Photochemical Nickel-Catalyzed C-H Arylation: Synthetic Scope and Mechanistic Investigations.

Response to NMETH-{type:entrez-nucleotide,attrs:{text:C14399,term_id:1569106,term_text:C14399}}C14399: A battery of new mechanistic investigations will be required to provide a full explanation of the observation that individual, small-molecule compounds, referred to here as 'protective agents', have the capacity to promote dramatic enhancements to overall fluorophore performance1. As Tinnefeld and Cordes suggest, cycles of reduction (red) and oxidation (ox) - and/or the reverse -may confer a 'self-healing' property to the fluorogenic center. This could indeed be achieved by a single neighboring molecule, like Trolox, facilitating the fluorophore's rapid return to the ground state from relatively long-lived, non-fluorescent, radical intermediates through 'ping-pong' red-ox chemistry. However, this model requires that the rates of red-ox cycling be properly matched for benefits to be achieved. Further insights into the prevalence and lifetimes of charged intermediates for each molecule will need to be quantified to validate this model. Alternative mechanisms for photostabilization, which may play a significant or even dominant role, will also need to be carefully considered and quantified. Previous investigations, largely motivated by the once vigorous dye-laser industry, suggest that meaningful contributions to fluorophore performance may arise from changes in the rates of internal conversion and/or the introduction of mechanisms for triplet-triplet energy transfer and exciplex-type relaxation pathways2. Triplet-triplet energy transfer, a mechanism that would also fall into the 'self-healing' category, could provide substantial benefits to fluorophore performance by reducing the lifetime of non-fluorescent triplet states from which photobleaching and/or radical states can occur. Given our estimates of the triplet energy and red-ox potential of cyclooctatetraene (unpublished data), this mechanism may potentially be the dominant pathway of cyanine fluorophore photostabilization. Triplet-triplet energy transfer can be differentiated from red-ox-type chemistries by quantifying changes in triplet state lifetimes and charged, intermediate species. Other pathways may also exist that are distinct from the 'self-healing' variety. For example, a 'self-protecting' mechanism that reduces the probability of transitions into damaged states in the first place would also give rise to enhancements in fluorophore performance. Single-molecule imaging efforts can play an important role in the characterization of fluorophore performance by giving direct access to the frequency and duration of fluorescent and non-fluorescent states as well as a fluorophore’s total photon output prior to blinking or photobleaching. However, a quantitative understanding of the distinct mechanisms for enhancing fluorophore performance can only be delineated with confidence when married with bulk electrochemical and spectroscopic investigations. These combined approaches, while requiring large quantities of material, could provide grounded insights into the impact and relative weighting of 'self-healing' and 'self-protecting' mechanisms for distinct fluorophore types. Progress on this front will enable both further improvements in the performances of known protective agents and the search for new compounds with similar or improved properties. Developments of this kind may ultimately facilitate the design and synthesis of new classes of next-generation fluorophores spanning the visible spectrum that exhibit enhancements in performance even greater than those observed for the cyanine class (see Correspondence by Altman et al) and tailored properties for distinct experimental demands.

Synthesis of unsymmetrically disubstituted ethynes by the palladium/copper(I)-cocatalyzed sila-Sonogashira–Hagihara coupling reactions of alkynylsilanes with aryl iodides, bromides, and chlorides through a direct activation of a carbon–silicon bond

In this paper, we explore the copper/palladium-cocatalyzed cross-coupling reactions of 1-aryl-2-trimethylsilylethynes with aryl iodides, bromides, and chlorides as coupling partners, to furnish unsymmetrically disubstituted ethynes in moderate to excellent yields. Various aryl iodides were subjected to reaction under the optimized conditions with 5 mol % of Pd(PPh 3 ) 2 and 50 mol % of CuCl. The steric properties of the aryl iodide proved more influential to the outcome of the cross-coupling reaction than electronic factors. In addition, we succeeded in synthesizing unsymmetrical diarylethynes using two different aryl iodides in one-pot. Furthermore, under the same reaction conditions with 10 mol % of PdCl 2 , 40 mol % of P(4-FC 6 H 4 ) 3 , and 50 mol % of CuCl as catalyst, we succeeded in synthesizing unsymmetrical diarylethynes from various aryl bromides. Finally, we explored reactions with aryl chlorides and duly discovered that unsymmetrical diarylethynes were obtainable in moderate to good yields when 10 mol % of Pd(OAc) 2 , 10 mol % of (−)-DIOP, and 10 mol % of CuCl were used. These reactions proceed through a direct activation of a carbon–silicon bond in alkynylsilanes by CuCl to generate the corresponding alkynylcopper species via transmetalation from silicon to copper. Mechanistic investigations on the reaction of alkynylsilanes with aryl bromides confirmed that the trimethylsilyl bromide generated in situ retarded both transmetalation steps between CuCl and alkynylsilane, and between palladium(II) species formed by oxidative addition and alkynylcopper species.

The selective oxidation of methylbenzene to value-added products is of indisputable importance in organic synthesis. Although photocatalytic oxidation reactions of toluene have achieved great success for the preparation of its oxidative products, such as carboxylic acids, benzaldehyde, and benzoate, there remains a lack of a unified photocatalytic system for the selective preparation of these oxidation products. Herein, we report a metal- and additive-free photocatalytic protocol enabled by aryl halides using O2 as a green oxidant for the selective synthesis of the above-mentioned three oxidation products by adjusting the reaction solvent. This strategy features many advantages, including environmentally friendly and mild reaction conditions, broad substrate applicability and functional group tolerance, and potential practical application for the synthesis of aromatic carboxylic drugs and polymer materials and degradation of polystyrene waste. The continuous-flow system was utilized for the oxidation of toluene, which resulted in a reduced reaction time and increased production efficiency. Detailed mechanistic investigation revealed that the hydrogen atom transfer process was facilitated by the bromine radical from aryl halides for further oxidation, and an electron donor-acceptor complex of methylbenzene and aryl halides may exist.

Dissolved organic matter (DOM) is a major scavenger of bromine radicals (e.g., Br• and Br2•-) in sunlit surface waters and during oxidative processes used in water treatment. However, the literature lacks quantitative measurements of reaction rate constants between bromine radicals and DOM and lacks information on the extent to which these reactions form brominated organic byproducts. Based on transient kinetic analysis with different fractions and sources of DOM, we determined reaction rate constants for DOM with Br• ranging from <5.0 × 107 to (4.2 ± 1.3) × 108 MC-1 s-1, which are comparable with those of HO• but higher than those with Br2•- (k = (9.0 ± 2.0) × 104 to (12.4 ± 2.1) × 105 MC-1 s-1). Br• and Br2•- attack the aromatic and antioxidant moieties of DOM via the electron transfer mechanism, resulting in Br- release with minimal substitution of bromine into DOM. For example, the total organic bromine was less than 0.25 μM (as Br) at environmentally relevant bromine radicals' exposures of ∼10-9 M·s. The results give robust evidence that the scavenging of bromine radicals by DOM is a crucial step to prevent inorganic bromine radical chemistry from producing free bromine (HOBr/OBr-) and subsequent brominated byproducts.

A metal-free, photosensitized 1,2-imino-thiocarbamation of olefins was developed using a custom-designed bifunctional reagent, diphenylmethanone O-dimethylcarbamothioyl oxime. A broad range of olefins with diverse electronic features were successfully transformed to the corresponding β-imino-thioesters, with yields ranging from moderate to high. This protocol offers several advantages, including metal-free process, 100% atom economy, simple operation, and scalability. Mechanistic investigations indicate that the triplet-triplet energy transfer and the intrinsic resonance of O-centered/S-centered carbamate radical species are crucial to the success of this strategy.

A simple and mild methodology is reported for visible-light-promoted synthesis of unsymmetrical chalconides ena- bled by dimsyl anion in the absence of transition-metals or photoredox catalysts. The cross-coupling reaction between aryl halides and diaryl dichalconides proceeds in good to excellent yields with electron-rich, electron-poor, and heteroaromatic moieties. Mechanistic investigations using UV−Vis spectroscopy, time-dependent density functional theory (DFT) calculations, and control reactions suggest that dimsyl anion forms an electron-donor-acceptor (EDA) complex capable of absorbing blue light, leading to a charge transfer responsible for generation of aryl radicals from aryl halides. This previously unreported mechanistic pathway may be applied to other light-induced transformations performed in DMSO in the presence of bases and aryl halides.

We report a regioselective, visible‐light‐mediated synthesis of 1(2 H )‐isoquinolones, which was achieved through photocatalytic denitrogenation of 1,2,3‐benzotriazin‐4(3 H )‐ones followed by regioselective radical addition to allenes. Selective formation of the aromatized 1(2 H )‐isoquinolone product was observed, with DFT studies suggesting that selectivity for this isomer is due to a kinetically favorable nitrogen‐mediated hydrogen atom shift. The mild protocol developed allows for the rapid construction of a broad range of 1(2 H )‐isoquinolones derivatives with good functional group tolerance for N ‐substitution of the 1,2,3‐benzotriazin‐4(3 H )‐ones, although a limited range of allenes were tolerated. Control experiments and mechanistic investigations using UV–vis spectroscopy revealed that photoactive electron donor–acceptor complexes form, although photon absorption by the iridium photocatalyst is the main product‐forming pathway.

Abstract1,3,2‐diazaphospholenes hydrides (DAP‐Hs) are highly nucleophilic organic hydrides serving as main‐group catalysts for a range of attractive transformations. DAP hydrides can act as stoichiometric hydrogen atom transfer agents in radical reactions. Herein, we report a DAP‐catalyzed reductive radical cyclization of a broad range of aryl and alkyl halides under mild conditions. The pivotal DAP catalyst turnover was achieved by a DBU‐assisted σ‐bond metathesis between the formed DAP halide and HBpin, which rapidly regenerates DAP‐H. The transformation is significantly accelerated by irradiation with visible light. Mechanistic investigations indicate that visible light irradiation leads to the formation of DAP dimers, which are in equilibrium with DAP radicals and accelerate the cyclization. The direct use of (DAP)2 enabled a catalytic protocol in the absence of light.

1,3,2‐diazaphospholenes hydrides (DAP‐Hs) are highly nucleophilic organic hydrides serving as main‐group catalysts for a range of attractive transformations. DAP hydrides can act as stoichiometric hydrogen atom transfer agents in radical reactions. Herein, we report a DAP‐catalyzed reductive radical cyclization of a broad range of aryl and alkyl halides under mild conditions. The pivotal DAP catalyst turnover was achieved by a DBU‐assisted σ‐bond metathesis between the formed DAP halide and HBpin, which rapidly regenerates DAP‐H. The transformation is significantly accelerated by irradiation with visible light. Mechanistic investigations indicate that visible light irradiation leads to the formation of DAP dimers, which are in equilibrium with DAP radicals and accelerate the cyclization. The direct use of (DAP)2 enabled a catalytic protocol in the absence of light.

Catalytic cross-coupling between aryl halides and alkynes is considered an extremely important organic transformation (popularly known as the Sonogashira coupling) and it requires a transition metal-based catalyst. Accomplishing such transformation without any transition metal-based catalyst in the absence of any external stimuli such as heat, photoexcitation or cathodic current is highly challenging. This work reports transition-metal-free cross-coupling between aryl halides and alkynes synthesizing a rich library of internal alkynes without any external stimuli. A chemically double-reduced phenalenyl (PLY)-based molecule with the super-reducing property was employed for single electron transfer to activate aryl halides generating reactive aryl radicals, which subsequently react with alkyne. This protocol covers not only various types of aryl, heteroaryl and polyaryl halides but also applies to a large variety of aromatic alkynes at room temperature. With a versatile substrate scope successfully tested on more than 75 entries, this radical-mediated pathway has been explained by several control experiments. All the key reactive intermediates have been characterized with spectroscopic evidence. Detailed DFT calculations have been instrumental in portraying the mechanistic pathway. Furthermore, we have successfully extended this transition-metal-free catalytic strategy for the first time towards solvent-free cross-coupling between solid aryl halide and alkyne substrates.

Synthesis of phenyliodine(III) bis(3-bromopropionate) for an organocatalyzed Markovnikov-type bromo-aminoxidation of vinylarenes

Triplet-triplet energy transfer (EnT) is a fundamental activation pathway in photocatalysis. In this work, we report the mechanistic origins of the triplet excited state of carbazole-cyanobenzene donor-acceptor (D-A) fluorophores in EnT-based photocatalytic reactions and demonstrate the key factors that control the accessibility of the 3LE (locally excited triplet state) and 3CT (charge-transfer triplet state) via a combined photochemical and transient absorption spectroscopic study. We found that the energy order between 1CT (charge transfer singlet state) and 3LE dictates the accessibility of 3LE/3CT for EnT, which can be effectively engineered by varying solvent polarity and D-A character to depopulate 3LE and facilitate EnT from the chemically more tunable 3CT state for photosensitization. Following the above design principle, a new D-A fluorophore with strong D-A character and weak redox potential is identified, which exhibits high efficiency for Ni(II)-catalyzed cross-coupling of carboxylic acids and aryl halides with a wide substrate scope and high selectivity. Our results not only provide key fundamental insight on the EnT mechanism of D-A fluorophores but also establish its wide utility in EnT-mediated photocatalytic reactions.

The catalytic aminocarbonylation of (hetero)aryl halides is widely applied in the synthesis of amides but relies heavily on the use of precious metal catalysis. Herein, we report an aminocarbonylation of (hetero)aryl halides using a simple cobalt catalyst under visible light irradiation. The reaction extends to the use of (hetero)aryl chlorides and is successful with a broad range of amine nucleophiles. Mechanistic investigations are consistent with a reaction proceeding via intermolecular charge transfer involving a donor–acceptor complex of the substrate and cobaltate catalyst.

A methodology is reported for visible-light-promoted synthesis of unsymmetrical chalcogenides enabled by dimsyl anion in the absence of transition-metals or photoredox catalysts. The cross-coupling reaction between aryl halides and diaryl dichalcogenides proceeds with electron-rich, electron-poor, and heteroaromatic moieties. Mechanistic investigations using UV-Vis spectroscopy, time-dependent density functional theory (TD-DFT) calculations, and control reactions suggest that dimsyl anion forms an electron-donor-acceptor (EDA) complex capable of absorbing blue light, leading to a charge transfer responsible for generation of aryl radicals from aryl halides. This previously unreported mechanistic pathway may be applied to other light-induced transformations performed in DMSO in the presence of bases and aryl halides.