Transient Radical Cation Research Articles

Revisiting the Reaction of IPr with Tritylium: An Alternative Mechanistic Pathway.

Despite a recent proposal on the mechanism of a single-electron transfer (SET) process between tritylium and 2,6-bis(diisopropylphenyl)imidazol-2-ylidene (IPr) based on evidence of transient IPr radical cation intermediate ([IPr]⋅+ ) formation, such oxidation is still contentious because of the high oxidation potential of N-heterocyclic carbenes. Our experimental analysis indicates that the appearance of deep purple color, previously considered to be from transient [IPr]⋅+ , originates from a zwitterionic intermediate (3 a), not a radical cation. Here, we propose an alternative mechanism for the reaction involving tritylium and IPr. This mechanism is noteworthy for explaining how [NHC-H]+ can be generated without the formation of transient [NHC]⋅+ , which has been frequently proposed as an intermediate for the reaction between NHC and oxidants. These results also show that a transient strong single-electron donor (3 a) could be generated by the alternative mechanism for oxidants using NHCs, which is a more feasible explanation for the reactivity of NHCs with oxidants.

Oxidative N-Dealkylation of N,N-Dimethylanilines by Non-Heme Manganese Catalysts

Non-heme manganese(II) complexes [(IndH)MnIICl2] (1) and [(N4Py*)MnII(CH3CN)](ClO4)2 (2) with tridentate isoindoline and pentadentate polypyridyl ligands (IndH = 1,3-bis(2′-pyridylimino)isoindoline; N4Py* = N,N-bis(2-pyridylmethyl)-1,2- di(2-pyridyl)ethylamine) proved to be suitable to catalyze the oxidative demethylation of N,N-dimethylaniline (DMA) with various oxidants such as tert-butyl hydroperoxide (TBHP), peracetic acid (PAA), and meta-chloroperoxybenzoic acid (mCPBA), resulting N-methylaniline (MA) as a main product with N-methylformanilide (MFA) as a result of a free-radical chain process under air. The effect of electron-donating and electron-withdrawing substituents on the aromatic ring on the relative reactivity of the substrates and on the product composition (MA/MFA) was also studied and showed a significant impact on the catalytic N-demethylation reaction. Based on the Hammett correlation with ρ = −0.38 (PAA), −0.45 (mCPBA), and −0.63 (TBHP) for 1 and ρ = −0.38 (PAA) and −0.37 (mCPBA) for 2, an electrophilic intermediate is suggested as the key oxidant. Furthermore, the spectral investigation (UV-Vis) resulted in direct evidence for the formation of a high-valent oxomanganese(IV) and a transient radical cation intermediate, p-Me-DMA•+, suggesting that the initial step in the manganese-catalyzed oxidations is a fast electron-transfer between the amine and the high valent oxometal species. The mechanisms of the subsequent steps are discussed.

Disclosing Cyclic(Alkyl)(Amino)Carbenes as One-Electron Reductants: Synthesis of Acyclic(Amino)(Aryl)Carbene-Based Kekulé Diradicaloids.

Herein, we disclose cyclic(alkyl)(amino)carbenes (CAACs) to be one‐electron reductants under the formation of a transient radical cation as indicated by EPR spectroscopy. The disclosed CAAC reducing reactivity was used to synthesize acyclic(amino)(aryl)carbene‐based Thiele and Chichibabin hydrocarbons, a new class of Kekulé diradicaloids. The results demonstrate CAACs to be potent organic reductants. Notably, the acyclic(amino)(aryl)carbene‐based Chichibabin's hydrocarbon shows an appreciable population of the triplet state at room temperature, as evidenced by both variable‐temperature NMR and EPR spectroscopy.

Cover Feature: Exploiting Transient Radical Cations as Brønsted Acids for Allylic C–H Heteroarylation of Enol Silyl Ethers (Chem. Eur. J. 36/2021)

The reaction pathways of transient radical species are difficult to control, like the soap bubbles in the wind depicted in the cover image. Yet, these short-lived intermediates, when one encounters another, readily assemble into a united structure, as two bubbles fuse into a bigger single bubble. The enol silyl ether-derived radical cations with a highly acidic allylic proton facilitates the single-electron reduction of cyanopyridines via protonation. The resulting two radical intermediates successively engage in the radical−radical coupling to produce heteroarylated enol silyl ethers. More information can be found in the Communication by T. Ooi et al. (DOI: 10.1002/chem.202101352).

Exploiting Transient Radical Cations as Brønsted Acids for Allylic C-H Heteroarylation of Enol Silyl Ethers.

Intermediary radical cations, generated through single-electron oxidation of enol silyl ethers by excited Ir-based photocatalysts, can be exploited as Brønsted acids for the activation of heteroarylcyanides. This strategy enables the direct allylic C-H heteroarylation of enol silyl ethers under visible-light irradiation.

Detection of Fleeting Amine Radical Cations and Elucidation of Chain Processes in Visible-Light-Mediated [3 + 2] Annulation by Online Mass Spectrometric Techniques.

Visible-light-mediated photoredox reactions have recently emerged as a powerful means for organic synthesis and thus have generated significant interest from the organic chemistry community. Although the mechanisms of these reactions have been probed by a number of techniques such as NMR, fluorescence quenching, and laser flash photolysis and various degrees of success has been achieved, mechanistic ambiguity still exists (for instance, the involvement of the chain mechanism is still under debate) because of the lack of structural information about the proposed and short-lived intermediates. Herein, we present the detection of transient amine radical cations involved in the intermolecular [3 + 2] annulation reaction of N-cyclopropylaniline (CPA, 1) and styrene 2 by electrospray ionization mass spectrometry (ESI-MS) in combination with online laser irradiation of the reaction mixture. In particular, the reactive CPA radical cation 1+•, the reduced photocatalyst Ru(I)(bpz)3+, and the [3 + 2] annulation product radical cation 3+• are all successfully detected and confirmed by high-resolution MS. More importantly, the post-irradiation reaction with an additional substrate, isotope-labeled CPA, following photolysis of 1, 2, and Ru catalyst provides strong evidence to support the chain mechanism in the [3 + 2] annulation reaction. Furthermore, the key step of the proposed chain reaction, the oxidation of CPA 1 to amine radical cation 1+• by product radical cation 3+• (generated using online electrochemical oxidation of 3), is successfully established. Additionally, the coupling of ESI-MS with online laser irradiation has been successfully applied to probe the photostability of photocatalysts.

Understanding the Reactivity of Enol Ether Radical Cation: Investigation of Electrochemical [2 + 2] Cycloaddition Reactions

Electrochemical process has proven to be powerful tool to form carbon-carbon bond and has widely used to construct various carbon skeletons. Especially, the electrochemical carbon-carbon bond forming reactions have demonstrated to afford complicated ring systems effectively, including naturally occurring compounds. For example, enol ether radical cations are readily produced in anodic oxidations of enol ethers and provide versatile reactive intermediates. This reaction is synthetically intriguing due to the umpolung process that polarity of nucleophilic enol ethers is reversed to give enol ether radical cations which function as electrophilic species. We have developed the electrochemical reactions in lithium perchlorate/nitromethane (LPC/NM) electrolyte solution, which exhibits a remarkable accelerating property as a Lewis acid catalyst and stabilize carbocation intermediates. The feature of LPC/NM allows facile synthesis of biologically relevant compounds, such as dihydrobenzofuran derivatives1 and azanucleoside derivatives.2 In LPC/NM, unactivated olefins can serve as efficient nucleophiles to trap anodically generated cationic species. In this context, we also have developed electrochemical [2 + 2] cycloaddition reactions between enol ethers and unactivated olefins, affording cyclobutane products(Scheme 1).3 The reaction was initiated by anodic oxidation of enol ether (1) and thus generated enol ether radical cation (2) was trapped by unactivated olefin nucleophile to give transient cyclobutyl radical cation (3). In order for successful cyclobutane formation, electron rich aromatic ring was required as an electron donor to form relatively long lived aromatic ring radical cation (4), which was finally reduced by cathode or starting enol ether, affording neutral cycloadduct (5) (Scheme 2).Although our previous work have focused on the use of enol ether (1) for electrochemical [2 + 2] cycloaddition reactions, the reactivity of enol ether radical cation (2) still remains unclear. To investigate the reactivity of such enol ether radical cations, we designed and synthesized several types of new substrates and then subjected them to the electrochemical [2 + 2] cycloaddition reactions(Scheme 3). Synthetic and mechanistic details would be discussed in the presentation. Reference (1) Kim, S.; Hirose, K.; Uematsu, J.; Mikami, Y.; Chiba,K. Chem. – Eur. J. 2012, 18, 6284–6288.(2) Kim, S.; Shoji, T.; Kitano, Y.; Chiba, K. Chem. Commun. 2013, 49, 6525–6527.(3) (a) Yamaguchi, Y.; Okada, Y.; Chiba, K. J. Org. Chem., 2013, 78, 2626–2638. (b) Yamaguchi, Y.; Okada, Y.; Chiba, K. Electrochemistry 2013, 81, 331–333 and references therein.

A comparative study of radical cations of thiourea, thiosemicarbazide, and diethylthiourea in aqueous sulphuric acid media employing pulse radiolysis technique

The generation of radical cations of thiourea [(NH2)2C=S], thiosemicarbazide [(NH2―NH)(NH2)C=S], and diethylthiourea [(C2H5―NH)2C=S] in aqueous sulphuric acid media of low to high acid strengths utilizing the pulse radiolysis technique is reported. In this system, the decay half‐life of radical cations of thiourea and its derivatives observed were longer (ranging from 45 to 100 µs at acid strength pH/H0 = −4.1), and the formation times could be altered with the change in acid strengths. By doing so, a wide range in half‐life of radical cations of thiosemicarbazide (0.7 to 100 µs) was observed in contrast to thiourea and diethylthiourea with the variation in acid strengths (pH/H0) from 0.7 to −4.1. This perhaps helps in studying the spectral and kinetic properties of transient radical cations comfortably. The general mechanism for the formation of radical cations of the aforementioned compounds in radiolysis has been revisited in which the electron transfer reactions are active. Copyright © 2013 John Wiley & Sons, Ltd.

Catalyzing Pyramidal Inversion: Configurational Lability of P-Stereogenic Phosphines via Single Electron Oxidation

We report that pyramidal inversion of trivalent phosphines may be catalyzed by single electron oxidation. Specifically, a series of P-stereogenic (aryl)methylphenyl phosphines are shown to undergo rapid racemization at ambient temperature when exposed to catalytic quantities of a single electron oxidant in solution. Under these conditions, transient phosphoniumyl radical cations (R3P(•+)) are formed, and computational models indicate that the pyramidal inversion barriers for these open-shell intermediates are on the order of ∼5 kcal/mol. The observed 10(20)-fold rate enhancement over uncatalyzed pyramidal inversion opens new opportunities for the dynamic stereochemistry of phosphines and may hold additional implications for the configurational stability of P-stereogenic phosphine ligands on high-valent oxidizing transition metals.

Flavonoid Deactivation of Excited State Flavins: Reaction Monitoring by Mass Spectrometry

Flavin mononucleotide (FMN, as a B(2) vitamin model) was shown to induce dimerization of flavonoids (flavanone, apigenin, naringenin, eriodictyol, taxifolin, catechin, kaempferol, luteolin, quercetin, rutin, and seven smaller model phenols studied) as the major photoreaction, when aqueous solutions were exposed to visible light using a new, real-time electrospray ionization mass-spectrometric (ESI-MS) technique supported by LC-MS and MS(2) analysis. Electrophilic intermediates such as transient radical cations, o-quinones, and p-quinone methide were proposed to be involved in the coupling process. The C(3)-OH in flavon-3-ols gave rise to atypical compounds such as a depside or a dioxane-linked dimer. Flavonoid dimers, formed in vegetal extracts added to food during storage in light and for which structures are proprosed based on MS and MS(2), may affect colloidal stability, color, astringency, and antioxidative capacity.

Enantioselective organo-SOMO cycloadditions: a catalytic approach to complex pyrrolidines from olefins and aldehydes.

A new method to rapidly generate pyrrolidines via a SOMO-activated enantioselective (3 + 2) coupling of aldehydes and conjugated olefins has been accomplished. A radical-polar crossover mechanism is proposed wherein olefin addition to a transient enamine radical cation and oxidation of the resulting radical furnish a cationic intermediate which is vulnerable to nucleophilic addition of a tethered amine group. A range of olefins, including styrenes and dienes, are shown to provide stereochemically complex pyrrolidine products with high chemical efficiency and enantiocontrol.

Electron-transfer properties of a nonheme manganese(iv)–oxo complex acting as a stronger one-electron oxidant than the iron(iv)–oxo analogue

Electron-transfer properties of a nonheme Mn(IV)-oxo complex, [(Bn-TPEN)Mn(IV)(O)](2+), reveals that Mn(IV)-oxo complex acts as a stronger one-electron oxidant than the Fe(IV)-oxo analogue. As a result, an electron transfer process in N-dealkylation has been detected by a transient radical cation intermediate, para-Me-DMA˙(+), in the oxidation of para-Me-DMA by [(Bn-TPEN)Mn(IV)(O)](2+).

Neighboring Pyrrolidine Amide Participation in Thioether Oxidation. Methionine as a “Hopping” Site

Methionine residues have been shown to function as efficient "hopping" sites in long-range electron transfer in model polyprolyl peptides. We suggest that a key to this ability of methionine is stabilization of the transient sulfur radical cation by neighboring proline amide participation. That is, in a model system a neighboring pyrrolidine amide lowers the oxidation potential of the thioether by over 0.5 V by formation of a two-center three-electron SO bond.

Enantioselective Organo-SOMO Cascade Cycloadditions: A Rapid Approach to Molecular Complexity from Simple Aldehydes and Olefins

A highly selective, radical-mediated (4 + 2) coupling reaction of aldehydes and conjugated olefins has been achieved through asymmetric SOMO-catalysis. A radical-polar crossover mechanism is proposed wherein olefin addition to a transient enamine radical cation and oxidation of the resulting radical furnishes a cation which is vulnerable to nucleophilic addition. A range of aromatic aldehydes are shown to couple with styrenes and dienes to provide cyclic products with high chemical efficiency, regioselectivity, and stereoselectivity.

Novel Reactions of One-Electron Oxidized Radicals of Selenomethionine in Comparison with Methionine

Pulse radiolysis studies on hydroxyl (*OH) radical reactions of selenomethionine (SeM), a selenium analogue of methionine, were carried out, and the resultant transient radical cations and their subsequent reactions have been reported. At pH<3, the >Se*-OH radical adducts produced on reaction of SeM with *OH radical were converted to selenium centered radical cations (Se*+M), which react with another molecule of SeM to form dimer radical cation M(Se therefore Se)M+. At pH 7, the >Se*-OH radical adducts were converted to a monomer radical of the type (Se therefore N)M+ that acquires intramolecular stability through interaction with the lone pair of the N atom and this radical is denoted as SeM*+. SeM*+ decayed by first order kinetics, and the reduction potential of the couple SeM*+/SeM was determined to be 1.21+/-0.05 V vs NHE at pH 7. SeM*+ oxidized ABTS2- and TMPD with rate constants of (2.5+/-0.1)x10(8) and (6.1+/-0.2)x10(8) M(-1) s(-1), respectively, and reacted with hydroxide ion with a rate constant of (3.8+/-0.9)x10(5) M(-1) s(-1). SeM*+ reacts with molecular oxygen, and the rate constant for this reaction was determined to be (4.3+/-0.2)x10(8) M(-1) s(-1); similar reaction with methionine could not be observed experimentally. Like methionine radical cations, SeM*+ undergoes decarboxylation, although with lesser yield, to produce reducing 3-methyl-selenopropyl amino radicals (referred as alpha-amino radicals). The formation of these radicals was confirmed both by the estimation of the liberated CO2 and by one-electron reduction of MV2+, thionine, and PNAP. These results have been supported by quantum chemical calculations. Implications of these results in the biological role of SeM have also been briefly discussed.

Long-range charge transport through double-stranded DNA mediated by manganese or iron porphyrins

Guanine oxidation by electron transfer results in the formation of a guanine radical cation, which is at the origin of long-range charge transport through double-stranded DNA. It is possible to observe guanine lesions at a long distance from the oxidative reagent covalently bound to DNA owing to the migration of the positive hole in the DNA pi-stacks. This phenomenon of long-range hole transport is classically studied in the literature with photosensitizers used as one-electron oxidants. It is shown in the present work that the process of long-range charge transport and the concomitant formation of guanine lesions at a long distance can be observed also in the case of two-electron oxidants. This is the signature of the formation of a transient guanine radical cation in the course of the two-electron abstraction process and consequently evidence of the separated one plus one electron abstraction steps. Long-range charge transport is likely to be a universal mechanism for any two-electron oxidant acting by electron abstraction provided that the second electron abstraction is slower than hole transfer.

ChemInform Abstract: Radical Cations in Electrospray Mass Spectrometry: Formation of Open‐Shell Species, Examination of the Fragmentation Behavior in ESI‐MSn and Reaction Mechanism Studies by Detection of Transient Radical Cations

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Radical Cations in Electrospray Mass Spectrometry: Formation of Open‐Shell Species, Examination of the Fragmentation Behaviour in ESI‐MSn and Reaction Mechanism Studies by Detection of Transient Radical Cations

AbstractThe ion formation mechanism in electrospray MS is reviewed, with special focus on the electrochemical red/ox reactions responsible for the formation of radical molecular ions. Prerequisites influencing the likelihood of formation and observation of a particular compound as an open‐shell molecular species in ESI‐MS (i.e., the structure and the oxidation potential of the analyte, the solvent and additives) are evaluated. For illustration of the ESI phenomena governing radical cation formation, an ESI‐MS study of tetra(aryl)benzidine compounds is presented. The facile formation of abundant radical molecular cations in ESI‐MS demonstrates imposingly that the basicity of the analyte's nitrogen atoms is strongly overcompensated by the ability to stabilize unpaired electrons. ESI‐MSn spectra of the tetra(aryl)benzidine molecular ions exhibit a characteristic feature in the loss of radicals. This process is the major fragmentation pathway of open‐shell molecular precursor ions in their MS2 spectra, and also that of even‐electron ions in sequential MSn spectra. The collision‐induced dissociation (CID) behaviour suggests a general assumption: easily oxidizable compounds (e.g., hydrocarbon polyenes, polycyclic aromatic hydrocarbons, porphyrins etc.) generating predominantly molecular radical cations in ESI‐MS contradict the even electron rule in ESI‐MSn experiments. The strong ability to stabilize unpaired electrons is preserved in product ions and makes the formation of open‐shell species energetically less demanding. A selection of solution‐phase reaction mechanistic studies in which open‐shell intermediates were detected and structurally characterized by ESI‐MS and ESI‐MS/MS, respectively, is presented. The merits of ESI‐MS and ESI‐MSn for mechanistic studies of chemical reaction are critically discussed.(© Wiley‐VCH Verlag GmbH &amp; Co. KGaA, 69451 Weinheim, Germany, 2007)

Peptide derivatization as a strategy to form fixed‐charge peptide radicals

As a means of generating fixed-charge peptide radicals in the gas phase we have examined the collision-induced dissociation (CID) chemistry of ternary [Cu(II)(terpy)(TMPP-M)]2+ complexes, where terpy = 2,2':6'2''-terpyridine and TMPP-M represents a peptide (M) modified by conversion of the N-terminal amine to a [tris(2,4,6-trimethoxyphenyl)phosphonium]acetamide (TMPP-) fixed-charge derivative. The following modified peptides were examined: oligoglycines, (Gly)n (n = 1-5), alanylglycine, glycylalanine, dialanine, trialanine and leucine-enkephaline (YGGFL). The [Cu(II)(terpy)(TMPP-M)]2+ complexes are readily formed upon electrospray ionization (ESI) of a mixture of derivatized peptide and [Cu(II)(terpy)(NO3)2] and generally fragment to form transient peptide radical cations, TMPP-M+*, which undergo rapid decarboxylation for the simple aliphatic peptides. This is contrasted with the complexes containing the unmodified peptides, which predominantly undergo fragmentation of the coordinated peptide. These differences demonstrate the importance of proton mobility in directing fragmentation of ternary copper(II) peptide complexes. In the case of leucine-enkephaline, a sufficient yield of the radical cation was obtained to allow further CID. The TMPP-YGGFL+* ion showed a rich fragmentation chemistry, including CO2 loss, side-chain losses of an isopropyl radical, 2-methylpropene and p-quinomethide, and *a1 and *a4 sequence ion formation. In contrast, the even-electron TMPP-YGGFL+ ion fragments to form *a(n) and *b(n) sequence ions as well as the [*b4 + H2O]+ rearrangement ion.

Electron transfer reactions of tris(polypyridine)ruthenium(III) complexes with organic sulfides: importance of hydrophobic interaction

Ruthenium(III)–polypyridyl complexes, generated from the photochemical oxidation of Ru(II) complexes with molecular oxygen, undergo facile electron transfer reaction with dialkyl and aryl methyl sulfides. The rate controlling electron transfer process is confirmed from the absorption spectrum of the transient sulfide radical cation. The spectrophotometric kinetic study shows that the reaction is of total second order, first order in Ru(III) complex and in the organic sulfide. The reaction rate is susceptible to the change of ligand in [Ru(NN) 3] 3+ and the structure of organic sulfide.