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, Just Accepted. 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, Advance Article. 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.

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.

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.


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.


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.


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.


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.


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.


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.