Skeletal editing enables precise structure modifications by inserting, deleting, or rearranging atoms to achieve diversification. Building on previous computational studies that highlighted the potential for cycloreversion of trans-cyclohexenes as a means of diene synthesis, and motivated by our ongoing interest in molecular transducers, we present the first experimental evidence for the retro-Diels-Alder reaction of trans-4-phenyl-3,6-dihydro-2H-pyran. Energy transfer photocatalysis leads to isomerization to the strained trans-isomer, where the strain energy is exploited to drive cycloreversion, yielding both diene and formaldehyde. Mechanistic studies support a charge-separated transition state, while computational models explain the unique reactivity of this heterocyclic ring. We employed sequential cycloreversion/cycloaddition reactions in a one-pot sequence to convert the parent aryldihydropyrans into [4+2] adducts with dienophiles, in addition to preparing 4-vinylcyclohexenes via self-dimerization and dihydroterphenyl cores by addition of 1,1-diarylethylene. This new photo-driven strategy facilitates the use of dihydropyrans as diene synthons, providing routes to arylcyclohexenes via atom-pair swap skeletal editing.

The selective activation of carbon-fluorine bonds represent a longstanding challenge in organic synthesis due to their exceptional strength and inertness. Recent work by Wang and co-workers introduces a pyridine-boryl radical-mediated "link-and-lose" strategy for iterative C-F bond functionalization of polyfluoroarenes, enabling selective transformation of the second, third, and even fourth C-F bonds and affording diverse fluorinated scaffolds with significant relevance to medicinal chemistry.

The torsional strain of trans-configured medium-sized (6-8) cycloalkenes imparts substantial potential energy efficiently toward ionic additions through generated reactive carbenium species. These reactions have been underexplored due to a historical necessity for harsh ultraviolet irradiation. We report here the Friedel-Crafts (FC) type reactivity of arylcycloalkenes (ACs) and π-nucleophiles for the first time with weak Brønsted acid and visible light energy transfer catalysis. Following optimizations using p-fluorophenyl cyclohexene as the AC and 2-methylfuran as the nucleophile, model conditions were obtained to probe the respective influence of the acid catalyst, aryl component of AC, nucleophile, and alicyclic component of AC on the desired FC reactivity. Each parameter was found to critically influence the course of the reaction. Ultimately, a mild, visible light-driven method for the preparation of a variety of 1,1-diarylcyclohexane and 4,4-diarylpiperidine derivatives that is mechanistically distinct from and complementary to other methods of preparation is outlined.

Continuous pressure to shorten synthetic sequences along with the concomitant expansion of scope makes the use of alkyl bromides, chlorides, and oxygen based leaving groups- which are abundant and readily available feedstocks, highly attractive for C-C bond synthesis. However, selective activation of these bonds to generate radical intermediates remains challenging and is generally unfeasible using traditional activation strategies. Herein, we report a dual catalytic activation strategy to access primary, secondary, and tertiary alkyl radicals from respective alkyl chlorides and bromides, as well as primary tosylates and trifluoroacetates. While the method relies on visible light and a photocatalyst to facilitate electron transfer, based on reduction potentials, the substrates are not expected to be reduceable, and yet they are reduced in the presence of lutidine. Ultimately, our investigation revealed that lutidine was a precatalyst and ultimately led to the use of lutidinium iodide salt which served as a critical cocatalyst that resulted in improved reaction profiles. Our studies revealed two critical roles that lutidinium iodide salts play which made it possible to engage otherwise unreactive substrates: nucleophilic exchange and halogen atom transfer by the lutidinium radical. In short, this work converts unactivated alkyl chlorides, bromides, tosylates, and trifluoroacetates to radicals that can be used for C-C bond formation without the need for preactivation─effectively expediting synthesis.

The benzocycloheptene core is structurally important motif that appears within a wide array of natural products, and benzocycloheptene has recently been demonstrated to undergo [3+2] photo-sensitized cycloaddition reactions. Thus, there is a need for efficient synthetic protocols to access this motif. Herein, we provide efficient strategies to achieve highly functionalized benzocycloheptene derivatives starting from commercially available 1-benzosuberone and 1-tetralone. We anticipate that these benzocycloheptene compounds will serve as excellent precursors for a diverse array of chemical reactions.

Dynamic photogeneration of ephemeral and reactive species is enabling for chemical reactions, providing spatial and temporal control. A previous study from our group established the ability of 6,7-dihydro-5H-benzo[7]annulene, benzocycloheptene (BC7), to convert photochemical energy into ring strain, enabling the rapid cycloaddition of alkyl azides with the reversibly formed and transient trans-isomer, affording versatile nonaromatic triazolines. Despite the conceptual advances of the previous study, some challenges remained: the fragility of the triazoline products, the low regioselectivity for the cycloaddition, a need for an iridium-based photosensitizer and organic-based solvents, and a lack of convenient linchpin functional group handles. Herein, we communicate the development of a second generation of BC7 molecules that overcome the issues of the first generation. A method to convert fragile triazoline products to stable triazoles was developed. The alkene component was polarized with a carbonyl group, dramatically improving the regioselectivity while simultaneously red-shifting the absorbance of the cycloalkene into the visible region, which was expected to facilitate direct excitation and eliminate the need for photocatalysts. However, experiments indicated that the cycloaddition involved passage through a triplet manifold, complicating the direct excitation strategy. This was successfully overcome by attaching a bromine atom directly to the alkene moiety, which accelerated singlet-to-triplet intersystem crossing by the heavy atom effect. Further exploration identified sites of substitution that can increase the water solubility and provide a handle for the loading of chemical tools and probes.

Benzyl radicals are an important class of intermediate. The use of visible light to generate them directly from their respective halides is an ideal synthetic strategy. The central impediment associated with their direct single-electron reduction (photo- or electro-) lies in their highly variable and structurally dependent reduction potential, which combine to make the identification of a general set of conditions difficult. Herein, we have employed a strategy of nucleophilic cooperative catalysis in which catalytic lutidine undergoes halide substitution, which decreases and levels the reduction potential. This allows a general set of photocatalytic conditions to transform a broad range of benzyl halides into radicals that can be used in the synthesis of more complex molecules, exemplified here by Giese coupling with electron-deficient alkenes.

Phytochemicals derived from the plant Cannabis sativa hold promise in terms of medicinal value. Cannabinoids such as Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD), and cannabinol (CBN) are arguably the best characterized and known to possess wide-ranging therapeutic benefits. The mechanism of action for these therapeutic effects remains to be fully elucidated, however, the anti-inflammatory actions are of particular interest. Maximizing therapeutic effects while limiting adverse effects is crucial in pharmaceutical development. Fluorination of natural products often yields molecules with enhanced biological properties and provides opportunities for intellectual property protection not available to the natural product. Herein, we describe four novel cannabinoids (a deoxy trifluoroCBN analog (F3CBN), the racemic cis-deoxy-trifluoro-THC (F3THC), and truncated pyridine analogs of an intermediate in route to the THC and CBN, SG126 and SG154. Importantly, we provide the initial assessment of the biologic activity of these molecules, by investigating the in vitro effects on metabolic activity (via 3-[4,5-dimethylthiazol-2-yl]-2,5,-diphenyltetrazolium bromide, MTT assay) and cytokine expression (via enzyme linked immunosorbent assay, ELISA) in human C20 microglial cells. The cannabinoids examined had minimal to no effect on metabolic activity up to 10 µM. Notably, F3CBN and F3THC potentiated interleukin-1 β (IL-1β)-induced expression of interferon-γ inducible protein 10 (CXCL10) and IL-6 expression whereas, SG126 and SG154 were inhibitory. These findings are foundational for new lines of investigation into the therapeutic potential of four novel fluorinated cannabinoids.

In this study we synthesized a library of 12 novel adsorbent materials that utilize a chemically well-defined silica support for superior removal of PFAS from real groundwater from a contaminated United States Air Force base. The library of sorbents probed the importance of a fluorous, hydrophobic, and electrostatic components in the removal efficacy. The materials were assessed in batch studies with PFOA, PFOS, and PFBA and compared directly to GAC and Ion Exchange resin. Adsorption kinetics with PFOS were best fit to a pseudo-second order model and equilibrium data fit well to a Langmuir isotherm model. The results were also validated externally, and the best performing material removed greater than 90% of 8 PFAS tested and was able to be regenerated up to 5 cycles. The results provide a top performing material that with further testing can be used to clean up environmentally contaminated water and provide support for the theory that a fluorous component when combined with the electrostatic and hydrophobic components, imparts both enhanced PFAS selectivity and functional resilience to the material.

Starting with highly fluorinated benzoates, we develop the directed photocatalytic hydrodefluorination (HDF) of fluorinated aryl benzoates and demonstrate its synergistic use with other HDF strategies, along with C-H arylation, decarboxylative coupling, and decarboxylative protonation, to access most fluorination patterns found in benzoate derivatives and by extension benzene derivatives via a molecular sculpting approach. Mild reaction conditions and excellent regioselectivity make the approach ideal for synthesis. This approach provides access to 16 benzoate derivatives with different fluorination patterns from just a couple of highly fluorinated, commercially available benzoic acids. We synthesize key intermediates or the active pharmaceutical ingredient for sitagliptin, diflunisal, and other pharmaceutically important molecules. Importantly, we provide key insights into relative rates of defluorination and strategies to alter these rates. We provide demonstrations of the synergistic use of HDF and related technologies to rapidly enhance the synthetic complexity of these simple commercially available perfluoroarenes to form complex partially fluorinated molecules.

A series of thirteen 4-arylbut-3-ene-2-amines were prepared and subjected to photosensitization experiments to interrogate their photostationary state (PS) composition of geometrical olefin isomers (E and Z). The amine PS compositions were found to depend on arene structure and temperature, while being largely independent of nitrogen substitution, solvent, or presence of triplet-quenching oxygen. Photonic efficiency of isomerization (zeta p) was found to depend on amine structure, solvent choice, and presence of quencher. With the proper choice of conditions, zeta p was able to closely approach the theoretical maximum value of 0.5. Instantiated with a set of styrylamines, parameters affecting photosensitized alkene geometrical isomerization were investigated. Raised temperature was found to reduce inherent Z-enrichment, bulky arenes reinforced Z-enrichment, and certain heterocycles favored accumulation of E isomer. Actinometric assessment was made on the influence of arene bulk, solvent, and presence of oxygen on the reaction rate.image

Currentmethods of urethane preparation from amines invariablyinvolve high-energy and often toxic or cumbersome molecules to makethe process exergonic. CO2 aminoalkylation using olefinsand amines represents an attractive albeit endergonic alternative.We report a moisture-tolerant method that uses visible light energyto drive this endergonic process (+25 kcal/mol at STP) using sensitizedarylcyclohexenes. They convert much of the photon's energyto strain upon olefin isomerization. This strain energy greatly enhancesalkene basicity, allowing for sequential protonation by and interceptionof ammonium carbamates. Following optimization steps and amine scopeevaluation, an example product arylcyclohexyl urethane underwent transcarbamoylationwith some demonstrative alcohols to form more general urethanes withconcomitant regeneration of the arylcyclohexene. This represents aclosure of the energetic cycle, producing H2O as the stoichiometricbyproduct.

We report herein a method for the contra-thermodynamic protection and thermodynamic deprotection of alcohols in which all reagents are returned to their original state. This is accomplished by the use of visible light photochemical energy to drive the formation of a highly strained trans-(Z)-cyclohexene. At STP the product ethers contain more potential energy than the starting materials and, thus, can be catalytically returned to the starting materials, effectively realizing a protection-deprotection scheme paid for with an energy currency.

Herein, we investigate the use of visible light to indirectly drive ring opening in unstrained 6- and 7-membered ring systems via reaction with a transiently generated trans-cycloalkene. Identification of conditions that capture visible light energy in the form of ring strain was key to success. Under mildly acidic conditions, cycloalkenols were shown to undergo formally endothermic ring-opening isomerization to give acyclic exo-methylene and distal ketones or aldehydes in high yields. Ultimately, this work demonstrates the ability of cycloalkenes to capture visible light energy and its use to drive both kinetically and thermally unfavorable rearrangements.

[387859-70-3] C33H18F6IrN3 (MW 762.74) InChI = 1S/3C11H6F2N.Ir/c3*12-8-4-5-9(10(13)7-8)11-3-1-2-6-14-11;/h3*1-4,6-7H; InChIKey = GFSFWLGQTIKUOK-UHFFFAOYSA-N Alternative Names: tris[2-(4,6-difluorophenyl)pyridinato-C2,N]iridium(III), tris[2-(2,4-difluorophenyl)pyridine]iridium(III). Physical Data: yellow solid at room temperature. Soluble in N-methyl 2-pyrrolidinone, tetrahydrofuran, dichloromethane, and N,N-dimethylformamide. Not soluble in water.1 Preparative Methods: tris-cyclometalation with 2-(2,4-difluorophenyl)pyridine and IrCl3 at 205 °C in H2O at 97% yield.2 Purification: preparation of catalyst generally results in pure product. Further purification possible through flash chromatography (dry loaded) using hexane:ethyl acetate on a silica column.3 Handling and Storage: generally considered bench stable and air and moisture insensitive as a solid.

Within the framework of discovery chemistry, polyfluorination remains a synthetic challenge despite its ability to provide useful characteristics, such as a reduction in the number of hydrogen bond donors and metabolic stability. Coupling a reversal of this methodology with photocatalysis has been demonstrated to allow the rapid synthesis of previously difficult or impossible targets by starting with fluorines everywhere and selectively removing or functionalizing them. Herein, we demonstrate a novel method to synthesize 1,4-cyclohexadienes through a dearomative photocatalytic C-C coupling reaction. This allows for access to materials that are orthogonal to the selectivity of the Birch reaction and are more functional-group-tolerant. The reaction also allows the efficient synthesis of polyfluorinated cannabinoids. While the yields are modest, the access to the new chemical space provided by the reaction is unprecedented by any means. The trifluorinated analog of THC, 1-deoxy-1,2,4-trifluoro-THC, is synthesized, demonstrating the importance of discovery chemistry and the ability to explore otherwise unknown structure-activity relationships.

Photocatalysis can generate radicals in a controlled fashion and has become an important synthetic strategy. However, limitations due to the reducibility of alkyl halides prevent their broader implementation. Herein we explore the use of nucleophiles that can substitute the halide and serve as an electron capture motif that normalize the variable redox potentials across substrates. When used with photocatalysis, bench-stable, commercially available collidinium salts prove to be excellent radical precursors with a broad scope.

This chemistry establishes a method for the synthesis of per- and poly-fluoroaryl acid amides, utilizing nucleophilic aromatic substitution. Traditionally, such amides are constructed in a two-step process, namely, ammonolysis and then N-acylation. Herein, good yields of N-polyfluoroaryl acid amides were achieved in a single step under mild reaction conditions. Key to achieving optimal yields is the use of two equivalents of the nucleophile. In addition, the mechanism of the reaction is discussed which has implications for other related nucleophilic substitutions.