Hydrogen Abstraction Research Articles

Decatungstate‐Photocatalyzed Diastereoselective Dearomative Hydroalkylation of Indoles

AbstractIn this study, we present an efficient and straightforward dearomative hydroalkylation of indoles. By utilizing alkanes or ethers as alkyl radical sources and employing TBADT as a cost‐effective photocatalyst for direct hydrogen atom transfers (HAT), we achieved successful conversion of these heterocyclic derivatives into 2‐alkylindolines with good to excellent yields and high diastereoselectivity under mild reaction conditions.

Reversal of the Regioselectivity of Iron-Promoted Hydrogenation and Hydrohalogenation of gem-Difluoroalkenes.

The reaction regioselectivity of gem-difluoroalkenes is dependent on the intrinsic polarity. Thus, the reversal of the regioselectivity of the addition reaction of gem-difluoroalkenes remains a formidable challenge. Herein, we described an unprecedented reversal of regioselectivity of hydrogen atom transfer (HAT) to gem-difluoroalkenes triggered by Fe-H species for the formation of difluoroalkyl radicals. Hydrogenation of the in situ generated radicals gave difluoromethylated products. Mechanism experiments and theoretical studies revealed that the kinetic effect of the irreversible HAT process resulted in the reversal of the regioselectivity of this scenario, leading to the formation of a less stable α-difluoroalkyl radical regioisomer. On basis of this new reaction of gem-difluoroalkene, the iron-promoted hydrohalogenation of gem-difluoroalkenes for the efficient synthesis of aliphatic chlorodifluoromethyl-, bromodifluoromethyl- and iododifluoromethyl-containing compounds was developed. Particularly, this novel hydrohalogenation of gem-difluoroalkenes provided an effect and large-scale access to various iododifluoromethylated compounds of high value for synthetic application.

Unified Approach to Deamination and Deoxygenation Through Isonitrile Hydrodecyanation: A Combined Experimental and Computational Investigation

AbstractHerein, we describe a general hydrodefunctionalization protocol of alcohols and amines through a common isonitrile intermediate. To cleave the relatively inert C−NC bond, we leveraged dual hydrogen atom transfer (HAT) and photoredox catalysis to generate a nucleophilic boryl radical, which readily forms an imidoyl radical intermediate from the isonitrile. Rapid β‐scission then accomplishes defunctionalization. This method has been applied to the hydrodefunctionalization of both amine and alcohol‐containing pharmaceuticals, natural products, and biomolecules. We extended this approach to the reduction of carbonyls and olefins to their saturated counterparts, as well as the hydrodecyanation of alkyl nitriles. Both experimental and computational studies demonstrate a facile β‐scission of the imidoyl radical, and reconcile differences in reactivity between nitriles and isonitriles within our protocol.

Unified Approach to Deamination and Deoxygenation Through Isonitrile Hydrodecyanation: A Combined Experimental and Computational Investigation.

Herein, we describe a general hydrodefunctionalization protocol of alcohols and amines through a common isonitrile intermediate. To cleave the relatively inert C-NC bond, we leveraged dual hydrogen atom transfer (HAT) and photoredox catalysis to generate a nucleophilic boryl radical, which readily forms an imidoyl radical intermediate from the isonitrile. Rapid β-scission then accomplishes defunctionalization. This method has been applied to the hydrodefunctionalization of both amine and alcohol-containing pharmaceuticals, natural products, and biomolecules. We extended this approach to the reduction of carbonyls and olefins to their saturated counterparts, as well as the hydrodecyanation of alkyl nitriles. Both experimental and computational studies demonstrate a facile β-scission of the imidoyl radical, and reconcile differences in reactivity between nitriles and isonitriles within our protocol.

Reversal of the Regioselectivity of Iron‐Promoted Hydrogenation and Hydrohalogenation of gem‐Difluoroalkenes

AbstractThe reaction regioselectivity of gem‐difluoroalkenes is dependent on the intrinsic polarity. Thus, the reversal of the regioselectivity of the addition reaction of gem‐difluoroalkenes remains a formidable challenge. Herein, we described an unprecedented reversal of regioselectivity of hydrogen atom transfer (HAT) to gem‐difluoroalkenes triggered by Fe−H species for the formation of difluoroalkyl radicals. Hydrogenation of the in situ generated radicals gave difluoromethylated products. Mechanism experiments and theoretical studies revealed that the kinetic effect of the irreversible HAT process resulted in the reversal of the regioselectivity of this scenario, leading to the formation of a less stable α‐difluoroalkyl radical regioisomer. On basis of this new reaction of gem‐difluoroalkene, the iron‐promoted hydrohalogenation of gem‐difluoroalkenes for the efficient synthesis of aliphatic chlorodifluoromethyl‐, bromodifluoromethyl‐ and iododifluoromethyl‐containing compounds was developed. Particularly, this novel hydrohalogenation of gem‐difluoroalkenes provided an effect and large‐scale access to various iododifluoromethylated compounds of high value for synthetic application.

Hydrosulfonylation of Alkynes for Stereodivergent Synthesis of Vinyl Sulfones: Synthetic Strategy and Mechanistic Insights.

Direct synthesis of thermodynamically less favorable (Z)-vinyl sulfones presents a notable challenge in organic synthesis. In addition, the development of a stereodivergent synthesis for (E)- and (Z)-vinyl sulfones is crucial but remains elusive. In this study, we present a hydrosulfonylation of aryl-substituted alkynes, achieving a stereodivergent synthesis of (E)- and (Z)-vinyl sulfones by leveraging both thermodynamic and kinetic controls. Notably, the synthesis of challenging (Z)-vinyl sulfones was achieved through a kinetically controlled process without the need for a catalyst. To synthesize (E)-vinyl sulfones, unconventional visible light-mediated isomerization was employed as a means of facilitating the transition to the thermodynamically favored form. The present study encompasses a comprehensive experimental and computational investigation, which provides valuable insights into the reaction mechanism. This investigation reveals two plausible isomerization pathways: a novel double spin-flip mechanism and a hydrogen atom transfer process in the presence of eosin Y. This study not only advances our understanding of isomerization mechanisms beyond conventional energy-transfer routes but also offers a robust and switchable strategy for synthesizing (E)- and (Z)-vinyl sulfones, thereby providing a versatile avenue for the creation of valuable compounds in the fields of organic synthesis and medicinal chemistry.

Selecting phenolics by means of thermodynamics for scavenging free radicals in camellia oil induced by heating

Phenolics have been employing as promising scavengers for free radicals, theoretical calculation is a convenient method for selecting excellent phenolics. In this study, the efficiencies of 33 phenolics scavenging free radicals were confirmed by means of Bond Dissociation Enthalpy (BDE) of active group and Gibbs Free Energy Change (ΔG) of scavenging reaction computed by Quantum Chemical Calculations. Ultimately, the preferable phenolics were picked out for scavenging free radicals in camellia oil induced by heating. These phenolics scavenged free radicals via Hydrogen Atom Transfer (HAT) mechanism. Specifically, (−)-epigallocatechin gallate (EGCG), myricetin and piceatannol performed the top-ranking efficiencies in camellia oil under 120 °C for 50 min, with the inhibition ratios of 75.7 ± 4.1%, 72.9 ± 5.4% and 69.4 ± 11.0%, respectively. The results indicated that the efficiencies of phenolics were predominantly affected by the amount of hydroxyl groups attached to aromatic ring and the BDE of O−H bond. In phenolic acids, the hydroxyl group in ortho-position of the active site was in favor of reinforcing the efficiency. In flavonoids, the hydroxyl group in B-ring and the functional groups of C2=C3 and 4-carbonyl in C-ring were prone to elevating the efficiency.

PolyBorylated Alkenes as Energy-Transfer Reactive Groups: Access to Multi-Borylated Cyclobutanes Combined with Hydrogen Atom Transfer Event.

While polyborylated alkenes are being recognized for their elevated status as highly valuable reagents in modern organic synthesis, allowing efficient access to a diverse array of transformations, including the formation of C-C and C-heteroatom bonds, their potential as energy-transfer reactive groups has remained unexplored. Yet, this potential holds the key to generating elusive polyborylated biradical species, which can be captured by olefins, thereby leading to the construction of new highly-borylated scaffolds. Herein, we report a designed energy-transfer strategy for photosensitized [2+2]-cycloadditions of poly-borylated alkenes with various olefins enabling the regioselective synthesis of diverse poly-borylated cyclobutane motifs, including the 1,1-di-, 1,1,2-tri-, and 1,1,2,2-tetra-borylated cyclobutanes. In fact, these compounds belong to a family that presently lacks efficient synthetic pathways. Interestingly, when α-methylstyrene was used, the reaction involves an interesting 1,5-hydrogen atom transfer (HAT). Mechanistic deuterium-labeling studies have provided insight into the outcome of 1,5-hydrogen atom transfer process. In addition, the polyborylated cyclobutanes are then demonstrated to be useful in selective oxidation processes resulting in the formation of cyclobutanones and γ-lactones.

PolyBorylated Alkenes as Energy‐Transfer Reactive Groups: Access to Multi‐Borylated Cyclobutanes Combined with Hydrogen Atom Transfer Event

AbstractWhile polyborylated alkenes are being recognized for their elevated status as highly valuable reagents in modern organic synthesis, allowing efficient access to a diverse array of transformations, including the formation of C−C and C‐heteroatom bonds, their potential as energy‐transfer reactive groups has remained unexplored. Yet, this potential holds the key to generating elusive polyborylated biradical species, which can be captured by olefins, thereby leading to the construction of new highly‐borylated scaffolds. Herein, we report a designed energy‐transfer strategy for photosensitized [2+2]‐cycloadditions of poly‐borylated alkenes with various olefins enabling the regioselective synthesis of diverse poly‐borylated cyclobutane motifs, including the 1,1‐di‐, 1,1,2‐tri‐, and 1,1,2,2‐tetra‐borylated cyclobutanes. In fact, these compounds belong to a family that presently lacks efficient synthetic pathways. Interestingly, when α‐methylstyrene was used, the reaction involves an interesting 1,5‐hydrogen atom transfer (HAT). Mechanistic deuterium‐labeling studies have provided insight into the outcome of 1,5‐hydrogen atom transfer process. In addition, the polyborylated cyclobutanes are then demonstrated to be useful in selective oxidation processes resulting in the formation of cyclobutanones and γ‐lactones.

Photoredox Synthesis of Silicon-Containing Isoindolin-1-ones and Deuterated Analogues Through Hydrosilylation and Deuterium-silylation.

An efficient, practical, and metal-free protocol for the synthesis of silicon-containing isoindolin-1-ones and deuterated analogues via the synergistic combination of an organic photoredox and hydrogen atom transfer process is described. This strategy features mild reaction conditions, high atom economy, and excellent functional group compatibility, delivering a myriad of structurally diverse and valuable products with good to excellent yields.

Triplet State Radical Chemistry: Significance of the Reaction of 3SO2 with HCOOH and HNO3.

The triplet excited states of sulfur dioxide can be accessed in the UV region and have a lifetime large enough that they can react with atmospheric trace gases. In this work, we report high level ab initio calculations for the reaction of the a3B1 and b3A2 excited states of SO2 with weak and strong acidic species such as HCOOH and HNO3, aimed to extend the chemistry reported in previous studies with nonacidic H atoms (water and alkanes). The reactions investigated in this work are very versatile and follow different kinds of mechanisms, namely, proton-coupled electron transfer (pcet) and conventional hydrogen atom transfer (hat) mechanisms. The study provides new insights into a general and very important class of excited-state-promoted reactions, opening up interesting chemical perspectives for technological applications of photoinduced H-transfer reactions. It also reveals that atmospheric triplet chemistry is more significant than previously thought.

Identification, Characterization, and Electronic Structures of Interconvertible Cobalt-Oxygen TAML Intermediates.

The reaction of Li[(TAML)CoIII]·3H2O (TAML = tetraamido macrocyclic tetraanionic ligand) with iodosylbenzene at 253 K in acetone in the presence of redox-innocent metal ions (Sc(OTf)3 and Y(OTf)3) or triflic acid affords a blue species 1, which is converted reversibly to a green species 2 upon cooling to 193 K. The electronic structures of 1 and 2 have been determined by combining advanced spectroscopic techniques (X-band electron paramagnetic resonance (EPR), electron nuclear double resonance (ENDOR), X-ray absorption spectroscopy/extended X-ray absorption fine structure (XAS/EXAFS), and magnetic circular dichroism (MCD)) with ab initio theoretical studies. Complex 1 is best represented as an S = 1/2 [(Sol)(TAML•+)CoIII---OH(LA)]- species (LA = Lewis/Brønsted acid and Sol = solvent), where an S = 1 Co(III) center is antiferromagnetically coupled to S = 1/2 TAML•+, which represents a one-electron oxidized TAML ligand. In contrast, complex 2, also with an S = 1/2 ground state, is found to be multiconfigurational with contributions of both the resonance forms [(H-TAML)CoIV═O(LA)]- and [(H-TAML•+)CoIII═O(LA)]-; H-TAML and H-TAML•+ represent the protonated forms of TAML and TAML•+ ligands, respectively. Thus, the interconversion of 1 and 2 is associated with a LA-associated tautomerization event, whereby H+ shifts from the terminal -OH group to TAML•+ with the concomitant formation of a terminal cobalt-oxo species possessing both singlet (SCo = 0) Co(III) and doublet (SCo = 1/2) Co(IV) characters. The reactivities of 1 and 2 at different temperatures have been investigated in oxygen atom transfer (OAT) and hydrogen atom transfer (HAT) reactions to compare the activation enthalpies and entropies of 1 and 2.

Asymmetric Three-Component Radical Alkene Carboazidation by Direct Activation of Aliphatic C-H Bonds.

Azide compounds are widely present in natural products and drug molecules, and their easy-to-transform characteristics make them widely used in the field of organic synthesis. The merging of transition-metal catalysis with radical chemistry offers a versatile platform for radical carboazidation of alkenes, allowing the rapid assembly of highly functionalized organic azides. However, the direct use of readily available hydrocarbon feedstocks as sp3-hybridized carbon radical precursors to participate in catalytic enantioselective carboazidation of alkenes remains a significant challenge that has yet to be addressed. Herein, we describe an iron-catalyzed asymmetric three-component radical carboazidation of electron-deficient alkenes by direct activation of aliphatic C-H bonds. This approach involves intermolecular hydrogen atom transfer between a hydrocarbon and an alkoxy/aryl carboxyl radical, leading to the formation of a carbon-centered radical. The resulting radical then reacts with electron-deficient alkenes to generate a new radical species that undergoes chiral iron-complex-mediated C-N3 bond coupling. An array of valuable chiral azides bearing a quaternary stereocenter were directly accessed from widely available chemical feedstocks, and their synthetic potential is further demonstrated through more facile transformations to give other valuable enantioenriched building blocks.

Synthesis, characterization, and comprehensive computational analysis of aromatic hydrazone compounds: Unveiling quantum parameters, evaluating antioxidant activity, and investigating molecular docking interactions

This study presents a synergistic approach encompassing experimental synthesis, computational analysis, and antioxidant activity evaluation of two aromatic hydrazone compounds, namely 4-[(2E)-2-(2-nitrobenzylidene) hydrazinyl] benzoic acid (NBHZ) and 4-[(2E)-2-(2-hydroxybenzylidene) hydrazinyl] benzoic acid (HBHZ). Efficient synthesis yielded impressive quantities (70 % and 58 %, respectively), and structural characterization employed IR, UV–Vis, and NMR spectroscopy. Antioxidant potential was assessed using the DPPH free radical scavenging assay, revealing distinct capabilities of NBHZ and HBHZ, each featuring a nitro (NO2) and a hydroxy (OH) group, respectively, at the ortho position. HBHZ exhibited superior efficacy (IC50 = 1.15 μg/mL) compared to NBHZ (IC50 = 2.1 μg/mL) and the standard antioxidant BHT (IC50 = 1.83 μg/mL). Computational analyses using Gaussian 09 at the B3LYP/6–311 G(d,p) level elucidated electronic characteristics, molecular electrostatic potential (MEP), HOMO-LUMO energies, and global reactivity descriptors. VEDA 4 further investigated vibrational behavior and potential energy distribution (PED), topological analyses electron localization function (ELF), localized orbital locator (LOL), average localized ionization energy (ALIE), and reduced density gradient (RDG) were identified to evaluate their interactions. Thermochemical parameters explored antioxidant mechanisms (hydrogen atom transfer (HAT), single electron transfer–proton transfer (SET–PT), and sequential proton loss electron transfer (SPLET)). Molecular docking via iGEMDOCK revealed binding interactions with the target NADPH oxidase. These findings not only provide insights into the compounds' antioxidant potential but also underscore the impact of specific molecular features on their properties. This integrated approach contributes to advancing the understanding of hydrazone compounds, guiding the design of materials with tailored functionalities for applications in oxidative stress mitigation.

Flavonoid Oxidation Potentials and Antioxidant Activities-Theoretical Models Based on Oxidation Mechanisms and Related Changes in Electronic Structure.

Herein, I will review our efforts to develop a comprehensive and robust model for the estimation of the first oxidation potential, Ep1, and antioxidant activity, AA, of flavonoids that would, besides enabling fast and cheap prediction of Ep1 and AA for a flavonoid of interest, help us explain the relationship between Ep1, AA and electronic structure. The model development went forward with enlarging the set of flavonoids and, that way, we had to learn how to deal with the structural peculiarities of some of the 35 flavonoids from the final calibration set, for which the Ep1 measurements were all made in our laboratory. The developed models were simple quadratic models based either on atomic spin densities or differences in the atomic charges of the species involved in any of the three main oxidation mechanisms. The best model takes into account all three mechanisms of oxidation, single electron transfer-proton transfer (SET-PT), sequential proton loss electron transfer (SPLET) and hydrogen atom transfer (HAT), yielding excellent statistics (R2 = 0.970, S.E. = 0.043).

Pyridine N-oxides as hydrogen atom transfer reagents for site-selective photoinduced C(sp3)–H functionalization

Pyridine N-oxides as hydrogen atom transfer reagents for site-selective photoinduced C(sp3)–H functionalization

Complexes of Borane and 1,3,5‐Triazinane‐Derived Carbenes

AbstractComplexes of borane with six‐membered N‐heterocyclic carbenes derived from readily accessible 1,3,5‐triazinium salts are described. Similar to the widely used imidazolium‐type borane complex, the obtained complexes behave as agents for the hydrogen atom transfer in the Giese reaction and as sources of the boryl radicals in addition to imines. The amine nitrogen of these complexes does not undergo alkylation, but it can bind with another borane molecule.

Direct C(sp3)-H functionalization with thiosulfonates via photoredox catalysis

While C(sp3)-S bonds exist in many biologically active compounds, the direct catalytic C(sp3)-H thiolation remains elusive. Herein, we report a convenient and green C(sp3)-H thiolation approach mediated by using tetrabutylammonium decatungstate (TBADT) as a hydrogen atom transfer (HAT) photocatalyst. A wide range of C(sp3)-H bond-containing etheric, allylic, alkyl, ketonic, amidic substrates and sulfonyl-based SOMOphiles participated in the reaction, producing thioethers with high efficiency. The present protocol features green characteristics, such as being free of harmful oxidants and additives; step-economic; redox-neutral; and amenable to scale-up assisted by continuous-flow technology.

Theoretical Study of Radical Scavenging Antioxidant Activity of Coumarin Derivatives in Licorice Using DFT

Nowdays, much research is focused on exploring antioxidant activity based on natural compounds. Licorice, a traditional natural product rich in antioxidant components, has been widely used in clinical medicine. However, there is a lack of theoretical studies on the active components in licorice. In this context, the antioxidant activity of several common active components of coumarin derivatives in licorice was investigated using a density flooding theory (DFT) approach. The free radical scavenging ability of the compounds was achieved by hydrogen atom transfer (HAT), sequential electron transfer proton transfer (SET-PT) and sequential proton loss electron transfer (SPLET) mechanisms. The effect of solvent on antioxidant activity was also investigated. It was found that in the gas and benzene phases, the compounds studied preferred to undergo the HAT mechanism, while SPLET was favoured in polar solvents. In addition to the above mechanism, the HOMO and LUMO energies of the compounds as well as molecular descriptors and electrostatic potential maps were calculated and applied to predict the antioxidant activity of the compounds. The above studies allow a better understanding of the mechanism of free radical scavenging activity of coumarin derivatives from licorice.

Metal Free Functionalization of Saturated Heterocycles with Vinylarenes and Pyridine Enabled by Photocatalytic Hydrogen Atom Transfer.

Saturated heterocycles are important class of structural scaffolds in small-molecule drugs, natural products, and synthetic intermediates. Here, we disclosed a metal free, mild, and scalable functionalization of saturated heterocycles using vinylarenes as a linchpin approach. Key to success of this transformation is the employing of simple and cheap benzophenone as a hydrogen atom transfer (HAT) catalyst. This operationally robust process was used for the making of diverse functionalized saturated heterocycles. Furthermore, aldehydes, alkane, and alcohol have been functionalized under the optimized conditions. The potential pharmaceutical utility of the procedure has also been demonstrated by late-stage functionalization of bioactive natural compounds and pharmaceutical molecules. Initial mechanism studies and control experiments were performed to elucidate the mechanism of the reactions.