Radical Moiety Research Articles

A redox-mediated Kemp eliminase

The acid/base-catalysed Kemp elimination of 5-nitro-benzisoxazole forming 2-cyano-4-nitrophenol has long served as a design platform of enzymes with non-natural reactions, providing new mechanistic insights in protein science. Here we describe an alternative concept based on redox catalysis by P450-BM3, leading to the same Kemp product via a fundamentally different mechanism. QM/MM computations show that it involves coordination of the substrate’s N-atom to haem-Fe(II) with electron transfer and concomitant N–O heterolysis liberating an intermediate having a nitrogen radical moiety Fe(III)–N· and a phenoxyl anion. Product formation occurs by bond rotation and H-transfer. Two rationally chosen point mutations cause a notable increase in activity. The results shed light on the prevailing mechanistic uncertainties in human P450-catalysed metabolism of the immunomodulatory drug leflunomide, which likewise undergoes redox-mediated Kemp elimination by P450-BM3. Other isoxazole-based pharmaceuticals are probably also metabolized by a redox mechanism. Our work provides a basis for designing future artificial enzymes.

N2 elimination thermolysis reactions of 9-(4- and 5-substituted-1,2,3-triazol-1-yl)acridines to produce 1H-pyrido-[4,3,2-kl] derivatives – A theoretical study

9-azidoacridine reacts under 1,3-dipolar reaction with alkyne derivatives to yield 9-(4- and 5-substituted-1,2,3-triazol-1-yl)acridine derivatives. The extrusion of N2 from these compounds leads to formation of carbene and biradical intermediates. Radical moieties interact with the acridine ring to form 1H-pyrido-[4,3,2-kl] derivatives. The focus of this study was on the theoretical and computational studies of the pathways of the products. The energy levels of the reactant species, TS forms (transition states), products, the free energies of reaction (ΔrG and ΔG#), HOMO & LUMO orbital levels, the ΔEHOMO-LUMO, dipolmoments, rate constants by using Eyring's equation (k and k′), structural data were calculated by DFT (B3LYP/6-31G∗) method. The relative energies (in kcalmol−1) of the transition states as well as the biradical (singlet (S) and triplet (T); and carbene (singlet (S) and triplet (T); intermediates of the pyrolysis reactions on the reactants were investigated as well. The stepwise of the N2 elimination reactions have also investigated. The values of the free activation energy (ΔG#) in the concerted N2 elimination pyrolysis reactions were correlated to the decomposition temperature (TDecom.) of reactants.

A nitroxide diradical containing a ferrocen-1,1′-diyl-substituted 1,3-diazetidine-2,4-diimine coupler

An Aza-Wittig reaction of 1,1′-bis(triphenylphosphoranylidenamino)-ferrocene with 3-isocyanato-2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrol-1-oxyl and subsequent intramolecular [2+2]-cycloaddition of the bis(carbodiimide) intermediate was used for the synthesis of a 1,3-diazetidine-2,4-diimine moiety bearing two radical groups and bridging the cyclopentadienyl (Cp) rings. According to single-crystal X-ray data, the planar 2,4-diimino-1,3-diazetidine moiety adopts a perpendicular orientation with respect to the eclipsed Cp rings. One of the radical groups lies almost within the plane of the four-membered 1,3-diazetidine ring, while the other has a conformationally preferred orientation with dihedral angles ±62.3°. The two Cp rings are constricted by the 1,3-diazetidine-2,4-diimine moiety so that the angle between their planes is 11.0°. The synthesized diradical contains ferrocene and nitroxide redox signaling units that can be oxidized step-by-step at E1/2=0.26 and 0.48V (vs Fc/Fc+), respectively. Electron spin resonance spectroscopy revealed a moderate exchange interaction (|J|∼aN) between the two nitroxide radical moieties and the following values of zero-field splitting parameters: ∣D∣=3.5mT and E/D=0 were obtained. These data were in agreement with density functional theory calculations. The newly developed approach to multispin systems may be interesting for the construction of weakly coupled rigid polyradicals for quantum technologies, the molecular design of magnets, and the creation of ferrocene-based electron-paramagnetic-resonance–active chemical sensors.

Synthesis and Characterization of Ethylenedithio-MPTTF-PTM Radical Dyad as a Potential Neutral Radical Conductor

During the last years there has been a high interest in the development of new purely-organic single-component conductors. Very recently, we have reported a new neutral radical conductor based on the perchlorotriphenylmethyl (PTM) radical moiety linked to a monopyrrolo-tetrathiafulvalene (MPTTF) unit by a π-conjugated bridge (1) that behaves as a semiconductor under high pressure. With the aim of developing a new material with improved conducting properties, we have designed and synthesized the radical dyad 2 which was functionalized with an ethylenedithio (EDT) group in order to improve the intermolecular interactions of the tetrathiafulvalene (TTF) subunits. The physical properties of the new radical dyad 2 were studied in detail in solution to further analyze its electronic structure.

Functionalization of sterically hindered catechol and o-benzoquinone with 2,2,6,6-tetramethylpiperidine 1-oxyl

Sterically hindered 4,6-di-tert-butyl-3-formylcatechol and 3,6-di-tert-butyl-o-benzoquinone react with 4-amino-2,2,6,6-tetramethylpiperidine 1-oxyl to give new chelate ligands of the o-quinone type bearing a 2,2,6,6-tetramethylpiperidine 1-oxyl neutral radical moiety. Structures of the synthesized compounds were established by ESR spectroscopy, IR spectroscopy, mass spectrometry, and X-ray diffraction analysis.

Why Is There a Barrier in the Coupling of Two Radicals in the Water Oxidation Reaction?

Two radicals can form a bond without an energetic barrier. However, the radical coupling mechanism in ruthenium-catalyzed water oxidation has been found to be associated with substantial activation energies. Here we have investigated the coupling reaction of [Ru═O(bda)L2]+ catalysts with different axial L ligands. The interaction between the two oxo radical moieties at the Ru(V) state was found to have a favorable interaction in the transition state in comparison to the prereactive complex. To further understand the existence of the activation energy, the activation energy has been decomposed into distortion energy and interaction energy. No correlation between the experimental rates and the calculated coupling barriers of different axial L was found, showing that more aspects such as solvation, supramolecular properties, and solvent dynamics likely play important roles in the equilibrium between the free RuV═O monomer and the [RuV═O···O═RuV] dimer. On the basis of our findings, we give general guidelines...

Schiff’s base derivatives of murrayanine demonstrated enhanced anti-oxidant activity than its parent moiety

Abstract: Objective: Free radicals like superoxide anion radical (O2.-), hydroxyl radical (HO.), alkyl radical (R.), alkoxy radical (RO.), peroxy radical (ROO.) and nitric oxide radical (NO.) often leads to oncogenic proliferation, damage deoxyribosyl backbone of DNA, accelerate oxidation of polydesaturated fatty acids, amino acids, and several other co-factors. Several carbazole moieties present in M. koenigii L. like murrayanine, mahanimbine, curryanine, kurryam have been reported to exhibit good anti-oxidant activity. The present research represents an effort to develop few novel hybridized derivatives of murrayanine (an active carbazole derivative) by reacting with various small ligands like urea, semi carbazide and thio semi carbazide with an intention to develop Schiff’s base compounds with higher and potent anti-oxidant activity than its parent moiety (murrayanine). Methods: The study protocol involved DPPH radical scavenging assay and determining in vitro reducing activity of the semi-synthetic derivatives. Results: The study revealed that compound 5 exhibited highest anti-oxidant activity (IC50 of 6.5 μM), followed by derivative 3 which displayed activity at IC50 value of 7.3 μM, which was superior as compared to murrayanine 1 which scavenge the radical at IC50 of 7.6 μM. However, two semi-synthetic compounds (2 and 4) exhibited lesser activity compared to murrayanine, IC50s of 7.8 and 8.1μM, respectively. The compounds exhibited absorbance in range 0.76-1.3. Highest absorbance of 1.079 was demonstrated by 5. Conclusion: This study can be concluded that these derivatives may have enough potential to be used as antioxidants and open new doors for research perspectives towards the development of novel radical scavenging moiety. Key words: Murrayanine, Carbazole, Schiff’s base, Anti-oxidant, Semi-synthetic.

Radical Cation of an Oligoarylamine Having a Nitroxide Radical Substituent: A Coexistent Molecular System of Localized and Delocalized Spins.

A trimer derivative of oligotriarylamine bearing a nitroxide radical substituent as a localized spin center {N,N-bis[4-(di-4-anisylamino)phenyl]-N-[3-tert-butyl-5-(N-tert-butyl-N-oxylamino)phenyl]amine (1)} was characterized by electrochemical, spectroelectrochemical, and electron paramagnetic resonance spectroscopic measurements. The first and second oxidations of 1 occurred from the triamine moiety, leaving the nitroxide radical moiety intact. The delocalized polaronic state in the triamine moiety was generated by one-electron oxidation of 1, indicating the coexistence of localized and delocalized spins on 1+, where an intramolecular antiferromagnetic interaction was detected.

Synthesis and Straightforward Quantification Methods of Imino Nitroxide-Based Hexaradical Architecture on a Cyclotriphosphazene Scaffold.

The synthesis of a homogeneous neutral hexaradical architecture consisting of six imino nitroxide radical moieties covalently bonded on a cyclotriphosphazene scaffold was reported. The synthesis of hexaradical imino nitroxide compounds follows the Ullman procedure involving the condensation of 2,3-bis(hydroxylamino)-2,3-dimethylbutane with hexa-(4-formylphenoxy)cyclotriphosphazene (3) followed by oxidation of the condensation product hexa-[4-(1-hydroxy-4,4,5,5-tetramethyl-2-imidazoline-2-yl)phenoxy]cyclotriphosphazene (2) by NaIO4. Characterization of hexaradical was performed by X-ray and SQUID in solid state and by EPR, absorption spectroscopy, and electrochemistry in solution. CV of 1 shows an oxidation peak at 1.184 V (vs SCE) and a reduction peak at -0.883 V, both characteristics of the presence of phenyl imino nitroxide (7) moieties, suggesting that the contribution of the cyclotriphosphazene core is negligible. Attention was particularly focused on developing methods, UV-vis spectroscopy and square-wave voltammetry, to quantify the number of radicals in a way to confirm easily and rapidly the polyradicals' structure.

Surface carboxylation of cellulose nanowhiskers using mPEG-TEMPO: its recovery and recycling

Surface carboxylation of cellulose nanowhiskers (CNWs) was performed using mPEG2000-TEMPO, a 2,2,6,6-tetramethyl-1-piperidinyloxy radical moiety grafted to monomethoxy poly(ethylene glycol) 2000. After the oxidation step, the used mPEG2000-TEMPO was recovered by extraction with dichloromethane and reused for further oxidation cycles. mPEG2000-TEMPO could be used for the surface oxidation of CNWs for at least three repeated cycles, although the degree of oxidation in the second and third cycles was reduced to 60% of that in the first cycle. The recovery of mPEG2000-TEMPO after every cycle was not complete (~80%), thus suggesting an irreversible adsorption of mPEG2000-TEMPO on the surface of the CCNWs.

Self-Assembled Fibers Containing Stable Organic Radical Moieties: Alignment and Magnetic Properties in Liquid Crystals.

Macroscopically oriented stable organic radicals have been obtained by using a liquid-crystalline (LC) gel composed of an l-isoleucine-based low molecular weight gelator containing a 2,2,6,6-tetramethylpiperidine 1-oxyl moiety. The LC gel has allowed magnetic measurements of the oriented organic radical. The gelator has formed fibrous aggregates in liquid crystals via intermolecular hydrogen bonds. The fibrous aggregates of the radical gelator are formed and oriented on cooling by applying a magnetic field to the mixture of liquid crystals and the gelator. Superconducting quantum interference device (SQUID) measurements have revealed that both oriented and nonoriented fibrous aggregates exhibited antiferromagnetic interactions, in which super-exchange interaction constant J is estimated as -0.89 cm(-1) .

4‐Amino‐TEMPO as N‐Nucleophile in Palladium‐Catalyzed Aminocarbonylation

Palladium‐catalyzed aminocarbonylation of iodobenzene and iodoalkenes (1‐iodocyclohexene, 4‐tert‐butyl‐1‐iodocyclohexene, α‐iodostyrene, 17‐iodoandrost‐16‐ene) was carried out using a free radical (4‐amino‐TEMPO) for the first time. Its reduced form (4‐amino‐2,2,6,6‐tetramethylpiperidine) was also used as N‐nucleophile. The free radical was partially reduced under aminocarbonylation conditions; however, the isolation of carbonylated products bearing a stable radical moiety was successfully accomplished. It was proved that the reduction of the 1‐oxyl functionality took place to higher extent when more severe conditions (40 bar CO pressure) were used. The mixture of carboxamide and 2‐ketocarboxamide products was obtained using iodobenzene because of single and double carbon monoxide insertion, respectively. In turn, carboxamide derivatives were formed exclusively when iodoalkenes were used as substrates.

Diastereoselective Synthesis of 6″-(Z)- and 6″-(E)-Fluoro Analogues of Anti-hepatitis B Virus Agent Entecavir and Its Evaluation of the Activity and Toxicity Profile of the Diastereomers.

A method for the diastereoselective synthesis of 6″-(Z)- and 6″-(E)-fluorinated analogues of the anti-HBV agent entecavir has been developed. Construction of the methylenecyclopentane skeleton of the target molecules has been accomplished by radical-mediated 5-exo-dig cyclization of the selenides 6 and 15 having the phenylsulfanylethynyl structure as a radical accepting moiety. In the radical reaction of the TBS-protected precursor 6, (Z)-anti-12 was formed as a major product. On the other hand, TIPS-protected 15 gave (E)-anti-12. The sulfur-extrusive stannylation of anti-12 furnished a mixture of geometric isomers of the respective vinylstannane, whereas benzoyl-protected 17 underwent the stannylation in the manner of retention of configuration. Following XeF2-mediated fluorination, introduction of the purine base and deoxygenation of the resulting carbocyclic guanosine gave the target (E)- and (Z)-3 after deprotection. Evaluation of the anti-HBV activity of 3 revealed that fluorine-substitution at the 6″-position of entecavir gave rise to a reduction in the cytotoxicity in HepG2 cells with retention of the antiviral activity.

Porphyrin Cobalt(III) "Nitrene Radical" Reactivity; Hydrogen Atom Transfer from Ortho-YH Substituents to the Nitrene Moiety of Cobalt-Bound Aryl Nitrene Intermediates (Y = O, NH).

In the field of cobalt(II) porphyrin-catalyzed metallo-radical reactions, organic azides have emerged as successful nitrene transfer reagents. In the pursuit of employing ortho-YH substituted (Y = O, NH) aryl azides in Co(II) porphyrin-catalyzed nitrene transfer reactions, unexpected hydrogen atom transfer (HAT) from the OH or NH2 group in the ortho-position to the nitrene moiety of the key radical-intermediate was observed. This leads to formation of reactive ortho-iminoquinonoid (Y = O) and phenylene diimine (Y = NH) species. These intermediates convert to subsequent products in non-catalyzed reactions, as is typical for these free organic compounds. As such, the observed reactions prevent the anticipated cobalt-mediated catalytic radical-type coupling of the nitrene radical intermediates to alkynes or alkenes. Nonetheless, the observed reactions provide valuable insights into the reactivity of transition metal nitrene-radical intermediates, and give access to ortho-iminoquinonoid and phenylene diimine intermediates from ortho-YH substituted aryl azides in a catalytic manner. The latter can be employed as intermediates in one-pot catalytic transformations. From the ortho-hydroxy aryl azide substrates both phenoxizinones and benzoxazines could be synthesized in high yields. From the ortho-amino aryl azide substrates azabenzene compounds were obtained as the main products. Computational studies support these observations, and reveal that HAT from the neighboring OH and NH2 moiety to the nitrene radical moiety has a low energy barrier.

Gas-Phase Unimolecular Dissociation Reveals Dominant Base Property of Protonated Homocysteine Sulfinyl Radical Ions.

Homocysteine sulfinyl radical ((SO⋅) Hcy) is a reactive intermediate involved during oxidative damage of DNA in the presence of high concentrations of homocysteine (Hcy). The short lifetime of (SO⋅) Hcy makes its preparation, isolation, and characterization challenging using traditional chemical measurement tools. Herein, we demonstrate the first study on mass-selected protonated (SO⋅) Hcy ions in the gas phase by investigating its unimolecular dissociation pathways from low energy collision-induced dissociation (CID). Tandem mass spectrometry (MS/MS), stable-isotope labeling, and theoretical calculations were employed to rationalize the observed fragmentation pathways. The dominant dissociation channel of protonated (SO⋅) Hcy was a charge-directed H2 O loss from the protonated sulfinyl radical (-SO⋅) moiety, forming a thiyl radical (-S⋅), which further triggered sequential radical-directed ⋅SH loss through multiple pathways. Compared to cysteine sulfinyl radical ((SO⋅) Cys), the small structural change induced by one additional methylene group in the side chain of (SO⋅) Hcy significantly promotes its base property while reducing the radical reactivity of sulfinyl radical. This observation provides new insight into studying reactions of (SO⋅) Hcy with biomolecules, which are critical in understanding toxicity induced by high levels of Hcy in biological conditions.

Investigation of the mechanism of electron capture and electron transfer dissociation of peptides with a covalently attached free radical hydrogen atom scavenger

The mechanisms of electron capture and electron transfer dissociation (ECD and ETD) are investigated by covalently attaching a free-radical hydrogen atom scavenger to a peptide. The 2,2,6,6-tetramethylpiperidin-l-oxyl (TEMPO) radical was chosen as the scavenger due to its high hydrogen atom affinity (ca. 280kJ/mol) and low electron affinity (ca. 0.45eV), and was derivatized to the model peptide, FQXTEMPOEEQQQTEDELQDK. The XTEMPO residue represents a cysteinyl residue derivatized with an acetamido-TEMPO group. The acetamide group without TEMPO was also examined as a control. The gas phase proton affinity (882kJ/mol) of TEMPO is similar to backbone amide carbonyls (889kJ/mol), minimizing perturbation to internal solvation and sites of protonation of the derivatized peptides. Collision-induced dissociation (CID) of the TEMPO-tagged peptide dication generated stable odd-electron b and y type ions without indication of any TEMPO radical induced fragmentation initiated by hydrogen abstraction. The type and abundance of fragment ions observed in the CID spectra of the TEMPO and acetamide tagged peptides are very similar. However, ECD of the TEMPO-labeled peptide dication yielded no backbone cleavage. We propose that a labile hydrogen atom in the charge reduced radical ions is scavenged by the TEMPO radical moiety, resulting in inhibition of NCα backbone cleavage processes. Supplemental activation after electron attachment (ETcaD) and CID of the charge-reduced precursor ion generated by electron transfer of the TEMPO-tagged peptide dication produced a series of b+H (bH) and y+H (yH) ions along with some c ions having suppressed intensities, consistent with stable OH bond formation at the TEMPO group. In summary, the results indicate that ECD and ETD backbone cleavage processes are inhibited by scavenging of a labile hydrogen atom by the localized TEMPO radical moiety. This observation supports the conjecture that ECD and ETD processes involve long-lived intermediates formed by electron capture/transfer in which a labile hydrogen atom is present and plays a key role with low energy processes leading to c and z ion formation. Ab initio and density functional calculations are performed to support our conclusion, which depends most importantly on the proton affinity, electron affinity and hydrogen atom affinity of the TEMPO moiety.

Fundamental Charge Transfer Processes in Stable Free-Radical Organic Polymer Systems

Polymers with stable pendant radical groups are a unique class of redox-active materials emerging as potentially the next generation energy storage breakthrough. These polymers facilitate apparently remarkably rapid, efficient and reversible multi-step charge-transfer processes. The focus of this project is to advance the fundamental understanding of the structure-property relationships associated with the mechanism(s) of electron transfer and ion transport, along with associated interfacial mass-transfer processes that impact the charge-transfer processes of a unique class of organic free-radical polymeric redox active materials. The project involves an integrated approach of chemical synthesis, electrochemistry, spectroscopy and theoretical modeling of a series of stable organic radical materials. Initially, we have focused on the 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO) organic radical moiety incorporated into a complex materials set of poly(4-methacryloyloxy-2,2,6,6-tetramethylpiperidine-N-oxyl) (PTMA). We focused our work to probe, and establish, the charge-transfer mechanisms of a series of the TEMPO-containing macromolecules with varying chain lengths and side-chain compositions. We have investigated the model compound, 4-oxo-2,2,6,6-tetramethylpiperidine-N-oxyl (4-oxo-TEMPO), and compared the results to those for non-cross-linked and cross-linked PTMA oligomers and polymers with: (i) various oligomer chain-lengths; and (ii) controlled densities of the TEMPO radical moieties along the chain (i.e. with some TEMPO-methacrylate units replaced by methyl methacrylate). Our presentation will discuss a complete electrochemical analysis of the TEMPO polymeric materials. The discussion will include the correlation of electron-transfer rates and ionic mobility in various electrochemical solvents, and the role that radical content has on both the heterogeneous electron-transfer rate and the self-exchange charge transfer mechanism of the various materials.

Positional Isomers of Tetramethoxypyrene-based Mono- and Biradicals.

The positional isomers of tert-butylnitroxide (NO) substituted 4,5,9,10-tetramethoxypyrene-based mono- and biradical are synthesized. While the biradical 2,7-TMPNO in which two NO radical moieties are attached at the nodal plane of pyrene adopts a semiquinoid structure, the 1,6- and 1,8-isomers of the same exist in biradical form. The tuning of the antiferromagnetic exchange interactions is achieved by synthesizing the positional isomers of the biradical while maintaining the same radical moiety as well as the π spacer.

Terminal Fluorinated Nitroxide Radical Liquid Crystalline Compounds

We have synthesized a new series of all-organic paramagnetic liquid crystalline (LC) compounds, which include a five-membered ring nitroxide radical (NR) moiety in the mesogen core and fluorine atoms as terminal substituents. These new compounds are the structural analogs of the previously reported NR-LC compounds, and showed remarkable fluorine substituent effects. The introducing fluorine atom into terminal unit stabilizes nematic phase. However, an excess of fluorination leads to the destabilization of nematic phase.

Reaction Pathways for Water Oxidation to Molecular Oxygen Mediated by Model Cobalt Oxide Dimer and Cubane Catalysts

Hybrid density functional theory calculations have been employed to investigate the water oxidation reaction on model cobalt oxide dimer and cubane complexes. Electronic structure and energetics of these model compounds were thoroughly investigated. The thermodynamically lowest energy pathway on the dimer catalyst proceeds through a nucleophilic attack of a solvent water molecule to Co(V)-O radical moiety. The lowest energy pathway on the cubane catalyst involves a geminal coupling of Co(V)-O radical oxo group with bridging oxo sites. Model systems were found to be very sensitive to the positions of ligands and to the hydrogen-bonding environment leading to different isomer energies.