Diradical Formation Research Articles

The Lewis Acid Induced Formation of a Stable Diradical with an Intramolecular Ion Pairing State.

A stable cross-conjugated diradical was prepared by the reaction of a donor-acceptor-donor (D-A-D) molecule with B(C6F5)3. Its geometry and electronic structure were characterized by single crystal X-ray diffraction, EPR spectroscopy, SQUID measurement, UV/vis spectroscopy, and DFT calculation. It has an open-shell singlet ground state with a thermally excited triplet state. It can be viewed as an intramolecular radical ion pair, and the formation mechanism is proposed as an intramolecular single electron transfer that occurs from the bis(triarylamine) donor fragment to the central dioxophenyl acceptor moiety, induced by the acidic boron atom. This work provides a Lewis acid induced approach to the formation of neutral and cross-conjugated diradicals.

Characterization and initial demonstration of in vivo efficacy of a novel heat-activated metalloenediyne anti-cancer agent

Background Enediynes are anti-cancer agents that are highly cytotoxic due to their propensity for low thermal activation of radical generation. The diradical intermediate produced from Bergman cyclization of the enediyne moiety may induce DNA damage and cell lethality. The cytotoxicity of enediynes and difficulties in controlling their thermal cyclization has limited their clinical use. We recently showed that enediyne toxicity at 37 °C can be mitigated by metallation, but cytotoxic effects of ‘metalloenediynes’ on cultured tumor cells are potentiated by hyperthermia. Reduction of cytotoxicity at normothermia suggests metalloenediynes will have a large therapeutic margin, with cell death occurring primarily in the heated tumor. Based on our previous in vitro findings, FeSO4-PyED, an Fe co-factor complex of (Z)-N,N′-bis[1-pyridin-2-yl-meth-(E)-ylidene]oct-4-ene-2,6-diyne-1,8-diamine, was prioritized for further in vitro and in vivo testing in normal human melanocytes and melanoma cells. Methods Clonogenic survival, apopotosis and DNA binding assays were used to determine mechanisms of enhancement of FeSO4-PyED cytotoxicity by hyperthermia. A murine human melanoma xenograft model was used to assess in vivo efficacy of FeSO4-PyED at 37 or 42.5 °C. Results FeSO4-PyED is a DNA-binding compound. Enhancement of FeSO4-PyED cytotoxicity by hyperthermia in melanoma cells was due to Bergman cyclization, diradical formation, and increased apoptosis. Thermal enhancement, however, was not observed in melanocytes. FeSO4-PyED inhibited tumor growth when melanomas were heated during drug treatment, without inducing normal tissue damage. Conclusion By leveraging the unique thermal activation properties of metalloenediynes, we propose that localized moderate hyperthermia can be used to confine the cytotoxicity of these compounds to tumors, while sparing normal tissue.

Unraveling the Bonding Nature Along the Photochemically Activated Paterno-Büchi Reaction Mechanism.

The photochemically activated Paterno-Büchi reaction mechanism following the singlet excited-state reaction path was analyzed based on a bonding evolution framework. The electronic rearrangements, which describe the mechanism of oxetane formation via carbon-oxygen attack (C-O), comprises of the electronic activation of formaldehyde and accumulation of pairing density on the O once the reaction system is approaching the conical intersection point. Our theoretical evidence based on the ELF topology shows that the C-O bond is formed in the ground-state surface (via C-O attack) returning from the S1 surface accompanied by 1,4-singlet diradical formation. Subsequently, the reaction center is fully activated near the transition state (TS), and the ring-closure (yielding oxetane) involves the C-C bond formation after the TS. For the carbon-carbon attack (C-C), both reactants (formaldehyde and ethylene) are activated, leading to C-C bond formation in the S1 excited state before reaching the conical intersection region. Finally, the C-O formation occurs in the ground-state surface, resulting from the pair density flowing primarily from the C to O atom.

Diradicals or Zwitterions: The Chemical States of m -Benzoquinone and Structural Variation after Storage of Li Ions

Diradicals or Zwitterions: The Chemical States of <i>m</i> -Benzoquinone and Structural Variation after Storage of Li Ions

Hydrogen Migration-Triggered Diradicaloid Singlet-Fission Switch

We present a theoretical design of the singlet-fission (SF) interconversion between two hydrogen tautomers to attract attention to electronic devices such as switches in the SF field. We develop a tuned π-electron conjugation strategy based on single-hydrogen migration to introduce diradical character and yield low-lying E(T1) levels. Specifically, these objectives could be accomplished by moving one hydrogen from a dihydrogen-substituted pyrazine-fused ring to another unsubstituted pyrazine-fused ring in tetraazatetracenes. The predicted SF efficiency would be expected to exceed 120%. To guide future SF design development, one rule of thumb regarding the S0-state and T1-state emerges from our research: In the S0-state, single-hydrogen migration is crucial for effectively localized electrons, which are the key factor in the formation of diradicals. Conversely, single-hydrogen migration induces a large area of π-electron conjugation in the T1-state, which is completely applied to the electron-hole interaction in the S0 → T1 transition, thereby providing low-lying E(T1) levels. Furthermore, a series of hydrogen tautomers of tetraazaacenes have been proposed as diradicaloid SF switches to verify the reliability of the above rule of thumb. This study will not only help researchers in the photovoltaic field to obtain the desired E(T1) in the future but also broaden the application of hydrogen migration in photovoltaic switch research and supplement the SF database.

Shining Visible Light on Vinyl Halides: Expanding the Horizons of Photocatalysis.

ConspectusOver the past decade, photoredox catalysis has blossomed as a powerful methodology because of its wide applicability in sustainable free-radical-mediated processes, in which light is used as a cleaner energy source to alter the redox properties of organic molecules and to drive unique chemical transformations. Numerous examples of highly selective C-C and C-heteroatom bond formation processes have been achieved this way in an efficient and waste-reducing way. Therein, the activation of widely available organic halides via single-electron reduction has been broadly applied for organic synthesis. However, in comparison with alkyl and aryl halides, the analogous utilization of vinyl halides is less developed, most likely as a consequence of the highly unstable vinyl radicals generated as intermediates along with their strong tendency to abstract hydrogen atoms from a suitable source (e.g., the solvent), resulting in a synthetically less useful reduction.Nevertheless, during the last years, a number of photocatalytic processes involving vinyl halides have been developed, featuring the generation of vinyl radicals, diradicals, or radical cations as the key transient species. Moreover, photoredox processes in which a radical reacts with a vinyl halide or with an in situ-generated vinylmetal halide have been developed. Thus, identifying suitable conditions to generate and manipulate these reactive species has resulted in novel synthetic processes in a controllable manner. Moreover, in view of the great versatility of vinyl halides in palladium-catalyzed cross-coupling reactions, their activation by visible light might provide an attractive alternative to such processes, especially when non-noble metals could be used as photoinitiators in the future.In this Account, we discuss the various strategies of photoredox processes involving vinyl halides, classifying the material into four categories: (a) formation of a vinyl radical upon receipt of an electron from the photocatalyst, (b) formation of a radical cation after donation of an electron to the photocatalyst, (c) energy transfer corresponding to diradical formation upon triplet-triplet sensitization, and (d) dual transition metal and photocatalysis employing vinyl halides as precursors. While in the first three approaches the activation of vinyl halides is part of the photochemical step, the fourth one involves the interaction of a photochemically generated radical with a vinylnickel(II) halide obtained in turn by the oxidative addition of nickel(0) to the vinyl halide. Therefore, we highlight these important developments for conceptual comparison to the direct activation of vinyl halides by light, but they are not covered in depth in this Account.

Enhanced Photoinduced Electron Transfer and Stability of Diradicals in Neutral Extended Pyridine N-Oxides

Photoinduced intramolecular electron transfer and the formation of diradicals for neutral nonclassical viologens, pyridine N-oxides, were observed for the first time which broadens the understandin...

The Outliers: Metal-Mediated Radical Reagents for Biological Substrate Degradation.

The predictable and controllable interaction of small organic or peptidic molecules with biological substrates is the primary reason most pharmaceuticals are narrowly decorated carbon frameworks. The inhibition or activation binding models are measurable and without side reactions that can cause pathological angst. Yet many diseases, especially those involving rapid proliferation of cells (i.e., cancer) or aggregation of peptides (e.g., heart disease, Alzheimer's disease) have not yet been cured by inhibition therapeutics. Additionally, interventional medicine is often required to alleviate such maladies by physical removal first, followed by molecular-level therapy as a second stage. Thus, there appears to be a niche for more aggressive therapeutics that may employ harsher chemical processes to realize clinical efficacy, albeit without causing catastrophic side effects. Molecules that may be considered for this challenge are not typically biomimetic, nor do they fit the traditional pharmaceutical paradigm. They may have unusual modes of action or undesired reactivity that can be lethal if not controlled. These are the outliers; potential pharmacophores that biology does not know how to manage or adapt to. This is why they may be an intriguing class of agents that needs continuous development. In this Account, we connect the under-developed enediyne family of compounds and our metalloenediyne derivatives to existing radical-based therapeutics such as bleomycin and doxorubicin to illustrate that controlled diradical reactivity, although an outlier mechanism, has a place in the therapeutic portfolio. This is self-evident in that of the 11 natural product enediynes known, 2 have clinical impact, a strong ratio. We expand on the chemical diversity of potential enediyne constructs and focus on the accessible trigger mechanisms to activate diradical formation as a method to control toxicity. Moreover, we further illustrate how electromagnetic fields can be employed to activate both molecular and larger nanomaterial constructs that carry highly concentrated payloads of reactive reagent. Finally, we describe how controlled diradical reactivity can reach beyond traditional therapeutic targets such as DNA, to peptide aggregates found in blood clots, neural fibrils, and membrane scaffolds. It is our belief that cleverly constructed frameworks with well-designed and controlled activation/reaction schemes can lead to novel therapeutics that can challenge evolving viral and bacterial invaders. From this evangelical perspective, our hope is that the conceptual framework, if not the specific designs in this Account, stimulate the readership to develop out-of-the-box therapeutic designs that may combat resistant disease targets.

Study of the oxidized and non- oxidized bitumen modified with additive «Adgezolin» by using electron paramagnetic resonance

Cationic surfactant (adhesion additive) «Adgezolin» has been developed. It is shown that introduction of «Adgezolin» into the oxidized bitumen increases the relative amount of asphaltenes and monocyclearomatic hydrocarbons. By means of electron paramagnetic resonance (EPR) it is demonstrated that the introduction of additive «Adgezolin» increases the number of paramagnetic «free» carbon radicals (FR) in the oxidized bitumen and decreases that in the unoxidized species. In both types of bitumen shift from the Lorentzian to Gaussian EPR lineshape of FR is obtained that could be connected with as an increase of the samples homogeneity. It is supposed that while in the oxygenated bitumens introduction of additives leads to the disaggregation of asphaltene-resins compounds, in the unoxidized samples the balance is shifted towards formation of di-radicals.

Molecular dynamics simulation of the high-temperature pyrolysis of methylcyclohexane

To better understand the initiation and intermediate reaction mechanisms associated with the high-temperature pyrolysis of methylcyclohexane (MCH), the dissociation of MCH is investigated using reactive molecular dynamics (RMD) and density functional theory (DFT) calculations. It is observed that the pyrolysis of MCH is initiated by four types of reaction channels. The initiation of the decomposition is mainly through the CC bond homolysis of the six-membered ring, leading to ring opening and the formation of C7H14 diradicals. Subsequently, the biradicals undergo successive decomposition by the β-scission of the CC bonds to form ethylene. Furthermore, to provide a detailed description of the pyrolysis behavior of MCH, the distributions of key products, intermediate reactions and corresponding kinetic behavior are systematically analyzed at the atomic level. The apparent activation energy extracted from the RMD simulations is 263.60 kJ/mol at temperatures from 2300 K to 3100 K, which is reasonably consistent with the experimental results.

Photoactivated Transition-Metal Triggers for Ambient Temperature Enediyne and Dienyne Cyclization: Ruthenium-η6-Naphthalene Complexes

A persistent challenge confronting potential applications of the Bergman cycloaromatization reaction is the development of methods for spatiotemporal control of diradical formation. Photochemical variants (photo-Bergman cycloaromatizations) have thus far met with limited success, failing completely in the case of acyclic enediynes. Here we describe the development of efficient photoactivated transition-metal complexes that allow for spatiotemporal control of enediyne cycloaromatization at ambient temperatures. This strategy relies on air- and moisture-stable ruthenium naphthalene complexes that undergo photochemical dissociation of the naphthalene ligand, thereby generating coordination sites for enediyne binding and cycloaromatization. The same ruthenium naphthalene complexes also trigger dienyne cyclization under photochemical conditions.

Radical and Diradical Formation in Naphthalene Diimides through Simple Chemical Oxidation.

We successfully synthesized, for the first time, a naphthalene diimide (NDI) radical and diradical by simple chemical oxidation using lead(IV) dioxide. The formation of the (di)radical is confirmed by UV/Vis/NIR absorption, 1 H NMR, and electron paramagnetic resonance (EPR) measurements. In particular, temperature-dependent EPR, SQUID (superconducting quantum interference device) measurements, and quantum calculations demonstrated that the generated NDI diradical has a singlet diradical character of y=0.69 in the ground state. Subsequent characterization of this (di)radical revealed its stabilities, large two-photon absorption cross-section, and short excited-state lifetime.

Molecular Design and Characterization of High-Cetane Alkyl Diamondoid Fuels

Four alkyl diamondoids, 1-pentyladamantane (PA), 2-butyladamantane (BA), 2-propyladamantane (2-PrA), and 2-ethyladamantane (EA), were synthesized on a preparative scale, and key fuel properties, including density, net heat of combustion, low-temperature viscosity, and derived cetane number (DCN), were measured. The fuel molecules had densities up to 17% higher than conventional jet fuel and volumetric net heats of combustion comparable to or exceeding that of the synthetic missile fuel JP-10. Remarkably, the alkyl diamondoid fuels had DCNs in the range of 42–49, which should allow for their efficient combustion in diesel engines. PA, BA, and 2-PrA all had essentially the same DCN (∼49), while the short alkyl chain in EA lowered the value to 42.7. Bond dissociation energies for the formation of diradicals from 2-PrA and PA were calculated with density functional theory methods to gain a qualitative understanding of potential combustion mechanisms. Ring opening of the adamantane core during combustion is pr...

Photochemistry of 1,4-Dihydropyridine Derivatives: Diradical Formation, Delocalization and Trapping as a Route to Novel Tricyclic and Tetracyclic Nitrogen Heterocyclic Ring Systems.

Irradiation of an acetonitrile solution of 4-aryl-3,5-dibenzoyl-1,4-dihydropyridine derivatives 1a–c and maleimides 2a–c using medium pressure Hg-arc lamp (λ > 290) nm afforded three different cycloadducts 4, 5, 6 in addition to the oxidation products 3. These results indicate that compounds 1a–c undergoes intermolecular cycloaddition reaction through three biradical intermediates and behave photochemically different than those reported previously for the analogous 3,5-diacetyl and 3,5-dicarboxylic acid derivatives. The present work also offers simple access to novel tricyclic and tetracyclic nitrogen heterocyclic ring systems of potential biological and synthetic applications. The structure of the photoproducts was established spectroscopically and by single crystal X-ray crystallography.

Solving the puzzling competition of the thermal C(2)-C(6) vs Myers-Saito cyclization of enyne-carbodiimides.

The mechanism of the thermal cyclization of enyne-carbodiimides 7a–c has been studied computationally by applying the DFT method. The results indicate that enyne-carbodiimides preferentially follow the C2–C6 (Schmittel) cyclization pathway in a concerted fashion although the Myers–Saito diradical formation is kinetically preferred. The experimentally verified preference of the C2–C6 over the Myers–Saito pathway is guided by the inability of the Myers–Saito diradical to kinetically compete in the rate-determining trapping reactions, either inter- or intramolecular, with the concerted C2–C6 cyclization. As demonstrated with enyne-carbodiimide 11, the Myers–Saito channel can be made the preferred pathway if the trapping reaction by hydrogen transfer is no more rate determining.

Cyclopropenyl Anions: Carbon Tunneling or Diradical Formation? A Contest between Jahn-Teller and Hund.

The π bond shifting (automerization) by carbon tunneling of cyclopropenyl anions was computationally analyzed by the small curvature tunneling methodology. Similar to other antiaromatic cases, the process is hindered by substituents departing from planarity, since these groups must be realigned along with the π bond shifting. With hydrogens as substituents the tunneling is extremely fast, in a case of both heavy and light atom tunneling. But, with more massive substituents (such as Me and F), and especially with longer groups (such as CN), the tunneling probability is reduced or even virtually canceled. The automerization of triphenylcyclopropyl anion by tunneling was supposed to be impossible due to the high mass of the phenyl groups. However, it was found that the ground state of this species is actually a D3h aromatic triplet, a single-well system that cannot undergo automerization. For this and other systems with π acceptor groups, the superposition of states that generates the second-order Jahn-Teller distortion is diminished, and by Hund's rule, the triplet results in the ground state.

Chelation-induced diradical formation as an approach to modulation of the amyloid-β aggregation pathway.

Current approaches toward modulation of metal-induced Aβ aggregation pathways involve the development of small molecules that bind metal ions, such as Cu(ii) and Zn(ii), and interact with Aβ. For this effort, we present the enediyne-containing ligand (Z)-N,N'-bis[1-pyridin-2-yl-meth(E)-ylidene]oct-4-ene-2,6-diyne-1,8-diamine (PyED), which upon chelation of Cu(ii) and Zn(ii) undergoes Bergman-cyclization to yield diradical formation. The ability of this chelation-triggered diradical to modulate Aβ aggregation is evaluated relative to the non-radical generating control pyridine-2-ylmethyl-(2-{[(pyridine-2-ylmethylene)-amino]-methyl}-benzyl)-amine (PyBD). Variable-pH, ligand UV-vis titrations reveal pKa = 3.81(2) for PyBD, indicating it exists mainly in the neutral form at experimental pH. Lipinski's rule parameters and evaluation of blood-brain barrier (BBB) penetration potential by the PAMPA-BBB assay suggest that PyED may be CNS+ and penetrate the BBB. Both PyED and PyBD bind Zn(ii) and Cu(ii) as illustrated by bathochromic shifts of their UV-vis features. Speciation diagrams indicate that Cu(ii)-PyBD is the major species at pH 6.6 with a nanomolar Kd, suggesting the ligand may be capable of interacting with Cu(ii)-Aβ species. In the presence of Aβ40/42 under hyperthermic conditions (43 °C), the radical-generating PyED demonstrates markedly enhanced activity (2-24 h) toward the modulation of Aβ species as determined by gel electrophoresis. Correspondingly, transmission electron microscopy images of these samples show distinct morphological changes to the fibril structure that are most prominent for Cu(ii)-Aβ cases. The loss of CO2 from the metal binding region of Aβ in MALDI-TOF mass spectra further suggests that metal-ligand-Aβ interaction with subsequent radical formation may play a role in the aggregation pathway modulation.

Computational Investigation of the Competition between the Concerted Diels–Alder Reaction and Formation of Diradicals in Reactions of Acrylonitrile with Nonpolar Dienes

The energetics of the Diels-Alder cycloaddition reactions of several 1,3-dienes with acrylonitrile, and the energetics of formation of diradicals, were investigated with density functional theory (B3LYP and M06-2X) and compared to experimental data (Hall et al., J. Org. Chem.1993, 58, 7049-7058). For the reaction of 2,3-dimethyl-1,3-butadiene with acrylonitrile, the concerted reaction is favored over the diradical pathway by 2.5 kcal/mol using B3LYP/6-31G(d); experimentally, this reaction gives both cycloadduct and copolymer. The concerted cycloaddition of cyclopentadiene with acrylonitrile is preferred computationally over the stepwise pathway by 5.9 kcal/mol; experimentally, only the Diels-Alder adduct is formed. For the reactions of (E)-1,3-pentadiene and acrylonitrile, both cycloaddition and copolymerization were observed experimentally; these trends were mimicked by the computational results, which showed only a 1.2 kcal/mol preference for the concerted pathway. For the reactions of (Z)-1,3-pentadiene and acrylonitrile, the stepwise pathway is preferred by 3.9 kcal/mol, in agreement with previous experimental findings that only polymerization occurs. M06-2X is known to give more accurate activation and reaction energetics (Pieniazek, et al., Angew. Chem. Int.2008, 47, 7746-7749), but the energies of diradicals are too high.

Reactions of Singly-Reduced Ethylene Carbonate in Lithium Battery Electrolytes: A Molecular Dynamics Simulation Study Using the ReaxFF

We have conducted quantum chemistry calculations and gas- and solution-phase reactive molecular dynamics simulation studies of reactions involving the ethylene carbonate (EC) radical anion EC(-) using the reactive force field ReaxFF. Our studies reveal that the substantial barrier for transition from the closed (cyclic) form, denoted c-EC(-), of the radical anion to the linear (open) form, denoted o-EC(-), results in a relatively long lifetime of the c-EC(-) allowing this compound to react with other singly reduced alkyl carbonates. Using ReaxFF, we systematically investigate the fate of both c-EC(-) and o-EC(-) in the gas phase and EC solution. In the gas phase and EC solutions with a relatively low concentration of Li(+)/x-EC(-) (where x = o or c), radical termination reactions between radical pairs to form either dilithium butylene dicarbonate (CH(2)CH(2)OCO(2)Li)(2) (by reacting two Li(+)/o-EC(-)) or ester-carbonate compound (by reacting Li(+)/o-EC(-) with Li(+)/c-EC(-)) are observed. At higher concentrations of Li(+)/x-EC(-) in solution, we observe the formation of diradicals which subsequently lead to formation of longer alkyl carbonates oligomers through reaction with other radicals or, in some cases, formation of (CH(2)OCO(2)Li)(2) through elimination of C(2)H(4). We conclude that the local ionic concentration is important in determining the fate of x-EC(-) and that the reaction of c-EC(-) with o-EC(-) may compete with the formation of various alkyl carbonates from o-EC(-)/o-EC(-) reactions.

Conformational and Electronic Consequences in Crafting Extended, π-Conjugated, Light-Harvesting Macrocycles

The synthesis of a new series of free-base, Ni(II) and Zn(II) 2,3,12,13-tetra(ethynyl)-5,10,15,20-tetraphenyl porphyrins is described. Upon heating, two of the four ethynyl moieties undergo Bergman cyclization to afford the monocyclized 2,3-diethynyl-5,20-diphenylpiceno[10,11,12,13,14,15-jklmn]porphyrin in 30 %, 10 %, and trace yields, respectively. The structures of all products were investigated by using quantum chemical calculations and the free-base analogue was isolated and crystallized; all compounds show significant deviation from the idealized planar structure. No fully-cyclized bispiceno[20,1,2,3,4,5,10,11,12,13,14,15-fghij]porphyrin was isolated from the reaction mixture. To understand why only two of the four enthynyl groups undergo Bergman cyclization, the reaction coordinates were examined by using DFT at the PWPW91/cc-pVTZ(-f) level coupled to a continuum solvation model. The barrier to cyclization of the second pair of ethynyl groups was found to be 5.5 kcal mol(-1) higher than the first, suggesting a negative cooperative effect and significantly slower rate for the second cyclization. Cyclization reactions for model porphyrin-enediynes with ethene- and H-functionality substitutions at the meso-phenyl rings were also examined, and found to have a similar barrier to diradical formation for the second cyclization event as for the first in these highly planar molecules. By enforcing an artificial 30° cant in two of the pyrrole rings of the porphyrin, the second barrier was increased by 2 kcal mol(-1) in the ethene model system; this suggests that the disruption of the π conjugation of the extended porphyrin structure is the cause of the increased barrier to the second cyclization event.