Radical Substitution Research Articles

Green One-Pot Syntheses of 2-Sulfoximidoyl-3,6-dibromo Indoles Using N-Br Sulfoximines as Both Brominating and Sulfoximinating Reagents.

A green one-pot 2,3,6-trifunctionalization of N-alkyl/aryl indoles was achieved by adding three equivalents of N-Br sulfoximine to the indole solution. A variety of 2-sulfoximidoyl-3,6-dibromo indoles were prepared with 38-94% yields using N-Br sulfoximines as both brominating and sulfoximinating reagents. Based on the results of controlled experiments, we propose that a radical substitution involving 3,6-dibromination and 2-sulfoximination occurs in the reaction process. This is first time that 2,3,6-trifunctionalization of indole in one pot has been achieved.

Interactive Organic Reaction Trajectory Animation iPhone Application (iORA) and Web Site (webORA)

Organic reaction trajectories show atomic motion and molecular reorganization of reactants during a single product-forming collision. iORA is a free (available from the Apple App Store), easy to use, highly interactive iPhone application that provides on-the-fly 3D rendering of organic reaction trajectories calculated with density functional theory (DFT) direct dynamics simulations. Visualization of trajectories using iORA enables qualitative and quantitative learning about organic reaction pathways. iORA users can interactively zoom, rotate, and translate the reaction animations. Users can track distances, angles, and dihedral angles. Other iORA features include buttons to jump to the transition state, control the animation speed, and 3D image display. Currently available reaction classes include Bronsted acid–base, alkyl substitution, alkene addition, alkyne addition, diene addition, rearrangement, oxidation, reduction, carbonyl addition, radical, pericyclic, and aromatic substitution. WebORA is a web-based site that also displays interactive DFT-based organic reaction trajectory simulations from these reaction classes. It can be used by all web browsers and operating systems. iORA and webORA also offer brief trajectory descriptions.

Interplay of diruthenium catalyst in controlling enantioselective propargylic substitution reactions with visible light-generated alkyl radicals

Transition metal-catalyzed enantioselective free radical substitution reactions have recently attracted attention as convenient and important building tools in synthetic chemistry, although construction of stereogenic carbon centers at the propargylic position of propargylic alcohols by reactions with free radicals remains unchallenged. Here we present a strategy to control enantioselective propargylic substitution reactions with alkyl radicals under photoredox conditions by applying dual photoredox and diruthenium catalytic system, where the photoredox catalyst generates alkyl radicals from 4-alkyl-1,4-dihydropyridines, and the diruthenium core with a chiral ligand traps propargylic alcohols and alkyl radicals to guide enantioselective alkylation at the propargylic position, leading to high yields of propargylic alkylated products containing a quaternary stereogenic carbon center at the propargylic position with a high enantioselectivity. The result described in this paper provides the successful example of transition metal-catalyzed enantioselective propargylic substitution reactions with free alkyl radicals.

Characteristics of TOC Treatment for Industrial Wastewater Treatment -Characteristics of Industrial Wastewater TOC Treatment Status and TOC Treatment by Ozone and Advanced Oxidation Process-

Objectives:As the organic pollutant indicator is changed from COD<sub>Mn</sub> to TOC and the demand for TOC treatment of industrial wastewater increasing, the current situation of TOC treatment of wastewater discharge facilities of each industrial category is analyzed, and it is intended to consider the possibility of residual TOC treatment by ozone and advanced oxidation process.Methods:To review the TOC treatment situations of wastewater discharge facilities of each industrial category, the field survey data (46 sites) by Environment Ministry and Korea Environment Corporation were analyzed according to inflow TOC concentrations, direct/indirect discharge type, and main treatment process of wastewater treatment facilities. To review the characteristics of TOC treatment by ozone and advanced oxidation processes, previous studies and the results of field pilot tests conducted by ozone companies were comprehensively analyzed.Results and Discussion:The TOC treatment level varies depending on the inflow TOC concentrations to each industrial wastewater treatment facility, direct/indirect discharge type depending on the location of the wastewater treatment facilities, and the main treatment process of the wastewater treatment facility. In particular, the TOC removal rate differed by more than 20% depending on the presence or absence of biological treatment. The wastewater treatment facilities that require additional treatment of residual TOC were divided as follows (1) when the facility has biological treatment as main process, increasing unexpected inflow TOC load in treatment facilities or the condition of the biological treatment become worsen. (2) when the facility has phy-chemical treatment as main process, increasing unexpected inflow TOC load. (3) extending the replacement cycle of activated carbon to save maintenance cost. The advance oxidation process decomposes easily by OH radicals through the radical substitution of unsaturated hydrocarbons and aromatic compounds, so the removal rate of TOC by the O<sub>3</sub>+H<sub>2</sub>O<sub>2</sub> advanced oxidation pilot test was 14.7~93.5%, higher than that of ozone oxidation. The specific ozone consumption per TOC removal amount (O<sub>3</sub>/ΔTOC) by O<sub>3</sub>+H<sub>2</sub>O<sub>2</sub> advanced oxidation is 8.5~22.5mgO<sub>3</sub>/mgTOC, which is 1/5 of that of ozone oxidation only. In addition, comparing ozone demand by COD<sub>Mn</sub> and TOC removal, ozone demand of O<sub>3</sub>+H<sub>2</sub>O<sub>2</sub> advanced oxidation to remove TOC is 2.7 to 4.3 times compared to that by O<sub>3</sub> oxidation to remove COD<sub>Mn</sub>.Conclusion:In order to reduce residual TOC from industrial wastewater effluent, it is necessary to secure stability of the existing main treatment process in preparation for load fluctuations, and the technologies research on complex advanced oxidation processes, hybrid advanced oxidation processes, and pretreatment technology to reduce ozone demand is needed for economical field application.

A reductive Sandmeyer-type reaction for the synthesis of sulfoxides from anilines under photocatalysis

A reductive Sandmeyer-type sulfinylation reaction of aryldiazonium salts with sodium sulfinates is reported, affording a range of valuable sulfoxides in a radical substitution pathway.

Dense 1,2,4,5-tetramethylimidazolium-functionlized anion exchange membranes based on poly(aryl ether sulfone)s with high alkaline stability for water electrolysis

Anion exchange membranes with enough alkaline stability and ionic conductivity are essential for water electrolysis. In this work, a class of anion exchange membranes (PAES-TMI-x) with dense 1,2,4,5-tetramethylimidazolium side chains based on poly(aryl ether sulfone)s are prepared by aromatic nucleophilic polycondensation, radical substitution and Menshutkin reaction. Their chemical structure and hydrophilic/hydrophobic phase morphology are characterized by hydrogen nuclear magnetic resonance (1H NMR) and atomic force microscope (AFM), respectively. The water uptake, swelling ratio and ionic conductivity for PAES-TMI-x are in the range of 23.8%–48.3%, 8.3%–14.3% and 18.22–96.31 mS/cm, respectively. These AEMs exhibit high alkaline stability, and the ionic conductivity for PAES-TMI-0.25 remains 86.8% after soaking in 2 M NaOH solution at 80 °C for 480 h. The current density of 1205 mA/cm2 is obtained for the water electrolyzer equipped with PAES-TMI-0.25 in 2 M NaOH solution at 2.0 V and 80 °C, and the electrolyzer also has good operation stability at current density of 500 mA/cm2. This work is expected to provide a valuable reference for the selection and design of cations in high-performance AEMs for water electrolysis.

Mixed bromine/chlorine transformation products of tetrabromobisphenol A formed in the combustion of printed circuit boards: Emission characteristics and transformation pathways

Recently, mixed bromine/chlorine transformation products of tetrabromobisphenol A (ClyBrxBPAs) were found to be possibly related to the thermal treatment processes of electronic wastes. To explore their emission characteristics and formation mechanism, printed circuit board scraps were combusted in a tube furnace, under the temperature from 25 °C to 600 °C. The emission factor of the debromination products of tetrabromobisphenol A (BrxBPAs) was the highest, whereas that of ClyBrxBPAs was the lowest. Among three phases, most of the target compounds were partitioned into the oil and particle phases, and only negligible gaseous 2-BrBPA and bisphenol A were detected. The emission rates of most compounds were fastest at 300 °C, although 2-BrBPA, 2,6-Br2BPA, and 2-Cl-6-BrBPA peaked at 350 °C. Among the chemicals in total emission, 2-BrBPA was the dominant congener in BrxBPAs, whereas 2-Cl-2′,6,6′-Br3BPA, 2-Cl-2′,6#-Br2BPA, and Σ2Cl1Br1BPAs shared similar proportions in ClyBrxBPAs. Meanwhile, the composition profiles at 300 °C showed that 2,2′,6-Br3BPA and 2-Cl-2′,6,6′-Br3BPA occupied the largest proportions in BrxBPAs and ClyBrxBPAs, respectively. To reveal the possible transformation pathways, the Gibbs free energy was calculated based on a radical substitution reaction. After “•Br” removal from tetrabromobisphenol A or other BrxBPAs, the intermediate was more easily combined with “•H” than with “•Cl.” In addition, the ClyBrxBPA formation via “–•H + •Cl” by BrxBPAs is nonspontaneous, thus limiting the further generation of ClyBrxBPAs. This study not only provides ideas for the study of other mixed halogenated products, but also provides constructive suggestions for environmental source analysis by combining previous research on the occurrence of ClyBrxBPAs in various environmental matrices.

Light-Promoted Dearylation of Perfluorinated Aryl Sulfides with N-Heterocyclic Carbene-Borane.

The removal of the tetrafluoropyridinyl group tethered to a sulfur atom using a complex of N-heterocyclic carbene (NHC) with borane is described. The reaction is performed under blue light irradiation with a disulfide as radical initiator. The selective cleavage of S-Ar in preference to the weaker S-Alk bond is achieved as a result of aromatic radical substitution of the thiyl group by a NHC-stabilized boron-centered radical. Alkyl thiols, which are the primary products of the dearylation, are in situ oxidized or alkylated, affording disulfides or sulfides, respectively.

A Single Nucleotide Polymorphism Translates into a Radical Amino Acid Substitution at the Ligand-Binding Site in Fasciola hepatica Carboxylesterase B.

Fasciola hepatica anthelmintic resistance may be associated with the catalytic activity of xenobiotic metabolizing enzymes. The gene expression of one of these enzymes, identified as carboxylesterase B (CestB), was previously described as inducible in adult parasites under anthelmintic treatment and exhibited a single nucleotide polymorphism at position 643 that translates into a radical amino acid substitution at position 215 from Glutamic acid to Lysine. Alphafold 3D models of both allelic sequences exhibited a significant affinity pocket rearrangement and different ligand-docking modeling results. Further bioinformatics analysis confirmed that the radical amino acid substitution is located at the ligand affinity site of the enzyme, affecting its affinity to serine hydrolase inhibitors and preferences for ester ligands. A field genotyping survey from parasite samples obtained from two developmental stages isolated from different host species from Argentina and Mexico exhibited a 37% allele distribution for 215E and a 29% allele distribution for 215K as well as a 34% E/K heterozygous distribution. No linkage to host species or geographic origin was found in any of the allele variants.

Photoinduced degradation of three azole compounds from 3rd EU watchlist monitored by high-resolution higher-order mass spectrometry – Part I: A mechanistic study

• Nine new degradation and transformation products of azoles were identified. • HR-MS and HR-MS/MS revealed structures from hydroxyl radical and photo-absorption induced reactions. • Direct and indirect mechanism of degradation could be discerned. Pesticides are found in water bodies worldwide. Among them, there are azoles which are used as fungizides. Hence, tebuconazole, imazalil and penconazole have been included into the 3 rd EU watchlist to survey their presence in water bodies. Pesticides mostly enter the aquatic environment through leaching from agriculture, fruit washing or via conventional sewage water treatment plants, which are often not able to completely eliminate these pesticides. Advanced purification processes have become intensely researched. The advanced oxidation process, UVC and UVA irradiation and addition of the radical scavenger tert -butanol, was investigated using high-resolution higher-order mass spectrometry to gain kinetic and mechanistic insight. Structure elucidation of degradation and transformation products revealed fragments and also multiple hydroxylated intermediates depending on the UV source and the presence of radical scavenger. Hydroxyl radical-induced indirect degradation was found to dominate a direct photoreaction pathway induced by photo-absorption by the initial substance. The indirect mechanism did not occur during UVA irradiation due to the lack of hydroxyl radicals. The radical scavenger decelerated or prevented degradation. In total, nine new degradation and transformation products were identified. Mass spectrometry revealed product structures of the pesticides substituted with one or more hydroxyl radical groups, cyclization and substitution of chlorine by a hydroxyl radical.

α-Sulfenylation between 4-Hydroxydithiocoumarin and 1,3-Dicarbonyl Compounds: A Key Precursor for the Synthesis of New Pyrazole Derivatives

AbstractAn efficient synthetic protocol for the α-sulfenylation of 1,3-dicarbonyl compounds is reported through a cross dehydrogenative coupling reaction with 4-hydroxydithiocoumarins in the presence of 10 mol% KI and 1 equiv. TBHP in toluene under reflux conditions. Some of the products are utilized for the synthesis of substituted new pyrazole derivatives on reaction with phenylhydrazine in ethanol at room temperature. In addition, α-benzylation is also achieved on treatment with benzyl bromide using K2CO3/CH3CN under mild conditions. The salient features of the present protocol are good yields, mild reaction conditions, shorter reaction time, no byproducts were formed (sulfoxide/sulfone), and no deacylation occurs during the process. In the present protocol, 4-hydroxydithiocoumarin is converted into a suitable electrophile through a radical substitution pathway, which undergoes ultimately C–S bond formation with 1,3-dicarbonyl compounds by a nucleophilic substitution reaction.

Electrochemically driven regioselective C−H phosphorylation of group 8 metallocenes

Metallocenes are privileged backbones for synthesis and catalysis. However, the direct dehydrogenative C−H functionalization of unsymmetric metallocenes suffers from reactivity and selectivity issues. Herein, we report an electrochemically driven regioselective C−H phosphorylation of group 8 metallocenes. Mechanistic investigations indicate this dehydrogenative cross coupling occurs through an electrophilic radical substitution of the metallocene with a phosphoryl radical, facilitated by the metallocene itself. This work not only offers an efficient and divergent synthesis of phosphorylated metallocenes, but also provides a guide to interpret the reactivity and regioselectivity for the C−H functionalization of unsymmetric metallocenes.

Gas-Phase Preparation of Silyl Cyanide (SiH3CN) via a Radical Substitution Mechanism.

The silyl cyanide (SiH3CN) molecule, the simplest representative of a fully saturated silacyanide, was prepared in the gas phase under single-collision conditions via a radical substitution mechanism. The chemical dynamics were direct and revealed a pronounced backward scattering as a consequence of a transition state with a pentacoordinated silicon atom and almost colinear geometry of the attacking cyano radical and leaving hydrogen. Compared to the isovalent cyano (CN)-methane (CH4) system, the CN-SiH4 system dramatically reduces the energy of the transition state to silyl cyanide by nearly 100 kJ mol-1, which reveals a profound effect on the chemical bonding and reaction mechanism. In extreme high-temperature environments including circumstellar envelopes of IRC +10216, this versatile radical substitution mechanism may synthesize organosilicon molecules via reactions of silane with doublet radicals. Overall, this study provides rare insights into the exotic reaction mechanisms of main-group XIV elements in extreme environments and affords deeper insights into fundamental molecular mass growth processes involving silicon in our universe.

Evolutionary changes between pre- and post-vaccine South African group A G2P[4] rotavirus strains, 2003-2017.

The transient upsurge of G2P[4] group A rotavirus (RVA) after Rotarix vaccine introduction in several countries has been a matter of concern. To gain insight into the diversity and evolution of G2P[4] strains in South Africa pre- and post-RVA vaccination introduction, whole-genome sequencing was performed for RVA positive faecal specimens collected between 2003 and 2017 and samples previously sequenced were obtained from GenBank (n=103; 56 pre- and 47 post-vaccine). Pre-vaccine G2 sequences predominantly clustered within sub-lineage IVa-1. In contrast, post-vaccine G2 sequences clustered mainly within sub-lineage IVa-3, whereby a radical amino acid (AA) substitution, S15F, was observed between the two sub-lineages. Pre-vaccine P[4] sequences predominantly segregated within sub-lineage IVa while post-vaccine sequences clustered mostly within sub-lineage IVb, with a radical AA substitution R162G. Both S15F and R162G occurred outside recognised antigenic sites. The AA residue at position 15 is found within the signal sequence domain of Viral Protein 7 (VP7) involved in translocation of VP7 into endoplasmic reticulum during infection process. The 162 AA residue lies within the hemagglutination domain of Viral Protein 4 (VP4) engaged in interaction with sialic acid-containing structure during attachment to the target cell. Free energy change analysis on VP7 indicated accumulation of stable point mutations in both antigenic and non-antigenic regions. The segregation of South African G2P[4] strains into pre- and post-vaccination sub-lineages is likely due to erstwhile hypothesized stepwise lineage/sub-lineage evolution of G2P[4] strains rather than RVA vaccine introduction. Our findings reinforce the need for continuous whole-genome RVA surveillance and investigation of contribution of AA substitutions in understanding the dynamic G2P[4] epidemiology.

Photo-induced catalytic C−H heteroarylation of group 8 metallocenes

Possessing a characteristic sandwich-type structure, metallocenes have been widely used by the chemistry community. However, the direct catalytic C−H heteroarylation of metallocenes still remains underexplored. Here, we report an efficient catalytic protocol for C−H heteroarylation of group 8 metallocenes (M = Fe, Ru) under light irradiation. This intermolecular cross coupling features directing group free, mild conditions and a wide substrate scope. Preliminary mechanistic studies suggest that the newly formed C−C bond is constructed through electrophilic radical substitution of the metallocene with a heteroaryl radical, which is generated via an oxidative quenching pathway.

Photobromination (S<SUB>R</SUB>) and Corresp. S<SUB>N</SUB>1 Reactions – Key Reactions for the Development and the Application of the Concept of Hyperconjugation

This article first describes photochemical bromination reactions of two different reactants proceeding via electron septet intermediates according to the radical substitution reaction mechanism (SR). The case comparison is intended to enable learners – high school or university first-year organic chemistry students – to work out the concept of hyperconjugation, which is very significant for organic chemistry, by intertwining experimental results and theoretical interpretation (of free radical intermediates) closely. Since students often do not succeed in transferring concepts they have already learned from one mechanism to another, the second step will be to transfer and apply the concept of hyperconjugation to carbenium ions as reactive intermediates by means of an analogous experimental case comparison of first-order nucleophilic substitution reactions (SN1).

New Catalytic Radical Process Involving 1,4-Hydrogen Atom Abstraction: Asymmetric Construction of Cyclobutanones.

While alkyl radicals have been well demonstrated to undergo both 1,5- and 1,6-hydrogen atom abstraction (HAA) reactions, 1,4-HAA is typically a challenging process both entropically and enthalpically. Consequently, chemical transformations based on 1,4-HAA have been scarcely developed. Guided by the general mechanistic principles of metalloradical catalysis (MRC), 1,4-HAA has been successfully incorporated as a key step, followed by 4-exo-tet radical substitution (RS), for the development of a new catalytic radical process that enables asymmetric 1,4-C-H alkylation of diazoketones for stereoselective construction of cyclobutanone structures. The key to success is the optimization of the Co(II)-based metalloradical catalyst through judicious modulation of D2-symmetric chiral amidoporphyrin ligand to adopt proper steric, electronic, and chiral environments that can utilize a network of noncovalent attractive interactions for effective activation of the substrate and subsequent radical intermediates. Supported by an optimal chiral ligand, the Co(II)-based metalloradical system, which operates under mild conditions, is capable of 1,4-C-H alkylation of α-aryldiazoketones with varied electronic and steric properties to construct chiral α,β-disubstituted cyclobutanones in good to high yields with high diastereoselectivities and enantioselectivities, generating dinitrogen as the only byproduct. Combined computational and experimental studies have shed light on the mechanistic details of the new catalytic radical process, including the revelation of facile 1,4-HAA and 4-exo-tet-RS steps. The resulting enantioenriched α,β-disubstituted cyclobutanones, as showcased with several enantiospecific transformations to other types of cyclic structures, may find useful applications in stereoselective organic synthesis.

Front Cover: Synthesis of Difluoroglycine Derivatives from Amines, Difluorocarbene, and CO2: Computational Design, Scope, and Applications (Chem. Eur. J. 39/2021)

An Artificial Force Induced Reaction (AFIR) on a super computer has led to a new three-component reaction (3CR) of amines, difluorocarbene, and the inexpensive and non-toxic C1 source CO2. This reaction produces a broad range of α,α-difluoroglycine derivatives that are bioisosteres of natural glycine. The versatility of these products is very broad; i.e., they can be used as new difluorocarbene sources, substrates for radical substitution reactions, and precursors for new NHC ligands. More information can be found in the Full Paper by S. Maeda, T. Mita et al. (DOI: 10.1002/chem.202100812).

Synthesis of Difluoroglycine Derivatives from Amines, Difluorocarbene, and CO2: Computational Design, Scope, and Applications

A three-component reaction (3CR) for the synthesis of difluoroglycine derivatives has been achieved using amines, difluorocarbene (generated in situ ), and the abundant, inexpensive, and non-toxic C1 source CO 2 . Various tert -amines and pyridine, (iso)quinoline, imidazole, thiazole, and pyrazole derivatives were incorporated, and the corresponding products were isolated in solid form without purification using column chromatography on silica gel. Detailed reaction profiles of the 3CR were obtained via computational analysis using DFT calculations, and the results critically suggest that simple ammonia is not applicable to this reaction. In addition, strongly supported by computational predictions, a new reagent that can generate difluorocarbene at 0 °C without any additives was discovered. Furthermore, radical substitution reactions of the obtained difluoroglycine derivatives under photoredox conditions, as well as a synthetic application as an N -heterocyclic carbene ligand are shown.

Advancing chemical kinetic modeling

Chemical Engineering Quantitative prediction of the time evolution of chemical mixtures is the central problem of reactive chemical engineering. This is a challenging task because of the thousands of elementary chemical reactions that must be considered in chemical kinetic modeling. Usually, such models are developed and refined gradually over many years. Using broadband rotational spectroscopy, combined with automated ab initio transition state theory–based master equation calculations and high-level thermochemical parametrization, Zaleski et al. reveal an important role of a variety of radical substitution reactions in the flash pyrolysis of acetone that was previously omitted in the corresponding combustion mechanisms. Their unified combination of modeling, experiment, and theory is a promising approach in the development of comprehensive chemical kinetic models. J. Am. Chem. Soc. 143 , 3124 (2021).