Electrochemical Asymmetric Radical Functionalization of Aldehydes Enabled by a Redox Shuttle.

Aminocatalysis is a well-established tool that enables the production of enantioenriched compounds under mild conditions. Its versatility is underscored by its seamless integration with various synthetic approaches. While the combination of aminocatalysis with metal catalysis, photochemistry, and stoichiometric oxidants has been extensively explored, its synergy with electrochemical activation remains largely unexplored. Herein, we present the successful merger of electrochemistry and aminocatalysis to perform SOMO-type transformations, expanding the toolkit for asymmetric electrochemical synthesis. The methodology harnesses electricity to drive the oxidation of catalytically generated enamines, which ultimately partake in enantioselective radical processes, leading to α-alkylated aldehydes. Crucially, mechanistic studies highlight how this electrochemical strategy is enabled by the use of a redox shuttle, 4,4'-dimethoxybiphenyl, to prevent catalyst degradation and furnishing the coveted compounds in good yield and high enantioselectivity.

C1-4 Alkylation of Aryl Bromides with Light Alkanes enabled by Metallaphotocatalysis in Flow.

@AntonioPulcine1, @KenYamazaki5, @EvelineTiekink, @TrevorAHamlin, @tnoel82, @HimsUva, @VU Science, @NoelGroupUvA.The homologous series of gaseous C1-4 alkanes represents one of the most abundant sources of short alkyl fragments. However, their application in synthetic organic chemistry is exceedingly rare due to the challenging C-H bond cleavage, which typically demands high temperatures and pressures, thereby limiting their utility in the construction of complex organic molecules. In particular, the formation of C(sp2)-C(sp3) bonds is crucial for constructing biologically active molecules, including pharmaceuticals and agrochemicals. In this study, we present the previously elusive coupling between gaseous alkanes and (hetero)aryl bromides, achieved through a combination of Hydrogen Atom Transfer (HAT) photocatalysis and nickel-catalyzed cross coupling at room temperature. Utilizing flow technology allowed us to conduct this novel coupling reaction with reduced reaction times and in a scalable fashion, rendering it practical for widespread adoption in both academia and industry. Density Functional Theory (DFT) calculations unveiled that the oxidative addition constitutes the rate-determining step, with the activation energy barrier increasing with smaller alkyl radicals. Furthermore, radical isomerization observed in propane and butane analogues could be attributed to the electronic properties of the bromoarene coupling partner, highlighting the crucial role of oxidative addition in the observed selectivity of this transformation.

Rapid and Direct Photocatalytic C(sp3 )-H Acylation and Arylation in Flow.

Herein, we report a photocatalytic procedure that enables the acylation/arylation of unfunctionalized alkyl derivatives in flow. The method exploits the ability of the decatungstate anion to act as a hydrogen atom abstractor and produce nucleophilic carbon-centered radicals that are intercepted by a nickel catalyst to ultimately forge C(sp3 )-C(sp2 ) bonds. Owing to the intensified conditions in flow, the reaction time can be reduced from 12-48 hours to only 5-15 minutes. Finally, kinetic measurements highlight how the intensified conditions do not change the reaction mechanism but reliably speed up the overall process.

Synthetic Methods Driven by the Photoactivity of Electron Donor-Acceptor Complexes.

The association of an electron-rich substrate with an electron-accepting molecule can generate a new molecular aggregate in the ground state, called an electron donor-acceptor (EDA) complex. Even when the two precursors do not absorb visible light, the resulting EDA complex often does. In 1952, Mulliken proposed a quantum-mechanical theory to rationalize the formation of such colored EDA complexes. However, and besides a few pioneering studies in the 20th century, it is only in the past few years that the EDA complex photochemistry has been recognized as a powerful strategy for expanding the potential of visible-light-driven radical synthetic chemistry. Here, we explain why this photochemical synthetic approach was overlooked for so long. We critically discuss the historical context, scientific reasons, serendipitous observations, and landmark discoveries that were essential for progress in the field. We also outline future directions and identify the key advances that are needed to fully exploit the potential of the EDA complex photochemistry.

Asymmetric Photocatalytic C-H Functionalization of Toluene and Derivatives.

Reported herein is a visible-light-mediated organocatalytic direct C-H functionalization of toluene derivatives to afford enantioenriched ß-benzylated aldehydes from the corresponding enals. The process combines the oxidative power of a chiral excited-state iminium ion and the basic nature of its counteranion to trigger the generation of benzylic radicals by means of a sequential multisite proton-coupled electron transfer mechanism. This study shows that feedstock chemicals generally used as solvents, such as toluene and xylene derivatives, can be used as substrates for making chiral molecules with high enantioselectivity.

Electrochemical Ferrier Rearrangement of Glycals.

The Ferrier rearrangement (FR) is a well-documented reaction that relies on strong acids or oxidants to convert glycals into unsaturated glycosyl derivatives. In this work, we introduce an electrochemical variant of the FR, offering a broad substrate compatibility. Various nucleophiles and glycal derivatives afford 2,3-unsaturated glycosyl derivatives in high yields with excellent diastereoselectivities. This sustainable method promises to expand the electrochemistry applications in sugar chemistry.

A unified flow strategy for the preparation and use of trifluoromethyl-heteroatom anions.

The trifluoromethyl group (CF3) is a key functionality in pharmaceutical and agrochemical development, greatly enhancing the efficacy and properties of resulting compounds. However, attaching the CF3 group to heteroatoms such as sulfur, oxygen, and nitrogen poses challenges because of the lack of general synthetic methods and reliance on bespoke reagents. Here, we present a modular flow platform that streamlines the synthesis of heteroatom-CF3 motifs. Our method uses readily available organic precursors in combination with cesium fluoride as the primary fluorine source, facilitating the rapid generation of N-trifluoromethyl(R) [NCF3(R)], SCF3 (trifluoromethylthio), and OCF3 (trifluoromethoxy) anions on demand without reliance on perfluoroalkyl precursor reagents. This strategy offers a more environmentally friendly synthesis of trifluoromethyl(heteroatom)-containing molecules, with the potential for scalability in manufacturing processes facilitated by flow technology.

In-Flow Generation of Thionyl Fluoride (SOF2) Enables the Rapid and Efficient Synthesis of Acyl Fluorides from Carboxylic Acids.

Herein, we report an approach for generating thionyl fluoride (SOF2) from the commodity chemicals thionyl chloride (SOCl2) and potassium fluoride (KF). The methodology relies on a microfluidic device that can efficiently produce and dose this toxic gaseous reagent under extremely mild and safe conditions. Subsequently, the in situ-generated thionyl fluoride is reacted with an array of structurally and electronically differing carboxylic acids, leading to the direct and efficient synthesis of highly sought-after acyl fluorides. Importantly, our investigation also highlights the inherent modularity of this flow-based platform. We demonstrate the adaptability of this approach by not only synthesizing acyl fluorides but also directly converting carboxylic acids into a diverse array of valuable compounds such as esters, thioesters, amides, and ketones. This versatility showcases the potential of this approach for a wide range of synthetic applications, underscoring its significance in the realm of chemical synthesis.

Scale-Up of Photochemical Reactions: Transitioning from Lab Scale to Industrial Production.

In the past two decades, we have witnessed a rapid emergence of new and powerful photochemical and photocatalytic synthetic methods. Although these methods have been used mostly on a small scale, there is a growing need for efficient scale-up of photochemistry in the chemical industry. This review summarizes and contextualizes the advancements made in the past decade regarding the scale-up of photo-mediated synthetic transformations. Simple scale-up concepts and important fundamental photochemical laws have been provided along with a discussion concerning suitable reactor designs that should facilitate scale-up of this challenging class of organic reactions.

Photocatalytic (3 + 2) dipolar cycloadditions of aziridines driven by visible-light.

Herein, we document the design and development of a novel (3 + 2) cycloaddition reaction aided by the activity of an organic photocatalyst and visible light. The process is extremely fast, taking place in a few minutes, with virtually complete atom economy. A large variety of structurally diverse aziridines were used as masked ylides in the presence of different types of dipolarophiles (28 examples with up to 94% yield and >95 : 5 dr). Mechanistic insights obtained from photophysical, electrochemical and experimental studies highlight that the chemistry is driven by the in situ generation of the reactive ylide through two consecutive electron-transfer processes. We also report an aerobic cascade process, where an additional oxidation step grants access to a vast array of pyrrole derivatives (19 examples with up to 95% yield). Interestingly, the extended aromatic core exhibits a distinctive absorption and emission profile, which can be easily used to tag the effectiveness of this covalent linkage.

The Merger of Benzophenone HAT Photocatalysis and Silyl Radical-Induced XAT Enables Both Nickel-Catalyzed Cross-Electrophile Coupling and 1,2-Dicarbofunctionalization of Olefins.

A strategy for both cross-electrophile coupling and 1,2-dicarbofunctionalization of olefins has been developed. Carbon-centered radicals are generated from alkyl bromides by merging benzophenone hydrogen atom transfer (HAT) photocatalysis and silyl radical-induced halogen atom transfer (XAT) and are subsequently intercepted by a nickel catalyst to forge the targeted C(sp3)-C(sp2) and C(sp3)-C(sp3) bonds. The mild protocol is fast and scalable using flow technology, displays broad functional group tolerance, and is amenable to a wide variety of medicinally relevant moieties. Mechanistic investigations reveal that the ketone catalyst, upon photoexcitation, is responsible for the direct activation of the silicon-based XAT reagent (HAT-mediated XAT) that furnishes the targeted alkyl radical and is ultimately involved in the turnover of the nickel catalytic cycle.

Homogeneous catalytic C(sp3)-H functionalization of gaseous alkanes.

The conversion of light alkanes into bulk chemicals is becoming an important challenge as it effectively avoids the use of prefunctionalized alkylating reagents. The implementation of such processes is, however, hampered by their gaseous nature and low solubility, as well as the low reactivity of the C-H bonds. Efforts have been made to enable both polar and radical processes to activate these inert compounds. In addition, these methodologies also benefit significantly from the development of a suitable reactor technology that intensifies gas-liquid mass transfer. In this review, we critically highlight these developments, both from a conceptual and a practical point of view. The recent expansion of these mechanistically-different methods have enabled the use of various gaseous alkanes for the development of different bond-forming reactions, including C-C, C-B, C-N, C-Si and C-S bonds.

Catalytic asymmetric C-C cross-couplings enabled by photoexcitation.

Enantioselective catalytic processes are promoted by chiral catalysts that can execute a specific mode of catalytic reactivity, channeling the chemical reaction through a certain mechanistic pathway. Here, we show how by simply using visible light we can divert the established ionic reactivity of a chiral allyl-iridium(III) complex to switch on completely new catalytic functions, enabling mechanistically unrelated radical-based enantioselective pathways. Photoexcitation provides the chiral organometallic intermediate with the ability to activate substrates via an electron-transfer manifold. This redox event unlocks an otherwise inaccessible cross-coupling mechanism, since the resulting iridium(II) centre can intercept the generated radicals and undergo a reductive elimination to forge a stereogenic centre with high stereoselectivity. This photochemical strategy enables difficult-to-realize enantioselective alkyl-alkyl cross-coupling reactions between allylic alcohols and readily available radical precursors, which are not achievable under thermal activation.

Photochemical generation of acyl and carbamoyl radicals using a nucleophilic organic catalyst: applications and mechanism thereof.

We detail a strategy that uses a commercially available nucleophilic organic catalyst to generate acyl and carbamoyl radicals upon activation of the corresponding chlorides and anhydrides via a nucleophilic acyl substitution path. The resulting nucleophilic radicals are then intercepted by a variety of electron-poor olefins in a Giese-type addition process. The chemistry requires low-energy photons (blue LEDs) to activate acyl and carbamoyl radical precursors, which, due to their high reduction potential, are not readily prone to redox-based activation mechanisms. To elucidate the key mechanistic aspects of this catalytic photochemical radical generation strategy, we used a combination of transient absorption spectroscopy investigations, electrochemical studies, quantum yield measurements, and the characterization of key intermediates. We identified a variety of off-the-cycle intermediates that engage in a light-regulated equilibrium with reactive radicals. These regulated equilibriums cooperate to control the overall concentrations of the radicals, contributing to the efficiency of the overall catalytic process and facilitating the turnover of the catalyst.