Homoconjugation and Tautomeric Isomerism in Triptycene-Fused Pyridylbenzimidazoles.

The facile, metal-free synthesis and characterization of three new series of triptycene-fused pyridylbenzimidazoles are reported; such compounds possess an imidazole moiety fused within the benzene rings of the trypticene and a pyridine ring installed at position 2 of the imidazole rings. The position of the nitrogen atom of the pyridyl moiety linked to position 2 of the fused benzimidazole scaffold is systematically changed from the ortho to para position. The number of substituted blades bearing the pyridyl-substituted fused benzimidazole scaffolds has been increased from one to three. Such a library of compounds allowed us to evaluate the enhancement of two main effects: tautomeric isomerism and homoconjugation. The characteristic dynamic equilibrium between different isomers induced by prototropic tautomerization was examined by 1H nuclear magnetic resonance spectroscopy. By comparison of the photophysical properties of the new compounds with those of classical planar pyridylbenzimidazoles, the presence of the homoconjugation effect between the different triptycene blades was demonstrated. Fine details of the electronic structure of the new derivatives were unraveled by a computational analysis. The novel compounds can be employed for the construction of intriguing self-assembled supramolecular architectures.

Direct Photocatalyzed Hydrogen Atom Transfer (HAT) for Aliphatic C-H Bonds Elaboration.

Direct photocatalyzed hydrogen atom transfer (d-HAT) can be considered a method of choice for the elaboration of aliphatic C-H bonds. In this manifold, a photocatalyst (PCHAT) exploits the energy of a photon to trigger the homolytic cleavage of such bonds in organic compounds. Selective C-H bond elaboration may be achieved by a judicious choice of the hydrogen abstractor (key parameters are the electronic character and the molecular structure), as well as reaction additives. Different are the classes of PCsHAT available, including aromatic ketones, xanthene dyes (Eosin Y), polyoxometalates, uranyl salts, a metal-oxo porphyrin and a tris(amino)cyclopropenium radical dication. The processes (mainly C-C bond formation) are in most cases carried out under mild conditions with the help of visible light. The aim of this review is to offer a comprehensive survey of the synthetic applications of photocatalyzed d-HAT.

Direct Synthesis of Thioesters from Feedstock Chemicals and Elemental Sulfur.

The development of a mild, atom- and step-economical catalytic strategy that effectively generates value-added molecules directly from readily available commodity chemicals is a central goal of organic synthesis. In this context, the thiol-ene click chemistry for carbon-sulfur (C-S) bond construction has found widespread applications in the synthesis of pharmaceuticals and functional materials. In contrast, the selective carbonyl thiyl radical addition to carbon-carbon multiple bonds remains underdeveloped. Herein, we report a carbonyl thiyl radical-based thioester synthesis through three-component coupling from feedstock aldehydes, alkenes, or alkynes and elemental sulfur by direct photocatalyzed hydrogen atom transfer. This method represents an orthogonal strategy to the conventional thiol-based nucleophilic substitution and exhibits a remarkably broad substrate scope ranging from simple commodity chemicals such as ethylene and acetylene to complex pharmaceutical molecules. This protocol can be easily extended to the synthesis of thiolactones, oligomer/polymers, and thioacids. Its synthetic utility has been demonstrated by a two-step synthesis of the drug esonarimod. Mechanistic studies indicate that the use of elemental sulfur to trap acyl radicals is both thermodynamically and kinetically favored, illustrating its great potential for the synthesis of sulfur-containing molecules.

Photoinduced Halogen-Atom Transfer by N-Heterocyclic Carbene-Ligated Boryl Radicals for C(sp3)-C(sp3) Bond Formation.

Herein, we present a comprehensive study on the use of N-heterocyclic carbene (NHC)-ligated boryl radicals to enable C(sp3)-C(sp3) bond formation under visible-light irradiation via Halogen-Atom Transfer (XAT). The methodology relies on the use of an acridinium dye to generate the boron-centered radicals from the corresponding NHC-ligated boranes via single-electron transfer (SET) and deprotonation. These boryl radicals subsequently engage with alkyl halides in an XAT step, delivering the desired nucleophilic alkyl radicals. The present XAT strategy is very mild and accommodates a broad scope of alkyl halides, including medicinally relevant compounds and biologically active molecules. The key role of NHC-ligated boryl radicals in the operative reaction mechanism has been elucidated through a combination of experimental, spectroscopic, and computational studies. This methodology stands as a significant advancement in the chemistry of NHC-ligated boryl radicals, which had long been restricted to radical reductions, enabling C-C bond formation under visible-light photoredox conditions.

Diradicals Photogeneration from Chloroaryl-Substituted Carboxylic Acids.

With the aim of generating new, thermally inaccessible diradicals, potentially able to induce a double-strand DNA cleavage, the photochemistry of a set of chloroaryl-substituted carboxylic acids in polar media was investigated. The photoheterolytic cleavage of the Ar-Cl bond occurred in each case to form the corresponding triplet phenyl cations. Under basic conditions, the photorelease of the chloride anion was accompanied by an intramolecular electron-transfer from the carboxylate group to the aromatic radical cationic site to give a diradical species. This latter intermediate could then undergo CO2 loss in a structure-dependent fashion, according to the stability of the resulting diradical, or abstract a hydrogen atom from the medium. In aqueous environment at physiological pH (pH=7.3), both a phenyl cation and a diradical chemistry was observed. The mechanistic scenario and the role of the various intermediates (aryl cations and diradicals) involved in the process was supported by computational analysis.

Catalyst-free [2 + 2] photocycloadditions between benzils and olefins under visible light.

The catalyst-free [2 + 2] photocycloaddition between benzils and simple olefins is reported. The adoption of visible light proved essential for the transformation, as shorter wavelengths led to uncontrolled decomposition. When cyclic olefins were used, the reaction occurred smoothly to afford the expected oxetanes regio- and stereoselectively after 24 h of irradiation. In contrast, in the case of acyclic olefins, longer reaction times were typically required and small amounts (ca. 20%) of [4 + 2] photocycloadducts and by-products deriving from competitive hydrogen atom abstraction were observed. The selectivity of the transformation could be consistently improved by decreasing the reaction temperature, thus restoring the desired [2 + 2] reactivity. An overall mechanistic picture is also offered based on the chemical and photophysical quenching experiments and the stereochemical output is rationalized based on Griesbeck models.

Direct Decarboxylative Functionalization of Carboxylic Acids via O-H Hydrogen Atom Transfer.

Decarboxylative functionalization via hydrogen atom transfer offers an attractive alternative to standard redox approaches to this important class of transformations. Herein, we report a direct decarboxylative functionalization of aliphatic carboxylic acids using N-xanthylamides. The unique reactivity of amidyl radicals in hydrogen atom transfer enables decarboxylative xanthylation under redox-neutral conditions. This platform provides expedient access to a range of derivatives through subsequent elaboration of the xanthate group.

Photocatalytic Isocyanide-Based Multicomponent Domino Cascade toward the Stereoselective Formation of Iminofurans.

A visible-light-promoted three-component isocyanide-based synthesis of iminofurans is herein reported. The reaction proved to be general in scope and proceeds through a triple domino process. Control experiments with 18O-labeled water and TEMPO provided key mechanistic insights for delineating the reactivity paradigms crucial to design efficient photoredox isocyanide-based domino transformations.

Substituent Effects on NMR Spectroscopy of 2,2-Dimethylchroman-4-one Derivatives: Experimental and Theoretical Studies.

The attribution of 1H and 13C NMR signals of a library of 5-, 6- and 7-substituted 2,2-dimethylchroman-4-one derivatives is reported. Substituent effects were interpreted in terms of the Hammett equation, showing a good correlation for carbons para- to the substituent group, not for the meta- ones. Similarly, the Lynch correlation shows the additivity of the substituent chemical shifts in the case of both H and C nuclei, again with the exception of the carbons in the meta- position. Density Functional Theory (DFT)-predicted 1H and 13C chemical shifts correspond closely with experimentally observed values, with some exceptions for C NMR data; however, the correlation is valid only for the aromatic moiety and cannot be extended to the heterocyclic ring of the chroman-4-one scaffold.

Photocatalyzed syntheses of phenanthrenes and their aza-analogues. A review.

Phenanthrenes and their aza-analogues have important applications in materials science and in medicine. Aim of this review is to collect recent reports describing their synthesis, which make use of radical cyclizations promoted by a visible light-triggered photocatalytic process.

Voltammetric Determination of Binding Constant and Stoichiometry of Albumin (Human, Bovine, Ovine)-Drug Complexes.

The parameters characterizing the formation of complexes with albumin (in particular, human serum albumin (HSA)) are fundamental for the characterization of a drug for commercialization purposes and for the determination of common pharmacokinetic parameters. Electrochemical methods appear particularly attractive for the determination of the complexation constant, complex stoichiometry, and percentage of free/bound drug, due to the ease of operation and the wide availability. In this article, we propose an electrochemical method based on differential pulse voltammetry for the determination of albumin-drug interaction parameters, including the replacement of the drug-albumin adduct by a competitive compound, sulfanilamide. The formation of either single or multiple complexes between the considered drug and albumin has been considered. Typically, the method operates with a glassy carbon electrode in NaCl 0.9% as the supporting electrolyte.

Identifying Amidyl Radicals for Intermolecular C-H Functionalizations.

Recent studies have demonstrated the capabilities of amidyl radicals to facilitate a range of intermolecular functionalizations of unactivated, aliphatic C-H bonds. Relatively little information is known regarding the important structural and electronic features of amidyl and related radicals that impart efficient reactivity. Herein, we evaluate a diverse range of nitrogen-centered radicals in unactivated, aliphatic C-H chlorinations. These studies establish the salient features of nitrogen-centered radicals critical to these reactions in order to expedite the future development of new site-selective, intermolecular C-H functionalizations.

Wavelength dependence and wavelength selectivity in photochemical reactions.

The concepts of wavelength dependence and wavelength selectivity have been commonly used by organic photochemists for a long time. The aim of the present article is to offer a selection of relevant cases where the choice of the irradiation wavelength played a key role in the outcome of a photochemical path. Wavelength dependence can be related to the variation in the efficiency (but not the fate) of a process. Herein, three cases have been recognized where a wavelength-selectivity paradigm operates. Indeed, a different wavelength may (i) activate a different chromophore in a single molecule, (ii) induce the population of different reactive excited states and (iii) sequentially populate the excited state of a compound and the excited state of an intermediate photogenerated from it, which show a different reactivity.

Precursor-Dependent Photocatalytic Activity of Carbon Dots.

This work systematically compares both structural features and photocatalytic performance of a series of graphitic and amorphous carbon dots (CDs) prepared in a bottom-up manner from fructose, glucose, and citric acid. We demonstrate that the carbon source and synthetic procedures diversely affect the structural and optical properties of the CDs, which in turn unpredictably influence their photo electron transfer ability. The latter was evaluated by studying the photo-reduction of methyl viologen. Overall, citric acid-CDs were found to provide the best photocatalytic performance followed by fructose- and glucose-CDs. However, while the graphitization of glucose- and citric acid-CDs favored the photo-reaction, a reverse structure-activity dependence was observed for fructose-CDs due to the formation of a large graphitic-like supramolecular assembly. This study highlights the complexity to design in advance photo-active bio-based carbon nanomaterials.

Merging Photocatalysis with Electrochemistry: The Dawn of a new Alliance in Organic Synthesis.

The merging of a homogeneous photocatalytic system with an electrochemical cell, having exchanged electrons as the only common point, has been recently demonstrated. This combination opens unexplored pathways in synthesis and allowed net-oxidative photocatalytic processes to be realized in the absence of a chemical oxidant, including: 1) the C-H alkylation of heteroarenes and 2) the coupling of azoles with arenes in the presence of an electrogenerated photocatalyst.

Carbon-Carbon Bond Forming Reactions via Photogenerated Intermediates.

The present review offers an overview of the current approaches for the photochemical and photocatalytic generation of reactive intermediates and their application in the formation of carbon-carbon bonds. Valuable synthetic targets are accessible, including arylation processes, formation of both carbo- and heterocycles, alpha- and beta-functionalization of carbonyls, and addition reactions onto double and triple bonds. According to the recent advancements in the field of visible/solar light catalysis, a significant part of the literature reported herein involves radical ions and radicals as key intermediates, with particular attention to the most recent examples. Synthetic application of carbenes, biradicals/radical pairs and carbocations have been also reported.

Selective C(sp3 )-H Aerobic Oxidation Enabled by Decatungstate Photocatalysis in Flow.

A mild and selective C(sp3 )-H aerobic oxidation enabled by decatungstate photocatalysis has been developed. The reaction can be significantly improved in a microflow reactor enabling the safe use of oxygen and enhanced irradiation of the reaction mixture. Our method allows for the oxidation of both activated and unactivated C-H bonds (30 examples). The ability to selectively oxidize natural scaffolds, such as (-)-ambroxide, pregnenolone acetate, (+)-sclareolide, and artemisinin, exemplifies the utility of this new method.

Decatungstate Anion for Photocatalyzed "Window Ledge" Reactions.

The majority of organic reactions are commonly carried out inside a lab, under a fume hood. A particular case is that of photochemical reactions, a field where the pioneering experiments by Giacomo Ciamician demonstrated more than one century ago that different processes can be carried out outdoors, for example, on the balcony of his own department, upon exposure of the reacting mixtures to sunlight. The main problem related to this chemistry of the "window ledge" is that most organic compounds are colorless and their absorption in the solar light region is in most cases negligible. Recently, the impressive development in the use of visible light absorbing photocatalysts (e.g., RuII or IrIII complexes, as well as organic dyes) made light-induced processes convenient even for non-photochemistry practitioners. It is thus possible to easily perform the reactions by simply placing the reaction vessel in a sunny place outside the lab. However, most of these processes are based on single electron transfer (SET) reactions (photoredox catalysis). Other photocatalysts able to activate substrates via alternative paths, such as hydrogen atom transfer (HAT), are emerging. In the last years, we were deeply involved in the use of the decatungstate anion ([W10O32]4-, a polyoxometalate) in synthesis. Indeed, such a versatile species is able to promote the photocatalytic C-H activation of organic compounds via either SET or HAT reactions. Interestingly, though the absorption spectrum of [W10O32]4- does not extend into the visible region, it shows an overlap with solar light emission. In this Account, we provide an overview on the application of decatungstate salts as photocatalysts in window ledge chemistry. We initially discuss the nature of the photogenerated species involved in the mechanism of action of the anion, also supported by theoretical simulations. The first-formed excited state of the decatungstate anion decays rapidly to the active species, a dark state tagged wO, featuring the presence of electron-deficient oxygen centers. Next, we describe the main applications of decatungstate chemistry. A significant part of this Account is devoted to photocatalyzed synthesis (C-X bond formation, with X = C, N, O, and oxidations) carried out by adopting sunlight (or simulated solar light). This synthetic approach is versatile, and most of the reactions involved C-H activation in cycloalkanes, alkylaromatics, amides, ethers (1,4-dioxane, oxetane, benzodioxole, and THF), aldehydes, nitriles, and cyclopentanones, and the ensuing addition of the resulting radicals onto electron-deficient olefins. Finally, the increasing role of the decatungstate anion in water depollution and polymerization is briefly discussed.

Vinylpyridines as Building Blocks for the Photocatalyzed Synthesis of Alkylpyridines.

The photocatalyzed addition of several hydrogen donors (ethers, aldehydes, alkanes, amides) onto vinylpyridines was achieved. This approach provided access to alkylpyridines, which are important building blocks for the preparation of compounds with biological activity. The strategy was very simple and straightforward because it required only a small amount of a cheap decatungstate salt as photocatalyst. As an added advantage, the reaction could be performed under sunlight irradiation as well as under flow conditions.

Cooperative Polar/Steric Strategy in Achieving Site-Selective Photocatalyzed C(sp3 )-H Functionalization.

Synergistic control over the SH 2 transition states of hydrogen abstraction exploiting polar and steric effects provides a promising cooperative strategy for site-selective C(sp3 )-H functionalization using decatungstate anion photocatalysis. By using this photocatalytic approach, the C-H bonds of substituted lactones and cyclic ketones were functionalized selectively. In the remarkable case of 2-isoamyl 4-tert-butyl cyclohexanone (1 t) bearing five methyl, five methylene, and three methine C-H bonds, one methine C-H bond in the isoamyl tether was selectively functionalized.