Radical Cross-coupling Reaction Research Articles

Stabilization of Two Radicals with One Metal: A Stepwise Coupling Model for Copper-Catalyzed Radical\u2013Radical Cross-Coupling

Transition metal-catalyzed radical–radical cross-coupling reactions provide innovative methods for C–C and C–heteroatom bond construction. A theoretical study was performed to reveal the mechanism and selectivity of the copper-catalyzed C–N radical–radical cross-coupling reaction. The concerted coupling pathway, in which a C–N bond is formed through the direct nucleophilic addition of a carbon radical to the nitrogen atom of the Cu(II)–N species, is demonstrated to be kinetically unfavorable. The stepwise coupling pathway, which involves the combination of a carbon radical with a Cu(II)–N species before C–N bond formation, is shown to be probable. Both the Mulliken atomic spin density distribution and frontier molecular orbital analysis on the Cu(II)–N intermediate show that the Cu site is more reactive than that of N; thus, the carbon radical preferentially react with the metal center. The chemoselectivity of the cross-coupling is also explained by the differences in electron compatibility of the carbon radical, the nitrogen radical and the Cu(II)–N intermediate. The higher activation free energy for N–N radical–radical homo-coupling is attributed to the mismatch of Cu(II)–N species with the nitrogen radical because the electrophilicity for both is strong.

KMnO4-mediated direct selective radical cross-coupling: An effective strategy for C2 arylation of quinoline N-oxide with arylboronic acids

Direct CH functionalization of quinoline N-oxides with arylboronic acids is achieved using KMnO4 as the sole and efficient oxidative system. This method provides an efficient protocol to construct regioselectively 2-arylquinoline N-oxides via radical cross-coupling reaction in moderated to good yields under mild conditions.

Metal-Free Difunctionalization of Alkynes with 2-Chlorodithiane for Synthesis of β-Ketodithianes.

Dithianes are versatile umpolung intermediates in organic synthesis but have rarely been employed in radical cross-coupling reactions. Here we describe the oxidative coupling method for alkyne difunctionalization under metal-catalyst-free conditions. The efficient protocol directly affords a variety of β-ketodithianes in good to excellent yields with high regioselectivities. It provides a general pathway for accessing valuable dithianes with controlled formation of a new C-C bond and a C-O bond via a radical coupling pathway.

Radical Chemistry from Diazonium-Terminated Surfaces

Active diazonium groups are attached onto surfaces via oxidative grafting of the 4-phenylacetic diazonium salt. The fraction of the anchored aryldiazonium accessible to (electro)chemical transformation is determined by electrochemical interrogation. Because enough sites are available to react with radical traps, the ability of the aryldiazonium-anchored surfaces to induce radical surface chemistry is tested. Particularly, a new route to grow polymer brushes from surfaces under ATRP conditions is presented. Such an example of a controlled coupling reaction demonstrates how aryldiazoniums, which are irreversible sources of Ar• radicals, can sustain long-term radical cross-coupling reactions. Such a strategy of generating dormant radical sources from diazonium precursors is fruitful to the simple, versatile, and sustainable chemical decoration of materials.

ChemInform Abstract: Potassium tert‐Butoxide Mediated Heck‐Type Cyclization/Isomerization—Benzofurans from Organocatalytic Radical Cross‐Coupling Reactions.

AbstractA transition metal‐free Heck‐type cyclization/isomerization reaction mediated by KOtBu and phenanthroline is described.

Potassium tert-butoxide mediated Heck-type cyclization/isomerization–benzofurans from organocatalytic radical cross-coupling reactions

A transition metal-free Heck-type cyclization/isomerization reaction has been developed. Mediated by potassium tert-butoxide and phenanthroline a variety of benzofuran derivatives have been synthesized.

Hydroxycinnamates in lignification

Hydroxycinnamates incorporate into lignins by various mechanisms. The polysaccharide esters of ferulate, in particular, and the range of dehydrodiferulates and higher oligomers in grasses, participate in free-radical (cross-)coupling reactions during lignification to become integrally bound into the lignin polymer, resulting in extensive cross-linking between lignins and polysaccharides. Monolignol-hydroxycinnamate (primarily monolignol-p-coumarate) conjugates are primary building blocks for lignins, again in grasses (but analogously with monolignol acetates and p-hydroxybenzoates in other plants); radical coupling reactions of the monolignol moiety of the conjugate result in lignins with pendant p-coumarate units acylating a variety of lignin structures. Recent evidence suggests that even the hydroxycinnamic acids themselves can be monomers in lignification in wild-type and transgenic plants, undergoing radical cross-coupling reactions to incorporate into the polymer with interesting consequences. The compatibility of ferulate, in particular, with lignification suggests that plants able to utilize monolignol-ferulate conjugates in their primary monomer supply will be particularly well suited for subsequent chemical delignification, potentially improving processes for biomass conversion to biofuels, and for chemical pulping.

Synthesis of Heterotelechelic Polymers for Conjugation of Two Different Proteins.

In this report we describe a straightforward approach to synthesize polymers with end-groups that bind site-specifically to two different proteins. Telechelic biotin, maleimide poly(N-isopropylacrylamide) (pNIPAAm) was synthesized for the formation of streptavidin (SAv)-bovine serum albumin (BSA) polymer conjugates. Reversible addition-fragmentation chain transfer (RAFT) polymerization of NIPAAm was conducted in the presence of biotinylated chain transfer agents (CTAs) with either ester or amide linkages, and the resultant α-biotinylated pNIPAAm were formed with low polydispersity indices (PDI ≤ 1.09). UV-Vis analysis of the trithiocarbonate chain-ends indicated 88% or greater retention of the group. A maleimide was introduced to the ω chain-end via a radical cross-coupling reaction with a functionalized azo-initiator. The polymer structures were characterized by 1H NMR spectroscopy and gel permeation chromatography (GPC). The resultant biotin-maleimide heterotelechelic polymer was used to form a SAv-BSA heterodimer conjugate. Bioconjugate formation was confirmed by gel electrophoresis.

Comparative toxicities of putative phagocyte-generated oxidizing radicals toward a bacterium ( Escherichia coli) and a yeast ( Saccharomyces cerevisiae)

Toxicities of the radiolytically generated oxidizing radicals HO , CO 3 − a, and NO 2 toward suspension cultures of a bacterium ( Escherichia coli) and a yeast ( Saccharomyces cerevisiae) were examined. As demonstrated by the absence of protection from the membrane-impermeable HO scavenger polyethylene glycol (PEG), externally generated HO was not bactericidal under these conditions; however, partial protection by PEG was observed for S. cerevisiae, indicating the presence of a fungicidal pathway involving external HO . For both organisms, conversion of external HO to the secondary radical, CO 3 − , by reaction with HCO 3 − increases their susceptibility to radiolytic killing. In contrast, externally generated NO 2 exhibited toxicity comparable to that of CO 3 − toward E. coli, but completely blocked the extracellular toxicity of HO toward S. cerevisiae. Cogeneration of equal fluxes of NO 2 − and either HO or CO 3 − also essentially eliminated the extracellular microbicidal reactions. This behavior is consistent with expectations based upon relative rates of radical–radical self-coupling and cross-coupling reactions. The different patterns of toxicity observed imply fundamentally different microbicidal mechanisms for the two organisms, wherein the bacterium is susceptible to killing by oxidation of highly reactive targets on its cellular envelope but, despite undergoing similar oxidative insult, the fungus is not.

Heterobimetallic Reductive Cross-Coupling of Benzonitrile with Carbon Dioxide, Pyridine, and Benzophenone

Described herein are heterobimetallic radical cross-coupling reactions between the benzonitrile adduct of the molybdenum(III) complex Mo(N[t-Bu]Ar)3 (Ar = 3,5-C6H3Me2) and titanium(III) complexes with carbon dioxide, pyridine, and benzophenone. The titanium(III) system employed was either Ti(N[t-Bu]Ar)3 (Ar = 3,5-C6H3Me2) or Ti(N[t-Bu]Ph)3. Crystal structure studies are described for the Mo/PhCN/CO2/Ti coupled system and for an analogue of the Mo/PhCN/Ph2CO/Ti coupled system in which PhCN is replaced with 2,6-Me2C6H3CN. In the case of the couplings involving pyridine and benzophenone, C-C bond formation takes place with dearomatization, with the new C-C bond being formed between the nitrile carbon of PhCN and the para carbon of pyridine or one of the benzophenone phenyl groups. Of the radical metal complex/substrate adducts invoked in this work, that between titanium(III) and CO2 is the only one not directly observable. In all cases, the selective cross-coupling reactions are interpreted as arising by heterodimerization of titanium(III) substrate complexes (substrate = CO2, py, or Ph2CO) with the persistent molybdenum-PhCN radical adduct. All of the heterobimetallic coupling products are diamagnetic, and the metal ions Ti and Mo in them both are assigned to the formal 4+ oxidation state.

Enantioselective Radical Cross-Coupling Reactions of Silyl Enol Ethers Using Chiral Oxovanadium

Abstract Asymmetric induction was observed in radical cross-coupling reactions of silyl enol ethers using chiral oxovanadium generated in situ from 8-phenylmenthol and vanadium oxytrichloride in the presence of MS4A (molecular sieves-4A).

Cobalt-catalyzed tandem radical cyclization and cross-coupling reaction: its application to benzyl-substituted heterocycles.

Cobalt-catalyzed tandem radical cyclization and cross-coupling reaction: its application to benzyl-substituted heterocycles.

Lignin–ferulate cross-links in grasses. Part 4.1–3 Incorporation of 5–5-coupled dehydrodiferulate into synthetic lignin

Ferulates and dehydrodiferulates have a significant role in cross-linking polysaccharides to lignin in grass cell walls. Among the various ferulate dehydrodimers, the 5–5-coupled dehydrodimer (E,E)-4,4′-dihydroxy-3,3′-dimethoxy-5,5 ′-bicinnamate is capable of the most extensive cross-linking into lignin, forming major branch-points. However, current literature fails to recognise the role of radical cross-coupling reactions with lignin monomers/oligomers. Here we demonstrate that a synthetic model for 5–5-coupled dehydrodiferulate polysaccharide esters in grass cell walls biomimetically incorporates into synthetic lignins via radical coupling mechanisms to produce a range of cross-coupled structures. The incorporation profile is remarkably similar to that for ferulate. Importantly, significant coupling at the cinnamoyl 8-position readily occurs. Evidence for the expected incorporation of the 5–5-coupled dehydrodiferulate into the newly discovered dibenzodioxocine structures is readily apparent in HMQC or HSQC spectra. Since some of the structures that dehydrodiferulates are involved in cannot be hydrolytically cleaved, their current ‘quantification’ is a significant underestimation of the importance of these species. What is clear is that dehydrodiferulates can have a powerful role in effecting lignin–polysaccharide cross-linking.

Lignin-ferulate cross-links in grasses: active incorporation of ferulate polysaccharide esters into ryegrass lignins

Active incorporation of ferulate polysaccharide esters into ryegrass lignins has been demonstrated by NMR spectroscopy of uniformly 13C-labeled ryegrass. Observation, in the HMBC spectrum, of products of ferulate at its 8-position coupling with hydroxycinnamyl alcohols at the β-position (producing 8-β′-linked structures) is proof that ferulate-lignin radical cross-coupling reactions occur in vivo. Correlations of H-α′ (hydroxycinnamyl alcohol moiety) with guaiacyl and syringyl 1-, 2-, and 6-aromatic carbons in 8-β′ structures indicates that ferulates couple with both coniferyl and sinapyl alcohol monomers. As notable as the presence of this and other ferulate products is the absence of coupling of ferulate at its 8-position with the 5- and O-4-positions of lignin units. Such structures were significant when ferulate was biomimetically incorporated into a synthetic lignin. Since hydroxycinnamyl alcohols couple almost exclusively at their β-position in cross-coupling reactions, the 8-5′ and 8- O-4′ structures would only be formed by coupling with higher lignin oligomers (with no side-chain conjugation). Exclusive reaction of ferulates with lignin monomers is the first real evidence that ferulate polysaccharide esters in grasses are acting as initiation or nucleation sites for lignification and are critical entities in directing cell-wall cross-linking during plant growth and development.