Radical Precursors Research Articles

Radical Replacement Process for Ligated Boryl Radical-Mediated Activation of Unactivated Alkyl Chlorides for C(sp3)-C(sp3) Bond Formation.

The ligated boryl radical (LBR) has emerged as a potent tool for activating alkyl halides in radical transformations through halogen-atom transfer (XAT). However, unactivated alkyl chlorides still present an open challenge for this strategy. We herein describe a new activation mode of the LBR for the activation of unactivated alkyl chlorides to construct a C(sp3)-C(sp3) bond. Mechanistic studies reveal that the success of the protocol relies on a radical replacement process between the LBR and unactivated alkyl chloride, forming an alkyl borane intermediate as the alkyl radical precursor. Aided with the additive K3PO4, the alkyl borane then undergoes one-electron oxidation, generating an alkyl radical. The incorporation of the radical replacement activation model to activate unactivated alkyl chlorides significantly enriches LBR chemistry, which has been applied to activate alkyl iodides, alkyl bromides, and activated alkyl chlorides via XAT.

Emerging Advances of the Radical Pathway Glycosylation Enabled by Bench‐Stable Glycosyl Donors: Glycosyl Sulfoxides, Glycosyl Sulfones, and Glycosyl Sulfinates

AbstractIn synthetic carbohydrate chemistry, the modification of glycosyl radicals pathway stands as a central area of focus. The radical‐based reactions often demonstrate remarkable compatibility with various functional groups owing to the mild initiation conditions. In particular, the identification of novel glycosyl radical precursors, combined with advanced reaction techniques, has substantially broadened the scope of glycosyl compound synthesis. Despite the presence of versatile donors, the synthesis of noble donors is still addressed as a synthetic need and challenges associated with sugar chemistry. Currently, a new class of glycosyl radical precursors has been developed which enables the production of C‐, S‐, O‐, and N‐glycosides efficiently. In this light, we highlight strategies towards bench‐stable glycosyl sulfoxides, sulphone, and sulfite donors that can enable the site‐, regio‐ and stereoselective transformation of protected or naked sugar synthons in synthetic carbohydrate chemistry. Here, this review article covers the recent developments in the selective glycosyl radical diversification such as glycosyl alkylation, arylation, alkenylation, sulfuration, C−H activation, and DNA conjugation via the bench‐stable donors along with mechanistic aspects, challenges, and future directions.

A facile access to aliphatic trifluoromethyl ketones via photocatalyzed cross-coupling of bromotrifluoroacetone and alkenes.

Biological molecules incorporating trifluoromethyl ketones (TFMKs) have emerged as reversible covalent inhibitors, aiding in the management and treatment of inflammatory diseases, cancer, and respiratory conditions. TFMKs, renowned for their versatile binding properties and adaptability, are pivotal in the rational design of novel drugs for diverse diseases. The photocatalytic insertion of alkenes, abundant feedstocks, into the α-carbon of trifluoromethylacetone represents a highly effective and atom-economical method for synthesizing valuable TFMKs. However, these processes typically necessitate high-energy photoirradiation (λ > 300 nm, Hg lamp) and stoichiometric oxidants to generate the acetonyl radical from acetone. In our study, we demonstrate the visible-light photocatalytic radical addition into olefins using bromotrifluoroacetone as the trifluoroacetonyl radical precursor under mild conditions. Aliphatic trifluoromethyl ketones or the corresponding bromo-substituted products can be obtained by selecting an appropriate photocatalyst and solvent. Comprehensive experimental investigations, including cyclic voltammetry, Stern-Volmer quenching studies, and kinetic isotope effects, corroborate the synthesis of trifluoroacetonyl radical species from bromotrifluoroacetone under photoredox conditions. Further, we demonstrate the efficient synthesis of an oseltamivir derivative bearing a trifluoromethylketone moiety, which shows promising biological activity. Hence, this methodology will streamline the direct introduction of trifluoromethyl ketone into biological target molecules during drug discovery.

Stereospecific radical coupling with a non-natural photodecarboxylase.

Photoenzymes are light-powered biocatalysts that typically rely on the excitation of cofactors or unnatural amino acids for their catalytic activities1,2. A notable natural example is the fatty acid photodecarboxylase (FAP), which uses light energy to convert aliphatic carboxylic acids to achiral hydrocarbons3. Here, we report a way to design a non-natural photodecarboxylase based on the excitation of enzyme-bound catalytic intermediates, instead of relying on cofactor excitation4. Iminium ions5, transiently generated from enals within the active site of an engineered class I aldolase6, can absorb violet light and function as single-electron oxidants. Activation of chiral carboxylic acids, followed by decarboxylation, generates two radicals that undergo stereospecific cross-coupling, yielding products with two stereocenters. Using the appropriate enantiopure chiral substrate, the desired diastereoisomeric product is selectively obtained with complete enantiocontrol. This finding underscores the active site's ability to transfer stereochemical information from the chiral radical precursor into the product, effectively addressing the longstanding problem of rapid racemization of chiral radicals. The resulting 'memory of chirality' scenario7 is a rarity in enantioselective radical chemistry.

Interlayer synergistic reaction of radical precursors for ultraefficient 1O2 generation via quinone-based covalent organic framework

Singlet oxygen (1O2) is important in the environmental remediation field, however, its efficient production has been severely hindered by the ultrafast self-quenching of the as-generated radical precursors in the Fenton-like reactions. Herein, we elaborately designed lamellar anthraquinone-based covalent organic frameworks (DAQ-COF) with sequential localization of the active sites (C═O) at molecular levels for visible-light-assisted peroxymonosulfate (PMS) activation. Theoretical and experimental results revealed that the radical precursors (SO5·-) were formed in the nearby layers with the migration distance less than 0.34 nm, via PMS donating electrons to the photogenerated holes. This interlayer synergistic effect eventually led to ultraefficient 1O2 production (14.8 μM s-1), which is 12 times that of the highest reported catalyst. As an outcome, DAQ-COF enabled the complete degradation of bisphenol A in 5 min with PMS under natural sunlight irradiation. This interlayer synergistic concept represents an innovative and effective strategy to increase the utilization efficiency of ultrashort-lived radical precursors, providing inspirations for subtle structural construction of Fenton-like catalysts.

Radical-triggered translocation of C-C double bond and functional group.

Multi-site functionalization of molecules provides a potent approach to accessing intricate compounds. However, simultaneous functionalization of the reactive site and the inert remote C(sp3)-H poses a formidable challenge, as chemical reactions conventionally occur at the most active site. In addition, achieving precise control over site selectivity for remote C(sp3)-H activation presents an additional hurdle. Here we report an alternative modular method for alkene difunctionalization, encompassing radical-triggered translocation of functional groups and remote C(sp3)-H desaturation via photo/cobalt dual catalysis. By systematically combining radical addition, functional group migration and cobalt-promoted hydrogen atom transfer, we successfully effectuate the translocation of the carbon-carbon double bond and another functional group with precise site selectivity and remarkable E/Z selectivity. This redox-neutral approach shows good compatibility with diverse fluoroalkyl and sulfonyl radical precursors, enabling the migration of benzoyloxy, acetoxy, formyl, cyano and heteroaryl groups. This protocol offers a resolution for the simultaneous transformation of manifold sites.

Bidirectional Electron Transfer Strategies for Anti-Markovnikov Olefin Aminofunctionalization via Arylamine Radicals.

Arylamines are common structural motifs in pharmaceuticals, natural products, and materials precursors. While olefin aminofunctionalization chemistry can provide entry to arylamines, classical polar reactions typically afford Markovnikov products. Nitrogen-centered radical intermediates provide the opportunity to access anti-Markovnikov selectivity; however, anti-Markovnikov arylamination is unknown in large part due to the lack of arylamine radical precursors. Here, we introduce bidirectional electron transfer processes to generate arylamine radical intermediates from N-pyridinium arylamines: Single-electron oxidation provides arylamine radicals that engage in anti-Markovnikov olefin aminopyridylation; single-electron reduction unveils arylamine radicals that engage in anti-Markovnikov olefin aminofunctionalization. The development of bidirectional redox processes complements classical design principles for radical precursors, which typically function via a single redox manifold. Demonstration of both oxidative and reductive mechanisms to generate arylamine radicals from a common N-aminopyridinium precursor provides complementary methods to rapidly construct and diversify arylamine scaffolds from readily available radical precursors.

Intracluster reaction dynamics of NO+(H2O)n.

Nitric oxide (NO) and NO-water clusters play crucial roles in the D-region of the atmosphere because it is postulated that NO+ reacts with H2O to produce nitrous acid (HONO) and H3O+. HONO is the major precursor of the hydroxyl radicals leading to the formation of secondary pollutants. The sources of atmospheric HONO, however, are not fully understood. Previously, the sequential H2O addition reaction, H2O + NO+(H2O)n, and the bi-molecular collision reaction, NO+ + (H2O)n, have been investigated by both experiments and theoretical calculations to determine the formation mechanism of HONO. However, the photo-reactions from NO(H2O)n neutral clusters were not considered for the formation mechanism of HONO. In this study, the intra-cluster reactions of NO+(H2O)n clusters, following ionization of the parent neutral cluster of NO(H2O)n, were investigated using the direct abinitio molecular dynamics method. When n = 4, [NO+(H2O)4]ver [vertical ionization state of NO(H2O)n] yielded HONO and hydrated H3O+ after the intra-cluster reaction, and the reaction time was calculated to be 150fs. The reaction is expressed as [NO+(H2O)n]ver → HONO + H3O+(H2O)n-2 (reactive) (n > 3). Larger clusters of [NO+(H2O)n]ver (n = 5-8) also yield HONO. In contrast, in smaller clusters (n = 1-3), only solvent re-orientation around NO+ occurred after the ionization: [NO+(H2O)n]ver → NO+(H2O)n (solvent re-orientation) (n = 1-3). The hydration energy of H3O+, which depends on the cluster size (n), plays an important role in promoting the formation of HONO. The reaction mechanism is discussed based on theoretical results.

Exploration of radical chemistry, precursor sensitivity and O3 control strategies in a provincial capital city, northwestern China

As the core city in northwestern China, Xi'an has suffered from serious O3 pollution in recent years. An observational model, coupled with the Master Chemical Mechanism (V3.3.1) and comprehensive data, analyzed atmospheric oxidation capacity (AOC), O3 formation mechanism, precursor sensitivity and control strategies in Xi'an. The study examined two periods (period I and II), with notable temperature and humidity differences. Despite lower precursor levels in period I, an O3 episode (peak value: 102.68 ppb) occurred only in period I, highlighting the crucial influence of meteorological conditions. Higher removal rate of primary pollutants occurs in period I, but meteorological conditions may not alter the dominant factor of AOC. Period I exhibited markedly high OH reactivity, with aromatics, alkenes, and NOx being the main contributors. HONO photolysis (50.78%) in the morning and O3 photolysis (34.13%) in the afternoon were the main HOx sources in period I, while HONO photolysis (62.86–80.68%) was significant at daytime for period II. Higher temperatures in period I accelerated all reaction rates involved in radical cycling, especially emphasizing RO2 + NO → RO + NO2. The results of sensitivity analysis showed that O3 sensitivity regime is VOC-limited in Xi'an, but the specific reactive species target VOC reductions emissions exhibited discrepancies for two distinct periods. A 20% decrease in VOCs and a 50% decrease in NOx (VOCs/NOx = 0.4) was proposed to be the optimal solution to achieve the O3 control target in period I. This study enhances our understanding of O3 formation under different meteorological conditions and provides scientific evidence for O3 pollution abatement policies in northwestern China, with potential applicability to other cities in this region and similar countries.

Recent Advances in Photoinduced Borylation via N-Heterocyclic Carbene Boryl Radicals

Organoboron compounds, recognized as essential synthetic intermediates in organic chemistry, have found broad applications in pharmaceutical and materials science. In recent years, the development of novel boronating reagents has opened new avenues for the synthesis of organoboron. Among these, NHC–boranes, with their unique advantages, have garnered sustained interest and have evolved into significant precursors for boron-centered radicals, participating in a diverse array of visible light-induced borylation reactions. This article primarily focuses on the visible light-induced radical borylation reactions involving NHC–boranes, summarizing the latest advancements in the field, and offering inspiration for subsequent research.

Relative humidity driven nocturnal HONO formation mechanism in autumn haze events of Beijing

Nitrous acid (HONO), a key precursor of hydroxyl radicals (OH), is one of the factors affecting atmospheric chemistry and air quality. Currently, the proposed sources of HONO are not able to fully explain observed HONO concentrations. In this study, a comprehensive field observation of HONO was conducted in the autumn of 2021 in urban Beijing. The box model using a default Master Chemical Mechanism (MCM) was unable to reproduce the observed HONO concentrations with a normalized mean bias (NMB) of −92.8%. The NMB improved to −46.1% after the inclusion of seven additional HONO formation pathways. Several factors like vehicle emission factor (1.23%) and nocturnal NO2 heterogeneous uptake coefficient on the ground surface (8.25 × 10−6) were calculated based on observational data. The enhancement factor for nocturnal NO2 heterogeneous conversion was established as a function of relative humidity (RH) and incorporated into the model, which compensated for the missing nocturnal HONO sources and well-reproduced the observed HONO concentrations, with an NMB of −5.1%. The major source of HONO at night was found to be the heterogeneous reaction of NO2 on the ground surface, contributing up to 85.6%. During the daytime, it was the homogeneous reaction of NO with OH, accounting for 41.8%. The daytime primary source of OH was mainly the photolysis of HONO, which constituted 73.6% and therefore promoted the formation of secondary pollutants and exacerbated haze events.

Radical Difunctionalization of Unsaturated Hydrocarbons Employing the Same Functional Reagent

AbstractThe radical difunctionalization of unsaturated hydrocarbons serves as an efficient means to rapidly construct molecular skeletons and synthesize‐highly valuable compounds. In this transformational process, diverse positions within unsaturated hydrocarbons are sequentially functionalized by a single radical precursor reagent, thereby achieving highly efficient and selective transformations that promote atom economy. Furthermore, this approach minimizes the generation of numerous byproducts stemming from cross‐coupling reactions between reactants, owing to the reduction of the number of participating components. Therefore, this review provides an in‐depth analysis of the radical difunctionalization of unsaturated hydrocarbons utilizing a single functional reagent in recent decades. The discussion is based on eight different radical classes (carbon‐, nitrogen‐, phosphine‐, oxygen‐, sulfur‐, selenium‐, tellurium‐, and chlorine‐centered radicals), emphasizing the mechanism of specific radical difunctionalization. It also analyzes in detail the regulation of key factors such as regional selectivity, and provides unique insights into reaction transformations.

Synthesis and Suzuki-Miyaura Cross-Coupling of Alkyl Amine-Boranes. A Boryl Radical-Enabled Strategy.

Alkyl organoborons are powerful materials for the construction of C(sp3)-C(sp2) bonds, predominantly via Suzuki-Miyaura cross-coupling. These species are generally assembled using 2-electron processes that harness the ability of boron reagents to act as both electrophiles and nucleophiles. Herein, we demonstrate an alternative borylation strategy based on the reactivity of amine-ligated boryl radicals. This process features the use of a carboxylic acid containing amine-ligated borane that acts as boryl radical precursor for photoredox oxidation and decarboxylation. The resulting amine-ligated boryl radical undergoes facile addition to styrenes and imines through radical-polar crossover manifolds. This delivers a new class of sp3-organoborons that are stable solids and do not undergo protodeboronation. These novel materials include unprotected α-amino derivatives that are generally unstable. Crucially, these aliphatic organoboron species can be directly engaged in Suzuki-Miyaura cross-couplings with structurally complex aryl halides. Preliminary studies suggest that they enable slow-release of the corresponding and often difficult to handle alkyl boronic acids.

Harnessing the potential of acyl triazoles in bifunctional cobalt-catalyzed radical cross-coupling reactions

Persistent radicals facilitate numerous selective radical coupling reactions. Here, we have identified acyl triazole as a new and versatile moiety for generating persistent radical intermediates through single-electron transfer processes. The efficient generation of these persistent radicals is facilitated by the formation of substrate-coordinated cobalt complexes, which subsequently engage in radical cross-coupling reactions. Remarkably, triazole-coordinated cobalt complexes exhibit metal-hydride hydrogen atom transfer (MHAT) capabilities with alkenes, enabling the efficient synthesis of diverse ketone products without the need for external ligands. By leveraging the persistent radical effect, this catalytic approach also allows for the development of other radical cross-coupling reactions with two representative radical precursors. The discovery of acyl triazoles as effective substrates for generating persistent radicals and as ligands for cobalt catalysis, combined with the bifunctional nature of the cobalt catalytic system, opens up new avenues for the design and development of efficient and sustainable organic transformations.

Aerobic Oxysulfonylation of Olefins Using N-Sulfonylaminophthalimides as Sulfonyl Radical Precursors.

Readily accessible N-sulfonylaminophthalimides were developed to be efficient sulfonyl radical precursors upon being treated with a base/oxidant under mild conditions. The method was applied to the oxysulfonylation of olefins, providing β-ketosulfones and isobenzofurans stereoselectively. On the basis of control experiments, density functional theory calculations, and the literature, a plausible radical mechanism was proposed. The findings offered a chance to develop novel radical precursors based on diversely substituted N-aminophthalimides, which might establish a universal mild approach for the generation of various radicals.

Nickel-Catalyzed Radical Hydroalkylative Dearomatization of Indoles with Alkyl Bromides

Dearomatization of indole derivatives offers a straightforward approach to accessing indoline framework. However, highly efficient dearomatization of indoles bearing electron-deficient groups remains underdeveloped. Herein, a nickel-catalyzed intermolecular hydroalkylative dearomatization reaction of indoles with simple alkyl bromides via single-electron-transfer process is reported. A wide variety of indole derivatives bearing versatile functional groups were compatible with this protocol, by reacting with primary, secondary, and tertiary bromides to afford a series of indolines in good yields (up to 82%) with excellent diastereoselectivity (up to >20:1). Notably, a nickel-mediated hydrogen atom transfer process was observed when terminal bromides were employed as the radical precursors, which resulted in the branched products.

Photocatalyzed 1,3-Bromodifluoroallylation of [1.1.1]Propellane with α-Trifluoromethylalkenes and KBr Salts.

Herein we unveil a visible-light-driven transition-metal-free 1,3-bromodifluoroallylation of [1.1.1]propellane. This reactivity is harnessed through organophotocatalysis, providing practical synthetic pathways to 1-brominated-3-gem-difluoroallylic bicyclo[1.1.1]pentane derivatives, particularly derived from readily available α-trifluoromethylalkenes and inexpensive KBr salts utilized as precursors for bromine radicals. Mechanistic investigations reveal that bromide anions quench the excited state of the photocatalyst, leading to the formation of bromine radicals, which react in a strain-release radical addition process rather than hydrogen atom abstraction with [1.1.1]propellane.

Copper‐Catalyzed Radical‐Induced Annulation‐Halo(bi)cyanomethylation of Indole‐Tethered 1,6‐Enynes toward Pyrrolo[1,2‐a]indoles

AbstractA copper‐catalyzed radical‐induced annulation‐halocyanomethylation of indole‐linked 1,6‐enynes has been established using haloacetonitrile as radical precursors, enabling the synthesis of 21 cyanomethylated pyrrolo[1,2‐a]indoles with yields ranging from 42% to 81% and a Z/E ratio up to 19:1. Moreover, by adjusting the reaction temperature, a variation of the annulation‐bromobicyanomethylation process was achieved, resulting in the production of 12 bicyanomethylated pyrrolo[1,2‐a]indole isomers in yields of 41–68%. The stereoisomeric mixture of bicyanomethylated products could be purified to their pure configurations through recrystallization. The proposed reaction mechanism was formulated through a series of control experiments.

Stereoselective Construction of Multifunctional C-Glycosides Enabled by Nickel-Catalyzed Tandem Borylation/Glycosylation.

Stereochemically pure saccharides have indispensable roles in fields ranging from medicinal chemistry to materials science and organic synthesis. However, the development of a simple, stereoselective, and efficient glycosylation protocol to access α- and β-C-glycosides (particularly 2-deoxy entities) remains a persistent challenge. Existing studies have primarily focused on C1 modification of carbohydrates and transformation of glycosyl radical precursors. Here, we innovate by harnessing the in situ generated glycosyl-Ni species to achieve one-pot borylation and glycosylation in a cascade manner, which is enabled by an earth-abundant nickel-catalyzed carboboration of readily accessible glycals without any ligand. This work reveals the potential for the development of a modular and multifunctional glycosylation platform to facilitate the simultaneous introduction of C-C and C-B bonds at the stereogenic center of saccharides, a largely unexploited research area. Preliminary experimental and computational studies indicate that the endocyclic O and the C3 group play important roles in stereoseclectively forging glycosidic bonds. As a result, a diverse range of C-R (R = alkyl, aryl, and alkenyl) and 2-deoxygenated glycosides bearing modifiable boron groups could be rapidly made with excellent stereocontrol and exhibit remarkable functional group tolerance. The synthetic potential is underscored in the late-stage glycosylation of natural products and commercial drugs as well as the facile preparation of various rare sugars, bioactive conjugates, and key intermediates to prorocentin, phomonol, and aspergillide A.

Oxidative Difunctionalization of N-Aryl Bicyclobutyl Amides with Aldehydes: Divergent Synthesis of Acylated and Alkylated 3-Spirocyclobutyl Oxindoles.

An efficient and operationally simple oxidative radical difunctionalization of N-aryl bicyclobutyl (BCB) amides with aldehydes is described. It was found that acylated 3-spirocyclobutyl oxindoles were generated from the coupling of BCB-amides and aromatic aldehydes, while reactions gave exclusively decarbonylative alkylarylation products using alkyl aldehydes as radical precursors.