Intramolecular Hydrogen Atom Transfer Research Articles

Copper‐Catalyzed Fluoroamide‐Directed Remote C(sp3)‐H Bond Functionalization Through Intramolecular Hydrogen Atom Transfer

AbstractDirect C−H functionalization is an important strategy for the rapid synthesis of valuable organic molecules. Radical‐involved remote C(sp3)‐H functionalization based on hydrogen atom transfer (HAT) becomes an important method enabling selective direct transformation of C(sp3)‐H bonds at specific distal position(s). In the recent years, copper‐catalyzed fluoroamide‐directed remote C(sp3)‐H bond functionalization through intramolecular HAT has served as a robust and elegant strategy for the assembly of a variety of functionalized (sulfon)amides and related derivatives. This review focuses on the recent advances in this area. These transformations proceed effectively with high selectivities and good functional group compatibility under mild conditions.

E-Selective Radical Difunctionalization of Unactivated Alkynes: Preparation of Functionalized Allyl Alcohols from Aliphatic Alkynes.

Radical difunctionalization of aliphatic alkynes provides direct access to valuable multi-substituted alkenes, but achieving a high level of chemo- and stereo-control remains a formidable challenge. Herein a novel photoredox neutral alkyne di-functionalization is reported through functional group migration followed by a radical-polar crossover and energy transfer-enabled stereoconvergent isomerization of alkenes. In this sequence, a hydroxyalkyl and an aryl group are incorporated concomitantly into an alkyne, leading to diversely functionalized E-allyl alcohols. The scope of alkynes is noteworthy, and the reaction tolerates aliphatic alkynes containing hydrogen donating C─H bonds that are prone to intramolecular hydrogen atom transfer. The protocol features broad functional group compatibility, high product diversity, and exclusive chemo- and stereoselectivity, thus providing a practical strategy for the elusive radical di-functionalization of unactivated alkynes.

Intramolecular Hydrogen Atom Transfer from Unactivated C(sp3)−H Bond to Alkyl Radical

AbstractRegioselective C(sp3)−H bond functionalization in atom‐ and step‐economic mode has long been recognized as a prominent and challenging task due to its application in late‐stage modification of complex skeletons, natural products and drugs. As a complement to transition metal‐catalyzed C−H activation and carbene/nitrene insertion reactions, hydrogen atom transfer (HAT) emerges as a versatile tool for C(sp3)−H bond functionalization and showcases significant and distinctive superiority in terms of selectivity trend and substrate scope. Intramolecular HAT processes initiated by nitrogen‐ and oxygen‐centered radicals, aryl radicals, and vinyl radicals, have already been well developed in the past century. In contrast, the development of alkyl radical‐mediated HAT reactions lagged behind, although generation methods of corresponding alkyl radicals under mild conditions have gained rapid growth. Especially, selective and efficient HAT from unactivated C(sp3)−H to alkyl radical is highly challenging due to their comparable BDEs and radical polarity. This Concept highlights recent advance in regioselective functionalization of ubiquitous unactivated C−H bonds enabled by intramolecular H‐atom transfer to alkyl radicals.

Transient Conformations Leading to Peptide Fragment Ion [c + 2H]+ via Intramolecular Hydrogen Bonding Using MALDI In-source Decay Mass Spectrometry of Serine-, Threonine-, and/or Cysteine-Containing Peptides

The formation of a peptide fragment ion [c + 2H]+ was examined using ultraviolet matrix-assisted laser desorption/ionization in-source decay mass spectrometry (UV/MALDI-ISD MS). Unusually, an ISD experiment with a hydrogen-abstracting oxidative matrix 4-nitro-1-naphthol (4,1-NNL) resulted in a [c + 2H]+ ion when the analyte peptides contained serine (Ser), threonine (Thr), and/or cysteine (Cys) residues, although the ISD with 4,1-NNL merely resulted in [a]+ and [d]+ ions. The [c + 2H]+ ion observed could be rationalized through intramolecular hydrogen atom transfer (HAT), like a Type-II reaction via a seven-membered conformation involving intramolecular hydrogen bonding (HB) between the active hydrogens (–OH and –SH) of the Ser/Thr/Cys residues and the backbone carbonyl oxygen at the adjacent amino (N)-terminal side residue. The ISD of the Cys-containing peptide resulted in the [c + 2H]+ ions, which originated from cleavage at the backbone N-Cα bonds far from the Cys residue, suggesting that the peptide molecule formed 16- and 22-membered transient conformations in the gas phase. The time-dependent density functional theory (TDDFT) calculations of the model structures of the Ser and Cys residues indicated that the Cys residue did not show a constructive bond interaction between the donor thiol (-SH) and carbonyl oxygen (=CO), while the Ser residue formed a distinct intramolecular HB.

Photochemically Induced Hydrogen Atom Transfer and Intramolecular Radical Cyclization Reactions with Oxazolones.

Photochemically induced intramolecular hydrogen atom transfer in oxazolones is reported. An acetal or thioacetal function at the side chain acts as a hydrogen donor while the photochemical exited oxazolone is the acceptor. A one-step process─the electron and the proton are simultaneously transferred─is productive, while electron transfer followed by proton transfer is inefficient. Radical combination then takes place, leading to the formation of a C-C or C-N bond. The regioselectivity of the reaction is explained by the diradical/zwitterion dichotomy of radical intermediates at the singlet state. In the present case, the zwitterion structure plays a central role, and intramolecular electron transfer favors spin-orbit coupling and thus the intersystem crossing to the singlet state. The reaction of corresponding thioacetal derivatives is less efficient. In this case, photochemical electron transfer is competitive. The photoproducts resulting from C-C bond formation easily undergo stepwise thermal decarboxylation in which zwitterionic and polar transition states are involved. A computational study of this step has also been performed.

Computational Analysis of Excited State Intramolecular Hydrogen Atom Transfer and Microsolvation Studies on 8-Acetyl-7-hydroxy-4-methylcoumarin using DFT and TDDFT

The computational calculations were carried out on 8-acetyl-7-hydroxy-4-methyl coumarin (AHM) and its water complex AHM+(H2O)4- [AHMH] at ground and excited states by employing density functional theory (DFT)/specific state time-dependent density functional theory (SS-TDDFT). In AHM and AHMH molecules, there is an intramolecular hydrogen bond between hydroxyl group and acetyl group along with inter-molecular hydrogen bonds in the hydrated molecule. The computational studies of molecular structural parameters, molecular electrostatic potential, natural bond orbital (NBO) analysis, the molecular orbital’s and UV-Vis spectra of both the molecules under polar solvents were explored by B3LYP/cc-pVDZ/PCM/EFP1 method. The intramolecular hydrogen atom transpired between hydroxyl to acetyl group in AHM/AHMH molecules from S0→S1 state but not in S0→S3/S0→S2 states even though the S3/S2 states have significant oscillation strengths. This indicates that intramolecular chage transfer (ICT) occurs within the molecules and it confirmed using potential energy surface (PES) scan studies.

Recent Advances in the Functionalization of Remote C−H Bonds by Hofmann‐Löffler‐Freytag‐type Reactions

AbstractNitrogen radicals are one of the most useful reactive intermediates for selective transposition via intramolecular hydrogen atom transfer (HAT). The Hofmann‐Löffler‐Freytag (HLF) reaction is a distinctive radical‐based approach in which nitrogen radicals are used for remote C−H bond functionalization via intramolecular HAT. Due to its excellent regioselectivity and atomic economy, the HLF reaction represents a new approach for the preparation of valuable functional molecules. In this review, we provide a brief overview of recent research advances in remote C−H bond functionalization via nitrogen radicals mediated HLF‐type reactions involving intermolecular cyclization, intramolecular cyclization, and remote δ‐site functionalization.

Ultrafast Dynamics of the Medicinal Pigment Curcumin inside the Imidazolium Surface Active Ionic Liquid Containing Giant Vesicles and White Light Generation via Triple-FRET Technique.

The naturally occurring yellow polyphenolic medicinal pigment curcumin shows ultrafast dynamics in the excited states. These ultrafast dynamics are strongly influenced by the rigidity of the environments of the systems. The present investigation unveils the ultrafast excited-state intramolecular hydrogen atom transfer (ESIHT) (which is involved in the antioxidant mechanism) and the solvation dynamics of curcumin inside the imidazolium surface active ionic liquid (SAIL), 1-hexadecyl-3-methylimidazolium chloride ([C16mim]Cl) micelle, and giant vesicles after introducing sorbitan monoesters (Span 20 and Span 80) in the aqueous medium. Interestingly, the short hydrocarbon chain containing Span 20 forms smaller, less rigid vesicles, and the long hydrocarbon chain containing Span 80 forms larger, more rigid giant vesicles after being assembled with [C16mim]Cl. The ESIHT and the solvation dynamics are slower in Span 80, containing rigid vesicles, than that in Span 20, comprising less rigid vesicles. Finally, we have established a three-component fluorescence resonance energy transfer (Triple-FRET) system to generate white light (WL) in the micelle and giant vesicles. Here the hydrophobic dye 1,6-diphenyl-1,3,5-hexatriene (DPH) acts as the donor, and the hydrophilic anticancer drug doxorubicin hydrochloride (DOX) serves as the acceptor along with the intermediate donor, curcumin. At a specific combination of the concentrations of these dyes in a particular self-assembled system, WL is generated due to the triple-FRET phenomena.

Catalytic valorization of glycerol in the absence of external hydrogen: Effect of the Cu/ZrO2 catalyst mass and solvent

The glycerol valorization by heterogeneous catalysis to produce high-value-added chemicals is mainly carried out in the presence of high pressures of molecular hydrogen, a highly flammable gas whose main production in our days depends on fossil fuels. Therefore, an attractive alternative to explore is hydrogen in-situ generation in the catalytic process. Herein, we investigated the liquid-phase catalytic valorization of 80% wt. glycerol in different solvents such as water, 2-propanol, and acetone using a Cu/ZrO2 catalyst in the absence of external hydrogen. Firstly, the mass effect of the Cu/ZrO2 in the glycerol aqueous medium was evaluated finding an optimum mass of 250 mg for glycerol conversion. At these conditions, an initial reaction rate value of 2.63 × 10−3 molgly·gcat−1·min−1 was observed while the main products were hydroxyacetone (HA) and 1,2-propanediol (1,2-PDO). The use of 2-propanol as solvent and hydrogen donor molecule in the glycerol conversion induced the hydrogenation of hydroxyacetone towards 1,2-PDO. The ratio between the selectivity of 1,2-PDO/HA was found to be higher than that observed for the catalytic experiment with water. For the conversion of glycerol in the presence of acetone as a solvent it was noted the occurrence of acetalization reaction of glycerol with acetone and the main product observed was 4-hydroxymethyl-2,2-dimethyl-1,3-dioxalane or solketal. Density functional theory (DFT) calculations were included to gain insight into the reaction mechanisms of the hydroxyacetone hydrogenation to the formation of 1,2-PDO on Cu/ZrO2 catalyst. Four possible pathways were considered. The elementary steps include several intramolecular hydrogen atom transfer steps and two hydrogen addition steps. The hydrogen sources would come from adsorbed hydroxyl species of the aqueous reaction medium on ZrO2 support.

Construction of a Bicyclo[2.2.2]octene Skeleton via a Visible-Light-Mediated Radical Cascade Reaction of Amino Acid Derivatives with N-(2-Phenyl)benzoyl Groups.

Bridged polycyclic ring systems constitute the core structures of numerous natural products and biologically active molecules. We found that simple biphenyl substrates derived from amino acids participate in a radical cascade reaction under visible light irradiation in the presence of [Ir{dF(CF3)ppy}2(dtbpy)]PF6 to enable the direct construction of bicyclo[2.2.2]octene structures. Isotopic labeling experiments suggested that intramolecular hydrogen atom transfer is involved in the cascade processes.

Enantiocontrolled Total Synthesis of (-)-Retigeranic Acid A.

The asymmetric total synthesis of (-)-retigeranic acid A has been realized. The key features of the current synthesis include (1) a Pt-catalyzed Conia-ene 5-exo-dig cyclization of enolyne to establish the key quaternary stereochemical center of C-10 (D/E ring), (2) an intramolecular diastereoselective Prins cyclization to construct the trans-hydrindane backbone (A/B ring), and (3) a late-stage intramolecular Fe-mediated hydrogen atom transfer (HAT) Baldwin-disfavored 5-endo-trig radical cyclization to rapidly assemble vicinal quaternary centers and the core structure of (-)-retigeranic acid A (C ring).

Photoredox-Catalyzed N-Directed Regioselective Difluoroalkylation of Unactivated C(sp3)-H Bonds.

We report a redox-neutral, visible-light-mediated difluoroalkylation of unactivated C(sp3)-H bonds in amides via nitrogen-centered radicals triggered intramolecular hydrogen atom transfer. Notably, all types (tertiary, secondary, and primary) of γ-C(sp3)-H bonds displayed excellent reactivity. This methodology presents a facile route for the regioselective introduction of α,α-difluoroketone fragments into organic molecules. Moreover, the resulting gem-difluoroketones can be readily converted to structurally diverse difluoro-containing molecules, offering broad potential applications in medicinal chemistry and chemical biology.

Short I⋯O Interactions in the Crystal Structures of Two 2-Iodo-Phenyl Methyl-Amides as Substrates for Radical Translocation Reactions

Radical translocation reactions are finding various uses in organic synthesis, in particular the stereospecific formation of complex natural products. In this work, the syntheses and single-crystal structures of two substituted 2-iodo-phenyl methyl-amides are reported, namely cyclo-propane carboxylic acid (2-iodo-phenyl)-methyl-amide, C11H12INO (1), and cyclo-heptane carboxylic acid (2-iodo-phenyl)-methyl-amide, C15H20INO (2). In each case, the methyl-amide group has a syn conformation, and this grouping is perpendicular to the plane of the benzene ring: these solid-state conformations appear to be well setup to allow an intramolecular hydrogen atom transfer to take place as part of a radical translocation reaction. Short intermolecular I⋯O halogen bonds occur in each crystal structure, leading to [010] chains in 1 [I⋯O = 3.012 (2) Å] and isolated dimers in 2 [I⋯O = 3.024 (4) and 3.057 (4) Å]. The intermolecular interactions are further quantified by Hirshfeld surface analyses.

Converging Stereodivergent Reactions - Highly Stereoselective Formal anti-Markovnikov Addition of H2O to Mixtures of Olefins.

We describe a highly diastereo- and enantioselective two-step formal anti-Markovnikov addition of H2O to diastereomeric mixtures of olefins. Our approach relies on the highly enantioselective syn-specific Shi-epoxidation of both olefin isomers and a stereoconverging epoxide hydrosilylation featuring a directional isomerization step via a configurationally labile radical intermediate that is reduced by a syn-selective intramolecular hydrogen atom transfer from a Ti-H bond.

Enantioselective Total Syntheses of Grayanane Diterpenoids and (+)-Kalmanol: Evolution of the Bridgehead Carbocation-Based Cyclization and Late-Stage Functional Group Manipulation Strategies

Grayanane diterpenoids contain over 300 highly oxidized and structurally complex members, many of which possess important biological activities. Full details are provided for the development of the concise, enantioselective and divergent total syntheses of grayanane diterpenoids and (+)-kalmanol. The unique 7-endo-trig cyclization based on a bridgehead carbocation was designed and implemented to construct the 5/7/6/5 tetracyclic skeleton, demonstrating the practical value of the bridgehead carbocation-based cyclization strategy. Extensive studies of late-stage functional group manipulation were performed to forge the C1 stereogenic center, during which a photoexcited intramolecular hydrogen atom transfer reaction was discovered and the mechanism was further studied through density functional theory (DFT) calculations. The biomimetic 1,2-rearrangement from the grayanoid skeleton provided a 5/8/5/5 tetracyclic framework and resulted in the first total synthesis of (+)-kalmanol.

Syntheses and Redox Properties of Carboxylate-Ligated Hexanuclear Ce(IV) Clusters and Their Photoinduced Homolysis of the Ce(IV)–Ligand Covalent Bond

Oxo- and hydroxo-bridged hexanuclear Ce(IV) clusters surrounded by 12 carboxylate ligands, Ce6O4(OH)4(O2CR)12(L)n (R = 2,6-Me2-4-MeOC6H2 (1a), 2,6-Me2-4-tBuC6H2 (1b), 2,4,6-Me3C6H2 (1c), 2,6-Me2C6H3 (1d), 2,6-Me2-4-FC6H2 (1e), 2,6-Me2-4-ClC6H2 (1f), 9-anthracenyl (1g), and CH2tBu (1h), L = H2O or RCO2H), were synthesized by treating Ce(OtBu)4 with the corresponding carboxylic acids (2-3 equiv.) in acetone or toluene, and the molecular structures of 1d and 1g were clarified by X-ray diffraction studies. UV-vis analyses of the clusters showed broad absorption corresponding to the ligand-to-metal charge transfer (LMCT) in the ultraviolet A (315-400 nm) to blue light region; density functional theory (DFT) studies of the simplified Ce(IV) and related Zr(IV) clusters, M6O4(OH)4(O2CR)12 (M = Ce, Zr, R = Ph, Me), revealed that the low-lying vacant 4f-orbitals of the Ce(IV) were responsible for absorption in the ultraviolet A to blue light region. Irradiation of blue LED light to 1a-f under an argon atmosphere resulted in the formation of 7-methylisobenzofuran-1(3H)-one (2a-f), which involved the following four steps: photoinduced homolysis of the Ce(IV)-OCOR bond, intramolecular hydrogen atom transfer to generate the corresponding benzyl radical, oxidation to the benzyl cation, and intramolecular cyclization. Cyclic voltammetry of cerium clusters 1a-f having 2,6-dimethyl-4-substituted arylcarboxylate ligands showed electrochemically irreversible redox waves in the range of -0.79 to -0.38 V (vs [Cp2Fe]+/Cp2Fe for E1/2). The one-electron-reduced Ce(III)Ce(IV)5 clusters 3a-h were isolated by reducing 1a-h with Cp*2Co to give [Cp*2Co][Ce6O4(OH)4(O2CR)12(thf)n] (3a-h); cluster 3d was the first structurally determined hexanuclear cerium cluster containing a [Ce6O4(OH)4]11+ core.

Rapid Gas-Phase Autoxidation of Nicotine in the Atmosphere.

Nicotine is the most abundant alkaloid chemical in smoke emission. In this work, we investigated the gas-phase oxidation mechanism of nicotine initiated by its reactions with the OH radical and ozone. Both initiation reactions start dominantly by hydrogen atom abstractions from the C1, C3, and -CH3 groups of the methylpyrrolidinyl group and form radicals nicotinyl-1, nicotinyl-3, and nicotinyl-6, respectively. The nicotinyl radicals would recombine rapidly with O2, forming RO2 with rapid intramolecular hydrogen-atom transfers (HATs) with rate coefficients from 4 s-1 to greater than 104 s-1. The rapid HATs in peroxy radicals suggest rapid autoxidation of nicotine in the gas phase. Formation of HCNO and HC(O)NH2, being observed in previous studies, arises likely from secondary reactions or photolysis of intermediate products.

Copper-Catalyzed Hydrogen Atom Transfer and Aryl Migration Strategy for the Arylalkylation of Activated Alkenes.

Herein, we describe the copper-catalyzed arylalkylation of activated alkenes via hydrogen-atom transfer and aryl migration strategy. The reaction was carried out through a radical-mediated continuous migration pathway using N-fluorosulfonamides as the alkyl source. The primary, secondary, and tertiary alkyl radicals formed by intramolecular hydrogen-atom transfer proceeded smoothly. This methodology is an efficient approach for the synthesis of various amide derivatives possessing a quaternary carbon center with good yields and high regioselectivity.

Site-selective iodine atom transfer in fluorinated alkyl iodides via 1,5-hydrogen atom transfer

The direct and selective functionalization of inert C-H bonds via intramolecular hydrogen atom transfer (HAT) is an increasingly powerful tool in organic synthesis. Herein, we designed an efficient and facile iodine atom transfer in fluorinated alkyl iodides via 1,5-HAT. Our process enables site-selective iodination of unreactive C(sp3)-H bonds to afford di- and tri-fluorinated alkyl iodides in good yields. Furthermore, our process shows excellent atom economy and high functional group tolerance, including methyl, methoxy, chloro, cyano, and silyl moieties.

Theoretical Insights into the Intermolecular Hydrogen Bond Effect on ESIHT Process in 2′-Hydroxychalcone: A Combined DFT/TDDFT Study

Present computational study lighting up the ground and excited states properties of 2′-hydroxychalcone (2′-HC) and 2′-HC + (H2O)2-[2′-HCH] molecules by employing density functional theory (DFT) and time-dependent density functional theory (TD-DFT). Furthermore, micro-solvation, hydrogen bond dynamics and natural charge analysis studies have been done for both molecules at ground/excited states by using effective fragment potential (EFP1)/natural bond orbital (NBO) methods at 6-31G(d,p)/B3LYP level. The excited state intra-molecular hydrogen atom transfer (ESIHT) mechanism of 2′-HC was investigated via potential energy scans (PES). No hydrogen atom transfer is observed in the S3 state of 2′-HC and S1/S3 states of 2′-HCH. The optimized molecular structures, molecular orbital’s and electrostatic potential maps were depicted along with UV-Vis absorption spectra. Good consistency between experimental and computational absorption wavelength for a 2′-HC molecule with methanol as solvent.