Radical-radical Coupling Reactions Research Articles

Impact of Transition-State Aromaticity on Selective Radical-Radical Coupling of Triarylimidazolyl Radicals.

Radical coupling reactions are generally known to have a low selectivity due to the high reactivity of radicals. In this study, high regio and substrate selectivity was discovered in the dimerization of triarylimidazolyl radicals (TAIR), a versatile photochromic reaction. When two different radicals, 2-(4-cyanophenyl)-4,5-diphenyl-1H-imidazolyl radical (CN-TAIR) and 2-(4-methoxyphenyl)-4,5-diphenyl-1H-imidazolyl radical (OMe-TAIR), were simultaneously generated in situ, a hexaarylbiimidazole, formed by selective coupling at the nitrogen atom at position 1 of CN-TAIR and the carbon atom at position 2 of OMe-TAIR, was isolated with high selectivity as the main product among 24 possible radical dimer hexaarylbiimidazole derivatives. This high regio and substrate selectivity cannot be explained solely by the stability of the product and/or the electrophilicity and nucleophilicity of the radicals but originates from the aromaticity of the transition state in the radical-radical coupling reaction. To date, the selectivity of radical coupling reactions has been thought to be controlled by steric hindrance and radical spin density, but this study revealed a new factor for controlling radical coupling, that is, transition-state aromaticity. Aromaticity has been reported to have an important effect not only in the reactivity and structure of ground-state molecules but also on the electronically excited states and transition states in pericyclic reactions such as the Diels-Alder reaction and the Cope-Claisen rearrangement. This study demonstrated for the first time that radical coupling reactions can also be controlled by transition-state aromaticity.

Crystallization-Induced Dimerization and Solution-Phase Bond Dissociation of Stable Dibenzoolympicenyl Radicals.

Crystallization of organic materials can lead to different assembly structure with different reactivity, but this phenomenon is rarely observed for delocalized hydrocarbon radicals. This report introduces a crystallization-induced radical-radical coupling reaction, which employs a series of stable nonplanar organic π-radicals as reactants. Six stable radical congeners are synthesized, resulting in radical-radical coupling at the allenyl radical site during crystallization to produce close-shell dimers. This coupling reaction is absent in the solution phase, which highlights the importance of preorganization in the lattice. Remarkably, the attempts of cocrystallization of different congeners yielded homocoupling products instead of cross-coupling products. In specific cases, two distinct polymorphs are observed and their reactivity is different according to the distance of the reaction sites. Theoretical calculations indicate that the transition from a metastable preorganized monomer to a dimer is barrierless and spontaneous. The dimer could regenerate free radicals by heating or photoirradiation in the solution phase. This discovery may lead to controllable molecular switches.

Photoredox decarboxylative acylation of carboxylic acid by 4-acyl-1,2,3-triazoliums

Recent advancements in NHC-based radical coupling reactions have introduced NHC-derived ketyl radicals as innovative persistent radicals. However, current work involves NHC-based radical-radical coupling reactions that are limited to some stable alkyl radicals of the radical partners. This is mainly due to the high barriers among the transition state in the coupling process. Our study, supported by density functional theory (DFT) calculations, demonstrates that ketyl radicals derived from mesoionic carbenes (MICs) exhibit significantly lower barriers for radical-radical coupling. This facilitates rapid reactions with short-lived alkyl radicals. Herein, we disclose 4-acyl-1,2,3-triazoliums as versatile acylation reagents, which can be converted to MIC-derived ketyl radicals by photocatalyst. Photoredox decarboxylative acylation of primary, secondary, and tertiary carboxylic acids afford the corresponding ketones with broad substrate scope and excellent functional group tolerance.

α-C(sp3)-H (Hetero)Arylation of Thioethers Enabled by Photoexcited Triplet Ketone Catalysis.

We report herein α-C(sp3)-H (hetero)arylation of thioethers enabled by dual nickel and photoexcited triplet ketone catalysis. The mild reaction conditions of this protocol tolerate a variety of functional groups and further facilitate the late-stage functionalization of biologically relevant molecules to afford corresponding products in moderate to good yields. Preliminary mechanistic studies suggest that the generation of the α-thioalkyl radical takes place through a hydrogen atom transfer (HAT) event, which is involved in the rate-limiting step and in the nickel cycle, the reaction of the α-thioalkyl radical with Ni(0)Ln catalyst followed by oxidative addition of aryl bromide is the dominating pathway. Furthermore, the heteroaromatic benzylic thioethers can also be achieved from the corresponding reduced 4-cyano pyridine derivatives in the presence of a ketone catalyst through a radical-radical coupling reaction without metal. The increased yield of the products in the presence of DABCO might indicate a higher rate of α-thioalkyl radical formation from thioethers through the HAT event by DABCO radical cation.

Photoredox-catalyzed radical-radical cross coupling of ketyl radicals with unstabilized primary alkyl radicals.

Herein, a novel protocol dealing with the preparation of sterically hindered alcohols has been successfully developed via radical-radical coupling reactions enabled by mild and redox-neutral photocatalysis. With alkylsilicates as the radical precursors, a range of primary alkyl radicals bearing various functional groups could couple with a range of phthalimides and activated ketones.

A photoelectrocatalytic system as a reaction platform for selective radical-radical coupling.

The selection of electrode material is a critical factor that determines the selectivity of electrochemical organic reactions. However, the fundamental principles governing this relationship are still largely unexplored. Herein, we demonstrate a photoelectrocatalytic (PEC) system as a promising reaction platform for the selective radical-radical coupling reaction owing to the inherent charge-transfer properties of photoelectrocatalysis. As a model reaction, the radical trifluoromethylation of arenes is shown on hematite photoanodes without employing molecular catalysts. The PEC platform exhibited superior mono- to bis-trifluoromethylated product selectivity compared to conventional electrochemical methods utilizing conducting anodes. Electrochemical and density functional theory (DFT) computational studies revealed that controlling the kinetics of anodic oxidation of aromatic substrates is essential for increasing reaction selectivity. Only the PEC configuration could generate sufficiently high-energy charge carriers with controlled kinetics due to the generation of photovoltage and charge-carrier recombination, which are characteristic features of semiconductor photoelectrodes. This study opens a novel approach towards selective electrochemical organic reactions through understanding the intrinsic physicochemical properties of semiconducting materials.

Controlling Diradical Character of Photogenerated Colored Isomers of Phenoxyl-Imidazolyl Radical Complexes.

We propose a rational method for evaluating the diradical character of the photochromic phenoxyl-imidazolyl radical complex (PIC) derivatives based on their radical-radical coupling reaction rates. PIC consists of an imidazole ring, a phenoxyl ring, and a bridging unit that structurally connects them. The C-N bond formed between the imidazole and phenoxyl rings can be dissociated photochemically in a homolytic manner. The photochromism of PIC differs significantly from other photochromic molecules in that the transient colored open-ring isomer has a diradical character. The colored open-ring isomer returns promptly to the initial colorless closed-ring isomer by the intramolecular radical recombination reaction. By changing the aromaticity and substitution position of the bridging unit, it is possible to control the degree of contribution of the open-shell diradical and closed-shell quinoidal structures to the open-ring isomer. Systematic investigation of the photochromic reactions of several PIC derivatives revealed that the half-life of the open-ring isomers reflects the diradical character. Thus, the radical recombination reaction rate of the open-ring isomer of the PIC derivatives is an excellent parameter of the diradical character.

Combined Photoredox and Carbene Catalysis for the Synthesis of γ-Aryloxy Ketones.

N-heterocyclic carbenes (NHCs) have emerged as catalysts for the construction of C-C bonds in the synthesis of substituted ketones under single-electron processes. Despite these recent reports, there still remains a need to increase the utility and practicality of these reactions by exploring new radical coupling partners. Herein, we report the synthesis of γ-aryloxyketones via combined NHC/photoredox catalysis. In this reaction, an α-aryloxymethyl radical is generated via oxidation of an aryloxymethyl potassium trifluoroborate salt, which is then added into styrene derivatives to provide a stabilized benzylic radical. Subsequent radical-radical coupling reaction with an azolium radical affords the γ-aryloxy ketone products.

Oxidation Potential-Guided Electrochemical Radical-Radical Cross-Coupling Approaches to 3-Sulfonylated Imidazopyridines and Indolizines.

Oxidation potential-guided electrochemical radical-radical cross-coupling reactions between N-heteroarenes and sodium sulfinates have been established. Thus, simple cyclic voltammetry measurement of substrates predicts the likelihood of successful radical-radical coupling reactions, allowing the simple and direct synthetic access to 3-sulfonylated imidazopyridines and indolizines. The developed electrochemical radical-radical cross-coupling reactions to sulfonylated N-heteroarenes boast the green synthetic nature of the reactions that are oxidant- and metal-free.

Fused Quinoidal Dithiophene-Based Helicenes: Synthesis by Intramolecular Radical-Radical Coupling Reactions and Dynamics of Interconversion of Enantiomers.

A series of fused quinoidal dithiophene-based double and triple helicenes (1-M, 2-M, 2-M-Cl, 3-M, 3-M-Cl) were synthesized by intramolecular radical-radical coupling followed by oxidative dehydrogenation reaction. These helical molecules show dynamic interconversion of enantiomers in solution as revealed by variable-temperature NMR measurements, and the energy barriers are correlated to the substituents and topological structures. Notably, dynamic high performance liquid chromatography was used to quantitatively investigate the room-temperature racemization process between the (P,P,M)- and (P,M,M)- enantiomers of the triple helical 3-M-Cl, which gave an interconversion energy barrier in consistent with density functional theory calculations. Their optical and electrochemical properties are dependent on the fusion mode. Our studies provide both new synthetic strategy and new dynamic analytical method for helicenes with unique electronic structure.

Pyridylphosphonium salts as alternatives to cyanopyridines in radical-radical coupling reactions.

Radical couplings of cyanopyridine radical anions represent a valuable technology for functionalizing pyridines, which are prevalent throughout pharmaceuticals, agrochemicals, and materials. Installing the cyano group, which facilitates the necessary radical anion formation and stabilization, is challenging and limits the use of this chemistry to simple cyanopyridines. We discovered that pyridylphosphonium salts, installed directly and regioselectively from C–H precursors, are useful alternatives to cyanopyridines in radical–radical coupling reactions, expanding the scope of this reaction manifold to complex pyridines. Methods for both alkylation and amination of pyridines mediated by photoredox catalysis are described. Additionally, we demonstrate late-stage functionalization of pharmaceuticals, highlighting an advantage of pyridylphosphonium salts over cyanopyridines.

Sonochemiluminescence of lucigenin using amines as coreactant: Reactivity and mechanism studies

Sonochemiluminescence (SCL) from aqueous solution of lucigenin (Luc2+) has been studied using aliphatic amines as coreactant. The SCL intensity are strongly dependent on the dissolved gases such as air, oxygen, nitrogen and argon. The most strong SCL signals are observed from oxygen saturated alkaline solution containing Luc2+ when small amount of trialkylamine, such as tripropylamine (TPrA) was added into the solution. In an ultrasonic field, TPrA can adsorb onto the cavitation bubble/solution interface where TPrA is oxidized by OH to form a radical cation TPrA+ and subsequently produce a highly reducing TPrA species through a deprotonation reaction of the TPrA+. TPrA is suggested to initiate the reduction reactions of Luc2+ and molecule oxygen to produce Luc+ and superoxide radical anion (O2−), respectively. The radical-radical coupling reaction between Luc+ and O2− is expected to initiate the light emission. The production of O2− is examined by spectrofluorometric method using 2-(2-pyridyl)benzothiazoline as a fluorescent probe. The results show that the production of O2− by ultrasound was more efficient in oxygen saturated solution in the presence of coreactants, consistent with the results with SCL measurements.

Iron-Catalyzed Cleavage Reaction of Keto Acids with Aliphatic Aldehydes for the Synthesis of Ketones and Ketone Esters.

The radical-radical coupling reaction is an important synthetic strategy. In this study, the iron-catalyzed radical-radical cross-coupling reaction based on the decarboxylation of keto acids and decarbonylation of aliphatic aldehydes to obtain valuable aryl ketones is reported for the first time. Remarkably, when tertiary aldehydes were used as carbonyl sources, ketone esters were selectively obtained instead of ketones. The gram-scale preparation of aryl ketone through this strategy was easily achieved by using only 3 mol % of the iron catalyst. As a proof-of-concept, the bioactive molecule flurprimidol was synthesized in two steps by using this strategy.

Generation of Extremely Long-lived Localized Singlet Diradicals: New Insights into Bond-homolysis Process and Discovery of Novel Bonding System (C-π-C)

Localized singlet diradicals are key intermediates in bond-homolyses. Thorough studies of the reactive species are essential to clarify the mechanisms of the homolytic bond-cleavage and -formation processes. In general, the singlet diradicals are quite short-lived due to the fast radical-radical coupling reactions. The short-lived characteristic has retarded the thorough study on bond-homolyses. In the last two decades, the author and his research group have enjoyed conducting fundamental studies of generating spectroscopically detectable singlet diradicals to clarify the chemistry of localized singlet diradicals. Recently, a new series of long-lived singlet diradicals, viz. 1,2-diazacyclopentane-3,5-diyl and singlet diradical having macrocyclic structures, have been identified, and their electronic structures and novel reactivities were thoroughly studied using laser-flash photolysis (LFP), product analysis, emission analyses, and computational studies. During the research study, two new concepts in chemistry have emerged; (1) π-single bonding (C-π-C) and (2) the third isomer in bond-homolysis processes, i.e. puckered singlet diradicals. This article describes first a short history of localized diradicals, then, the nitrogen-atom effect on the reactivity of singlet diradicals, the chemistry of π-single bonded species, the stereoselectivity in the photochemical denitrogenation reactions, and the adiabatic bond-homolysis process in the electronically excited states.

1,2-Diazacyclopentane-3,5-diyl Diradicals: Electronic Structure and Reactivity.

Localized singlet diradicals are key intermediates in bond homolysis. A thorough study of the reactive species is needed to clarify the mechanisms of the homolytic bond cleavage and formation processes. In general, the singlet diradicals are quite short-lived because of the fast radical-radical coupling reactions. The short-lived characteristic has retarded the thorough study on bond homolysis. In this study, a new series of long-lived singlet diradicals, viz., 1,2-diazacyclopentane-3,5-diyl, were identified, and their electronic structures and novel reactivities were thoroughly studied using laser-flash photolysis (LFP), product analysis, and computational studies. A direct observation of the thermal equilibration (fast process) between the singlet diradicals and the corresponding ring-closing compounds was undertaken on the submicrosecond time scale. The solvent and substituent effects on the equilibration constant and rate constants for the ring-closing reaction and ring-opening reaction clarify the novel nitrogen-atom effect on the localized singlet 1,3-diyl diradicals. Two types of alkoxy-migrated compounds, 9 and 10, were isolated with high yields as the final products. Crossover, spin-trapping, and LFP experiments for the formation of alkoxy-group migration products (i.e., 9 versus 10) revealed the unique temperature effect on the product ratio of the two types of alkoxy-migration products. The temperature-insensitive intersystem crossing process (slow process, millisecond time scale) was found to be a key step in the formation of 9, which is an entropy-controlled pathway. An intramolecular migration process was identified for the formation of 10 that was accelerated by a polar solvent in an enthalpy-controlled process. This unique heteroatom effect has opened up a new series of localized singlet diradicals that are crucial intermediates in bond homolysis.

Understanding titanium-catalysed radical-radical reactions: a DFT study unravels the complex kinetics of ketone-nitrile couplings.

The computational investigation of a titanium-catalysed reductive radical-radical coupling is reported. The results match the conclusions from an earlier experimental study and enable a further interpretation of the previously observed complex reaction kinetics. Furthermore, the interplay between neutral and cationic reaction pathways in titanium(iii)-catalysed reactions is investigated for the first time. The results show that hydrochloride additives and reaction byproducts play an important role in the respective equilibria. A full reaction profile is assembled and the computed activation barrier is found to be in reasonable agreement with the experiment. The conclusions are of fundamental importance to the field of low-valent titanium catalysis and the understanding of related catalytic radical-radical coupling reactions.

Hemin‐Graphene Derivatives with Increased Peroxidase Activities Restrain Protein Tyrosine Nitration

Protein tyrosine nitration is implicated in the occurrence and progression of pathological conditions involving free radical reactions. It is well recognized that hemin can catalyze protein tyrosine nitration in the presence of nitrite and hydrogen peroxide. Generally, the catalytic efficiency is positively correlated to its peroxidase activity. In this study, however, it is found that the efficiency of hemin in catalyzing protein tyrosine nitration is largely suppressed after functionalization with graphene derivatives, even though its peroxidase-like activity is more than quadrupled. Further studies show that the oxidation of tyrosine is still observed for these composites; dityrosine formation, however, is greatly inhibited. Furthermore, these composites also exhibit strong effects on the oxidation of nitrite into nitrate. Therefore, we propose a mechanism in which hemin-graphene derivatives facilitate the oxidation of tyrosine and nitrite to produce tyrosyl radicals and nitrogen dioxide radicals in the presence of hydrogen peroxide, but graphene interlayers serve as barriers that hinder radical-radical coupling reactions; consequently, protein tyrosine nitration is restrained. This property of hemin-graphene derivatives, by which they catalyze substrate oxidation but suppress radical-radical coupling reactions, shows their great potential in selective oxidation procedures for byproduct removal.

Direct assembly of multiply oxygenated carbon chains by decarbonylative radical-radical coupling reactions.

Pentoses and hexoses contain more than three oxygen-bearing stereocentres and are ideal starting materials for the synthesis of multiply oxygenated natural products such as sagittamide D, maitotoxin and hikizimycin. Here we demonstrate new radical-radical homocoupling reactions of sugar derivatives with minimal perturbation of their chiral centres. The radical exchange procedure using Et3B/O2 converted sugar-derived α-alkoxyacyl tellurides into α-alkoxy radicals via decarbonylation and rapidly dimerized the monomeric radicals. The robustness of this process was demonstrated by a single-step preparation of 12 stereochemically diverse dimers with 6-10 secondary hydroxy groups, including the C5-C10 stereohexad of sagittamide D and the enantiomer of the C51-C60 stereodecad of maitotoxin. Furthermore, the optimally convergent radical-radical cross-coupling reaction achieved a one-step assembly of the protected C1-C11 oxygenated carbon chain of the anthelmintic hikizimycin. These exceptionally efficient homo- and heterocoupling methods together provide a powerful strategy for the expedited total synthesis of contiguously hydroxylated natural products.

Trimeric Structure of (+)-Pinoresinol-forming Dirigent Protein at 1.95 Å Resolution with Three Isolated Active Sites

Control over phenoxy radical-radical coupling reactions in vivo in vascular plants was enigmatic until our discovery of dirigent proteins (DPs, from the Latin dirigere, to guide or align). The first three-dimensional structure of a DP ((+)-pinoresinol-forming DP, 1.95 Å resolution, rhombohedral space group H32)) is reported herein. It has a tightly packed trimeric structure with an eight-stranded β-barrel topology for each DP monomer. Each putative substrate binding and orientation coupling site is located on the trimer surface but too far apart for intermolecular coupling between sites. It is proposed that each site enables stereoselective coupling (using either two coniferyl alcohol radicals or a radical and a monolignol). Interestingly, there are six differentially conserved residues in DPs affording either the (+)- or (-)-antipodes in the vicinity of the putative binding site and region known to control stereoselectivity. DPs are involved in lignan biosynthesis, whereas dirigent domains/sites have been implicated in lignin deposition.

Solution Effect on Diazonium-Modified Au(111): Reactions and Structures

Surface modifications of a Au(111) electrode with 4-bromobenzenediazonium tetrafluoroborate (BBD) in acetonitrile (ACN) and 0.1 M HClO4 have been characterized by scanning tunneling microscopy (STM). In ACN, STM results reveal the formation of disordered thin organic films. The involvement of the radical as an intermediate is evidenced by the negative effect of radical scavengers on organic thin film formation. In contrast, the 4,4'-dibromobiphenyl monolayer is observed when the aqueous solution is used as a medium to carry out the grafting experiment. The biphenyl compound is considered to be generated by a radical-radical coupling reaction.