Radical Migration Research Articles

Unravelling the favorability of radical-directed xn-H2O dissociation at serine and threonine

Among tandem-mass-spectrometry approaches, radical-directed dissociation (RDD) is uniquely sensitive to molecular structure because the location and types of cleavage observed are dictated by radical migration propensities. Although the underlying chemistry for many RDD fragmentation pathways has been previously explained, xn-H2O fragment ions that occur exclusively at serine and threonine residues, have not been examined in detail. Creation of this fragment type inherently requires two dissociation events, one to lose water and another to cleave the peptide backbone. Double dissociations are typically disfavored relative to pathways requiring a single cleavage, yet xn-H2O fragment ions are abundant in RDD spectra. To understand why this fragmentation pathway is favorable, we used a combination of computational chemistry and experiments on peptides with a variety of covalent modifications. Our results explore the energetics, location, and migration of the radical in each step of the mechanism, revealing that favorability can be attributed to the stability of the required radical intermediates and access to low-energy pathways connecting them. Ultimately, the abundant nature of xn-H2O ions and the selectivity associated with their exclusive generation at Ser/Thr provides high value sequence information in RDD experiments.

Direct oxygen insertion into C-C bond of styrenes with air.

Skeletal editing of single-atom insertion to basic chemicals has been demonstrated as an efficient strategy for the discovery of structurally diversified compounds. Previous endeavors in skeletal editing have successfully facilitated the insertion of boron, nitrogen, and carbon atoms. Given the prevalence of oxygen atoms in biologically active molecules, the direct oxygenation of C-C bonds through single-oxygen-atom insertion like Baeyer-Villiger reaction is of particular significance. Herein, we present an approach for the skeletal modification of styrenes using O2 via oxygen insertion, resulting in the formation of aryl ether frameworks under mild reaction conditions. The broad functional-group tolerance and the excellent chemo- and regioselectivity are demonstrated in this protocol. A preliminary mechanistic study indicates the potential involvement of 1,2-aryl radical migration in this reaction.

Remote Boryl and Alkenyl Radical Migration of Olefin-Bearing Aryl Bromides

Remote Boryl and Alkenyl Radical Migration of Olefin-Bearing Aryl Bromides

Comparison of the Backbone Dynamics of Dehaloperoxidase-Hemoglobin Isoenzymes.

Dehaloperoxidase (DHP) is a multifunctional hemeprotein with a functional switch generally regulated by the chemical class of the substrate. Its two isoforms, DHP-A and DHP-B, differ by only five amino acids and have an almost identical protein fold. However, the catalytic efficiency of DHP-B for oxidation by a peroxidase mechanism ranges from 2- to 6-fold greater than that of DHP-A depending on the conditions. X-ray crystallography has shown that many substrates and ligands have nearly identical binding in the two isoenzymes, suggesting that the difference in catalytic efficiency could be due to differences in the conformational dynamics. We compared the backbone dynamics of the DHP isoenzymes at pH 7 through heteronuclear relaxation dynamics at 11.75, 16.45, and 19.97 T in combination with four 300 ns MD simulations. While the overall dynamics of the isoenzymes are similar, there are specific local differences in functional regions of each protein. In DHP-A, Phe35 undergoes a slow chemical exchange between two conformational states likely coupled to a swinging motion of Tyr34. Moreover, Asn37 undergoes fast chemical exchange in DHP-A. Given that Phe35 and Asn37 are adjacent to Tyr34 and Tyr38, it is possible that their dynamics modulate the formation and migration of the active tyrosyl radicals in DHP-A at pH 7. Another significant difference is that both distal and proximal histidines have a 15-18% smaller S2 value in DHP-B, thus their greater flexibility could account for the higher catalytic activity. The distal histidine grants substrate access to the distal pocket. The greater flexibility of the proximal histidine could also accelerate H2O2 activation at the heme Fe by increased coupling of an amino acid charge relay to stabilize the ferryl Fe(IV) oxidation state in a Poulos-Kraut "push-pull"-type peroxidase mechanism.

A Deterministic Model to Predict Tacticity Changes During Controlled Degradation of Polypropylene

Controlled degradation of polypropylene (CPP) converts high-molecular-weight (Mw) polypropylene (PP) to lower Mw PP using peroxide-induced degradation. A deterministic model is developed to predict tacticity changes in isotactic PP. The model determines instantaneous rates of defective-pentad formation and tracks accumulation of these pentads using dynamic material balances. The model relies on the assumption that lifetimes of polymeric radicals are short compared to extruder residence times. Model predictions agree with previous Monte Carlo simulations that require long simulation times. Two versions of the model are proposed: one assumes that radical migration, also called chain walking, occurs via 1–6 isomerization and one assumes 1–8 isomerization. Chain-transfer-to-polymer and chain-walking parameters are estimated using 13C NMR data obtained using initiator levels between 0.006 and 0.52 wt%. Both 1–6 and 1–8 isomerization models result in better fit to the data.

Improved Approach for ab Initio Calculations of Rate Coefficients for Secondary Reactions in Acrylate Free-Radical Polymerization.

Secondary reactions in radical polymerization pose a challenge when creating kinetic models for predicting polymer structures. Despite the high impact of these reactions in the polymer structure, their effects are difficult to isolate and measure to produce kinetic data. To this end, we used solvation-corrected M06-2X/6-311+G(d,p) ab initio calculations to predict a complete and consistent data set of intrinsic rate coefficients of the secondary reactions in acrylate radical polymerization, including backbiting, β-scission, radical migration, macromonomer propagation, mid-chain radical propagation, chain transfer to monomer and chain transfer to polymer. Two new approaches towards computationally predicting rate coefficients for secondary reactions are proposed: (i) explicit accounting for all possible enantiomers for reactions involving optically active centers; (ii) imposing reduced flexibility if the reaction center is in the middle of the polymer chain. The accuracy and reliability of the ab initio predictions were benchmarked against experimental data via kinetic Monte Carlo simulations under three sufficiently different experimental conditions: a high-frequency modulated polymerization process in the transient regime, a low-frequency modulated process in the sliding regime at both low and high temperatures and a degradation process in the absence of free monomers. The complete and consistent ab initio data set compiled in this work predicts a good agreement when benchmarked via kMC simulations against experimental data, which is a technique never used before for computational chemistry. The simulation results show that these two newly proposed approaches are promising for bridging the gap between experimental and computational chemistry methods in polymer reaction engineering.

Competitive Radical Migrations and Ribose Ring Cleavage in Adenosine and 2'-Deoxyadenosine Cation Radicals.

We report a combined experimental and computational study of adenosine cation radicals that were protonated at adenine and furnished with a radical handle in the form of an acetoxyl radical, •CH2COO, that was attached to ribose 5'-O. Radicals were generated by collision-induced dissociation (CID) and characterized by tandem mass spectrometry and UV-vis photodissociation action spectroscopy. The acetoxyl radical was used to probe the kinetics of intramolecular hydrogen transfer from the ribose ring positions that were specifically labeled with deuterium at C1', C2', C3', C4', C5', and in the exchangeable hydroxyl groups. Hydrogen transfer was found to chiefly involve 3'-H with minor contributions by 5'-H and 2'-H, while 4'-H was nonreactive. The hydrogen transfer rates were affected by deuterium isotope effects. Hydrogen transfer triggered ribose ring cleavage by consecutive dissociations of the C4'-O and C1'-C2' bonds, resulting in expulsion of a C6H9O4 radical and forming a 9-formyladenine ion. Rice-Ramsperger-Kassel-Marcus (RRKM) and transition-state theory (TST) calculations of unimolecular constants were carried out using the effective CCSD(T)/6-311++G(3d,2p) and M06-2X/aug-cc-pVTZ potential energy surfaces for major isomerizations and dissociations. The kinetic analysis showed that hydrogen transfer to the acetoxyl radical was the rate-determining step, whereas the following ring-opening reactions in ribose radicals were fast. Using DFT-computed energies, a comparison was made between the thermochemistry of radical reactions in adenosine and 2'-deoxyadenosine cation radicals. The 2'-deoxyribose ring showed lower TS energies for both the rate-determining 3'-H transfer and ring cleavage reactions.

Electrochemical synthesis of β-difluoromethylamide compounds by N-benzenesulfonylacrylamide with difluorine reagents.

A mild and efficient electrochemical method for radical addition, cyclization, and migration reaction was described in this work. A difluoromethyl radical was produced by anodizing CF2HSO2Na. The resulting product was then added to olefin, underwent Smiles cyclization, and migrated to form β-difluoromethamide compounds after the release of SO2. The process was free from metals and catalysts, gram-grade, and resistant to a variety of electron-rich substrates.

Thermal oxidation of blends of polypropylene and polyamide 6/66. Effect of inhibition

The thermal oxidation of the blends of isotactic polypropylene (PP) and mixed copolyamide PA6/66 has been studied in a wide range of compositions: 0, 5, 10, 20, 30, 40, 50 and 100 wt % PA6/66. Data obtained by differential scanning calorimetry (DSC) and FTIR indicate the immiscibility of two polymer phases in the blends. The melting enthalpy of mixtures is increased during oxidation that is explained by chemi-crystallization of PP under PP oxidation. PA6/66 component is found to retard the growth of PP enthalpy during PP oxidation. According to DSC data on the PP/PA6/66 blends in air, PA6/66 phase greatly enhances the oxidation onset temperature of the PP/PA6/66 blends thus indicating the improved thermal stability of new material. The oxygen consumption of the PP/PA6/66 blends at 130°C proceeds with a large oxidation induction time (OIT) which is increased with increase in PA6/66 content. After OIT is ended, a constant oxidation rate is established, which is characteristic of the autoxidation mechanism. Kinetic analysis of the thermal oxidation of the PP/PA6/66 blends was carried out on the base of two models of polyolefin autooxidation with hydroperoxide decomposition via the 1st or the 2nd order reaction. The both models were found to describe the experimental kinetic curves of the oxygen consumption. Two possible explanations of the inhibition of PP oxidation by PA6/66 phase are discussed. The migration of active radicals from the PP phase to the PA6/66 phase with their transformation into low-active PA6/66 radicals may be responsible for inhibition and an increase in OIT of PP. Another mechanism of OIT increase may be related with a change in the structure of the PP/PA6/66 blends depending on PA6/66 content.

Effect of α-methyl on the performance of photocurable 3D printing polyurethane materials

For photosensitive polyurethane systems, reactive diluents are indispensable components whose main role is to reduce the viscosity of the polyurethane prepolymer to meet the requirements of the photocurable 3D printing technology for high fluidity of the precursor solution. Generally, the reactive diluent would be involved in the photocuring reaction, which in turn has a remarkable impact on the mechanical, reaction kinetics, and thermodynamic characteristics of the photosensitive polyurethane system. However, this feature is usually neglected in the study of photosensitive urethane acrylate (PUA) systems, so there is a considerable necessity to investigate the mechanism of active diluents in the photocured reaction of PUA systems. In this work, the effects of α-methyl groups along the chains of diluent molecules on the photoreaction kinetics, photocurable 3D printing, mechanical and mechanical properties, and thermodynamic characteristics of PUAs were investigated employing hydroxyethyl methacrylate and hydroxyethyl acrylate as active diluents, respectively. The relationship between chemical structure and kinetics of PUA systems was also elucidated by using dynamic mechanical analysis tests. The results demonstrated that the α-methyl group blocks the migration of reactive radicals, reduces the efficiency of the photoreaction, and causes an increase in the rigidity and strength of the molecular chain. This study not only revealed the effect of α-methyl on the kinetic mechanical and thermal performance of PUA systems but also paves the way for the development of a new class of photosensitive PUA materials used for the photocurable 3D printing technology.

AAEM Species Migration/Transformation during Co-Combustion of Carbonaceous Feedstocks and Synergy Behavior on Co-Combustion Reactivity: A Critical Review

Co-combustion is a crucial route for the high-efficiency utilization and clean conversion of different carbonaceous feedstocks (biomass, coal, petroleum coke, etc.). The migration and transformation of alkali and alkaline earth metals (AAEMs) are not only related to ash-related issues in actual application, but also directly affect the reaction behavior of binary particles during co-conversion. This review paper summarizes research progress in the detection methods (online and offline) and influencing factors (feedstock type, feedstock blending ratio, reaction temperature, reaction time) of AAEMs migration and transformation during the co-combustion of carbonaceous feedstocks. Furthermore, it provides a detailed summary of research progress on factors (feedstock blending ratio, heating rate, etc.) influencing the co-combustion reactivity of carbonaceous feedstocks, synergy behavior, and its mechanisms. The influence of feedstock type on AAEMs migration and transformation during co-combustion is mainly related to the composition categories, chemical forms and contents of intrinsic mineral in binary feedstocks. The increase in the combustion temperature will intensify the release of inherent AAEMs in carbonaceous feedstocks, and promote AAEM deactivation. For high K and Cl-containing biomass, a higher biomass proportion in blends would result in more AAEMs release during the co-combustion process. Conversely, an increase in coal proportion in blends will directly favor the reduction or inhibition of AAEMs release. Synergy behavior during co-pyrolysis and subsequent char co-combustion is usually presented as an inhibition effect and an synergistic effect, respectively. The synergistic mechanisms of carbonaceous feedstock co-combustion reactions can be divided into two categories: non-catalytic synergistic mechanisms related to the excitation and migration of biomass-based free radicals and catalytic synergistic mechanisms related to biomass-based AAEMs catalysis. Additionally, future research prospects are also proposed based on the systematic review.

Decarboxylation of β-boryl NHPI esters enables radical 1,2-boron shift for the assembly of versatile organoborons

In recent years, numerous 1,2-R shift (R = aliphatic or aryl) based on tetracoordinate boron species have been well investigated. In the contrary, the corresponding radical migrations, especially 1,2-boryl radical shift for the construction of organoborons is still in its infancy. Given the paucity and significance of such strategies in boron chemistry, it is urgent to develop other efficient and alternative synthetic protocols to enrich these underdeveloped radical 1,2-boron migrations, before their fundamental potential applications could be fully explored at will. Herein, we have demonstrated a visible-light-induced photoredox neutral decarboxylative radical cross-coupling reaction, which undergoes a radical 1,2-boron shift to give a translocated C-radical for further capture of versatile radical acceptors. The mild reaction conditions, good functional-group tolerance, and broad β-boryl NHPI esters scope as well as versatile radical acceptors make this protocol applicable in modification of bioactive molecules. It can be expected that this methodology will be a very useful tool and an alternative strategy for the construction of primary organoborons via a novel radical 1,2-boron shift mode.

Atomic-level analysis of migration and transformation of organic sodium in high-alkali coal pyrolysis using reactive molecular dynamics simulations

Monitoring the migration and transformation of free radicals and alkali metals (such as tar- and organic gas-bonded sodium) in high-alkali coal pyrolysis through experimental methods alone is a challenging task. To address this challenge, in this work we employed reactive force field (ReaxFF) molecular dynamics simulations to model the transformation behavior of sodium at the atomic level. The different forms of sodium [sodium atoms (Na(g)), sodium hydroxide (NaOH(g)), tar-bonded sodium, and organic gas-bonded sodium] were carefully analyzed to gain insights into their migration during the pyrolysis process. The results show that inherent organic sodium forms binary or multiple coordination structures with oxygen atoms in the coal matrix during pyrolysis. During pyrolysis, inherent organic sodium was transformed into three main sodium species: Na atoms, NaOH, and Na·H2O. The repeated reactions between these sodium-containing intermediates and the coal matrix strengthen the three-dimensional network structure of the coal matrix and hinder its graphitization. The preponderance of Na(g) predominantly stems from organic sodium C1–40+Na, while NaOH and Na·H2O contribute to a lesser extent. The formation of NaOH and Na·H2O can be primarily attributed to the presence of Na(g), with merely a limited portion arising from organic sodium (C1–40+Na). The results also show that organic sodium inhibits char and tar formation at high temperatures, whereas at low temperatures it promotes char formation and inhibits tar production.

Photocatalyzed regioselective hydrosilylation for the divergent synthesis of geminal and vicinal borosilanes

Geminal and vicinal borosilanes are useful building blocks in synthetic chemistry and material science. Hydrosilylation/hydroborylation of unsaturated systems offer expedient access to these motifs. In contrast to the well-established transition-metal-catalyzed methods, radical approaches are rarely explored. Herein we report the synthesis of geminal borosilanes from α-selective hydrosilylation of alkenyl boronates via photoinduced hydrogen atom transfer (HAT) catalysis. Mechanistic studies implicate that the α-selectivity originates from a kinetically favored radical addition and an energetically favored HAT process. We further demonstrate selective synthesis of vicinal borosilanes through hydrosilylation of allyl boronates via 1,2-boron radical migration. These strategies exhibit broad scopes across primary, secondary, and tertiary silanes and various boron compounds. The synthetic utility is evidenced by access to multi-borosilanes in a diverse fashion and scaling up by continuous-flow synthesis.

Structural identification of carbohydrate isomers using ambient infrared-assisted dissociation

Informative dissociation of carbohydrates using an infrared (IR) irradiation system is demonstrated under ambient conditions without the instrumentation of a mass spectrometer. Structural identification of carbohydrates and associated conjugates is essential for understanding their biological functions, but identification remains challenging. Herein, an easy and rugged method is reported for the structural identification of model carbohydrates, including Globo-H, three trisaccharide isomers (nigerotriose/laminaritriose/cellotriose), and two hexasaccharide isomers (laminarihexaose/isomaltohexaose). For Globo-H, the numbers of cross-ring cleavages increased by factors of 4.4 and 3.4 upon ambient IR exposure, compared to an untreated control and a collision-induced dissociation (CID) sample. Moreover, 25–82% enhancement in the numbers of glycosidic bond cleavages upon ambient IR exposure was also obtained compared to untreated and CID samples. Unique features of first-generation fragments produced by ambient IR facilitated the differentiation of three trisaccharide isomers. Semi-quantitative analysis was achieved (coefficient of determination (R2) of 0.982) in a mixture of two hexasaccharide isomers via unique features generated upon ambient IR. Photothermal and radical migration effects induced by ambient IR were postulated as responsible for promoting carbohydrate fragmentation. This easy and rugged method could be a universally applicable protocol and complementary to other techniques for detailed structural characterization of carbohydrates.

C-H Functionalization of Heterocycles with Triplet Carbenes by means of an Unexpected 1,2-Alkyl Radical Migration.

The C-H functionalization of indole heterocycles constitutes a key strategy to leverage the synthesis of endogenous signaling molecules such as tryptamine or tryptophol. Herein, we report on the photocatalytic reaction of ethyl diazoacetate with indole, which shows an unusual solvent dependency. While C2-functionalization occurs under protic conditions, the use of aprotic solvents leads to a complete reversal of selectivity and exclusive C3-functionalization occurs. To rationalize for this unexpected reactivity switch, we have conducted detailed theoretical and experimental studies, which suggest the participation of a triplet carbene intermediate that undergoes initial C2-functionalization. A distinct cationic [1,2]-alkyl radical migration then leads to formation of C3-functionalized indole. We conclude with the application of this photocatalytic reaction to access oxidized tryptophol derivatives including gram-scale synthesis and derivatization reactions.

Probing radical versus proton migration in the aniline cation with IRMPD spectroscopy

Intramolecular radical and proton migration in the gas phase are important processes driving the dissociation reactions underlying common tandem mass spectrometry processes, such as collision-induced and electron-induced dissociation reactions (CID and ExD). Mechanistic insights in these processes requires experiments that probe the molecular structures of ions along the reaction pathways, usually combined with quantum-chemical calculations. The combination of ion trap mass spectrometry with IR laser spectroscopy, pioneered among others by Dieter Gerlich, provides a particularly effective method to explore details of the ion structures. In this work, we employ infrared multiple-photon dissociation (IRMPD) spectroscopy and density functional theory (DFT) calculations to probe the reactant and product ion structures of a homolytic bond cleavage reaction. First, we employ IRMPD spectroscopy to establish that protonation of the 4-bromoaniline precursor occurs on the amine moiety and then that C-Br homolytic cleavage produces the π-radical cation of aniline. Transition-state calculations are performed to compare the various pathways that connect reactant and product ions, including both proton and radical transfer mechanisms.

Photoinduced Remote C(sp3)-H Imination Enabled by Vinyl Radical-Mediated 1,5-Hydrogen Atom Transfer.

A vinyl radical-mediated 1,5-hydrogen atom transfer strategy for remote C(sp3)-H imination under visible-light-induced photochemical metal-free conditions afforded diverse γ-imino alkenes with excellent stereoselectivity. Oxime ester-based bifunctional reagents provided not only nucleophilic alkyl radicals for radical addition reactions with electron-deficient alkynes but also long-lived steady-state imine radicals for trapping alkyl radicals following the intramolecular 1,5-hydrogen migration of unstable olefin radicals.

Mechanistic Study into Free Radical-Activated Glycan Dissociations through Isotope-Labeled Cellobioses.

Inspired by the electron-activated dissociation technique, the most potent tool for glycan characterization, we recently developed free radical reagents for glycan structural elucidation. However, the underlying mechanisms of free radical-induced glycan dissociation remain unclear and, therefore, hinder the rational optimization of the free radical reagents and the interpretation of tandem mass spectra, especially the accurate assignment of the relatively low-abundant but information-rich ions. In this work, we selectively incorporate the 13C and/or 18O isotopes into cellobiose to study the mechanisms for free radical-induced dissociation of glycans. The eight isotope-labeled cellobioses include 1-13C, 3-13C, 1'-13C, 2'-13C, 3'-13C, 4'-13C, 5'-13C, and 1'-13C-4-18O-cellobioses. Upon one-step collisional activation, cross-ring (X ions), glycosidic bond (Y-, Z-, and B-related ions), and combinational (Y1 + 0,4X0 ion) cleavages are generated. These fragment ions can be unambiguously assigned and confirmed by the mass difference of isotope labeling. Importantly, the relatively low-abundant but information-rich ions, such as 1,5X0 + H, 1,4X0 + H, 2,4X0 + H-OH, Y1 + 0,4X0, 2,5X1-H, 3,5X0-H, 0,3X0-H, 1,4X0-H, and B2-3H, are confidently assigned. The mechanisms for the formations of these ions are investigated and supported by quantum chemical calculations. These ions are generally initiated by hydrogen abstraction followed by sequential β-elimination and/or radical migration. Here, the mechanistic study for free radical-induced glycan dissociation allows us to interpret all of the free radical-induced fragment ions accurately and, therefore, enables the differentiation of stereochemical isomers. Moreover, it provides fundamental knowledge for the subsequent development of bioinformatics tools to interpret the complex free radical-induced glycan spectra.

New insights into controlling radical migration pathways in heme enzymes gained from the study of a dye-decolorising peroxidase.

In heme enzymes, such as members of the dye-decolorising peroxidase (DyP) family, the formation of the highly oxidising catalytic Fe(iv)-oxo intermediates following reaction with hydrogen peroxide can lead to free radical migration (hole hopping) from the heme to form cationic tyrosine and/or tryptophan radicals. These species are highly oxidising (∼1 V vs. NHE) and under certain circumstances can catalyse the oxidation of organic substrates. Factors that govern which specific tyrosine or tryptophan the free radical migrates to in heme enzymes are not well understood, although in the case of tyrosyl radical formation the nearby proximity of a proton acceptor is a recognised facilitating factor. By using an A-type member of the DyP family (DtpAa) as an exemplar, we combine protein engineering, X-ray crystallography, hole-hopping calculations, EPR spectroscopy and kinetic modelling to provide compelling new insights into the control of radical migration pathways following reaction of the heme with hydrogen peroxide. We demonstrate that the presence of a tryptophan/tyrosine dyad motif displaying a T-shaped orientation of aromatic rings on the proximal side of the heme dominates the radical migration landscape in wild-type DtpAa and continues to do so following the rational engineering into DtpAa of a previously identified radical migration pathway in an A-type homolog on the distal side of the heme. Only on disrupting the proximal dyad, through removal of an oxygen atom, does the radical migration pathway then switch to the engineered distal pathway to form the desired tyrosyl radical. Implications for protein design and biocatalysis are discussed.