Benzyl Radicals Research Articles

Mechanistic insights into copper-mediated benzylic C(sp3)-H bond trifluoromethylation.

The mechanisms underlying copper-mediated trifluoromethylation of benzylic C(sp3)-H bonds were investigated using density functional theory (DFT) calculations. Two distinct pathways were identified: radical recombination/reductive elimination and single-electron transfer (SET). In the radical recombination/reductive elimination pathway, the CuII species recombines with benzyl radicals to generate a CuIII intermediate, which subsequently undergoes reductive elimination. Conversely, the SET pathway involves single-electron transfer from benzyl radicals to CuII species, forming a cationic benzylic intermediate and CuI species, followed by coupling with a CF3 group coordinated to Cu. DFT calculations revealed that the radical recombination/reductive elimination pathway is favoured for trifluoromethylation of primary and secondary benzylic C(sp3)-H bonds, with the reductive elimination step being rate-determining. In contrast, the SET pathway exhibits preference for trifluoromethylation of tertiary benzylic C(sp3)-H bonds. These mechanistic insights have significant implications for enhancing the selectivity of copper-mediated trifluoromethylation reactions.

Electrochemical ring-opening carboxylation of cyclic carbonate with carbon dioxide.

Electroreductive ring-opening carboxylation of styrene carbonates with CO2 to achieve dicarboxylic acids and/or β-hydroxy acids has been developed via the selective cleavage of the C(sp3)-O bond in cyclic carbonates. The product selectivity is probably determined by the stability and reactivity of the key benzylic radical and carbanion intermediate.

Photoredox Enabled Defluorinative Benzylation of Trifluoromethyl Alkenes with Alkylarenes.

Herein, we report a photoredox enabled defluorinative benzylation of trifluoromethyl alkenes with readily available alkylarenes, which provides convenient access to a series of structurally valuable benzylated gem-difluoroalkenes under mild reaction conditions. The synthetic value of this protocol has been demonstrated by the transformations of several substrates bearing drug moieties, gram-scale reactions, and various further derivatizations of the gem-difluoroalkene products. The preliminary mechanistic investigations suggest a reaction pathway with rate-determining benzyl C-H bond cleavage of toluene followed by benzylic radical formation.

Controlling the reactivity of La@C82 by reduction: reaction of the La@C82 anion with alkyl halide with high regioselectivity.

Endohedral metallofullerenes have excellent redox properties, which can be used to vary their reactivity to certain classes of molecules, such as alkyl halides. In this study, the thermal reaction of the La@C2v-C82 anion with benzyl bromide derivatives 1 at 110 °C afforded single-bonded adducts 2-5 with high regioselectivity. The products were characterized by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and visible-near infrared spectroscopy. The reaction of La@C2v-C82 with alkyl halides using the same conditions showed no consumption of La@C2v-C82, indicating that the reactivity of La@C2v-C82 toward alkyl halides was effectively increased by one-electron reduction. Single-crystal X-ray diffraction analysis of the single-bonded adduct 3a revealed the addition site of the p-methoxybenzyl group on La@C2v-C82. Theoretical calculations indicated that the addition site carbons in neutral La@C2v-C82 have high spin density, whereas those in the La@C2v-C82 anion do not have high charge densities. Thus, the reaction is believed to occur via electron transfer, followed by the radical coupling of La@C2v-C82 and benzyl radicals, rather than by bimolecular nucleophilic substitution reaction of La@C2v-C82 anion with 1.

Asymmetric Cross Couplings of Trifluoromethyl Radical to Vinylarenes with N‐Hydroxy‐oxazinediones and Subsequent Aerobic Oxidative Homocoupling of 2‐Naphthols Catalysed by Chiral Vanadyl Complexes

AbstractAsymmetric three‐component, 1,2‐aminoxy‐trifluoromethylation of styrenes with N‐hydroxy‐1,3‐benz/naphthoxazine‐2,4‐diones (i. e., N‐OH‐(B/Np)OxzOn) catalysed by chiral vanadyl complexes derived from N‐salicylidene‐L‐t‐leucinate were explored. Among 14 different solvents and 13 different catalysts screened, the best reaction scenarios were in 2‐propanol with 3‐(2,5‐dimethyl)phenyl‐5‐bromo (DMP), or 3‐t‐butyl‐5‐bromo substituted catalysts that led to the corresponding complementary (R)‐ and (S)‐products with potential biological activities in 45–91% yields and up to 85 and 75% ee, respectively. Further optimisation with the DMP catalyst led to the best combination of 3‐halo/3,5‐dihalo‐styrenes with 6‐/7‐Br−N−OH‐(B/Np)OxzOn as the trapping agents. The corresponding eight different products were isolated in 52–75% yields with ees in a range of 88–93% (R). Based on Density Functional Theory (DFT) calculations with conformational searches, the origin of enantiocontrol and the working mechanism were proposed by resorting to a bidentate‐chelation between the amide or carbamate C=O group and N−OH group in the trapping agent to the vanadyl center followed by asymmetric benzylic radical trapping in an SH2 fashion. Subsequent Fragment Molecular Orbital (FMO)/Pair Interaction Energy Decomposition Analysis (PIEDA) calculations with the DMP catalyst were carried out to rationalize the extent of asymmetric induction. One representative product derived from p‐methyl‐styrene and NpOxzOn was hydrolyzed in basic MeOH with decarboxylation to unmask its carbamate moiety. The resulting chiral (R)‐N‐benzoxy‐3‐hydroxy‐2‐naphthamide was subjected to aerobic, oxidative homo‐coupling catalysed by the DMP catalyst in CCl4. The corresponding 2,2‐binaphthol product was isolated in 90% (brsm) yield with nearly complete diastereo‐control at the created (M)‐axial chirality, allowing for sequential, bi‐functional asymmetric cross‐coupling applications.

Nickel-catalyzed cross-coupling between benzyl alcohols and alkenyl triflates assisted by titanium-mediated radical C–O bond cleavage

Abstract A Ni-catalyzed radical cross-coupling reaction between benzyl alcohols and alkenyl triflates was discovered. A benzyl radical was generated directly from alcohols by using low-valent Ti-mediated alcohol C–O bond homolysis and was successfully utilized in a Ni-catalyzed cross-coupling reaction. The addition of tetrabutylammonium iodide (n-Bu4NI) facilitated the reaction. n-Bu4NI was found to be instrumental in transforming alkenyl triflates into iodides, which are more reactive in the subsequent cross-coupling process.

Umpolung Isomerization in Radical Copolymerization of Benzyl Vinyl Ether with Pentafluorophenylacrylate Leading to Degradable AAB Periodic Copolymers

AbstractThis study revealed that benzyl vinyl ether (BnVE) shows a peculiar isomerization propagation in its radical copolymerization with an electron‐deficient acrylate carrying a pentafluorophenyl group (PFA). The co‐monomer pair inherently exhibits the cross‐over propagation feature due to the large difference in the electron density. However, the radical species of PFA was found to undergo a backward isomerization to the penultimate BnVE pendant giving a benzyl radical species prior to propagation with BnVE. The isomerization brings a drastic change in the character of the growing radical species from electrophilic to nucleophilic, and thus the isomerized benzyl radial species propagates with PFA. Consequently, the two monomers were consumed in the order AAB (A: PFA; B: BnVE) and the unique periodic consumption was confirmed by the pseudo‐reactivity ratios calculated by the penultimate model: r11=0.174 and r21=6600 for PFA (M1) with BnVE (M2). The pentafluorophenyl ester groups of the resulting copolymers are transformed into ester and amide groups by post‐polymerization alcoholysis and aminolysis modifications. The unique isomerization in the AAB sequence allowed the periodic introduction of a benzyl ether structure in the backbone leading to efficient degradation under acid conditions.

Umpolung Isomerization in Radical Copolymerization of Benzyl Vinyl Ether with Pentafluorophenylacrylate Leading to Degradable AAB Periodic Copolymers.

This study revealed that benzyl vinyl ether (BnVE) shows a peculiar isomerization propagation in its radical copolymerization with an electron-deficient acrylate carrying a pentafluorophenyl group (PFA). The co-monomer pair inherently exhibits the cross-over propagation feature due to the large difference in the electron density. However, the radical species of PFA was found to undergo a backward isomerization to the penultimate BnVE pendant giving a benzyl radical species prior to propagation with BnVE. The isomerization brings a drastic change in the character of the growing radical species from electrophilic to nucleophilic, and thus the isomerized benzyl radial species propagates with PFA. Consequently, the two monomers were consumed in the order AAB (A: PFA; B: BnVE) and the unique periodic consumption was confirmed by the pseudo-reactivity ratios calculated by the penultimate model: r11 =0.174 and r21 =6600 for PFA (M1 ) with BnVE (M2 ). The pentafluorophenyl ester groups of the resulting copolymers are transformed into ester and amide groups by post-polymerization alcoholysis and aminolysis modifications. The unique isomerization in the AAB sequence allowed the periodic introduction of a benzyl ether structure in the backbone leading to efficient degradation under acid conditions.

Selective Oxidative Methyl C-H Functionalization of Butylated Hydroxytoluene toward Arylimines/N-Heterocycles.

A metal-free and selective oxidative methyl C-H functionalization of BHT with aniline compounds has been developed. This innovative method enables the facile and efficient synthesis of a diverse array of BHT-functionalized N-containing skeletons, including arylamines, benzoxazoles, benzothiazoles, benzimidazoles, quinazolines, and quinazolinones, all of which are challenging to access. The control experiment involving TEMP18O suggests that the radical adduct of TEMPO with the benzyl radical of BHT may serve as an intermediate.

Isocyanides as Catalytic Electron Acceptors in the Visible Light Promoted Oxidative Formation of Benzyl and Acyl Radicals.

The recent disclosure of the ability of aromatic isocyanides to harvest visible light and act as single electron acceptors when reacting with tertiary aromatic amines has triggered a renewed interest in their application to the development of green photoredox catalytic methodologies. Accordingly, the present work explores their ability to promote the generation of both alkyl and acyl radicals starting from radical precursors such as Hantzsch esters, potassium alkyltrifluoroborates, and α-oxoacids. Mechanistic studies involving UV-visible absorption and fluorescence experiments, electrochemical measurements of the ground-state redox potentials along with computational calculations of both the ground- and the excited-state redox potentials of a set of nine different aromatic isocyanides provided key insights to promote a rationale design of a new generation of isocyanide-based organic photoredox catalysts. Importantly, the green potential of the investigated chemistry has been herein demonstrated by a direct and easy access to deuterium labeled compounds.

Co‐Catalyzed Reductive Cross‐Couplings of Csp3−S with Callyl−O Electrophiles to form Csp3−Csp3 Bonds

AbstractCross‐electrophilic coupling of various benzyl sulfonium salts with Callyl−O electrophiles is described using a simple Co−Mn catalytic system. This catalytic system is able to activate both the stable Csp3−S bond of sulfonium salts and the Csp3−O bond of allylic acetate or ether under mild reaction conditions to form various functionalized alkyl olefinic compounds. Allyl methyl ethers were employed for the first time in transition metal‐catalyzed cross‐electrophilic coupling to build Csp3−Csp3 bonds. Preliminary mechanistic studies suggested the involvement of benzyl radicals generated from C−S bond cleavage through a single electron transfer.

Nickel/Titanocene-Catalyzed Electrophilic Acylation Coupling of Styrene Oxides.

The cross-coupling of epoxides with acyl chlorides or anhydrides by a nickel/titanocene dual catalytic system is established. A variety of synthetically useful β-hydroxy ketones were obtained in good to high yields by using modified pyridine-oxazoline ligand. The reaction proceeds via the cooperation of titanocene-catalyzed ring-opening of epoxides and nickel-catalyzed acylation of the benzylic radical intermediate.

Effective Activation of Strong C−Cl Bonds for Highly Selective Photosynthesis of Bibenzyl via Homo‐Coupling

AbstractCarbon‐carbon (C−C) coupling of organic halides has been successfully achieved in homogeneous catalysis, while the limitation, e.g., the dependence on rare noble metals, complexity of the metal‐ligand catalylst and the poor catalyst stability and recyclability, needs to be tackled for a green process. The past few years have witnessed heterogeneous photocatalysis as a green and novel method for organic synthesis processes. However, the study on C−C coupling of chloride substrates is rare due to the extremely high bond energy of C−Cl bond (327 kJ mol−1). Here, we report a robust heterogeneous photocatalyst (Cu/ZnO) to drive the homo‐coupling of benzyl chloride with high efficiency, which achieves an unprecedented high selectivity of bibenzyl (93 %) and yield rate of 92 % at room temperature. Moreover, this photocatalytic process has been validated for C−C coupling of 10 benzylic chlorides all with high yields. In addition, the excellent stability has been observed for 8 cycles of reactions. With detailed characterization and DFT calculation, the high selectivity is attributed to the enhanced adsorption of reactants, stabilization of intermediates (benzyl radicals) for the selective coupling by the Cu loading and the moderate oxidation ability of the ZnO support, besides the promoted charge separation and transfer by Cu species.

Effective Activation of Strong C-Cl Bonds for Highly Selective Photosynthesis of Bibenzyl via Homo-Coupling.

Carbon-carbon (C-C) coupling of organic halides has been successfully achieved in homogeneous catalysis, while the limitation, e.g., the dependence on rare noble metals, complexity of the metal-ligand catalylst and the poor catalyst stability and recyclability, needs to be tackled for a green process. The past few years have witnessed heterogeneous photocatalysis as a green and novel method for organic synthesis processes. However, the study on C-C coupling of chloride substrates is rare due to the extremely high bond energy of C-Cl bond (327 kJ mol-1 ). Here, we report a robust heterogeneous photocatalyst (Cu/ZnO) to drive the homo-coupling of benzyl chloride with high efficiency, which achieves an unprecedented high selectivity of bibenzyl (93 %) and yield rate of 92 % at room temperature. Moreover, this photocatalytic process has been validated for C-C coupling of 10 benzylic chlorides all with high yields. In addition, the excellent stability has been observed for 8 cycles of reactions. With detailed characterization and DFT calculation, the high selectivity is attributed to the enhanced adsorption of reactants, stabilization of intermediates (benzyl radicals) for the selective coupling by the Cu loading and the moderate oxidation ability of the ZnO support, besides the promoted charge separation and transfer by Cu species.

Excited-state tris(pentafluorophenyl)borane as a strong single-electron oxidant: Photophysical properties and catalysis

The photophysical properties and photocatalysis of tris(pentafluorophenyl)borane [B(C6F5)3], known as a strong Lewis acid, were revealed. The excited-state B(C6F5)3 exerts single-electron oxidation capability with an oxidation potential (Ered* = 2.02 V vs SCE) close to those of electronically unbiased toluene derivatives (Eox = 2.01 to 2.29 V). This property was experimentally proven by the direct observation of the radical cation of the toluene dimer by the transient absorption spectroscopy of a mixture of B(C6F5)3 and toluene. In cooperation with a suitable Brønsted base catalyst, B(C6F5)3 catalytically generated benzylic radicals from toluene derivatives under photoirradiation for subsequent carbon-carbon bond-forming reactions.

Lutidyl Radical Photoelectron Spectra Reveal Additive Substituent Effects on Benzyl Derivatives' Ionization Energy.

Understanding how isomerism influences photoelectron spectra helps in the assignment and analysis of reactive mixtures, especially for heterocycles with numerous isomers. Threshold photoelectron spectra of lutidyl radical isomers, i. e., benzyl derivatives with a nitrogen heteroatom and a methyl substituent, are recorded using vacuum ultraviolet synchrotron radiation. The radicals are produced by flash pyrolysis from aminomethyl methylpyridine precursors. Experimental ionization energies are determined to be 7.54, 7.50, and 7.45 eV for 2,4-, 2,6- and 3,5-lutidyl, respectively, in excellent agreement with composite method calculations. Franck-Condon simulations aid the TPES assignment but are also shown to exhibit artifacts if large-amplitude motions, notably the methyl internal rotation are assumed to be active in the double harmonic approximation. Based on calculated adiabatic ionization energies (AIE) of benzyl, picolyl, and xylyl radicals, the N and CH3 substituent effects are found to be additive, position-dependent and decrease in the para>ortho≳meta order in magnitude with the nitrogen heteroatom increasing and the methyl substituent decreasing the AIE. These effects are discussed in light of the charge distribution upon ionization. The additivity of the substituent effects also helps predict the influence of substituents on the binding energy of the unpaired electron in analogous radicals.

Ni-Catalyzed Reductive Dibenzylation of Trifluoromethylalkenes for CF3-Containing All-Carbon Quaternary Center Construction.

A Ni-catalyzed reductive dicarbofunctionalization of α-CF3 styrenes with benzyl bromides has been accomplished. This transformation obviates the commonly facile β-F elimination effectively and enables the creation of CF3-substituted all-carbon quaternary centers of pharmaceutical interests. Preliminary mechanistic studies suggest a pathway consisting of benzyl radical addition and subsequent nickel-mediated benzylation of the resulting α-CF3-embedded tertiary C radical.

Photocatalytic C-O activation and biomass derived polymer precursor production with CO2 over redox centers spatially separated Sv-ZnIn2S4/BiVO4

It is a very important, promising and challenging exploration to achieve the CO2 transformation and renewable biomass utilization for value added chemical intermediate production. Herein, S vacancies enriched Z-scheme Sv-ZnIn2S4/BiVO4 was designed to achieve photocatalytic C-O activation and carboxylation with CO2 in the absence of sacrificial agent. Various aromatic alcohols could be utilized to prepare corresponding carbon chain increased aryl carboxylic acids through acetic anhydride assisted esterification, photogenerated holes oxidization induced benzyl radical generation and subsequent CO2 carboxylation. It is worth mentioning that furfuryl alcohol could also achieve the C-O activation and di-carboxylation to prepare biomass derived polymer precursor. In Z-scheme Sv-ZnIn2S4/BiVO4, spatially separating redox centers construction enhanced photogenerated holes and electrons separation was favorable for the benzyl radical generation and CO2 carboxylation. Moreover, the introduction of S vacancies was helpful for the photoinduced electrons enrichment and substrate capture ability improvement.

From‐Neutral‐to‐Neutral Reductive Radical Coupling of Non‐Activated Alcohols and Styrenes

AbstractA reductive radical coupling reaction between non‐activated aliphatic alcohols and styrenes has been discovered through the use of low‐valent Ti‐mediated C−O bond homolysis. A general application of styrene derivatives in radical coupling reactions remains a challenge in organic synthesis. The preliminary investigation revealed that the resulting benzyl radical intermediate behaves differently depending on minor steric differences around the spin center, which results in a lack of generality. The addition of 1,3,5‐trimethyl‐2,5‐cyclohexadiene uniformly hydrogenated the benzyl radicals irrespective of the steric environments of the attacking radicals. Under the optimal reaction conditions, all tertiary, secondary, and primary alcohols were applicable. In this study, alcohols were successfully used directly as radical sources and reacted with a large number of styrenes.

Ketones from aldehydes via alkyl C(sp3)−H functionalization under photoredox cooperative NHC/palladium catalysis

Direct synthesis of ketones from aldehydes features high atom- and step-economy. Yet, the coupling of aldehydes with unactivated alkyl C(sp3)-H remains challenging. Herein, we develop the synthesis of ketones from aldehydes via alkyl C(sp3)-H functionalization under photoredox cooperative NHC/Pd catalysis. The two-component reaction of iodomethylsilyl alkyl ether with aldehydes gave a variety of β-, γ- and δ-silyloxylketones via 1,n-HAT (n = 5, 6, 7) of silylmethyl radicals to generate secondary or tertiary alkyl radicals and following coupling with ketyl radicals from aldehydes under photoredox NHC catalysis. The three-component reaction with the addition of styrenes gave the corresponding ε-hydroxylketones via the generation of benzylic radicals by the addition of alkyl radicals to styrenes and following coupling with ketyl radicals. This work demonstrates the generation of ketyl radical and alkyl radical under the photoredox cooperative NHC/Pd catalysis, and provides two and three component reactions for the synthesis of ketones from aldehydes with alkyl C(sp3)-H functionalization. The synthetic potential of this protocol was also further illustrated by the late-stage functionalization of natural products.