Alkali‐Metal‐Ion‐Assisted Hydrogen Atom Transfer in the Homocysteine Radical

Intramolecular hydrogen atom transfer (HAT) was examined in homocysteine (Hcy) thiyl radical/alkali metal ion complexes in the gas phase by combination of experimental techniques (ion‐molecule reactions and infrared multiple photon dissociation spectroscopy) and theoretical calculations. The experimental results unequivocally show that metal ion complexation (as opposed to protonation) of the regiospecifically generated Hcy thiyl radical promotes its rapid isomerisation into an α‐carbon radical via HAT. Theoretical calculations were employed to calculate the most probable HAT pathway and found that in alkali metal ion complexes the activation barrier is significantly lower, in full agreement with the experimental data. This is, to our knowledge, the first example of a gas‐phase thiyl radical thermal rearrangement into an α‐carbon species within the same amino acid residue and is consistent with the solution phase behaviour of Hcy radical.     

Substrate‐Tuned Catalysis of the Radical S‐Adenosyl‐L‐Methionine Enzyme NosL Involved in Nosiheptide Biosynthesis

NosL is a radical S‐adenosyl‐L ‐methionine (SAM) enzyme that converts L ‐Trp to 3‐methyl‐2‐indolic acid, a key intermediate in the biosynthesis of a thiopeptide antibiotic nosiheptide. In this work we investigated NosL catalysis by using a series of Trp analogues as the molecular probes. Using a benzofuran substrate 2‐amino‐3‐(benzofuran‐3‐yl)propanoic acid (ABPA), we clearly demonstrated that the 5′‐deoxyadenosyl (dAdo) radical‐mediated hydrogen abstraction in NosL catalysis is not from the indole nitrogen but likely from the amino group of L ‐Trp. Unexpectedly, the major product of ABPA is a decarboxylated compound, indicating that NosL was transformed to a novel decarboxylase by an unnatural substrate. Furthermore, we showed that, for the first time to our knowledge, the dAdo radical‐mediated hydrogen abstraction can occur from an alcohol hydroxy group. Our study demonstrates the intriguing promiscuity of NosL catalysis and highlights the potential of engineering radical SAM enzymes for novel activities.     

Exploration of Dimethylzinc‐Mediated Radical Reactions

In this account, our studies on radical reactions that are promoted by dimethylzinc and air are described. Advantages of this reagent and differences from conventional radical initiators, such as triethylborane, are discussed.     

Mechanistic Studies of the Radical S‐Adenosylmethionine Enzyme DesII with TDP‐D‐Fucose

DesII is a radical S‐adenosylmethionine (SAM) enzyme that catalyzes the C4‐deamination of TDP‐4‐amino‐4,6‐dideoxyglucose through a C3 radical intermediate. However, if the C4 amino group is replaced with a hydroxy group (to give TDP‐quinovose), the hydroxy group at C3 is oxidized to a ketone with no C4‐dehydration. It is hypothesized that hyperconjugation between the C4 C? N/O bond and the partially filled p orbital at C3 of the radical intermediate modulates the degree to which elimination competes with dehydrogenation. To investigate this hypothesis, the reaction of DesII with the C4‐epimer of TDP‐quinovose (TDP‐fucose) was examined. The reaction primarily results in the formation of TDP‐6‐deoxygulose and likely regeneration of TDP‐fucose. The remainder of the substrate radical partitions roughly equally between C3‐dehydrogenation and C4‐dehydration. Thus, changing the stereochemistry at C4 permits a more balanced competition between elimination and dehydrogenation.     

Stereoselective Triplet‐Sensitised Radical Reactions of Furanone Derivatives

The stereo‐ and regioselectivity of triplet‐sensitised radical reactions of furanone derivatives have been investigated. Furanones 7 a , b were excited to the ³ππ* state by triplet energy transfer from acetone. Intramolecular hydrogen abstraction then occurred such that hydrogen was transferred from the tetrahydropyran to the β position of the furanone moiety. Radical combination of the tetrahydropyranyl and the oxoallyl radicals led to the final products 8 a , b . In the intramolecular reaction, overall, a pyranyl group adds to the α position of the furanone. The effect of conformation was first investigated with compounds 9 a , b carrying an additional substituent on the tether between the furanone and pyranyl moiety. Further information on the effect of conformation and the relative configuration at the pyranyl anomeric centre and the furanone moiety was obtained from the transformations of the glucose derivatives 12 , 14 , 17 and 18 . Radical abstraction occurred at the anomeric centre and at the 5′‐position of the glucosyl moiety. Computational studies of the hydrogen‐abstraction step were carried out with model structures. The activation barriers of this step for different stereoisomers and the abstraction at the anomeric centre and at the 6‘‐position of the tetrahydropyranyl moiety were calculated. The results of this investigation are in accordance with experimental observations. Furthermore, they reveal that the reactivity and regioselectivity are mainly determined in the hydrogen‐abstraction step. Intramolecular hydrogen abstraction (almost simultaneous electron and proton transfer) in ³ππ* excited furanones only takes place under restricted structural conditions in a limited number of conformations that are defined by the relative configuration of the substrates. It is observed that in the biradical intermediate, back‐hydrogen transfer occurs leading to the starting compound. In the case of glucose derivatives, this reaction led to epimerisation at the anomeric centre.     

Key Role of Intramolecular Metal Chelation and Hydrogen Bonding in the Cobalt‐Mediated Radical Polymerization of N‐Vinyl Amides

This work reveals the preponderance of an intramolecular metal chelation phenomenon in a controlled radical polymerization system involving the reversible trapping of the radical chains by a cobalt complex bis(acetylacetonato)cobalt(II). The cobalt‐mediated radical polymerization (CMRP) of a series of N‐vinyl amides was considered with the aim of studying the effect of the cobalt chelation by the amide moiety of the last monomer unit of the chain. The latter reinforces the cobalt? polymer bond in the order N‐vinylpyrrolidone<N‐vinyl caprolactam<N‐methyl‐N‐vinyl acetamide, and is responsible for the optimal control of the polymerizations observed for the last two monomers. Such a double linkage between the controlling agent and the polymer, through a covalent bond and a dative bond, is unique in the field of controlled radical polymerization and represents a powerful opportunity to fine tune the equilibrium between latent and free radicals. Possible hydrogen bond formation is also taken into account in the case of N‐vinyl acetamide and N‐vinyl formamide. These results are essential for understanding the factors influencing Co? C bond strength in general, and the CMRP mechanism in particular, but also for developing a powerful platform for the synthesis of new precision poly(N‐vinyl amide) materials, which are an important class of polymers that sustain numerous applications today.     

On the Radical Nature of Iron‐Catalyzed Cross‐Coupling Reactions

The radical nature of iron‐catalyzed cross‐coupling between Grignard reagents and alkyl halides has been studied by using a combination of competitive kinetic experiments and DFT calculations. In contrast to the corresponding coupling with aryl halides, which commences through a classical two‐electron oxidative addition/reductive elimination sequence, the presented data suggest that alkyl halides react through an atom‐transfer‐initiated radical pathway. Furthermore, a general iodine‐based quenching methodology was developed to enable the determination of highly accurate concentrations of Grignard reagents, a capability that facilitates and increases the information output of kinetic investigations based on these substrates.     

Atom‐Transfer Radical Addition Reactions Catalyzed by RuCp* Complexes: A Mechanistic Study

Kinetic and spectroscopic analyses were performed to gain information about the mechanism of atom‐transfer radical reactions catalyzed by the complexes [RuCl₂Cp*(PPh₃)] and [RuClCp*(PPh₃)₂] (Cp*=pentamethylcyclopentadienyl), in the presence and in the absence of the reducing agent magnesium. The reactions of styrene with ethyl trichloroacetate, ethyl dichloroacetate, or dichloroacetonitrile were used as test reactions. The results show that for substrates with high intrinsic reactivity, such as ethyl trichloroacetate, the oxidation state of the catalyst in the resting state is +3, and that the reaction is zero‐order with respect to the halogenated compound. Furthermore, the kinetic data suggest that the metal catalyst is not directly involved in the rate‐limiting step of the reaction.     

N‐Centered Radical Directed Remote C−H Bond Functionalization via Hydrogen Atom Transfer

The N‐centered radical directed remote C?H bond functionalization via hydrogen‐atom‐transfer at distant sites has developed as an enormous potential tool for the organic synthetic chemists. Unactivated and remote secondary and tertiary, as well as selected primary C?H bonds, can be utilized for functionalization by following these methodologies. The synthesis of the heterocyclic scaffolds provides them extra attention for the modern days′ developments in this field of unactivated remote C?H bonds functionalizations.     

亚胺自由基引发的1，5-氢原子转移反应研究进展

通过亚胺自由基引发的1,5-氢原子转移（Hydrogen Atom Transfer,HAT）途径实现C(sp³)−H键官能团化,可避免导向基团和当量氧化剂的使用,因而引起了研究人员的广泛关注。近年来,过渡金属和可见光氧化还原体系的发展为高效可控产生亚胺自由基提供了可靠的方法。本文根据亚胺自由基的来源分类总结了亚胺自由基引发的1,5-氢原子转移实现C(sp³)−H键官能团化反应。     

Design of Leaving Groups in Radical CC Fragmentations: Through‐Bond 2c–3e Interactions in Self‐Terminating Radical Cascades

Radical cascades terminated by β‐scission of exocyclic C?C bonds allow for the formation of aromatic products. Whereas β‐scission is common for weaker bonds, achieving this reactivity for carbon–carbon bonds requires careful design of radical leaving groups. It has now been found that the energetic penalty for breaking a strong σ‐bond can be compensated by the gain of aromaticity in the product and by the stabilizing two‐center, three‐electron “half‐bond” present in the radical fragment. Furthermore, through‐bond communication of a radical and a lone pair accelerates the fragmentation by selectively stabilizing the transition state. The stereoelectronic design of radical leaving groups leads to a new, convenient route to Sn‐functionalized aromatics.     

Recent Advances in Transition Metal‐Catalyzed Asymmetric Radical Reactions

Control of enantioselectivity in radical reactions was a formidable challenge for organic chemists for decades. Thanks to the key role of transition metal complexes both in promoting and highly enantioselectively controlling sophisticated synthetic routes, great improvements in this filed have been achieved by merging transition‐metal asymmetric catalysis with radical chemistry. Herein we provide a perspective of some of the most significant contributions in the field during the past decades. Accordingly, the major advances are classified based on different strategies for controlling stereoselectivity including: (1) chiral metal complex chelation, (2) chiral metal complex combined with radical species and reductive elimination, (3) chiral metal complex outer‐sphere substitution by radical intermediate. Brief discussion of mechanism is presented whenever relevant.     

Efficient Cu‐catalyzed Atom Transfer Radical Addition Reactions of Fluoroalkylsulfonyl Chlorides with Electron‐deficient Alkenes Induced by Visible Light

Fluoroalkylsulfonyl chlorides, R_fSO₂Cl, in which R_f=CF₃, C₄F₉, CF₂H, CH₂F, and CH₂CF₃, are used as a source of fluorinated radicals to add fluoroalkyl groups to electron‐deficient, unsaturated carbonyl compounds. Photochemical conditions, using Cu mediation, are used to produce the respective α‐chloro‐β‐fluoroalkylcarbonyl products in excellent yields through an atom transfer radical addition (ATRA) process. Facile nucleophilic replacement of the α‐chloro substituent is shown to lead to further diverse functionalization of the products.     

O‐Alkyl S‐3,3‐Dimethyl‐2‐oxobutyl Dithiocarbonates as Versatile Sulfur‐Transfer Agents in Radical C(sp3)?H Functionalization

Boiling of the title compounds in ethereal solvents or cycloalkanes in the presence of a radical initiator leads to radical C(sp³)? H functionalization, by which a sulfur atom is introduced into the ethereal solvents at the oxygenated carbon atom or into the cycloalkanes. Both acyclic and cyclic ethers, such as [18]crown‐6 and [D₈]THF, undergo the sulfur transfer. The reaction is useful for the synthesis of monothioacetals, thiols, and sulfides from simple starting materials.     

The Studies of Free Radical Cyclization Reactions Mediated by Sulfonyl Chloride (I)

A study of the free racinoal reaction of vinylcycloprelpane mediated by p-toluenesulfonyl chloride is described.     

Peroxyl Radical Reactions in Water Solution: A Gym for Proton‐Coupled Electron‐Transfer Theories

The reactions of alkylperoxyl radicals with phenols have remained difficult to investigate in water. We describe herein a simple and reliable method based on the inhibited autoxidation of water/THF mixtures, which we calibrated against pulse radiolysis. With this method we measured the rate constants k_inh for the reactions of 2‐tetrahydrofuranylperoxyl radicals with reference compounds: urate, ascorbate, ferrocenes, 2,2,5,7,8‐pentamethyl‐6‐chromanol, Trolox, 6‐hydroxy‐2,5,7,8‐tetramethylchroman‐2‐acetic acid, 2,6‐di‐tert‐butyl‐4‐methoxyphenol, 4‐methoxyphenol, catechol and 3,5‐di‐tert‐butylcatechol. The role of pH was investigated: the value of k_inh for Trolox and 4‐methoxyphenol increased 11‐ and 50‐fold from pH 2.1 to 12, respectively, which indicate the occurrence of a SPLET‐like mechanism. H(D) kinetic isotope effects combined with pH and solvent effects suggest that different types of proton‐coupled electron transfer (PCET) mechanisms are involved in water: less electron‐rich phenols react at low pH by concerted electron‐proton transfer (EPT) to the peroxyl radical, whereas more electron‐rich phenols and phenoxide anions react by multi‐site EPT in which water acts as proton relay.     

Isoprene‐Assisted Radical Coupling of (Co)polymers Prepared by Cobalt‐Mediated Radical Polymerization

Tackling blocks : The isoprene‐assisted radical coupling (I‐ARC) of polymers prepared by cobalt‐mediated radical polymerization (see picture) is the first efficient radical coupling method that is not restricted to short chains. When applied to AB diblock copolymers, I‐ARC constitutes a straightforward approach to the preparation of novel symmetrical ABA triblock copolymers.

     

Sustainable Electrochemically‐Mediated Atom Transfer Radical Polymerization with Inexpensive Non‐Platinum Electrodes

Electrochemically‐mediated atom transfer radical polymerization (eATRP) of oligo(ethylene oxide) methyl ether methacrylate in water is investigated on glassy carbon, Au, Ti, Ni, NiCr and SS304. eATRPs are performed both in divided and undivided electrochemical cells operating under either potentiostatic or galvanostatic mode. The reaction is fast, reaching high conversions in ≈4 h, and yields polymers with dispersity <1.2 and molecular weights close to the theoretical values. Most importantly, eATRP in a highly simplified setup (undivided cell under galvanostatic mode) with inexpensive nonnoble metals, such as NiCr and SS304, as cathode is well‐controlled. Additionally, these electrodes neither release harmful ions in solution nor react directly with the C X chain end and can be reused several times. It is demonstrated that Pt can be replaced with cheaper, and more readily available materials without negatively affecting eATRP performance.

     

Copper‐Catalyzed Double Additions and Radical Cyclization Cascades in the Re‐Engineering of the Antibacterial Pleuromutilin

A general synthetic sequence involving simply prepared starting materials provides rapid access to diverse, novel tricyclic architectures inspired by pleuromutilin. Sm^II‐mediated radical cyclization cascades of dialdehydes, prepared using a new, one‐pot, copper‐catalyzed double organomagnesium addition to β‐chlorocyclohexenone, proceed with complete sequence selectivity and typically with high diastereocontrol to give analogues of the target core. Our expedient approach (ca. 7 steps) allows non‐traditional, de novo synthetic access to analogues of the important antibacterial that can′t be prepared from the natural product by semisynthesis.