Radical Intermediates Research Articles

Photoinduced Radical Borylation of Alkyl Chlorides

AbstractThe traditional method for the preparation of alkylboronic esters involves transition metal catalysis or transition metal‐free methods relying on single electron transfer. Each method relies on the suitable choice of catalyst or electron transfer mediator. In this study, we have developed a new method for the synthesis of alkylboronic esters from alkyl chlorides and diboron(4) compounds, without the need for additional metal or non‐metal catalysts. We discovered that under 400 nm visible light irradiation, alkyl chlorides can be activated in the presence of bis(neopentyl glycolato)diboron and an alkoxide base to form alkyl radical intermediates, which then react with diboron(4) compounds, resulting in high yields of alkylboronic esters. The reaction is applicable to both primary and secondary alkyl chlorides. The simplicity of operation and the broad substrate scope of this method make it practical for the synthesis of valuable alkylboronic ester intermediates.

Co‐Catalyzed Peroxidation of Cyclic β‐Dicarbonyls

AbstractA Co‐catalyzed peroxidation of cyclic β‐dicarbonyls (cyclic 1,3‐diketones, 4‐hydroxy‐2(5H)‐furanones and Meldrum's acids) with TBHP has been disclosed. A series of the alkylperoxy derivatives of 4‐hydroxy‐2(5H)‐furanones and Meldrum's acids were synthesized in moderate to good yields (13–86 %). The functionalization of 4‐hydroxy‐2(5H)‐furanones by the tBuOO group was performed with high selectivity in the presence of the cocktail of reactive oxidizing species, including metal and radical intermediates. The key species in the peroxidation process are probably the tert‐butylperoxy radical or its Co(III) complex, which are generated from the Co(II)/TBHP system. Cycle cleavage, which would be expected for cyclic β‐dicarbonyls based on previous reports, was observed to a large extent only for cyclic 1,3‐diketones.

Generation and Radical-Radical Cross-Coupling of Alkenyloxy Radical.

Alkene-attached oxygen radicals are rarely used, as highly reactive oxygen radicals are incompatible with the alkene moiety. The direct radical-radical cross-coupling of O radicals is also challenging (limited to N-O bond formation) because of the lack of suitable persistent radical species. This study demonstrated the feasibility of using Breslow intermediate radical (BIR) as a persistent radical to capture unstable π-conjugated O radicals and allow the C-O radical-radical cross-coupling.

Influence of updated isoprene oxidation mechanisms on the formation of intermediate and secondary products in MCM v3.3.1

In this study, we developed an observation based photochemical box model with the measurement data collected at a suburban site (i.e., the Xianghe, XH site) of the Beijing-Tianjin-Hebei (BTH) region and the latest version of the Master Chemical Mechanism (MCM v3.3.1), which newly incorporated 498 reaction for the additional 155 species with the oxidation of isoprene by the OH radical. The influence of updated isoprene degradation on the radical budgets, formation of intermediate and secondary products by comparing the simulation results in the original version (MCM v3.2) was firstly analyzed to estimate whether the updates of precursors could influence the model performance on its evolution pathways and related products. The results demonstrated that though the input of isoprene could significantly decrease or increase the concentrations of OH and HO2 radicals in the model simulation, respectively, the difference in the simulated concentrations of these radicals with isoprene oxidation before and after the updates was not statistically significant. For intermediate products, the simulated concentrations of formaldehyde and methacrolein (MACR) did not significantly alter before and after the updates, while the abundance of methyl vinyl ketone (MVK) reduced obviously (the maximum reduction of 31%) due to lower reaction coefficient between ISOPBO2 and NO and the lower branching ratios caused by the newly added pathways involving CISOPA and TISOPA in the updated scheme. On the other hand, the simulation concentrations of acrolein (ACR), glyoxal (Gly) and methylglyoxal (Mgly) increased significantly after the model updates. The dominant pathway for the increment of ACR was the decomposition of CH2CHCH2O produced by PE4E2CO, while those of Gly and Mgly were associated with radicals of C537O and PACLOOA that were both from the new intermediate radical of CISOPC. In addition, 39 isoprene oxidation products among the 155 new added species were identified to partition in the formation of secondary organic aerosol (SOA), which were coupled in the gas-particle partitioning module to optimize the formation of SOA, contributing 1.15 μg m−3 to the increase of SOA mean concentration. The updates of isoprene degradation further resulted in the significant change for its sensitivity in SOA formation, making it as the secondary important SOA precursor at the XH site. Last but not the least, the influence on photochemical ozone formation related to updates of isoprene degradation was ignorable. Overall, the above results confirmed the insufficient description of the degradation of precursors indeed limited the simulation of the intermediate and secondary products, highlighting the needs of exploring and parameterizing the precursor degradation processes for better understanding of their behaviors and SOA formation in the atmosphere.

Electron spin resonance analysis of photoenzymatic catalysis.

This Perspective highlights recent research progress and prospects in elucidating the catalytic mechanism of photoenzymes using ESR (electron spin resonance) spectroscopy, which is emerging as a unique and crucial method for identifying radical intermediates, illustrating electron transfer events and the underlying mechanisms of photoenzymatic catalysis.

Using ‘designer’ coherences to control electron transfer in a model bis(hydrazine) radical cation: can we still distinguish between direct and superexchange mechanisms?

We have simulated two mechanisms, direct and superexchange, for the electron transfer in a model Bis(hydrazine) Radical Cation, which consists of two hydrazine moieties coupled by a benzene ring. The computations, that are inspired by the attochemistry approach, focus on the electron dynamics arising from a coherent superposition of four cationic states. The electron dynamics, originating from a solution of the time dependent Schrödinger equation within the Ehrenfest method, is coupled to the relaxation of the nuclei. Both direct (ca. 15 fs dynamics) and superexchange (ca. 2 fs dynamics) mechanisms are observed and turn out to lie on a continuum depending on the strength of the coupling of the benzene bridge electron dynamics with the hydrazine chromophore dynamics. This contrasts with the chemical pathway approach where the direct mechanism is completely non-adiabatic via a conical intersection, while the superexchange mechanism involves an intermediate radical with the unpaired electron localized on the benzene ring. Thus, with the attochemistry-inspired electron dynamics approach, one can distinguish direct from superexchange mechanisms depending on the strength of the coupling of two types of electron dynamics: the slow hydrazine dynamics (ca. 15 fs) and the fast benzene linker dynamics (ca. 2 fs). In this model bis(hydrazine) radical cation, only when the intermediate coupler is in an anti-quinoid state, does one see the coupling of the bridge and hydrazine chromophore dynamics.

Generation of 3-aminopropanamide and its cluster formation with nucleation precursors- a theoretical exploration

Aminoamides are formed in the atmospheric environments by the auto-oxidation of the parent diamines. In this work, the oxidation chemistry of diamine (1,3-Diaminopropane, Dap) to the amino amide (3- aminopropanamide, 3-APA) and its new particle formation potential with small atmospheric molecules such as NH3 (A), H2O (W) and H2SO4 (SA) are theoretically investigated using the M062X/6–311++G** theory. The bimolecular rate coefficient of the ·OH initiated H-atom abstraction is computed to be 1.01 × 10−11 cm3 molecule−1 s−1. Further reaction of the peroxy radical intermediate indicates that the pathway involving γ H- shift of the initially formed radical intermediates to be more favourable on kinetic grounds with the effective bimolecular rate coefficient of 3.87 × 10−14 cm3 molecule−1s−1. The thermodynamic barrier associated with the H-shifts involved in this pathway is in the range of 13–20 kcal/mol. The cluster formation of APA with SA is more favourable than the clusters with W and A, wherein the free energy of formation of (APA)(SA) and (APA)(SA)2 are −11.3 and −22.6 kcal/mol, respectively. However, the feasibility of cluster formation with W and A increases with the altitude and becomes spontaneous in the case of water at an altitude of 12 km. The present work indicates that aminoamides like 3-APA can participate in the initial stages of new particle formation events by forming clusters with SA molecules. The scattering parameters and topological analysis of different (Amide)(SA) clusters indicate more scattering properties for the (APA)(SA) cluster, which has an adverse effect on the atmosphere. Furthermore, topological analysis indicates that H-bond formation is more prominent in the (APA)(SA) cluster.

Radical dehydroxymethylative fluorination of aliphatic primary alcohols and diverse functionalization of α-fluoroimides via BF3·OEt2-catalyzed C‒F bond activation

Ag2CO3-promoted dehydroxymethylative fluorination of aliphatic alcohols has been achieved with Selectfluor as both oxidant and fluorine source. The reaction involves β-fragmentation of primary alkoxy radicals, followed by the fluorination of the resulting C-centered radical intermediates. The transformation proceeds under mild reaction conditions and exhibits a broad substrate scope, thus opening up a new entrance to the synthesis of fluorinated constructs including α-fluoroimides and 1-fluoroalkyl benzoates as well as secondary and tertiary alkyl fluorides like versatile 2-fluoro-2-alkyl 1,3-propandiol derivatives. The divergent functionalization of the obtained α-fluoroimides enables an efficient access to amine derivatives through C–F bond activation under the action of BF3·OEt2.

Deoxygenative Transformation of Alcohols via Phosphoranyl Radical from Exogenous Radical Addition

AbstractA general approach to the direct deoxygenative transformation of primary, secondary, and tertiary alcohols has been developed. It undergoes through phosphoranyl radical intermediates generated by the addition of exogenous iodine radical to trivalent alkoxylphosphanes. Since these alkoxylphosphanes are readily in situ obtained from alcohols and commercially available, inexpensive chlorodiphenylphosphine, a diverse range of alcohols with various functional groups can be utilized to proceed deoxygenative cross‐couplings with alkenes or aryl iodides. The selective transformation of polyhydroxy substrates and the rapid synthesis of complex organic molecules are also demonstrated with this method.

Deoxygenative Transformation of Alcohols via Phosphoranyl Radical from Exogenous Radical Addition.

A general approach to the direct deoxygenative transformation of primary, secondary, and tertiary alcohols has been developed. It undergoes through phosphoranyl radical intermediates generated by the addition of exogenous iodine radical to trivalent alkoxylphosphanes. Since these alkoxylphosphanes are readily in situ obtained from alcohols and commercially available, inexpensive chlorodiphenylphosphine, a diverse range of alcohols with various functional groups can be utilized to proceed deoxygenative cross-couplings with alkenes or aryl iodides. The selective transformation of polyhydroxy substrates and the rapid synthesis of complex organic molecules are also demonstrated with this method.

Radical SAM Enzyme PylB Generates a Lysyl Radical Intermediate in the Biosynthesis of Pyrrolysine by Using SAM as a Cofactor.

Pyrrolysine, the 22nd amino acid encoded by the natural genetic code, is essential for methanogenic archaea to catabolize methylamines into methane. The structure of pyrrolysine consists of a methylated pyrroline carboxylate that is linked to the ε-amino group of the l-lysine via an amide bond. The biosynthesis of pyrrolysine requires three enzymes: PylB, PylC, and PylD. PylB is a radical S-adenosyl-l-methionine (SAM) enzyme and catalyzes the first biosynthetic step, the isomerization of l-lysine into methylornithine. PylC catalyzes an ATP-dependent ligation of methylornithine and a second l-lysine to form l-lysine-Nε-methylornithine. The last biosynthetic step is catalyzed by PylD via oxidation of the PylC product to form pyrrolysine. While enzymatic reactions of PylC and PylD have been well characterized by X-ray crystallography and in vitro studies, mechanistic understanding of PylB is still relatively limited. Here, we report the first in vitro activity of PylB to form methylornithine via the isomerization of l-lysine. We also identify a lysyl C4 radical intermediate that is trapped, with its electronic structure and geometric structure well characterized by EPR and ENDOR spectroscopy. In addition, we demonstrate that SAM functions as a catalytic cofactor in PylB catalysis rather than canonically as a cosubstrate. This work provides detailed mechanistic evidence for elucidating the carbon backbone rearrangement reaction catalyzed by PylB during the biosynthesis of pyrrolysine.

Radical intermediates in the photolysis of the mixed benzoyl-substituted phosphonium-iodonium ylide in different solvents

Radical intermediates in the photolysis of the mixed benzoyl-substituted phosphonium-iodonium ylide in different solvents

Access to All-Carbon Quaternary Centers by Photocatalytic Fluoroalkylation of α-Halo Carbonyl Compounds.

Perfluoroalkyl groups have become significantly important in pharmaceutical and agrochemical applications. In this study, we present a visible light-mediated photoredox neutral strategy for the fluoroalkylation of tertiary alkyl chlorides under transition-metal-free conditions. This method allows for the facile synthesis of fluoroalkylated all-carbon quaternary centers, exhibiting excellent functional group compatibility. Mechanistic studies reveal the involvement of two reactive radical intermediates and the in situ formation of metal enolates in a radical-polar crossover manner. The versatility of this methodology is demonstrated through synthetic transformations based on the carbonyl group, showcasing its potential for the rapid assembly of diverse organic molecules bearing fluoroalkyl all-carbon quaternary centers.

Liposome encapsulated polydopamine nanoparticles: Enhancing ferroptosis and activating hypoxia prodrug activity

The short lifespan of active oxygen species and depressed O2 level during ferroptosis treatment in tumor cells weaken ferroptosis therapy. How to improve the utilization efficiency of active oxygen species generated in real time is pivotal for anticancer treatment. Herein, the tirapazamine (TPZ) loaded polydopamine-Fe nanoparticles (PDA-Fe-TPZ) was modified with unsaturated liposome (Lip), which was constructed to overcome the drawbacks of traditional ferroptosis therapy. The Lip@PDA-Fe-TPZ nanoliposomes can react with H2O2 to produce •OH by Fenton reaction, which then attacks Lip and transforms into radical intermediate (L•) and phospholipid peroxide radical (LOO•) to avoid the annihilation of •OH. The introduced Lip enhances lipid peroxidation and promotes oxygen consumption, resulting in increased hypoxia at tumor site. The introduced TPZ can be triggered by reductase in tumor cells under hypoxia, which can reduce to transient oxidative free radicals by reductase enzymes and destroy the structure of the surrounding biomacromolecules, thus achieving the synergistic treatment of ferroptosis and chemotherapy. In this work, we organically combined enhanced ferrroptosis with hypoxic activated chemotherapy to achieve efficient and specific tumor killing effect, which can sever as a promising treatment of cancer in the future.

TiN as Radical Scavenger in Fe─N─C Aerogel Oxygen Reduction Catalyst for Durable Fuel Cell.

Fe─N─C is the most promising alternative to platinum-based catalysts to lower the cost of proton-exchange-membrane fuel cell (PEMFC). However, the deficient durability of Fe─N─C has hindered their application. Herein, a TiN-doped Fe─N─C (Fe─N─C/TiN) is elaborately synthesized via the sol-gel method for the oxygen-reduction reaction (ORR) in PEMFC. The interpenetrating network composed by Fe─N─C and TiN can simultaneously eliminate the free radical intermediates while maintaining the high ORR activity. As a result, the H2O2 yields of Fe─N─C/TiN are suppressed below 4%, ≈4 times lower than the Fe─N─C, and the half-wave potential only lost 15mV after 30 kilo-cycle accelerated durability test (ADT). In a H2─O2 fuel cell assembled with Fe─N─C/TiN, it presents 980mAcm-2 current density at 0.6V, 880mWcm-2 peak power density, and only 17mV voltage loss at 0.80Acm-2 after 10 kilo-cycle ADT. The experiment and calculation results prove that the TiN has a strong adsorption interaction for the free radical intermediates (such as *OH, *OOH, etc.), and the radicals are scavenged subsequently. The rational integration of Fe single-atom, TiN radical scavenger, and highly porous network adequately utilize the intrinsic advantages of composite structure, enabling a durable and active Pt-metal-free catalyst for PEMFC.

Photocatalytic degradation process of antibiotic sulfamethoxazole by ZnO in aquatic systems: a dynamic kinetic model based on contributions of OH radical, oxygenated radical intermediates and dissolved oxygen

The photocatalytic degradation process of sulfamethoxazole (SMX) using ZnO in aquatic systems has been systematically studied by varying initial SMX concentration from 0 to 15 mgL−1 , ZnO dosage from 0 to 4 gL−1 and UV light intensity at the light source from 0 to 18 W(m-lamp length)−1 at natural pH. Almost complete degradations of SMX were achieved within 120 min for the initial SMX concentration ≤15 mgL−1 with ZnO dosage of 3 gL−1 and UV light intensity of 18 W(m-lamp length)−1. The photocatalytic degradation process was found to be interacted with the dissolved oxygen (DO) consumption. With oxygen supply through the gas-liquid free-surface, the DO concentration decreased significantly in the initial SMX degradation phase and increased asymptotically to the saturated DO concentration after achieving about 80% SMX degradation. The change in DO concentration was probably controlled by the oxygen consumption in the formation of oxygenated radical intermediates. A novel dynamic kinetic model based on the fundamental reactions of photocatalysis and the formation of oxygenated radical intermediates was developed. In the modeling the dynamic concentration profiles of OH radical and DO are considered. The dynamics of SMX degradation process by ZnO was simulated reasonably by the proposed model.

Direct Detection of the α-Carbon Radical Intermediate Formed by OspD: Mechanistic Insights into Radical S-Adenosyl-l-methionine Peptide Epimerization.

OspD is a radical S-adenosyl-l-methionine (SAM) peptide epimerase that converts an isoleucine (Ile) and valine (Val) of the OspA substrate to d-amino acids during biosynthesis of the ribosomally synthesized and post-translationally modified peptide (RiPP) natural product landornamide A. OspD is proposed to carry out this reaction via α-carbon (Cα) H-atom abstraction to form a peptidyl Cα radical that is stereospecifically quenched by hydrogen atom transfer (HAT) from a conserved cysteine (Cys). Here we use site-directed mutagenesis, freeze-quench trapping, isotopic labeling, and electron paramagnetic resonance (EPR) spectroscopy to provide new insights into the OspD catalytic mechanism including the direct observation of the substrate peptide Cα radical intermediate. The putative quenching Cys334 was changed to serine to generate an OspD C334S variant impaired in HAT quenching. The reaction of reduced OspD C334S with SAM and OspA freeze-quenched at 15 s exhibits a doublet EPR signal characteristic of a Cα radical coupled to a single β-H. Using isotopologues of OspA deuterated at either Ile or Val, or both Ile and Val, reveals that the initial Cα radical intermediate forms exclusively on the Ile of OspA. Time-dependent freeze quench coupled with EPR spectroscopy provided evidence for loss of the Ile Cα radical concomitant with gain of a Val Cα radical, directly demonstrating the N-to-C directionality of epimerization by OspD. These results provide direct evidence for the aforementioned OspD-catalyzed peptide epimerization mechanism via a central Cα radical intermediate during RiPP maturation of OspA, a mechanism that may extend to other proteusin peptide epimerases.

Cu-Catalyzed Coupling of Aliphatic Amines with Alkylboronic Esters.

We report a Cu-catalyzed oxidative coupling of aliphatic amines with benzylic and aliphatic boronic esters to give high value alkyl amines, products found widely in applications from medicinal chemistry to materials science. This operationally simple reaction, which can be performed on gram scale, runs under mild conditions and exhibits broad functional group tolerance. The terminal oxidant of the reaction is O2 from the air, avoiding the need for additional chemical oxidants. Investigation into the reaction mechanism suggests that the boronic ester is activated by an aminyl radical, formed through oxidation of the amine by the Cu catalyst, to give a key alkyl radical intermediate. To demonstrate its utility and potential for late-stage functionalization, we showcase the method as the final step in the total synthesis of a TRPV1 antagonist.

Operando film-electrochemical EPR spectroscopy tracks radical intermediates in surface-immobilized catalysts

The development of surface-immobilized molecular redox catalysts is an emerging research field with promising applications in sustainable chemistry. In electrocatalysis, paramagnetic species are often key intermediates in the mechanistic cycle but are inherently difficult to detect and follow by conventional in situ techniques. We report a new method, operando film-electrochemical electron paramagnetic resonance spectroscopy (FE-EPR), which enables mechanistic studies of surface-immobilized electrocatalysts. This technique enables radicals formed during redox reactions to be followed in real time under flow conditions, at room temperature and in aqueous solution. Detailed insight into surface-immobilized catalysts, as exemplified here through alcohol oxidation catalysis by a surface-immobilized nitroxide, is possible by detecting active-site paramagnetic species sensitively and quantitatively operando, thereby enabling resolution of the reaction kinetics. Our finding that the surface electron-transfer rate, which is of the same order of magnitude as the rate of catalysis (accessible from operando FE-EPR), limits catalytic efficiency has implications for the future design of better surface-immobilized catalysts.

Determining the Oxidation Mechanism through Radical Intermediates in Polysorbates 80 and 20 by Electron Paramagnetic Resonance Spectroscopy.

Polysorbates 20 and 80 (PS20 and PS80) are added to many commercial biologic and vaccine pharmaceuticals. It is commonly known that these polysorbates undergo a radical oxidation mechanism; however, the identity of these radical intermediates has not been clearly determined. Furthermore, PS20 and PS80 differ by the presence of a lauric acid instead of an oleic acid, respectively. The oxidation of PS80 is thought to be centered around the double bond of the oleic acid even though PS20 also undergoes oxidation, making the mechanism of oxidation unclear for PS20. Using commercial stocks of PS20 and PS80 alkyl (R•), alkoxyl (C-O•) and peroxyl (C-OO•) radicals were detected by electron paramagnetic resonance spectroscopy likely originating from radical-initiating species already present in the material. When dissolved in water, the peroxyl radicals (C-OO•) originally in the stocks were not detected but poly(ethylene oxide) radicals were. An oxidative pathway for polysorbates was suggested based on the radical species identified in the polysorbate stock material and solutions.