Arene Radical Cations Research Articles

Electrochemical Arene Radical Cation Promoted Spirocyclization of Biaryl Ynones: Access to Alkoxylated Spiro[5,5]trienones.

Herein, a novel electrochemical arene radical cation promoted dearomative spirocyclization of biaryl ynones with alcohols is described, providing a conceptually novel transformation mode for producing diverse alkoxylated spiro[5,5]trienones. The catalyst- and chemical-oxidant-free spirocyclization protocol features broad substrate scope and high functional group tolerance. Mechanistic studies reveal that the generation of arene radical cation via anodic single-electron oxidation is crucial, with sequential 6-endo-dig cyclization, dissociation of hemiketal, anodic oxidation, and nucleophilic attack of alcohols.

Regiodivergent C-H Acylation of Arenes by Switching from Ionic to Radical Type Chemistry Using NHC-Catalysis.

The Friedel-Crafts acylation which belongs to the class of electrophilic aromatic substitutions is a highly valuable and versatile reaction in synthesis. Regioselectivity is well predictable and determined by electronic as well as steric factors of the (hetero)arene substrate. In this communication, a radical approach for the acylation of arenes and heteroarenes is presented. C-H Acylation is achieved through mild cooperative photoredox/NHC radical catalysis with the cross coupling of an arene radical cation with an NHC-bound ketyl radical as a key step. As compared to the classical Friedel-Crafts acylation, a regiodivergent outcome is observed upon switching from the ionic to the radical mode. In these divergent reactions, aroyl fluorides act as the acylation reagents in both the ionic as well as the radical process.

Regiodivergente C−H‐Acylierung von Aromaten durch Wechsel von ionischer zu radikalischer Chemie unter Verwendung von NHC‐Katalyse

AbstractDie Friedel–Crafts‐Acylierung, die zur Klasse der elektrophilen aromatischen Substitutionen gehört, ist eine äußerst wertvolle und vielseitige Reaktion in der Synthese. Die Regioselektivität ist gut vorhersagbar und wird sowohl durch elektronische als auch durch sterische Faktoren des verwendeten (Hetero)Aromaten bestimmt. In dieser Mitteilung wird ein radikalischer Ansatz für die Acylierung von Aromaten und Heteroaromaten vorgestellt. Die C−H‐Acylierung erfolgt durch milde kooperative Photoredox/NHC‐Radikal‐Katalyse mit der Kreuzkupplung eines Arenradikalkations mit einem NHC‐gebundenen Ketylradikal als Schlüsselschritt. Im Vergleich zur klassischen Friedel–Crafts‐Acylierung wird beim Wechsel vom ionischen zum radikalischen Modus ein regiodivergentes Ergebnis beobachtet. Bei diesen divergenten Reaktionen fungieren Aroylfluoride als Acylierungsreagenzien sowohl im ionischen als auch im radikalischen Prozess.

I(III)-Mediated Arene C–H Amination Using (Hetero)Aryl Nucleophiles

Herein, we report the metal-free oxidative C-H amination of arenes via a "heterocyclic group transfer" reaction from an I(III) N-HVI reagent. N-Heterocycles serve as oxidatively masked amine nucleophiles, and the resulting N-arylpyridinium salts are inert to further oxidation. The reaction proceeds under mild conditions, and mechanistic studies indicate the intermediacy of an arene radical cation. Derivatizations of the resulting pyridinium salts to diverse aryl amine scaffolds are demonstrated.

Iron Catalysis of C(sp3)-H Azidation Using a Heteroarene Radical Cation Strategy.

The FeIII(phen)3 catalysis of the benzylic C(sp3)-H azidation of indoles has been investigated. The Fe(III) complex can selectively oxidize indoles to form arene radical cations, which are transformed into benzylic C(sp3) radical intermediates. This strategy exhibits a difference in reactivity between N-heteroarenes and benzene, which is difficult to achieve via direct hydrogen abstraction approaches. Various biorelevant azide precursors were constructed, highlighting the utility of this mild first-row transition-metal catalyst system.

P-Silylation of Arenes via Organic Photoredox Catalysis: Use of p-Silylated Arenes for Exclusive o-Silylation, o-Acylation, and o-Alkylation Reactions.

Photocatalytic regiospecific p-silylation of arenes has been achieved by the coupling of in situ generated silyl radical with arene radical cation. The strategy involves reductive activation of PhSe-SiR3 and single electron transfer from the electron rich arene to 9,10-dimethoxyanthracene radical cation (DMA•+). p-Silyl arenes, thus formed, are further utilized for exclusive o-silylation reaction and for regiospecific o-acylation as well as o-alkylation reaction.

Electrochemically Driven Radical Reactions: From Direct Electrolysis to Molecular Catalysis.

Organic radicals are versatile synthetic intermediates that provide reactivities and selectivities complementary to ionic species. Despite its long history, electrochemically driven radical reactions remain limited in scope. In the past few years, there have been dramatic increase in research activity in organic electrochemistry. We have been developing electrochemical and electrophotocatalytic methods for the generation and synthetic utilization of organic radicals. In our studies, various radical species such as alkene and arene radical cations and carbon- and heteroatom-centered radicals are generated from readily available precursors through direct electrolysis, molecular electrocatalysis or molecular electrophotocatalysis. These radical species undergo various inter- and intramolecular oxidative transformations to rapidly increase molecular complexity. The simultaneous occurrence of anodic oxidation and cathodic proton reduction allows the oxidative reactions to proceed through H2 evolution without external chemical oxidants.

Regioselective Arene C-H Alkylation Enabled by Organic Photoredox Catalysis.

Expanding the toolbox of C-H functionalization reactions applicable to the late-stage modification of complex molecules is of interest in medicinal chemistry, wherein the preparation of structural variants of known pharmacophores is a key strategy for drug development. One manifold for the functionalization of aromatic molecules utilizes diazo compounds and a transition-metal catalyst to generate a metallocarbene species, which is capable of direct insertion into an aromatic C-H bond. However, these high-energy intermediates can often require directing groups or a large excess of substrate to achieve efficient and selective reactivity. Herein, we report that arene cation radicals generated by organic photoredox catalysis engage in formal C-H functionalization reactions with diazoacetate derivatives, furnishing sp2 -sp3 coupled products with moderate-to-good regioselectivity. In contrast to previous methods utilizing metallocarbene intermediates, this transformation does not proceed via a carbene intermediate, nor does it require the presence of a transition-metal catalyst.

Regioselective Arene C−H Alkylation Enabled by Organic Photoredox Catalysis

AbstractExpanding the toolbox of C−H functionalization reactions applicable to the late‐stage modification of complex molecules is of interest in medicinal chemistry, wherein the preparation of structural variants of known pharmacophores is a key strategy for drug development. One manifold for the functionalization of aromatic molecules utilizes diazo compounds and a transition‐metal catalyst to generate a metallocarbene species, which is capable of direct insertion into an aromatic C−H bond. However, these high‐energy intermediates can often require directing groups or a large excess of substrate to achieve efficient and selective reactivity. Herein, we report that arene cation radicals generated by organic photoredox catalysis engage in formal C−H functionalization reactions with diazoacetate derivatives, furnishing sp2–sp3 coupled products with moderate‐to‐good regioselectivity. In contrast to previous methods utilizing metallocarbene intermediates, this transformation does not proceed via a carbene intermediate, nor does it require the presence of a transition‐metal catalyst.

Electrochemical Oxidation of Organic Molecules at Lower Overpotential: Accessing Broader Functional Group Compatibility with Electron-Proton Transfer Mediators.

Electrochemical organic oxidation reactions are highly appealing because protons are often effective terminal electron acceptors, thereby avoiding undesirable stoichiometric oxidants. These reactions are often plagued by high overpotentials, however, that greatly limit their utility. Single-electron transfer (SET) from organic molecules generates high-energy radical-cations. Formation of such intermediates often requires electrode potentials far above the thermodynamic potentials of the reaction and frequently causes decomposition and/or side reactions of ancillary functional groups. In this Account, we show how electrocatalytic electron-proton transfer mediators (EPTMs) address this challenge. EPTMs bypass the formation of radical-cation intermediates by supporting mechanisms that operate at electrode potentials much lower (≥1 V) than those of analogous direct electrolysis reactions.The stable aminoxyl radical TEMPO (2,2,6,6-tetramethylpiperidine N-oxyl) is an effective mediator for electrochemical alcohol oxidation, and we have employed such processes for applications ranging from pharmaceutical synthesis to biomass conversion. A complementary electrochemical alcohol oxidation method employs a cooperative Cu/TEMPO mediator system that operates at 0.5 V lower electrode potential than the TEMPO-only mediated process. This difference, which arises from a different catalytic mechanism, rationalizes the broad functional group tolerance of Cu/TEMPO-based aerobic alcohol oxidation catalysts.Aminoxyl mediators address long-standing challenges in the "Shono oxidation," an important method for α-C-H oxidation of tertiary amides and carbamates. Shono oxidations are initiated by a high-potential SET step that limits their utility. Aminoxyl-mediated Shono-type oxidations have been developed that operate at much lower potentials and tolerate diverse functional groups. Analogous reactivity underlies α-C-H cyanation of secondary cyclic amines, a new method that enables efficient diversification of piperidine-based pharmaceutical building blocks and preparation of non-natural amino acids.Electrochemical oxidations of benzylic C-H bonds are commonly initiated by SET to generate arene radical cations, but such methods are again plagued by large overpotentials. Mediated electrolysis methods that promote hydrogen-atom-transfer (HAT) from benzylic C-H bonds to Fe-oxo species and phthalimide N-oxyl (PINO) support C-H oxygenation, iodination, and oxidative-coupling reactions. A complementary method merges photochemistry with electrochemistry to achieve amidation of C(sp3)-H bonds. This unique process operates at much lower overpotentials compatible with diverse functional groups.These results have broad implications for organic electrochemistry, highlighting the importance of "overpotential" considerations and the prospects for expanding synthetic utility by using mediators to bypass high-energy outer-sphere electron-transfer mechanisms. Principles demonstrated here for oxidation are equally relevant to electrochemical reductions.

Recent progress in (hetero)arene cation radical-based heteroarene modification.

The transformation of (hetero)arene cation radicals has become a powerful tool for the construction of highly functionalized (hetero)arenes. These (hetero)arene cation radicals could be generated under electrochemical, photochemical or chemical oxidation systems. The in situ generated (hetero)arene cation radicals can be attacked by various nucleophiles, such as (hetero)aromatics and anions, yielding structurally diverse molecules. Recently, a large number of impressive heteroarene modifications have been designed by this strategy. This review summarizes the advances in heteroarene modification via reactions of in situ formed (hetero)arene cation radicals, ranging from 2010 to 2020.

Interplay of arene radical cations with anions and fluorinated alcohols in hole catalysis

Chemical reactions via radical cation intermediates are of great interest in photoredox catalysis and electrosynthesis, while their reactivities are not clearly understood. For example, how the counter anions correlate with the reactivity of radical cations is still ambiguous. Here we report the effect of anions and fluorinated alcohols on the reactivity of organic radical cations in hole catalysis. The addition of salts in a radical cation Diels–Alder reaction under photoredox catalysis demonstrates that common anions significantly decease the efficiency of hole catalysis. The use of 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) restores the reaction efficiency in the presence of salts, presumably due to solvation of the anions by HFIP to reduce their nucleophilicity. These findings enable hole catalysis under electrolytic conditions with greatly improved efficiency. The effect of anions and fluorinated alcohol described in this paper gives important insights on the fundamental understanding for the reactivity of arene radical cations.

External Oxidant‐Free Regioselective Cross Dehydrogenative Coupling of 2‐Arylimidazoheterocycles and Azoles with H2 Evolution via Photoredox Catalysis

AbstractIn this work, we achieved a site‐selective amination of 2‐arylimidazoheterocycles on the C3 position using photo‐induced external oxidant‐free strategy. The C−N bond formation with H2 evolution was realized via the oxidative C−H/N−H coupling. This protocol may have significant implications in the late‐modification of complicated drug molecules. In addition, we also used CV and DFT calculations to study the mechanism, which showed that the arene radical cation played an important role in accelerating the C−H amination process.magnified image

Guilty and charged: a stable solution of the hexamethylbenzene radical cation as a ligand forming oxidising agent.

While it is often longed for very gentle oxidising agents with ideally close to no interaction with the generated substrate, it may sometimes be beneficial to have an oxidising agent at hand which is able to stabilise a reactive species directly after its generation. Here we present the synthesis of the hexamethylbenzene radical cation as a ligand forming oxidising agent. Its utility was demonstrated by the exemplarily chosen access to the mono-arene complex-cations of univalent gallium and indium [M(C6Me6)]+[Al(ORF)4]- (M = Ga and In).

Visible-Light-Induced External Oxidant-Free Oxidative Phosphonylation of C(sp2)–H Bonds

Considering the synthetic value of phosphonates, developing powerful catalytic methods for the phosphonylation of C(sp2)–H bonds is important. Herein, we achieve a visible-light-induced external oxidant-free oxidative phosphonylation of C(sp2)–H bonds via the combination of photocatalysis and proton-reduction catalysis. Mechanistic studies indicate that the visible-light-induced electron-rich arene radical cation is the key reactive intermediate. The synthetic application of this approach is demonstrated in the late-stage functionalization of pharmaceutical molecules. This study may have significant implications for the functionalization of C(sp2)–H bonds, especially for those that are sensitive to oxidative conditions.

Iodine(III) Reagents in Radical Chemistry.

ConspectusThe chemistry of hypervalent iodine(III) compounds has gained great interest over the past 30 years. Hypervalent iodine(III) compounds show valuable ionic reactivity due to their high electrophilicity but also express radical reactivity as single electron oxidants for carbon and heteroatom radical generation. Looking at ionic chemistry, these iodine(III) reagents can act as electrophiles to efficiently construct C–CF3, X–CF3 (X = heteroatom), C–Rf (Rf = perfluoroalkyl), X–Rf, C–N3, C–CN, S–CN, and C–X bonds. In some cases, a Lewis or a Bronsted acid is necessary to increase their electrophilicity. In these transformations, the iodine(III) compounds react as formal “CF3+”, “Rf+”, “N3+”, “Ar+”, “CN+”, and “X+” equivalents. On the other hand, one electron reduction of the I(III) reagents opens the door to the radical world, which is the topic of this Account that focuses on radical reactivity of hypervalent iodine(III) compounds such as the Togni reagent, Zhdankin reagent, diaryliodonium salts, aryliodonium ylides, aryl(cyano)iodonium triflates, and aryl(perfluoroalkyl)iodonium triflates. Radical generation starting with I(III) reagents can also occur via thermal or light mediated homolysis of the weak hypervalent bond in such reagents. This reactivity can be used for alkane C–H functionalization. We will address important pioneering work in the area but will mainly focus on studies that have been conducted by our group over the last 5 years.We entered the field by investigating transition metal free single electron reduction of Togni type reagents using the readily available sodium 2,2,6,6-tetramethylpiperidine-1-oxyl salt (TEMPONa) as an organic one electron reductant for clean generation of the trifluoromethyl radical and perfluoroalkyl radicals. That valuable approach was later successfully also applied to the generation of azidyl and aryl radicals starting with the corresponding benziodoxole (Zhdankin reagent) and iodonium salts. In the presence of alkenes as radical acceptors, vicinal trifluoromethyl-, azido-, and arylaminoxylation products result via a sequence comprising radical addition to the alkene and subsequent TEMPO trapping. Electron-rich arenes also react with I(III) reagents via single electron transfer (SET) to give arene radical cations, which can then engage in arylation reactions. We also recognized that the isonitrile functionality in aryl isonitriles is a highly efficient perfluoroalkyl radical acceptor, and reaction of Rf-benziodoxoles (Togni type reagents) in the presence of a radical initiator provides various perfluoroalkylated N-heterocycles (indoles, phenanthridines, quinolines, etc.). We further found that aryliodonium ylides, previously used as carbene precursors in metal-mediated cyclopropanation reactions, react via SET reduction with TEMPONa to the corresponding aryl radicals. As a drawback of all these transformations, we realized that only one ligand of the iodine(III) reagent gets transferred to the substrate. To further increase atom-economy of such conversions, we identified cyano or perfluoroalkyl iodonium triflate salts as valuable reagents for stereoselective vicinal alkyne difunctionalization, where two ligands from the I(III) reagent are sequentially transferred to an alkyne acceptor.Finally, we will discuss alkynyl-benziodoxoles as radical acceptors for alkynylation reactions. Similar reactivity was found for the Zhdankin reagent that has been successfully applied to azidation of C-radicals, and also cyanation is possible with a cyano I(III) reagent. To summarize, this Account focuses on the design, development, mechanistic understanding, and synthetic application of hypervalent iodine(III) reagents in radical chemistry.

Azacalix[4]arene cation radicals: spin-delocalised doublet- and triplet-ground states observed in the macrocyclic m-phenylene system connected with nitrogen atoms

Electron paramagnetic resonance spectroscopy has unmasked for the first time the spin-delocalised doublet- and triplet-ground states of azacalix[4]arene cation radicals.

The Question of Aromaticity in Open-Shell Cations and Anions as Ion-Radical Offsprings of Polycyclic Aromatic and Antiaromatic Hydrocarbons

Arene cation-radicals and anion-radicals result directly from the one-electron oxidation and reduction of many aromatic hydrocarbons, yet virtually nothing is known of their intrinsic (thermodynamic) stability and hence "aromatic character". Since such paramagnetic ion radicals lie intermediate between aromatic (Hückel) hydrocarbons with 4n + 2-electrons and antiaromatic analogues with 4n-electrons, we can now address the question of pi-delocalization in these odd-electron counterparts. Application of the structure-based "harmonic oscillator model of aromaticity" or the HOMA method leads to the surprising conclusion that the aromaticity of these rather reactive, kinetically unstable arene cation and anion radicals (as measured by the HOMA index) is actually higher than that of their (diamagnetic) parent-contrary to conventional expectations.

Bimolecular processes on silica gel surfaces: energetic factors in determining electron-transfer rates

Triplet state and radical cation formation is observed following laser excitation of anthracene, phenanthrene and naphthalene (and their derivatives) adsorbed on silica gel. Energy- and electron-transfer reactions of these compounds with co-adsorbed azulene have been studied using a time-resolved diffuse reflectance laser flash photolysis technique. Triplet energy transfer from the arene derivative to azulene and electron transfer from azulene to the arene radical cation have been investigated in order to distinguish between diffusional and energetic control in these systems. Energy and electron transfer can be studied independently due to differing absorption properties and energy dependencies of production of the triplet states and radical cations. Transient decay kinetics for both electron and energy transfer have been modelled using two different rate constant distributions: a log Gaussian and a symmetrical Levy stable distribution. The latter model has also been demonstrated to be applicable to the decay of radical cations in the absence of an electron donor, which cannot be adequately described by the Gaussian model. Energy-transfer rates between the arene derivatives and azulene have been found to be close to the diffusion-controlled limit; however, in most cases, the rate of electron transfer is considerably lower. A correlation between the bimolecular rate constant and free energy of electron transfer has been found, indicating a Marcus inverted region. Compounds with bulky substituents show a further reduction in the rate of electron transfer, suggesting that an additional steric factor is involved in this process.

Gas Phase Reactions of Radical Cations of Halogenated Arenes and Alkenes: The Radical Cation Mediated Nucleophilic Substitution at C(sp2) Atom

Radial cations of unsaturated organic hydrocarbons are reactive intermediates of many important chemical reactions. In particular, the rate constants of the reactions of these deficient species with rich reactants are increased by several orders of magnitude compared to the reaction between neutral partners. This effects has been termed electron hole catalysis. To get insight into the mechanism(s) of these reactions and the nature of the electron hole catalysis the reactions have been investigated in the gas phase using Fourier-transform ion cyclotron resonance (FT-ICR) mass spectrometry, and by molecular orbital calculations. The studies included the reactions of mono- and dihalogenated benzenes and naphthalenes as well as mono- and dihalogenated alkenes. Halogen substituents were chosen for practical reasons since the loss of a halogen substituent during the process can be conveniently used as a monitor reaction. The first part of this account discusses the methods used to determine the kinetics of ion/molecule reactions, in particular FT-ICR-mass spectrometry, and the special features of ion/molecule-reactions in the diluted gas phase. The second part deals with the reactions of halogenated arene radical cations with ammonia and amines as nucleophiles. The reactions correspond to a substitution of one halogen substituent by a radical cation mediated nucleophilic aromatic substitution and are only moderately efficient. Contrary to chemical intuition, the reaction efficiency decreases in the series Cl, Br, and I as substituent. Further, a peculiar dependance on the position of a second substituent is observed. Both effects can be explained by a mechanism involving at least the two steps of an addition of the nucleophile and of an elimination of the substituent and involving a reaction intermediate corresponding to a distonic onium ion. According to the Shaik/Pross model the first step is rate determining and depends strongly on the difference of the ionization energies of the reactants. A second effect comes front the dipole moment of the (neutral) dihalogenated arene, showing a decrease in the activation energy of the addition with an increase in dipole moment. The third part presents results of reactions of the radical cations of rnono- and dihalogenated alkenes using ammonia, amines, and aliphatic alcohols as nucleophiles. These reactions are often efficient and may be collision controlled. Besides substitution of a halogen a variety of other reaction products is observed. The efficient reaction of alkene radical cations is in agreement with electron hole catalysis. An analysis by the Shaik/Pross model reveals that the initial addition step is now a very fast inner sphere transfer which occurs probably without any activation barrier. This is substantiated by molecular orbital calculations for selected reaction systems. Interestingly, experimental results show that addition of the nucleophile to the ionized C-C double bond competes even with intermolecular exothermic transfer and exothermic proton transfer. As a consequence, the beta-distonic onium ion, which is formed during the initial addition step, arises as a highly excited intermediate. The further course of the total reaction depends on the properties of this intermediate beta-distonic ion. The consequences of this reaction model for the individual reaction systems are discussed.