H-atom Transfer Process Research Articles

Photoactivation Inducing Multifunctional Coupling of Fluorophore for Efficient Tumor Therapy In Situ.

Photoactivatable molecules, with high-precision spatialtemporal control, have largely promoted bioimaging and phototherapy applications of fluorescent dyes. Here, the first photoactivatable sensor (BI) is described that can be triggered by broad excitation light (405-660 nm), which further undergoes intersystem crossing and H-atom transfer processes to forming superoxide anion radicals (O2 -• ) and carbon radicals. Particularly, the photoinduced gain of carbon-centered radicals (BI•) allows for radical-radical coupling to afford the combined crosslink product (BI─BI), which would be oxidized in the presence of O2 -• to produce an extended conjugate system with near infrared emission (820 nm). Besides, the photochemically generated product (Cy─BI) possesses ultra-high photothermal conversion efficiency up to 90.9%, which optimized phototherapy potential. What's more, Western Blot assay reveals that both BI and the photoproduct Cy─BI can efficiently inhibit the expression of CHK1, and the irradiation of BI and Cy─BI further induces apoptosis and ultimately enhances the phototherapeutic effects. Thus, the combination of cell cycle block inducing apoptosis, photodynamic therapy and photothermal therapy treatments significantly suppress solid tumor in vivo antitumor efficacy explorations. This is a novel finding in developing photoactivatable molecules, as well as the broad applicability of photoimaging and phototherapy in tumor-related areas.

Interrupted Homolytic Substitution Enables Organoboron Compounds to Inhibit Radical Chain Reactions Rather than Initiate Them.

The reactions of organoboranes with peroxyl radicals are key to their use as radical initiators for a vast array of radical chain reactions, particularly at low temperatures where high stereoselectivity or regioselectivity is desired. Whereas these reactions generally proceed via concerted homolytic substitution (SH2) mechanisms, organoboranes that bear groups that can stabilize tetracoordinate boron radical "ate" complexes (e.g., catecholboranes) undergo this reaction via a stepwise addition/fragmentation sequence and serve as useful stoichiometric alkyl radical precursors. Here we show that arylboronic esters and amides derived from catecholborane and diaminonaphthaleneborane, respectively, are potent radical-trapping antioxidants (RTAs). Mechanistic studies reveal that this is because the radical "ate" complexes derived from peroxyl radical addition to boron are sufficiently persistent to trap another radical in an interrupted SH2 reaction. Remarkably, the reactivity of these organoboranes as inhibitors of autoxidation was shown to translate from simple hydrocarbons to the phospholipids of biological membranes such that they can inhibit ferroptosis, the cell death modality driven by lipid autoxidation and relevant in neurodegeneration and other major pathologies. The unique mechanism of these organoboranes is one of only a handful of RTA mechanisms that are not based on H-atom transfer processes and provide a new dimension to boron chemistry and its applications.

Dual Photochemical H-Atom Transfer & Cobalt Catalysis for the Desaturative Synthesis of Phenols from Cyclohexanones.

Phenols are integral aromatic molecules widely encountered in the structure of natural products and routinely utilised for the synthesis of high-value materials. Accessing highly substituted derivatives can often be difficult especially when their functionalization pattern does not match the intrinsic reactivity leveraged by electrophilic aromatic substitution (SEAr) chemistry. Here we provide an alternative and mechanistically distinct approach for phenol synthesis using saturated cyclohexanone precursors. This process operates at ambient temperature, under simple purple light irradiation, and features a dual catalytic manifold carrying four sequential H-atom transfer processes.

Dualkatalytisch‐Photochemische H‐Atomtransfer/Kobaltkatalysesequenz Ermöglicht Desaturative Synthese von Phenolen aus Cyclohexanonen

AbstractPhenole gehören zu den grundlegendsten aromatischen Strukturen, die nicht nur in einer Vielzahl von Naturstoffen zu finden sind, sondern auch routinemäßig für die Herstellung von wertvollen Produkten eingesetzt werden. Die Synthese hochsubstituierter Phenolderivate kann jedoch äußerst komplex sein, wenn das gewünschte Substitutionsmuster nicht durch die dirigierenden Effekte der elektrophilen aromatischen Substitution (SEAr) erreicht werden kann. In diesem Aufsatz präsentieren wir einen alternativen und mechanistisch einzigarten Ansatz zur Phenolsynthese, der saturierte Cyclohexanone als Ausgangsstoffe verwendet. Dieser bei Raumtemperatur ablaufende Prozess wird durch die Nutzung von violettem Licht ermöglicht und kennzeichnet sich durch den Einsatz einer Anthrachinon‐Kobalt‐Dualkatalyse, welcher vier aufeinanderfolgende Wasserstoffatomtransfers ermöglicht.

Site-Selective Acceptorless Dehydrogenation of Aliphatics Enabled by Organophotoredox/Cobalt Dual Catalysis.

The value of catalytic dehydrogenation of aliphatics (CDA) in organic synthesis has remained largely underexplored. Known homogeneous CDA systems often require the use of sacrificial hydrogen acceptors (or oxidants), precious metal catalysts, and harsh reaction conditions, thus limiting most existing methods to dehydrogenation of non- or low-functionalized alkanes. Here we describe a visible-light-driven, dual-catalyst system consisting of inexpensive organophotoredox and base-metal catalysts for room-temperature, acceptorless-CDA (Al-CDA). Initiated by photoexited 2-chloroanthraquinone, the process involves H atom transfer (HAT) of aliphatics to form alkyl radicals, which then react with cobaloxime to produce olefins and H2. This operationally simple method enables direct dehydrogenation of readily available chemical feedstocks to diversely functionalized olefins. For example, we demonstrate, for the first time, the oxidant-free desaturation of thioethers and amides to alkenyl sulfides and enamides, respectively. Moreover, the system's exceptional site selectivity and functional group tolerance are illustrated by late-stage dehydrogenation and synthesis of 14 biologically relevant molecules and pharmaceutical ingredients. Mechanistic studies have revealed a dual HAT process and provided insights into the origin of reactivity and site selectivity.

Metal-Catalyzed Hydride Transfer from Alcohols to Photoexcited Dipyridophenazine.

Dipyridophenazine (dppz) is known to react with alcohols upon photoexcitation into an n-π* transition at 378 nm to yield dihydrodipyridophenazine (dppzH2 ). This process occurs via H-atom abstraction from alcohols and subsequent disproportionation of the dppzH• radical species, to the final product. This reaction shows a primary kinetic isotope effect (KIE = 4.9) in methanol/perdeuteromethanol solvents, consistent with H-atom transfer processes. Addition of excess Zn(II) ions to the dppz solution not only accelerates the rate of photoreduction, but also lowers the KIE to 1.7, indicating a change in reaction mechanism. We postulate that the coordination of the alcoholic solvent to Zn(II) activates the alcohol α C-H bonds toward hydride transfer processes which would be consistent with the lowered KIE and faster overall reduction of the aromatic ligand. Interestingly, this appears to be an intramolecular process in which the Zn(II) is coordinated to both the dppz ligand and the reactive alcohol, as a sharp inflection in the overall rate increase is observed at a Zn:dppz ratio of 2:1. At this ratio, the dominant dppz species involves a Zn(II) bound to one dppz and several solvent molecules (methanol and water).

Identification of an Emitting Metastable State of p-Fluorophenol-Ammonia 1:2 Complex by Laser-Induced Fluorescence Spectroscopy.

We have demonstrated here, for the first time to our knowledge, the formation of an emitting metastable species upon lowest electronic excitation (S1) of a hydrogen-bonded 1:2 complex of para-fluorophenol (pFP) with ammonia (NH3), which is known to be one of the smallest reactive complexes to undergo excited state H-atom transfer (HAT) reaction to produce •NH4(NH3) radical fragment. The emission spectrum of the species is characterized to be red-shifted, broad, and structureless. From the viewpoint of energy balance, an excited state proton transfer (ESPT) is unfavorable, but according to predicted electronic structure parameters, the metastable state species could be stabilized by charge transfer (CT) interaction at the hydrogen-bonded geometry of the complex. We propose that this species could act as an intermediate to the HAT process in the excited state. The observation of such a state could be valuable to understand the complex dynamics of similar events in biologically relevant systems.

Nonclassical Single-State Reactivity of an Oxo-Iron(IV) Complex Confined to Triplet Pathways.

C-H bond activation mediated by oxo-iron (IV) species represents the key step of many heme and nonheme O2-activating enzymes. Of crucial interest is the effect of spin state of the FeIV(O) unit. Here we report the C-H activation kinetics and corresponding theoretical investigations of an exclusive tetracarbene ligated oxo-iron(IV) complex, [LNHCFeIV(O)(MeCN)]2+ (1). Kinetic traces using substrates with bond dissociation energies (BDEs) up to 80 kcal mol-1 show pseudo-first-order behavior and large but temperature-dependent kinetic isotope effects (KIE 32 at -40 °C). When compared with a topologically related oxo-iron(IV) complex bearing an equatorial N-donor ligand, [LTMCFeIV(O) (MeCN)]2+ (A), the tetracarbene complex 1 is significantly more reactive with second order rate constants k'2 that are 2-3 orders of magnitude higher. UV-vis experiments in tandem with cryospray mass spectrometry evidence that the reaction occurs via formation of a hydroxo-iron(III) complex (4) after the initial H atom transfer (HAT). An extensive computational study using a wave function based multireference approach, viz. complete active space self-consistent field (CASSCF) followed by N-electron valence perturbation theory up to second order (NEVPT2), provided insight into the HAT trajectories of 1 and A. Calculated free energy barriers for 1 reasonably agree with experimental values. Because the strongly donating equatorial tetracarbene pushes the Fe-dx2-y2 orbital above dz2, 1 features a dramatically large quintet-triplet gap of ∼18 kcal/mol compared to ∼2-3 kcal/mol computed for A. Consequently, the HAT process performed by 1 occurs on the triplet surface only, in contrast to complex A reported to feature two-state-reactivity with contributions from both triplet and quintet states. Despite this, the reactive FeIV(O) units in 1 and A undergo the same electronic-structure changes during HAT. Thus, the unique complex 1 represents a pure "triplet-only" ferryl model.

ChemInform Abstract: High‐Valent Iron‐Oxo and ‐Nitrido Complexes: Bonding and Reactivity

AbstractReview: [47 refs.

High‐Valent Iron‐Oxo and ‐Nitrido Complexes: Bonding and Reactivity

AbstractMultiple‐bonded iron‐oxo and ‐nitrido species have been identified or proposed as key intermediates in a range of important chemical transformations. The reported model complexes feature various coordination geometries and distinct electronic structures, and therefore exhibit diverse reactivity. The present contribution highlights the synergy from both experimental and theoretical standpoints to elucidate their different bonding situations and delineate their common mechanistic features in hydrogen‐atom abstraction processes. Our analysis reveals that a radical centered on the abstracting atom E (E=O, N), which is generated via homolysis of covalent Fe−E bonds upon approaching the transition state, is an intrinsic C−H cleaving agent. The iron‐oxo species is predicted to be more reactive than its nitride congener, in general, because the O−H bond formed in the H‐atom transfer process is often stronger than the corresponding N−H bond.

Hydrogen Atom Transfer from Water or Alcohols Activated by Presolvated Electrons.

High-energy irradiation of protic solvents can transiently introduce excess electrons that are implicated in a diverse range of reductive processes. Here we report the evolution of electron solvation in water and in alcohols following photodetachment from aqueous hydroxide or the corresponding alkoxides studied by two- and three-pulse femtosecond spectroscopy and ab initio molecular dynamic simulations. The experiments reveal an ultrafast recombination channel of the excess electrons. Through the calculations this channel emerges as an H-atom transfer process to the hydroxyl or alkoxy radical species from neighboring solvent molecules, which are activated as the presolvated electron occupies their antibonding orbitals. The initially low activation barrier in the early stages of electron solvation was found to increase (from 12 to 44 kJ/mol in water) as full solvation proceeded.

Generation and reactivity of putative support systems, Ce-Al neutral binary oxide nanoclusters: CO oxidation and C–H bond activation

Both ceria (CeO2) and alumina (Al2O3) are very important catalyst support materials. Neutral binary oxide nanoclusters (NBONCs), CexAlyOz, are generated and detected in the gas phase and their reactivity with carbon monoxide (CO) and butane (C4H10) is studied. The very active species CeAlO4 (●) can react with CO and butane via O atom transfer (OAT) and H atom transfer (HAT), respectively. Other CexAlyOz NBONCs do not show reactivities toward CO and C4H10. The structures, as well as the reactivities, of CexAlyOz NBONCs are studied theoretically employing density functional theory (DFT) calculations. The ground state CeAlO4 (●) NBONC possesses a kite-shaped structure with an OtCeObObAlOt configuration (Ot, terminal oxygen; Ob, bridging oxygen). An unpaired electron is localized on the Ot atom of the AlOt moiety rather than the CeOt moiety: this Ot centered radical moiety plays a very important role for the reactivity of the CeAlO4 (●) NBONC. The reactivities of Ce2O4, CeAlO4 (●), and Al2O4 toward CO are compared, emphasizing the importance of a spin-localized terminal oxygen for these reactions. Intramolecular charge distributions do not appear to play a role in the reactivities of these neutral clusters, but could be important for charged isoelectronic BONCs. DFT studies show that the reaction of CeAlO4 (●) with C4H10 to form the CeAlO4H●C4H9 (●) encounter complex is barrierless. While HAT processes have been previously characterized for cationic and anionic oxide clusters, the reported study is the first observation of a HAT process supported by a ground state neutral oxide cluster. Mechanisms for catalytic oxidation of CO over surfaces of AlxOy∕MmOn or MmOn∕AlxOy materials are proposed consistent with the presented experimental and theoretical results.

Vibrational overtone induced elimination reactions within hydrogen-bonded molecular clusters: the dynamics of water catalyzed reactions in CH2FOH·(H2O)n

The dynamics of the light initiated OH-overtone induced elimination reactions CH(2)FOH.(H(2)O)(n) + hnu--> HF + CH(2)O + n(H(2)O), n = 1-3, are studied using classical trajectory simulations where the ab initio potential energy surface is computed "on-the-fly". Hydrogen bonding to the water is found to lower the barrier to reaction by over 20 kcal mol(-1) and modifies the mechanism to a concerted multiple H-atom transfer process. The reaction process is found to occur on a rapid timescale, <100 fs, and involves the hydronium ion as an intermediate. An essential aspect of dynamics is the successful competition of reaction with energy dissipation through water evaporation from the cluster.

Theoretical elucidation on mechanism and reactivity of bisphenol A derivatives as inhibitors and radical scavengers in methacrylate polymerization

To elucidate the mechanism and activity difference of bisphenol A derivatives (BSADs), i.e. hydroquinone, 2,2′-biphenol, 4,4′-biphenol, bisphenol A and diethylstilbestrol, as inhibitors and radical scavengers in methyl methacrylate (MMA) polymerization, a combined quantum chemical method, labeled as (RO)B3LYP/6-311+G(2d,2p)//AM1/AM1, was employed to calculate O–H bond dissociation enthalpies (BDEs) and ionization potentials (IPs) for these compounds. The calculation results reveal that BSADs scavenge radicals generated during MMA polymerization through a direct H-atom transfer process. Furthermore, the difference in inhibition activity and stoichiometric factors for BSADs was elucidated by the O–H BDEs. In addition, substituent effects on BDE were employed to give a deeper insight into the structure–activity relationships for BSADs.

Effect of deuteration on the fluorescence excitation spectrum of tropolone: a theoretical study

A combined ab initio+nuclear dynamics study is performed to theoretically analyze the intramolecular H-atom transfer process in mono- and bi-deuterated tropolones in both the ground (S 0) and first excited singlet (S 1) electronic states. From previous ab initio electronic calculations, reduced bidimensional energy surfaces are built up so that the nuclear wave functions for the nuclear motions in both electronic states are obtained. In particular we have analyzed the three isotopomers that result from deuteration of the tropolone ring: tropolone-3-d (3DT), tropolone-4-d (4DT) and tropolone-5-d (5DT). It is found that for the symmetric 5DT case the two lowest vibrational levels in both S 0 and S 1 appear as a quasi-degenerated tunneling doublet. The effect of the isotopic substitution is very modest so that it is predicted that the electronic spectrum of 5DT will be very similar to the one of the parent tropolone molecule. Conversely, for the non-symmetric structures 3DT and 4DT, the isotope induced asymmetry combined with the energy barrier in S 0, lead to a complete localization of the two lowest vibrational wave functions in S 0, whereas for S 1 the asymmetry and energy barriers are low enough so that some degree of delocalization of the two lowest vibrational wave functions is still seen. In light of our results we try to explain the appearance of the reported fluorescence excitation spectra for these species.

A theoretical study of the isotope effects on the fluorescence excitation spectrum of 5-aminotropolone

A combined ab initio+nuclear dynamics study is performed to theoretically analyze the intramolecular H-atom transfer process in 5-aminotropolone in both the ground (S0) and first excited (S1) singlet electronic states. A complete active space self-consistent field (CASSCF) method is used to optimize the geometries. Energies are then corrected through the second order Mo/ller–Plesset perturbation theory. These results are used to build up reduced bidimensional energy surfaces so that the nuclear wave functions for the nuclear motions in both electronic states are obtained. In particular we have analyzed the six isotopomers that result from deuteration of the amino and hydroxy groups of 5-aminotropolone. It is found that for symmetric structures (−OH/−NH2, −OH/−ND2, −OD/−NH2, and −OD/−ND2), the two lowest vibrational levels in both S0 and S1 appear as a quasidegenerated tunneling doublet. The tunneling splitting in S0 is much lower so that the doublet at the origin, seen in the fluorescence excitation spectra of 5-aminotropolone, can be entirely assigned to the S1 state. In agreement with the experimental findings, this splitting greatly diminishes when the transferring hydrogen is substituted by a deuterium, whereas deuteration of the amino group produces only a modest decrease of such a splitting. A quite different result is found for the nonsymmetric isotopically substituted structures (−OH/−NHD and −OD/−NHD), as the isotope induced asymmetry, combined with the high energy barrier in the S0 potential energy surface, leads to a complete localization of the two lowest vibrational wave functions in S0. On the other hand, for S1 the asymmetry and energy barriers are low enough so that an important degree of delocalization of the two lowest vibrational wave functions is found. These results are again in agreement with the presence of an isotope induced quartet in the fluorescence excitation spectra of these species.

Reaction mechanisms of peroxyl and c-centered radicals with sulfhydryls

Rate constants for reactions of a peroxyl (CCl 3OO·) and C-centered radicals, that is, phenyl (·C 6H 4CH 2COO −) and vinyl (uracil-5-yl), with an aromatic thiol (p-CH 3OC 6H 4SH) were measured over a pH range (3–12) to include ArSH and ArS − forms. The pH dependence of these rate constants indicates that peroxyl radicals react by a redox mechanism while the C-centered radicals react by an H-atom transfer process. The different mechanisms encountered in the repair of various radicals suggest design features to be incorporated into antiagents, such as radioprotectors and anticarcinogens.