Radical Substitution Research Articles

Asymmetric Induction and Enantiodivergence in Catalytic Radical C–H Amination via Enantiodifferentiative H-Atom Abstraction and Stereoretentive Radical Substitution

Control of enantioselectivity remains a major challenge in radical chemistry. The emergence of metalloradical catalysis (MRC) offers a conceptually new strategy for addressing this and other outstanding issues. Through the employment of D2-symmetric chiral amidoporphyrins as the supporting ligands, Co(II)-based MRC has enabled the development of new catalytic systems for asymmetric radical transformations with a unique profile of reactivity and selectivity. With the support of new-generation HuPhyrin chiral ligands whose cavity environment can be fine-tuned, the Co-centered d-radicals enable to address challenging issues that require exquisite control of fundamental radical processes. As showcased with asymmetric 1,5-C-H amination of sulfamoyl azides, the enantiocontrol of which has proven difficult, the judicious use of HuPhyrin ligand by tuning the bridge length and other remote nonchiral elements allows for controlling both the degree and sense of asymmetric induction in a systematic manner. This effort leads to successful development of new Co(II)-based catalytic systems that are highly effective for enantiodivergent radical 1,5-C-H amination, producing both enantiomers of the strained five-membered cyclic sulfamides with excellent enantioselectivities. Detailed deuterium-labeling studies, together with DFT computation, have revealed an unprecedented mode of asymmetric induction that consists of enantiodifferentiative H-atom abstraction and stereoretentive radical substitution.

Philicity of Acetonyl and Benzoyl Radicals: A Comparative Experimental and Computational Study.

In this work, the reactivities of acetonyl and benzoyl radicals in aromatic substitution and addition reactions have been compared in an experimental and computational study. The results show that acetonyl is more electrophilic than benzoyl, which is rather nucleophilic. A Hammett plot analysis of the addition reactions of the two radicals to substituted styrenes clearly support the nucleophilicity of benzoyl, but in the case of acetonyl, no satisfactory linear correlation with a single substituent-related parameter was found. Computational calculations helped to rationalize this effect, and a good linear correlation was found with a combination of polar parameters (σ+ ) and the radical stabilization energies of the formed intermediates. Based on the calculated philicity indices for benzoyl and acetonyl, a quantitative comparison of these two radicals with many other reported radicals is possible, which may help to predict the reactivities of other aromatic radical substitution reactions.

Electrons and Holes as Catalysts in Organic Electrosynthesis

AbstractThe injection (or removal) of electrons into (or from) a substrate by an electrode can effectively catalyze various redox‐neutral reactions that otherwise require harsh conditions and/or the use of reagents. Such processes involve the electrogeneration of an ionic or radical ionic species, which after a coupled chemical step either undergoes a backward electron exchange with the electrode (ECEb mechanism) or triggers a chain process in the bulk solution. Under these circumstances, sub‐stoichiometric amounts of charge are sufficient to achieve a full conversion and conceptionally, the electrons and holes can be understood as being catalysts. This principle has been successfully applied to accomplish a number of redox‐neutral transformations such as molecular rearrangements, Diels‐Alder‐type cycloadditions and radical substitution reactions (SRN1) in a mild and atom‐economical fashion. Although examples have been reported but sporadically since the early 1970s, a number of exciting recent developments have led us to review and discuss these cases using unifying mechanistic concepts that are described herein.

Computational study of polycyclic aromatic hydrocarbons growth by vinylacetylene addition

The growth of polycyclic aromatic hydrocarbons (PAH) can proceed via multiple chemical mechanisms. The mechanism of naphthyl radical and vinylacetylene (C4H4) addition reaction has been systematically investigated in this computational study. A combination of DFT/B3LYP/6-311+G(d,p), CCSD/6-311+G(d,p) and CBS-QB3 methods were performed to calculate the potential energy surfaces. It revealed that the products, including phenanthrene, anthracene, a PAH with a five-membered ring structure, and PAH with a C4H3 radical substitution, can be formed in A2-1 (1-naphthyl)+C4H4 and A2-2 (2-naphthyl) +C4H4 reaction networks. The reaction rate constants at 0.1-100 atm were evaluated by RRKM theory by solving the master equation in the temperature range of 800–2500 K, which showed that the rate constants of reactions A2-1 (A2-2)+C4H4→product+H are highly temperature-dependent but nearly pressure-independent. The distribution of products was investigated in a 0-D batch reactor, wherein the initial reactant concentrations were taken from experimental measurements. The results showed that adduct intermediates were the main products at low temperature (T < 1000 K), and the phenanthrene and PAH with C4H3 radical substitution became the dominant products at temperatures where PAHs and soot form in flames (T > 1000 K). It was observed that a significant amount of phenanthrene is formed from PAH with a C4H3 radical substitution with the assistance of H atom. Reaction pathway sensitivity analysis for the PAH radical+C4H4 reaction system was performed and showed that the new benzene rings are more likely to be generated near the zig-zag edge surface site instead of the free edge. For the development of a PAH mechanism, the analogous treatment of rate constants for larger PAH radical + C4H4 reaction system are discussed. The formation rate of naphthalene from the reaction of phenyl+C4H4 was found to be very close to that of phenanthrene from the reaction of naphthyl+C4H4, suggesting that the analogous treatment of the rates is reasonable in PAH mechanisms.

Understanding changes within business networks: evidences from the international expansion of fashion firms

PurposeThe purpose of this paper is to address the topic of business network dynamics and identify different relational paths, as forms of change in business relationships and related types of network change. The paper contributes to the literature on business network dynamics by providing an understanding of relational paths in the context of firms’ internationalization and shading light on different forms of change in business relationships and types of network change. The paper also contributes to the understanding of liabilities in internationalization that has to do with business networks, namely the liability of outsidership.Design/methodology/approachThis paper is based on qualitative research following the multiple case study research approach. The authors propose three cases of internationalizing firms in the fashion industry that follows relational paths corresponding to different forms of change in business relationships that imply different types of network change.FindingsChanges to a firm’s business network may be addressed through relational paths, namely creation of new business relationships (activation), maintenance of existing relationships (integration) and ending of existing relationships (substitution). These relational paths can be considered forms of incremental (integration) and radical (activation and substitution) change in business relationships and lead to different types of network change for business network dynamics that coexist and influence each other within the same firm.Originality/valueThis paper contributes to a better understanding of business network dynamics by showing how firms change their business relationships following different relational paths as the best way to respond to the challenges and new opportunities offered especially by international markets. The present paper has relevant managerial implications since coping with change in business relationships is perhaps one of the most critical and difficult tasks for management, even more critical if compared to the increasing complexity of doing business internationally and the liabilities that firms face in their internationalization process, especially the liability of outsidership.

Insertion of Molecular Oxygen into the Metal–Methyl Bonds of Platinum(II) and Palladium(II) 1,3-Bis(2-pyridylimino)isoindolate Complexes

Upon exposure of [(BPI)M(CH3)] (M = Pd, Pt, BPI = 1,3-bis(2-pyridylimino)isoindole) complexes to O2, direct insertion was observed to generate the O2 insertion products (BPI)M(OOCH3). Kinetic and mechanistic analyses of the O2 insertion reaction support a radical chain substitution mechanism. Reproducible kinetics were observed in the presence of a radical initiator. The release of methanol was subsequently observed from the M–OOCH3 products.

Bimolecular Reaction Dynamics in the Phenyl-Silane System: Exploring the Prototype of a Radical Substitution Mechanism.

We present a combined experimental and theoretical investigation of the bimolecular gas-phase reaction of the phenyl radical (C6H5) with silane (SiH4) under single collision conditions to investigate the chemical dynamics of forming phenylsilane (C6H5SiH3) via a bimolecular radical substitution mechanism at a tetracoordinated silicon atom. Verified by electronic structure and quasiclassical trajectory calculations, the replacement of a single carbon atom in methane by silicon lowers the barrier to substitution, thus defying conventional wisdom that tetracoordinated hydrides undergo preferentially hydrogen abstraction. This reaction mechanism provides fundamental insights into the hitherto unexplored gas-phase chemical dynamics of radical substitution reactions of mononuclear main group hydrides under single collision conditions and highlights the distinct reactivity of silicon compared to its isovalent carbon. This mechanism might be also involved in the synthesis of cyanosilane (SiH3CN) and methylsilane (CH3SiH3) probed in the circumstellar envelope of the carbon star IRC+10216.

Synthesis and Transformations of Aryl-Substituted Alkenes of the Adamantane Series

Aryl-substituted alkenes of the adamantane series, 1-[(Z,E)-3-phenylprop-2-en-1-yl]adamantane and 1-[(Z)-3-phenylprop-1-en-1-yl]adamantane, have been synthesized by the Wittig reaction. Their allylic bromination involves two concurrent reactions, radical substitution and raical addition. The different chemical behaviors of the aryl-substituted alkenes have been demonstrated in the Ritter reaction. Depending on the alkene structure and acid catalyst nature, the products are secondary amides, sulfonic acid derivatives, and homoadamantane γ-sultone.

Ion fragmentations via photoelectron activated radical relays and competed hole oxidization on semiconductor nanoparticles for mass spectrometry

Structural identification is challenging in mass spectrometric imaging because of inadequate sample quantities and limited sampling time in each pixel for tandem mass spectrometry (MS/MS) experiments, which are usually used for the generation of fragment ions. We report herein the observation of a cascade of highly specific chemical bond cleavages via a low-energy photoelectron activated radical relays and a competed hole oxidization on surfaces of (Bi2O3)0.07(CoO)0.03(ZnO)0.9 semiconductor nanoparticles irradiated with the 3rd harmonic (355 nm) of the Nd3+: YAG laser. Distinguished from high energy electron impact (EI), this approach generates gaseous radical anions through the exothermic capture of low-energy tunneling electrons that are not able to cause extensive vibrational excitations. It was found not only original radical center but also secondary or even tertiary radical centers cause specific bond cleavages exclusively on α positions. The original radical center directly activates the cleavages of α-positioned chemical bonds that cause the formation of secondary radical centers. Ion fragmentations proceed along the newly formed radical centers that further activate the cleavages of their α-positioned chemical bonds. Using 8 compounds, we have demonstrated various radical reactions involved in desulfonation, cyclization, and ring contraction reactions as well as competed hole oxidization-generated hydroxyl radical substitution reactions. The interpretable fragment ions provide unambiguous experimental evidences for structural elucidation of drug residues and metabolites in mass spectrometric imaging of tissue slices without tandem mass spectrometry (MS/MS).

Quantum chemical calculation of free radical substitution reaction mechanism of camptothecin

Free radical substitution reaction, which has low energy barrier and takes place in mild reaction conditions, is an important method for camptothecin's modification. The experimental data show that the free radical substitution reaction of camptothecin has high site selectivity, and prefers to take place at site 7. Up to now, few researches focus on the mechanism of it. In this study, the differences of the reaction rate constant (k) for the reactions at different sites, such as site of 7, 9, 10, 11, 12, were investigated with B3LYP of density functional theory at the 6-31+G (d, p) base set level and CPCM aqueous solvent model. It was found that the substitution reaction can be carried out in two steps in acidic condition. First, the methyl radical attacks the corresponding site to form an intermediate having methyl radical combined with the camptothecin skeleton, and then a hydrogen atom was abstracted by the singlet oxygen to form methyl camptothecin, wherein the first step was the rate control step of the reaction. The results show that site 7 has the higherreaction rate constant (k) than other examined sites, indicating that the reaction tends to take place on site 7 position, which is in agreement with the experimental results.

Investigation of the Iterative Methylations by a Cobalamin‐Dependent Radical SAM Methyltransferase

Natural products with branched alkoxy groups have been used widely in the development of bioactive compounds. However, the biosynthesis of branched alkoxy groups like the unique t‐butyl group is still poorly understood. The cystobactamids are a novel class of isopropyl substituted antibacterial compounds produced by myxobacteria. In the biosynthesis gene cluster of cystobactamid, CysS is assigned as a cobalamin‐dependent radical S‐adenosylmethionine (SAM) enzyme, which is proposed to catalyze the iterative methylations on the 3‐methoxy‐4‐aminobenzoic acid moieties of cystobactamids. To reconstitute CysS, different substrates analogs were synthesized. When the pantetheinyl substrate analogs were used, multiple methylations were observed to form ethyl, isopropyl, t‐butyl and sec‐butyl substituted products from a substrate methyl ether by CysS. These cobalamin dependent methylations also produce 5′‐deoxyadenosine(5′dA) and S‐adenosylhomocysteine (SAH) in equal amounts. The isotope labeling experiments suggest that the methyl group from SAM is first transferred to cobalamin followed by the attack of the substrate radical to give methylated products. A combinatorial antibiotic library of 25 cystobactamid analogs could potentially be built using CysS by Cystobacter sp. Different substituted substrate analogs were designed to trap the organic radical species, cobalamin intermediates and probe the radical substitution step. Here, we have showed the first in vitro reconstitution of a cobalamin‐dependent radical SAM enzyme catalyzing the conversion of a methyl group to a t‐butyl group by sequential methylations. The detailed mechanistic studies help us to unravel how CysS uses SAM, [4Fe–4S] cluster and cobalamin to perform iterative methylations on sp3‐hybridized carbon centers and better understand the mechanism of other widespread cobalamin‐dependent radical SAM methyltransferases.Support or Funding InformationThis work was supported by NIH (DK44083) and by the Robert A. Welch Foundation (A‐0034).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Organocatalytic Electrochemical C–H Lactonization of Aromatic Carboxylic Acids

An electrochemical strategy has been developed for radical arene carbon–oxygen bond formation. This reaction utilizes DDQ as a redox mediator, with inexpensive glassy carbon electrodes to facilitate an intramolecular lactonization of biphenyl-2-carboxylic acid derivatives via aromatic carboxyl radical substitution to give 6H-benzo[c]chromen-6-ones.

Identifying the Active Site of N-Doped Graphene for Oxygen Reduction by Selective Chemical Modification

N-doped carbon materials are promising electrocatalysts for oxygen reduction reaction (ORR). However, the lack of knowledge in the nature of active sites limits the rational design of this type of catalysts. Although pyridinic N species are proposed to be active for ORR, little experimental evidence is provided to reveal the reactive sites. Herein, we developed a surface-modification method to identify the ortho-carbon atom of the pyridinic ring as the reactive site for ORR on N-doped graphene. The pyridinic ring of N-doped graphene was selectively grafted by an acetyl group at pyridinic N and ortho-C atoms by electrophilic and radical substitution, respectively. The former remained most of ORR catalytic activity, while the latter lost its activity completely. DFT calculations confirm that O2 can get adsorbed and reduced favorably on the ortho-C atom of the pyridinic ring. This study provides new insight into the nature of active sites and the ORR mechanism for N-doped carbon materials.

Mechanistic Investigations of Lysine-Tryptophan Cross-Link Formation Catalyzed by Streptococcal Radical S-Adenosylmethionine Enzymes.

Streptide is a ribosomally synthesized and post-translationally modified peptide with a unique cyclization motif consisting of an intramolecular lysine-tryptophan cross-link. Three radical S-adenosylmethionine enzymes, StrB, AgaB, and SuiB from different species of Streptococcus, have been shown to install this modification onto their respective precursor peptides in a leader-dependent fashion. Herein, we conduct detailed investigations to differentiate among several plausible mechanistic proposals, specifically addressing radical versus electrophilic addition to the indole during cross-link formation, the role of substrate side chains in binding in the enzyme active site, and the identity of the catalytic base in the reaction cycle. Our results are consistent with a radical electrophilic aromatic substitution mechanism for the key carbon-carbon bond-forming step. They also elaborate on other mechanistic features that underpin this unique and synthetically challenging post-translational modification.

Structure of a product of free radical substitution of a chlorine atom for 1,3,5-trioxane in an iron(II) chlathrochelate

A tert-BuOOH/Fe(II) system is used for the free radical substitution of the chlorine atom at the rib of a boron capped iron(II) tris-dioximate chlathrochelate for 1,3,5-trioxane. The structure of the compound is determined by single crystal XRD and solution NMR.

Surface enhanced infrared absorption spectroscopy for graphene functionalization on copper

The monolayer form of CVD graphene is imposing crucial challenges in characterization of the targeted covalent functionalization due to the low amount of grafting moieties on the surface, which in turn hampers drawing conclusions about reactivity-properties relationships. Due to the growing interest in chemically modified graphene new, reliable and non-destructive methods for its characterization are critically required. Herein we demonstrate the use of surface-enhanced infrared absorption spectroscopy for detection of characteristic vibration modes of species being grafted to the material either via radical (Meerwein arylation) or nucleophilic substitution pathway on copper foil. The phenomenon is allowed by the appropriate metal surface morphology and no signal could have been obtained neither on Si/SiO2 substrate, nor on bare copper. The surface of copper foil exhibit partial corrosion during the reaction which leads to the creation of active substrate for SEIRA. The measurements were performed using reflection-absorption and attenuated total reflection modes with almost identical results, thus making this analytical approach feasible, practical, non-destructive and easy to use for routine characterization of graphene functionalization.

Selective Aliphatic Carbon-Carbon Bond Activation by Rhodium Porphyrin Complexes.

The carbon-carbon bond activation of organic molecules with transition metal complexes is an attractive transformation. These reactions form transition metal-carbon bonded intermediates, which contribute to fundamental understanding in organometallic chemistry. Alternatively, the metal-carbon bond in these intermediates can be further functionalized to construct new carbon-(hetero)atom bonds. This methodology promotes the concept that the carbon-carbon bond acts as a functional group, although carbon-carbon bonds are kinetically inert. In the past few decades, numerous efforts have been made to overcome the chemo-, regio- and, more recently, stereoselectivity obstacles. The synthetic usefulness of the selective carbon-carbon bond activation has been significantly expanded and is becoming increasingly practical: this technique covers a wide range of substrate scopes and transition metals. In the past 16 years, our laboratory has shown that rhodium porphyrin complexes effectively mediate the intermolecular stoichiometric and catalytic activation of both strained and nonstrained aliphatic carbon-carbon bonds. Rhodium(II) porphyrin metalloradicals readily activate the aliphatic carbon(sp3)-carbon(sp3) bond in TEMPO ((2,2,6,6-tetramethylpiperidin-1-yl)oxyl) and its derivatives, nitriles, nonenolizable ketones, esters, and amides to produce rhodium(III) porphyrin alkyls. Recently, the cleavage of carbon-carbon σ-bonds in unfunctionalized and noncoordinating hydrocarbons with rhodium(II) porphyrin metalloradicals has been developed. The absence of carbon-hydrogen bond activation in these systems makes the reaction unique. Furthermore, rhodium(III) porphyrin hydroxide complexes can be generated in situ to selectively activate the carbon(α)-carbon(β) bond in ethers and the carbon(CO)-carbon(α) bond in ketones under mild conditions. The addition of PPh3 promotes the reaction rate and yield of the carbon-carbon bond activation product. Thus, both rhodium(II) porphyrin metalloradical and rhodium(III) porphyrin hydroxide are very reactive to activate the aliphatic carbon-carbon bonds. Recently, we successfully demonstrated the rhodium porphyrin catalyzed reduction or oxidation of aliphatic carbon-carbon bonds using water as the reductant or oxidant, respectively, in the absence of sacrificial reagents and neutral conditions. This Account presents our contribution in this domain. First, we describe the chemistry of equilibria among the reactive rhodium porphyrin complexes in oxidation states from Rh(I) to Rh(III). Then, we present the serendipitous discovery of the carbon-carbon bond activation reaction and subsequent developments in our laboratory. These aliphatic carbon-carbon bond activation reactions can generally be divided into two categories according to the reaction type: (i) homolytic radical substitution of a carbon(sp3)-carbon(sp3) bond with a rhodium(II) porphyrin metalloradical and (ii) σ-bond metathesis of a carbon-carbon bond with a rhodium(III) porphyrin hydroxide. Finally, representative examples of catalytic carbon-carbon bond hydrogenation and oxidation through strategic design are covered. The progress in this area broadens the chemistry of rhodium porphyrin complexes, and these transformations are expected to find applications in organic synthesis.

Direct Functionalization of an Acid-Terminated Nanodiamond with Azide: Enabling Access to 4-Substituted-1,2,3-Triazole-Functionalized Particles

Azides on the periphery of nanodiamond materials (ND) are of great utility because they have been shown to undergo Cu-catalyzed and Cu-free cycloaddition reactions with structurally diverse alkynes, affording particles tailored for applications in biology and materials science. However, current methods employed to access ND featuring azide groups typically require either harsh pretreatment procedures or multiple synthesis steps and use surface linking groups that may be susceptible to undesirable cleavage. Here we demonstrate an alternative single-step approach to producing linker-free, azide-functionalized ND. Our method was applied to low-cost, detonation-derived ND powders where surface carbonyl groups undergo silver-mediated decarboxylation and radical substitution with azide. ND with directly grafted azide groups were then treated with a variety of aliphatic, aromatic, and fluorescent alkynes to afford 1-(ND)-4-substituted-1,2,3-triazole materials under standard copper-catalyzed cycloaddition conditions. Surface modification steps were verified by characteristic infrared absorptions and elemental analyses. High loadings of triazole surface groups (up to 0.85 mmol g-1) were obtained as determined from thermogravimetric analysis. The azidation procedure disclosed is envisioned to become a valuable initial transformation in numerous future applications of ND.

Строение продукта свободно-радикального замещения атома хлора в клатрохелате железа(II) на фрагмент 1,3,5-триоксана

Строение продукта свободно-радикального замещения атома хлора в клатрохелате железа(II) на фрагмент 1,3,5-триоксана

Porphyrins and Phthalocyanines Catalyzed Direct CH Arylation

AbstractCatalytic direct functionalization of unreactive CH bonds represents a sustainable and more atom economical transformation process. Porphyrin and phthalocyanine derivatives show promising catalytic activities in direct CH arylation reactions. These reactions share a common CC bond formation process via homolytic radical substitution. This review summarizes the catalytic direct CH arylation reactions catalyzed by metalloporphyrins, free base porphyrins and free base phthalocyanines.