Diradical Intermediates Research Articles

Stable meso-meso-Linked 2NH-Corrole Radical Dimers as a Key Intermediate to Corrole Tape.

While oxidation of 5,5',15,15'-tetramesityl-10-10'-linked 3NH-corrole dimer with DDQ gave the corresponding triply linked 2NH-corrole tape, the use of an equimolar amount of p-chloranil as a milder oxidant resulted in the formation of a 10-10'-linked neutral 2NH-corrole radical dimer as a stable product. The stability of this peculiar product is ascribed largely to strong antiferromagnetic interaction of the two spins. Further oxidation of this diradical produced corrole tape, suggesting its involvement as a reaction intermediate to the corrole tape. Oxidation of 10-10'-linked bis-pyridine-coordinated CoIII corrole dimer with DDQ produced a cobalt corrole radical dimer and a doubly linked corrole dimer both as stable compounds bearing pyridine and cyanide axial ligands. This type of oxidative transformation involving neutral diradical intermediates is a unique reaction mechanism specific for corrole dimers.

Does the photoredox reaction affect the photorelease of anthraquinone protected benzaldehyde? A time-resolved spectroscopic study.

In this study, combined time-resolved spectroscopies of femtosecond transient absorption, nanosecond transient absorption, and nanosecond time-resolved resonance Raman spectroscopies as well as DFT calculations were performed to unravel the photorelease reaction mechanism of anthraquinon-2-ylethyl-1,2-diol protected carbonyl compound (Aqe-diol-PPG). It was shown that the triplet state of Aqe-diol-PPG underwent a PCET process to form a xylylene intermediate. After the C-O bond cleavage, a diradical intermediate was generated, which further released the protected benzaldehyde with the by-product Aqe-diol. A comparison work suggested that Aqe-diol underwent a further photoredox reaction in aqueous solutions.

Facilitating Myers-Saito cyclization through acid-triggered tautomerization for the development of maleimide-based antitumor agents.

Enyne-allene compounds undergo Myers-Saito cyclization at physiological temperature to generate diradical intermediates that are capable of inducing DNA damage and cell death. The high reactivity of enyne-allene however limits their promising prospect as anticancer agents due to the spontaneous cyclization during storage and delivery. Regulating the cyclization process by taking advantage of the characteristics of a tumor cellular microenvironment, such as employing a low pH value to activate the cyclization process, is thus of essential importance. In this work, a novel enediyne (EDY) system with locked carbonyl groups was specifically designed and synthesized. Unlocking the protected carbonyl groups in the presence of acid would facilitate the rearrangement of propargyl moieties into an allene group, enabling the formation of an enyne-allene structure and occurrence of Myers-Saito cyclization. The pH-dependent diradical generation and DNA-cleavage ability of the designed EDY system were confirmed by electron paramagnetic resonance analysis and DNA gel electrophoresis. A promising cytotoxicity against HeLa cells with half inhibition concentrations (IC50) as low as 1.40 μM was obtained, which was comparable to those of many commercially applied anticancer drugs. Further in vitro experiments revealed that this EDY system induced intracellular DNA damage and subsequently resulted in S-phase arrest and cytotoxicity through programmed apoptosis.

Role of Singlet Oxygen in the Degradation of Selected Insensitive Munitions Compounds: A Comprehensive, Quantum Chemical Investigation.

DNAN (2,4-dinitroanisole), NTO (3-nitro-1,2,4-triazol-5-one), and NQ (nitroguanidine) are important energetic materials used in military applications. They may find their way to the environment during manufacturing, transportation, storage, training, and disposal. A detailed investigation of possible mechanisms for reactions of the nitrocompounds with singlet oxygen, one of the potential methods for their degradation, was performed by computational study using the PCM(Pauling)/M06-2X/6-311++G(d,p) approach. Obtained results suggest that reactivity of the investigated munitions compounds toward singlet oxygen follows the order: DNAN > NTO(anion) > NQ ≫ NTO. DNAN is involved in [4 + 2]-addition with oxygen, and further formation of diepoxide or epoxyketone through diradical intermediates have been predicted. The NTO may undergo intramolecular rearrangement with formation of peroxide compound or nitrite radical elimination, and NQ may be transformed into urea.

Self‐Delivery Nanoparticles of Amphiphilic Acyclic Enediynes for Efficient Tumor Cell Suppression

Summary of main observation and conclusionFour acyclic maleimide‐based enediyne compounds with different hydrophilicity were synthesized through Sonogashira reaction to reveal a self‐delivery antitumor drug platform. As proved by ESR analysis, the enediyne compounds undergo Bergman‐like cyclization and generate diradical intermediates at physiological temperature, which are able to induce DNA‐cleavage through the abstraction of H atoms from the sugar‐phosphate backbones. When the critical aggregation concentration is reached in water, the amphiphilic enediyne compounds self‐assemble into nanoparticles and possess the self‐delivery ability to be facilely admitted by tumor cells, resulting in greatly improved cytotoxicity (IC50 down to 10 μmol·L–1) and much higher tumor cell apoptosis rate (up to 86.6%) in comparison with either the hydrophilic or the lipophilic enediyne compound. The enhanced endocytosis of the amphiphilic enediyne compounds was further confirmed through confocal laser scanning microscopy analysis. The unveiled relationship between the hydrophilicity of enediyne drugs and their therapeutic efficacy will provide a guideline for the design of new self‐delivery drugs employed in medicinal applications.

Dimerization of substituted 4-aryl-1,3-diacetylenes – quantum chemical calculations and kinetic studies

Thermal dimerization of 4-aryl-1,3-diacetylenes resulting in diradical intermediates were investigated by experimental and quantum chemical studies.

Molecular dynamics of the intramolecular 1, 3-dipolar ene reaction of a nitrile oxide and an alkene: non-statistical behavior of a reaction involving a diradical intermediate

ABSTRACTPotential energy surfaces and molecular dynamics of the intramolecular 1, 3-dipolar cycloaddition and ene reaction of a nitrile oxide with an alkene were performed in the gas phase and in dichloromethane with density functional theory. One hundred trajectories were propagated in the gas phase and in dichloromethane, respectively. Twenty percent of the trajectories in the gas phase involve bicyclic intermediate and the mean time gap is 472fs. A dynamically stepwise reaction is observed. In dichloromethane, more reactive trajectories were obtained and the time gap is larger than that in the gas phase.

Concurrent Radical Addition and [3+2] Cycloaddition between Nitrones and Maleimide‐Based Acyclic Enediynes

AbstractEnediyne compounds undergo Bergman cyclization while being activated with thermal or UV‐light triggers, and generate benzyne diradical intermediates, endowing their great potential as antitumor agents. The radical nature of the Bergman cyclization is generally confirmed through radical trapping experiments. While using phenyl tert‐butyl nitrone (PBN) as a radical trapping agent to study the Bergman cyclization of maleimide‐based enediyne compounds, we uncovered concurrent radical addition and [3+2] cycloaddition reactions between nitrones and enediyne compounds. The radical addition between the diradical intermediates and PBN was revealed through EPR analysis, while the [3+2] cycloaddition products were separated out and their structures were confirmed by NMR, HRMS and single crystal XRD analysis. Computational investigations showed that the energy barrier of the [3+2] cycloaddition was much lower than that of the Bergman reaction, corroborating the dominance of [3+2] cycloaddition between nitrone and enediyne compounds.

An acyclic enediyne anticancer compound attributed to a Bergman cyclization at physiological temperature

Enediyne cytotoxic drugs have attracted much attention because of their unique structure and potent anticancer activity. However, acyclic enediynes are long considered as inactive at physiological temperature due to their long C1-C6 distance. By adjusting the steric bulkiness of the functional groups at the alkynyl termini and the electron-withdrawing effect at the ene moiety, herein, a simple acyclic enediyne was designed and synthesized to achieve the onset of thermal Bergman cyclization at physiological temperature in polar solvents. The spontaneous generation of diradical intermediates was confirmed through EPR analysis and further supported by spin trapping experiment, radical indicator experiment, and high resolution MS analysis. The reactive diradicals generated in aqueous media induced single and double stranded cleavage of DNA, and showed high cytotoxicity to Hela cells. The IC50 value of the enediyne compound is comparable to many clinical used anti-tumor agents.

Dimerization of Substituted Arylacetylenes-Quantum Chemical Calculations and Kinetic Studies.

The dimerization of substituted arylacetylenes is a very interesting tool to generate 1,3-butadiene 1,4-diradicals. Recently, it was shown that electron-withdrawing groups attached to the triple bond reduce the activation barrier and increase the stability of the diradical intermediates. Here, we investigate the influence of the π donor character of substituents, which are bound to the aryl system, on the dimerization reaction of arylacetylenes. Both quantum chemical calculations and kinetic studies reveal that the higher the π donor character of substituents, the lower the activation barrier. The highest observed difference between the model systems amounts to 4.0 kcal/mol, which represents an acceleration by a factor of 700. However, according to the calculations the π donor character of the substituents increases the diradical character of the intermediates.

Noninnocent Ligand in Rhodium(III)-Complex-Catalyzed C–H Bond Amination with Tosyl Azide

Six-coordinate rhodium(III) complexes coordinated by a planar trianionic ligand (L3-) are synthesized. One of the axial positions is occupied by chloride (Cl-), bromide (Br-), or iodide (I-), and another axial position is coordinated by a solvent molecule such as acetonitrile (AN), water (H2O), tetrahydrofuran (THF), or pyridine (PY) to complete an octahedral rhodium(III) center; [RhIII(L3-)(X)(Y)]- (1X/Y; X = Cl-, Br-, or I-, Y = AN, H2O, THF, or PY). Coordination of the AN, H2O, and THF ligands to the metal center is rather weak, so that these solvent molecules are easily replaced by PY to give [RhIII(L3-)(Cl)(PY)]-. In the electrochemical measurements, all complexes have two reversible redox couples based on the ligand-centered oxidation L3- to L•2- and to L-, as reflected by the very similar redox potentials regardless of the different axial ligands. The rhodium(III) complexes catalyze C-H bond amination of xanthene with tosyl azide (TsN3). Because the yields of the aminated product are nearly the same among the complexes, replacement of the axial solvent ligands with TsN3 readily occurs to give a nitrene-radical-bound rhodium(III) complex, [RhIII(L•2-)(N•Ts)(X)]-, as an active oxidant, which is generated by one-electron transfer from the trianionic L3- to the nitrene nitrogen atom. Generation of such a diradical intermediate was substantiated by the direct reaction of 1Cl/AN with TsN3 in the absence of the substrate (xanthene). In this case, a rhodium(III) iminosemiquinone complex, 2, was generated by the intramolecular reaction between the nitrene-radical moiety and the radical moiety of the ligand L•2-.

Bent Bonds (τ) and the Antiperiplanar Hypothesis-The Chemistry of Cyclooctatetraene and Other C8H8 Isomers.

The bent bond/antiperiplanar hypothesis (BBAH) has been applied to the thermal rearrangements of cyclooctatetraene and related C8H8 isomers. This novel orbital model shows that pyramidal singlet diradical intermediates produced from thermal vibrational states of C8H8 isomers account for their chemical reactivity.

Unanticipated formation of a novel octaazacyclodecane ring upon oxidation of a 1,1-bis-urazole.

Tetrahydrotetrazoles are a little-explored class of five-membered heterocycles with four contiguous singly-bonded N atoms. Recent work in our labs has demonstrated that urazole radicals are amenable to N-N bond formation via radical combination to form such a chain of four N atoms. Previously described 1,1-bis-urazole compounds appeared to be convenient precursors to the target tetrazoles via their oxidation to intermediate urazole diradicals, which upon N-N bond formation would complete the tetrazole framework. While oxidation proceeded smoothly, the novel 10-membered octaaza heterocycle 7,7,18,18-tetraacetyl-4,10,15,21-tetraphenyl-1,2,4,6,8,10,12,13,15,17,19,21-dodecaazapentacyclo[17.3.0.02,6.08,12.013,17]docosan-3,5,9,11,14,16,20,22-octone, C42H32N12O12, was obtained (36% yield) instead of the expected tetrazole product, as confirmed by X-ray crystallography. Calculations at the (U)B3LYP/6-311G(d,p) level of theory suggest that the desired tetrazoles have weak N-N bonds connecting the two urazole units.

Computational Analysis of 1,2‐dialkynylpyrroles

Computational chemistry can be used to quickly predict the properties of molecules. We are interested in studying the potential of 1,2‐dialkynylpyrroles to undergo a thermal Bergan cyclization‐triggered rearrangement to reactive diradical intermediates that display cytotoxic activity. These diradical intermediates have garnered much interest in the scientific community as a potential tumor suppressing compound. In order to analyze these diradicals, a B3LYP hybrid functional with a 6–31G** basis set was used to predict the electronic energy of each intermediate and transition state in the reaction. The electronic energy values for each step in the reaction were used to construct an energy diagram that quantified the energy gap between the intermediates and transition states. The goal of this experiment was to create an analogue of a dialkynylpyrrole that maximized the energy gap between the diradical singlet and the Retro Bergman transition state, and minimized the energy gap between the diradical singlet and the diradical triplet. An analogue that produced a diradical with these properties would be long lived and reactive.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

High-Temperature Isomerization of Benzenoid Polycyclic Aromatic Hydrocarbons. Analysis through the Bent Bond and Antiperiplanar Hypothesis Orbital Model.

L. T. Scott has discovered the 1,2-swapping of carbon and hydrogen atoms which is known to take place on benzenoid aromatics (up to ∼1000 °C range). For example, 13C-1-naphthalene is specifically converted to 13C-2-naphthalene, and there is evidence that this occurs through the formation of benzofulvene and a naphthalene-carbene intermediate. Application of the bent bond/antiperiplanar hypothesis leads to the postulate that higher in energy pyramidal singlet diradical intermediates can be used to propose a mechanism that rationalizes various atom rearrangements on benzenoid aromatics and related isomeric compounds.

Hydrogen Shifts in Aryl Radicals and Diradicals: The Role of m-Benzynes

Density functional and coupled cluster results are presented for hydrogen shifts in radicals derived from polycyclic aromatic hydrocarbons (PAHs) and for rearrangement mechanisms for several phenylenes. RCCSD(T)/cc-pVDZ//UBLYP/cc-pVDZ free energy barriers for 1,4-H shifts at 298 K are consistently predicted to be ca. 25 kcal/mol, whereas barriers for 1,5- and 1,6-shifts range from 6 to 28 kcal/mol. The barriers correlate reasonably well with the distance from the radical center to the shifting hydrogen in the reactant. Proposed mechanisms (via diradical intermediates) of known rearrangements of linear [3]phenylene, benzo[b]biphenylene, and angular [4]phenylene have BD(T)/cc-pVDZ//(U)BLYP/cc-pVDZ computed barriers of 74-82 kcal/mol, consistent with pyrolysis temperatures of 900 to 1100 °C. Hydrogen shift reactions in most of the aryl diradicals arising from phenylenes produce m-benzyne intermediates which, despite being 8-15 kcal/mol more stable than other diradicals involved in the pathways, do not significantly lower the computed overall free energies of activation.

Construction of Morphan Derivatives by Nitroso-Ene Cyclization: Mechanistic Insight and Total Synthesis of (±)-Kopsone.

A type II nitroso-ene cyclization was developed for the construction of morphan derivatives with good functional-group tolerance. DFT calculations revealed that the nitroso-ene reaction proceeds in a stepwise manner involving diradical or zwitterionic intermediates. The rate-determining step is C-N bond formation, followed by a rapid hydrogen-transfer step with a chair-conformation transition state. The current approach was also successfully applied in the first total synthesis of (±)-kopsone, a highly strained yet simple morphan-type alkaloid isolated from Kopsia macrophylla.

Construction of Morphan Derivatives by Nitroso–Ene Cyclization: Mechanistic Insight and Total Synthesis of (±)‐Kopsone

AbstractA type II nitroso–ene cyclization was developed for the construction of morphan derivatives with good functional‐group tolerance. DFT calculations revealed that the nitroso–ene reaction proceeds in a stepwise manner involving diradical or zwitterionic intermediates. The rate‐determining step is C−N bond formation, followed by a rapid hydrogen‐transfer step with a chair‐conformation transition state. The current approach was also successfully applied in the first total synthesis of (±)‐kopsone, a highly strained yet simple morphan‐type alkaloid isolated from Kopsia macrophylla.

Polycyclic Aromatic Hydrocarbon Growth by Diradical Cycloaddition/Fragmentation.

The recent theoretical and experimental investigations on the growth of polycyclic aromatic hydrocarbons in pyrolytic environments highlight the possible role of the 1,4-cycloaddition/fragmentation (1,4-CAF) steps in the formation of PAH intermediates and consequently soot. The present theoretical study explores the possibility to generalize such mechanism to reactions involving various diradical compounds and stable multiring structures. The calculations were performed using the uB3LYP/6-311G(d,p) method and different composite methods, when possible, for more accurate energy estimates. First, the complex potential energy surface for the reactions between o-benzyne and naphthalene was investigated, including the 1,4-CAF mechanism to form anthracene and acetylene through the dibenzobicyclo[2.2.2]octatriene intermediate. Moreover, the products of the addition reactions to the α- and β-carbons and to the ring-junction atoms were determined. The energies for the optimized CAF structures, which constitute the most-favorable pathway from an energetic point of view, were calculated using CBS-QB3, G3(MP2)B3, and G3B3 methods and compared to the corresponding values for the o-benzyne + benzene reactions. Additional calculations were focused on the possible CAF reactions between o-benzyne and larger multiring structures, such as anthracene, phenanthrene, pyrene, and the four-ring PAHs. The results indicate how the energetics of such reactions is influenced by both the size of the PAH compound and the position of the carbon atoms involved. In the second part of the study, the energy barriers necessary to form multiring diradicals from the corresponding radical molecules were analyzed at a G3(MP2)B3 level of theory. Such calculations are preliminary for the subsequent study on the CAF reactions between the different diradical intermediates and benzene. While the size of the diradical does not affect significantly the energy barriers, the position of the diradical site is critical. The concerted Diels-Alder reactions between the naphthynes and naphthalene were also studied in order to further clarify the analogies between the reactions involving different diradicals. Based on these results, kinetic considerations were provided based on the comparison with the simpler o-benzyne + benzene system, although further higher-level calculations and master equation kinetic analyses will be required to derive the general kinetic rules.

Dynamic effects in the didehydro‐Diels‐Alder (DDDA) reaction of enyne‐ketoenes: 50% stepwise bond formation in spite of concerted transition state

AbstractThe C2─C6/Diels‐Alder cyclization of enyne‐ketoene 1 was studied by experiments, theoretical calculations, and dynamic trajectory computations. The failure to trap possible intermediate(s), indicates a concerted reaction mechanism. A detailed search for stationary points revealed a concerted mechanism and surprisingly a diradical intermediate with no direct connection to the enyne‐ketoene 1. To probe the accessibility of this intermediate quasiclassical trajectories were initiated from the concerted transition state structure. Notably, 36% of the trajectories reach the product zone directly and 5% arrive at the product via the intermediate diradical. Additionally, 31% of the trajectories go to the intermediate zone and stay there within the simulation time limit.