carbocation intermediates via the mesolytic cleavage of alkoxyamine radical cations. In this process, electron transfer between an excited state oxidant and a TEMPO‐derived alkoxyamine substrate gives rise to a radical cation with a remarkably weak C−O bond. Spontaneous scission results in the formation of the stable nitroxyl radical TEMPO. as well as a reactive carbocation intermediate that can be intercepted by a wide range of nucleophiles. Notably, this process occurs under neutral conditions and at comparatively mild potentials, enabling catalytic cation generation in the presence of both acid sensitive and easily oxidized nucleophilic partners.
https://onlinelibrary.wiley.com/doi/full/10.1002/anie.201604619
Proton-Coupled Electron Transfer in Organic Synthesis: Fundamentals, Applications, and Opportunities
David C. Miller, Kyle T. Tarantino, Robert R. Knowles
Top. Curr. Chem. 2016, 374, 30. DOI: 10.1007/s41061-016-0030-6
Abstract: Proton-coupled electron transfers (PCETs) are unconventional redox pro-cesses in which both protons and electrons are exchanged, often in a concerted ele-mentary step. While PCET is now recognized to play a central a role in biological redoxcatalysis and inorganic energy conversion technologies, its applications in organicsynthesis are only beginning to be explored. In this chapter, we aim to highlight theorigins, development, and evolution of the PCET processes most relevant to applicationsin organic synthesis. Particular emphasis is given to the ability of PCET to serve as a non-classical mechanism for homolytic bond activation that is complimentary to more tra-ditional hydrogen atom transfer processes, enabling the direct generation of valuableorganic radical intermediates directly from their native functional group precursorsunder comparatively mild catalytic conditions. The synthetically advantageous featuresof PCET reactivity are described in detail, along with examples from the literaturedescribing the PCET activation of common organic functional groups.
https://www.readcube.com/articles/10.1007%2Fs41061-016-0030-6
Catalytic C–N Bond-Forming Reactions Enabled by Proton-Coupled Electron Transfer Activation of Amide N–H Bonds
Lucas Q. Nguyen, Robert R. Knowles
ACS Catal. 2016, 6, 2894–2903. DOI: 10.1021/acscatal.6b00486
Abstract: Over the past three years, our group has become interested in the ability of proton-coupled electron transfer (PCET) to facilitate direct homolytic bond activations of common organic functional groups that are challenging substrates for conventional hydrogen atom transfer catalysts. This perspective details our efforts to develop oxidative PCET platforms for activating the strong N–H bonds of amides, providing catalytic access to synthetically useful amidyl radicals. We successfully identified compatible combinations of one-electron oxidants and Brønsted bases that, although unable to activate the amide substrates independently, act concomitantly with the requisite energetics to selectively homolyze the N–H bond via concerted PCET. The resulting amidyls were utilized in the development of new catalytic protocols for alkene carboamination and hydroamidation. We also highlight our efforts to develop a PCET-based bond-weakening protocol for the catalytic conjugate aminations using amide substrates. In this work, coordination to a Ti(III) catalyst significantly decreases the strength of a ligated amide N–H bond, enabling a facile PCET event to occur with the weak H atom acceptor TEMPO. Although this discussion focuses on amide activation, we anticipate that the design parameters presented here are general and should provide a framework for the development of PCET catalyst systems for other challenging homolytic bond activations as well.
Discovery and mechanistic study of a photocatalytic indoline dehydrogenation for the synthesis of elbasvir
Hatice G. Yayla, Feng Peng, Ian K. Mangion, Mark McLaughlin, Louis-Charles Campeau, Ian W. Davies, Daniel A. DiRocco, Robert R. Knowles
Chem. Sci. 2016, 7, 2066–2073. DOI: 10.1039/C5SC03350K
Abstract: Elbasvir is a potent NS5A antagonist for the treatment of chronic hepatitis C. A seemingly trivial indoline oxidation en route to the target compound was complicated by epimerization of a stereogenic hemiaminal center under most standard oxidation conditions. To address this issue, a novel visible light photoredox process for indoline oxidation was developed involving an iridium photosensitizer and environmentally-benign perester oxidant. The reaction was discovered through a high-throughput experimentation campaign and the optimized process was demonstrated on 100 g scale in flow to afford a key intermediate towards the target compound. A battery of kinetic, electrochemical, and spectroscopic studies of this process indicates a radical chain mechanism of dehydrogenation involving selective HAT from the substrate by an alkoxy radicals. Notably, isotope effects were used to validate the chain mechanism when quantum yield data proved ambiguous.
https://pubs.rsc.org/en/content/articlelanding/2015/sc/c5sc03350k
Catalytic Olefin Hydroamidation Enabled by Proton-Coupled Electron Transfer
David C. Miller, Gilbert J. Choi, Hudson S. Orbe, Robert R. Knowles
J. Am. Chem. Soc. 2015, 137, 13492–13495. DOI: 10.1021/jacs.5b09671
Abstract: Here we report a ternary catalyst system for the intramolecular hydroamidation of unactivated olefins using simple N-aryl amide derivatives. Amide activation in these reactions occurs via concerted proton-coupled electron transfer (PCET) mediated by an excited state iridium complex and weak phosphate base to furnish a reactive amidyl radical that readily adds to pendant alkenes. A series of H-atom, electron, and proton transfer events with a thiophenol cocatalyst furnish the product and regenerate the active forms of the photocatalyst and base. Mechanistic studies indicate that the amide substrate can be selectively homolyzed via PCET in the presence of the thiophenol, despite a large difference in bond dissociation free energies between these functional groups.
Reaching Your Full (Over)Potential: A Novel Approach to Electrocatalytic Oxygen Reduction
Robert R. Knowles
ACS Cent. Sci. 2015, 1, 224–225. DOI: 10.1021/acscentsci.5b00257
Abstract: The next century’s energy needs demand novel catalysts. Robert Knowles discusses Gerken and Stahl’s system for oxygen reduction.
Catalytic Alkene Carboaminations Enabled by Oxidative Proton-Coupled Electron Transfer
Gilbert J. Choi, Robert R. Knowles
J. Am. Chem. Soc. 2015, 137, 9226–9229. DOI: 10.1021/jacs.5b05377
Abstract: Here we describe a dual catalyst system comprised of an iridium photocatalyst and weak phosphate base that is capable of both selectively homolyzing the N–H bonds of N-arylamides (bond dissociation free energies ~ 100 kcal/mol) via concerted proton-coupled electron transfer (PCET) and mediating efficient carboamination reactions of the resulting amidyl radicals. This manner of PCET activation, which finds its basis in numerous biological redox processes, enables the formal homolysis of a stronger amide N–H bond in the presence of weaker allylic C–H bonds, a selectivity that is uncommon in conventional molecular H atom acceptors. Moreover, this transformation affords access to a broad range of structurally complex heterocycles from simple amide starting materials. The design, synthetic scope, and mechanistic evaluation of the PCET process are described.
Bond-Weakening Catalysis: Conjugate Aminations Enabled by the Soft Homolysis of Strong N–H Bonds
Kyle T. Tarantino, David C. Miller, Ted A. Callon, Robert R. Knowles
J. Am. Chem. Soc. 2015, 137, 6440–6443. DOI: 10.1021/jacs.5b03428
Abstract: The ability of redox-active metal centers to weaken the bonds in associated ligands is well precedented, but has rarely been utilized as a mechanism of substrate activation in catalysis. Here we describe a catalytic bond-weakening protocol for conjugate amination wherein the strong N–H bonds in N-aryl amides (N–H bond dissociation free energies ∼100 kcal/mol) are destabilized by ∼33 kcal/mol upon by coordination to a reducing titanocene complex, enabling their abstraction by the weak H-atom acceptor TEMPO through a proton-coupled electron transfer process. Significantly, this soft homolysis mechanism provides a method to generate closed-shell, metalated nucleophiles under neutral conditions in the absence of a Brønsted base.
Proton-Coupled Electron Transfer in Organic Synthesis: Novel Homolytic Bond Activations and Catalytic Asymmetric Reactions with Free Radicals
Hatice G. Yayla, Robert R. Knowles
Synlett. 2014, 20, 2819–2826. DOI: 10.1055/s-0034-1379304
Abstract: Proton-coupled electron transfers (PCET) are unconventional redox processes in which an electron and proton are exchanged together in a concerted elementary step. While these mechanisms are recognized to play a central role in biological redox catalysis, their applications in synthetic organic chemistry have yet to be widely established. In this Account, we highlight two recent examples from our group outlining the use of concerted PCET as a platform for the development of catalytic and enantioselective reactions of neutral ketyl radicals. Central to this work was the recognition that PCET provides a mechanism for independent proton and electron donors to function jointly as a formal hydrogen atom donor competent to activate organic π systems that are energetically inaccessible using conventional H-atom transfer technologies. In addition, we found that neutral ketyls formed in the PCET event are remarkably strong hydrogen-bond donors and remain strongly associated to the conjugate base of the proton donor following the PCET event. When chiral proton donors are used, these successor H-bond complexes provide a basis for asymmetric induction in subsequent reactions of the ketyl radical.
https://www.thieme-connect.de/products/ejournals/abstract/10.1055/s-0034-1379304
Catalytic Olefin Hydroamination with Aminium Radical Cations: A Photoredox Method for Direct C–N Bond Formation
Andrew J. Musacchio, Lucas Q. Nguyen, G. Hudson Beard, Robert R. Knowles
J. Am. Chem. Soc. 2014, 136, 12217–12220. DOI: 10.1021/ja5056774
Abstract: While olefin amination with aminium radical cations is a classical method for C–N bond formation, catalytic variants that utilize simple 2° amine precursors remain largely undeveloped. Herein we report a new visible-light photoredox protocol for the intramolecular anti-Markovnikov hydroamination of aryl olefins that proceeds through catalytically generated aminium radical intermediates. Mechanistic studies are consistent with a process involving amine oxidation via electron transfer, turnover-limiting C–N bond formation, and a second electron transfer step to reduce a carbon-centered radical, rendering the overall process redox-neutral. A range of structurally diverse N-aryl heterocycles can be prepared in good to excellent yields under conditions significantly milder than those required by conventional aminium-based protocols.
Enantioselective Photoredox Catalysis Enabled by Proton-Coupled Electron Transfer: Development of an Asymmetric Aza-Pinacol Cyclization
Lydia J. Rono, Hatice G. Yayla, David Y. Wang, Michael F. Armstrong, Robert R. Knowles
J. Am. Chem. Soc. 2013, 135, 17735–17738. DOI: 10.1021/ja4100595
Abstract: The first highly enantioselective catalytic protocol for the reductive coupling of ketones and hydrazones is reported. These reactions proceed through neutral ketyl radical intermediates generated via a concerted proton-coupled electron transfer (PCET) event jointly mediated by a chiral phosphoric acid catalyst and the photoredox catalyst Ir(ppy)2(dtbpy)PF6. Remarkably, these neutral ketyl radicals appear to remain H-bonded to the chiral conjugate base of the Brønsted acid during the course of a subsequent C–C bond-forming step, furnishing syn 1,2-amino alcohol derivatives with excellent levels of diastereo- and enantioselectivity. This work provides the first demonstration of the feasibility and potential benefits of concerted PCET activation in asymmetric catalysis.
Catalytic Ketyl-Olefin Cyclizations Enabled by Proton-Coupled Electron Transfer
Kyle T. Tarantino, Peng Liu, Robert R. Knowles
J. Am. Chem. Soc. 2013, 135, 10022–10025. DOI: 10.1021/ja404342j
Abstract: Concerted proton-coupled electron transfer is a key mechanism of substrate activation in biological redox catalysis. However, its applications in organic synthesis remain largely unexplored. Herein, we report the development of a new catalytic protocol for ketyl-olefin coupling and present evidence to support concerted proton-coupled electron transfer being the operative mechanism of ketyl formation. Notably, reaction outcomes were correctly predicted by a simple thermodynamic formalism relating the oxidation potentials and pKa values of specific Brønsted acid/reductant combinations to their capacity to act jointly as a formal hydrogen atom donor.
