Photo- and electro-chemical strategies for the activations of strong chemical bonds.

The employment of light and/or electricity - alternatively to conventional thermal energy - unlocks new reactivity paradigms as tools for chemical substrate activations. This leads to the development of new synthetic reactions and a vast expansion of chemical spaces. This review summarizes recent developments in photo- and/or electrochemical activation strategies for the functionalization of strong bonds - particularly carbon-heteroatom (C-X) bonds - via: (1) direct photoexcitation by high energy UV light; (2) activation via photoredox catalysis under irradiation with relatively lower energy UVA or blue light; (3) electrochemical reduction; (4) combination of photocatalysis and electrochemistry. Based on the types of the targeted C-X bonds, various transformations ranging from hydrodefunctionalization to cross-coupling are covered with detailed discussions of their reaction mechanisms.

Photoredox catalysis harvesting multiple photon or electrochemical energies.

Photoredox catalysis (PRC) is a cutting-edge frontier for single electron-transfer (SET) reactions, enabling the generation of reactive intermediates for both oxidative and reductive processes via photon activation of a catalyst. Although this represents a significant step towards chemoselective and, more generally, sustainable chemistry, its efficacy is limited by the energy of visible light photons. Nowadays, excellent alternative conditions are available to overcome these limitations, harvesting two different but correlated concepts: the use of multi-photon processes such as consecutive photoinduced electron transfer (conPET) and the combination of photo- and electrochemistry in synthetic photoelectrochemistry (PEC). Herein, we review the most recent contributions to these fields in both oxidative and reductive activations of organic functional groups. New opportunities for organic chemists are captured, such as selective reactions employing super-oxidants and super-reductants to engage unactivated chemical feedstocks, and scalability up to gram scales in continuous flow. This review provides comparisons between the two techniques (multi-photon photoredox catalysis and PEC) to help the reader to fully understand their similarities, differences and potential applications and to therefore choose which method is the most appropriate for a given reaction, scale and purpose of a project.

Electron-Poor Acridones and Acridiniums as Super Photooxidants in Molecular Photoelectrochemistry by Unusual Mechanisms.

Electron-deficient acridones and in situ generated acridinium salts are reported as potent, closed-shell photooxidants that undergo surprising mechanisms. When bridging acyclic triarylamine catalysts with a carbonyl group (acridones), this completely diverts their behavior away from open-shell, radical cationic, 'beyond diffusion' photocatalysis to closed-shell, neutral, diffusion-controlled photocatalysis. Brønsted acid activation of acridones dramatically increases excited state oxidation power (by +0.8 V). Upon reduction of protonated acridones, they transform to electron-deficient acridinium salts as even more potent photooxidants (*E1/2 =+2.56-3.05 V vs SCE). These oxidize even electron-deficient arenes where conventional acridinium salt photooxidants have thusfar been limited to electron-rich arenes. Surprisingly, upon photoexcitation these electron-deficient acridinium salts appear to undergo two electron reductive quenching to form acridinide anions, spectroscopically-detected as their protonated forms. This new behaviour is partly enabled by a catalyst preassembly with the arene, and contrasts to conventional SET reductive quenching of acridinium salts. Critically, this study illustrates how redox active chromophoric molecules initially considered photocatalysts can transform during the reaction to catalytically active species with completely different redox and spectroscopic properties.

Shining Fresh Light on Complex Photoredox Mechanisms through Isolation of Intermediate Radical Anions.

Photoredox catalysis (PRC) has gained enormous and wide-ranging interest in recent years but has also been subject to significant mechanistic uncertainty, even controversy. To provide a method by which the missing understanding can begin to be filled in, we demonstrate herein that it is possible to isolate as authentic materials the one-electron reduction products of representative PRC catalysts (PCs). Specifically, KC8 reduction of both 9,10-dicyanoanthracene and a naphthalene monoamide derivative in the presence of a cryptand provides convenient access to the corresponding [K(crypt)+][PC·-] salts as clean materials that can be fully characterized by techniques including EPR and XRD. Because PC·- states are key intermediates in PRC reactions, such isolation allows for highly controlled study of these anions' specific reactivity and hence their mechanistic roles. As a demonstration of this principle, we show that these salts can be used to conveniently interrogate the mechanisms of recent, high-profile "conPET" and "e-PRC" reactions, which are currently the subject of both significant interest and acute controversy. Using very simple experiments, we are able to provide striking insights into these reactions' underlying mechanisms and to observe surprising levels of hidden complexity that would otherwise have been very challenging to identify and that emphasize the care and control that are needed when interrogating and interpreting PRC mechanisms. These studies provide a foundation for the study of a far broader range of questions around conPET, e-PRC, and other PRC reaction mechanisms in the future, using the same strategy of PC·- isolation.

Solvent Dependency of Catalyst-Substrate Aggregation Through π-π Stacking in Photoredox Catalysis.

Assemblies of photoredox catalysts and their target substrates prior to photoexcitation is a phenomenon naïvely overlooked by the majority of synthetic chemists, but can have profound influences on reactivity and selectivity in photocatalytic reactions. In this study, we determine the aggregation states of triarylamine radical cationic photocatalysts with various target arene substrates in different solvents by specifically parameterized polarizable molecular dynamics simulations. A π-stacking interaction previously implicated by more expensive, less-representative quantum calculations is confirmed. Critically, this study presents new insights on: i) the ability of solvents (MeCN vs DMF) to make or break a photocatalytic reaction by promoting (MeCN) or demoting (DMF) its catalyst-substrate assemblies, which is a determining factor for reactivity, ii) the average "lifetimes" of assemblies in solution from a dynamic simulation. We find that both in the ground state and the photoexcited state, the cationic radical assemblies remain intact for periods often higher than 60 ps, rendering them ideally suitable to undergo intra-assembly electron transfer reactions upon photoexcitation. Such aspects have not addressed by previous studies on synthetic photocatalytic reactions involving non-covalent assemblies.

Transient absorption spectroscopy based on uncompressed hollow core fiber white light proves pre-association between a radical ion photocatalyst and substrate.

We present a hollow-core fiber (HCF) based transient absorption experiment, with capabilities beyond common titanium:sapphire based setups. By spectral filtering of the HCF spectrum, we provide pump pulses centered at 425 nm with several hundred nJ of pulse energy at the sample position. By employing the red edge of the HCF output for seeding CaF2, we obtain smooth probing spectra in the range between 320 and 900 nm. We demonstrate the capabilities of our experiment by following the ultrafast relaxation dynamics of a radical cationic photocatalyst to prove its pre-association with an arene substrate, a phenomenon that was not detectable previously by steady-state spectroscopic techniques. The detected preassembly rationalizes the successful participation of radical ionic photocatalysts in single electron transfer reactions, a notion that has been subject to controversy in recent years.

Benzoates as photosensitization catalysts and auxiliaries in efficient, practical, light-powered direct C(sp3)-H fluorinations.

Of the methods for direct fluorination of unactivated C(sp3)-H bonds, photosensitization of SelectFluor is a promising approach. Although many substrates can be activated with photosensitizing catalysts, issues remain that hamper fluorination of complex molecules. Alcohol- or amine-containing functional groups are not tolerated, fluorination regioselectivity follows factors endogenous to the substrate and cannot be influenced by the catalyst, and reactions are highly air-sensitive. We report that benzoyl groups serve as highly efficient photosensitizers which, in combination with SelectFluor, enable visible light-powered direct fluorination of unactivated C(sp3)-H bonds. Compared to previous photosensitizer architectures, the benzoyls have versatility to function both (i) as a photosensitizing catalyst for simple substrate fluorinations and (ii) as photosensitizing auxiliaries for complex molecule fluorinations that are easily installed and removed without compromising yield. Our auxiliary approach (i) substantially decreases the reaction's induction period, (ii) enables C(sp3)-H fluorination of many substrates that fail under catalytic conditions, (iii) increases kinetic reproducibility, and (iv) promotes reactions to higher yields, in shorter times, on multigram scales, and even under air. Observations and mechanistic studies suggest an intimate 'assembly' of auxiliary and SelectFluor prior/after photoexcitation. The auxiliary allows other EnT photochemistry under air. Examples show how auxiliary placement proximally directs regioselectivity, where previous methods are substrate-directed.

α-Amino Radical Halogen Atom Transfer Agents for Metallaphotoredox-Catalyzed Cross-Electrophile Couplings of Distinct Organic Halides.

α-Amino radicals from simple tertiary amines were employed as halogen atom transfer (XAT) agents in metallaphotoredox catalysis for cross-electrophile couplings of organic bromides with organic iodides. This XAT strategy proved to be efficient for the generation of carbon radicals from a range of partners (alkyl, aryl, alkenyl, and alkynyl iodides). The reactivities of these radical intermediates were captured by nickel catalysis with organobromides including aryl, heteroaryl, alkenyl, and alkyl bromides, enabling six diverse C-C bond formations. Classic named reactions including Negishi, Suzuki, Heck, and Sonogashira reactions were readily achieved in a net-reductive fashion under mild conditions. More importantly, the cross coupling was viable with either organic bromide or iodide as limiting reactant based on the availability of substrates, which is beneficial to the late-stage functionalization of complex molecules. The scalability of this method in batch and flow was investigated, further demonstrating its applicability.

An organophotocatalytic late-stage N-CH3 oxidation of trialkylamines to N-formamides with O2 in continuous flow.

We report an organophotocatalytic, N-CH3-selective oxidation of trialkylamines in continuous flow. Based on the 9,10-dicyanoanthracene (DCA) core, a new catalyst (DCAS) was designed with solubilizing groups for flow processing. This allowed O2 to be harnessed as a sustainable oxidant for late-stage photocatalytic N-CH3 oxidations of complex natural products and active pharmaceutical ingredients bearing functional groups not tolerated by previous methods. The organophotocatalytic gas-liquid flow process affords cleaner reactions than in batch mode, in short residence times of 13.5 min and productivities of up to 0.65 g per day. Spectroscopic and computational mechanistic studies showed that catalyst derivatization not only enhanced solubility of the new catalyst compared to poorly-soluble DCA, but profoundly diverted the photocatalytic mechanism from singlet electron transfer (SET) reductive quenching with amines toward energy transfer (EnT) with O2.

Synthetic Molecular Photoelectrochemistry: New Frontiers in Synthetic Applications, Mechanistic Insights and Scalability.

Synthetic photoelectrochemistry (PEC) is receiving increasing attention as a new frontier for the generation and handling of reactive intermediates. PEC permits selective single-electron transfer (SET) reactions in a much greener way and broadens the redox window of possible transformations. Herein, the most recent contributions are reviewed, demonstrating exciting new opportunities, namely, the combination of PEC with other reactivity paradigms (hydrogen-atom transfer, radical polar crossover, energy transfer sensitization), scalability up to multigram scale, novel selectivities in SET super-oxidations/reductions and the importance of precomplexation to temporally enable excited radical ion catalysis.

Electro-mediated PhotoRedox Catalysis for Selective C(sp3 )-O Cleavages of Phosphinated Alcohols to Carbanions.

We report a novel example of electro-mediated photoredox catalysis (e-PRC) in the reductive cleavage of C(sp3 )-O bonds of phosphinated alcohols to alkyl carbanions. As well as deoxygenations, olefinations are reported which are E-selective and can be made Z-selective in a tandem reduction/photosensitization process where both steps are photoelectrochemically promoted. Spectroscopy, computation, and catalyst structural variations reveal that our new naphthalene monoimide-type catalyst allows for an intimate dispersive precomplexation of its radical anion form with the phosphinate substrate, facilitating a reactivity-determining C(sp3 )-O cleavage. Surprisingly and in contrast to previously reported photoexcited radical anion chemistries, our conditions tolerate aryl chlorides/bromides and do not give rise to Birch-type reductions.

Photocatalyst-Free, Visible-Light-Mediated C(sp3)-H Arylation of Amides via a Solvent-Caged EDA Complex.

A photocatalyst-free and mild visible light photochemical procedure for C(sp3)-H arylation of amides is described. The reaction proceeds via an electron donor-acceptor (EDA) complex between an electron-rich arene substrate and electron-poor persulfate oxidant. C(sp3)-H arylation of the amide occurs selectively with the most electron-rich arene of the substrate. Mechanistic studies corroborate the reaction taking place in a solvent cage holding components in a close proximity.

Photosensitized direct C-H fluorination and trifluoromethylation in organic synthesis.

The importance of fluorinated products in pharmaceutical and medicinal chemistry has necessitated the development of synthetic fluorination methods, of which direct C-H fluorination is among the most powerful. Despite the challenges and limitations associated with the direct fluorination of unactivated C-H bonds, appreciable advancements in manipulating the selectivity and reactivity have been made, especially via transition metal catalysis and photochemistry. Where transition metal catalysis provides one strategy for C-H bond activation, transition-metal-free photochemical C-H fluorination can provide a complementary selectivity via a radical mechanism that proceeds under milder conditions than thermal radical activation methods. One exciting development in C-F bond formation is the use of small-molecule photosensitizers, allowing the reactions i) to proceed under mild conditions, ii) to be user-friendly, iii) to be cost-effective and iv) to be more amenable to scalability than typical photoredox-catalyzed methods. In this review, we highlight photosensitized C-H fluorination as a recent strategy for the direct and remote activation of C-H (especially C(sp3)-H) bonds. To guide the readers, we present the developing mechanistic understandings of these reactions and exemplify concepts to assist the future planning of reactions.

C-Alkylation of alkali metal carbanions with olefins.

C-Alkylations of alkali metal carbanions with olefins, first reported five decades ago, is a class of reaction undergoing a resurgence in organic synthesis in recent years. As opposed to expectations from classical chemistry and transition metal-catalysis, here olefins behave as closed-shell electrophiles. Reactions range from highly reactive alkyllithiums giving rise to anionic polymerization, to moderately reactive alkylpotassium or alkylsodium compounds that give rise to defined, controlled and bimolecular chemistry. This review presents a brief historical overview on C-alkylation of alkali metal carbanions with olefins (typically mediated by KOtBu and KHMDS), highlights contemporary applications and features developing mechanistic understanding, thereby serving as a platform for future studies and the widespread use of this class of reaction in organic synthesis.

Correction: Base-catalyzed C-alkylation of potassium enolates with styrenes via a metal-ene reaction: a mechanistic study.

Correction for 'Base-catalyzed C-alkylation of potassium enolates with styrenes via a metal-ene reaction: a mechanistic study' by Joshua P. Barham et al., Org. Biomol. Chem., 2020, DOI: 10.1039/c9ob02495f.

Base-catalyzed C-alkylation of potassium enolates with styrenes via a metal-ene reaction: a mechanistic study.

Base-catalyzed, C-alkylation of potassium (K) enolates with styrenes (CAKES) has recently emerged as a highly practical and convenient method for elaboration or synthesis of pharmaceutically-relevant cores. K enolate-type precursors such as alkyl-substituted heterocycles (pyridines, pyrazines and thiophenes), ketones, imines, nitriles and amides undergo C-alkylation reactions with styrene in the presence of KOtBu or KHMDS. Surprisingly, no studies have probed the reaction mechanism beyond the likely initial formation of a K enolate. Herein, a synergistic approach of computational (DFT), kinetic and deuterium labelling studies rationalizes various experimental observations and supports a metal-ene-type reaction for amide CAKES. Moreover, our approach explains experimental observations in other reported C-alkylation reactions of other enolate-type precursors, thus implicating a general mechanism for CAKES.

Synthetic Photoelectrochemistry.

Photoredox catalysis (PRC) and synthetic organic electrochemistry (SOE) are often considered competing technologies in organic synthesis. Their fusion has been largely overlooked. We review state-of-the-art synthetic organic photoelectrochemistry, grouping examples into three categories: 1) electrochemically mediated photoredox catalysis (e-PRC), 2) decoupled photoelectrochemistry (dPEC), and 3) interfacial photoelectrochemistry (iPEC). Such synergies prove beneficial not only for synthetic "greenness" and chemical selectivity, but also in the accumulation of energy for accessing super-oxidizing or -reducing single electron transfer (SET) agents. Opportunities and challenges in this emerging and exciting field are discussed.

Microwave Flow: A Perspective on Reactor and Microwave Configurations and the Emergence of Tunable Single-Mode Heating Toward Large-Scale Applications.

Microwave heating in chemical reactions was first reported in 1986. There have since been many reports employing microwave heating in organic chemistry, where microwave heating has afforded higher yields of products in shorter time periods. However, such reactions are challenging to scale in batch due to the limited penetration depth of microwaves as well as the wave propagation dependence on cavity size. Continuous flow has addressed both these issues, enabling scalability of microwave processes. As such, a host of reports employing microwave flow chemistry have emerged, employing various microwave heating and reactor configurations in the context of either custom-built or commercial apparatus. The focus of this review is to present the benefits of microwave heating in the context of continuous flow and to characterize the different types of microwave flow apparatus by their design (oscillator, cavity type and reactor vessel). We advocate the adoption of tunable, solid-state oscillator single-mode microwave flow reactors which are more versatile heaters, impart better process control and energy efficiency toward laboratory and larger-scale synthetic chemistry applications.

Regio- and chemoselective Csp3-H arylation of benzylamines by single electron transfer/hydrogen atom transfer synergistic catalysis.

We present a highly regio- and chemoselective Csp3-H arylation of benzylamines mediated by synergy of single electron transfer (SET) and hydrogen atom transfer (HAT) catalysis. Under well precedented SET catalysis alone, the arylation reaction of N,N-dimethylbenzylamine proceeded via aminium radical cation formation and selectively targeted the N-methyl group. In contrast, addition of PhC(O)SH as a HAT catalyst precursor completely switched the regioselectivity to Csp3-H arylation at the N-benzylic position. Measurement of oxidation potentials indicated that the conjugate base of PhC(O)SH is oxidized in preference to the substrate amine. The discovery of the thiocarboxylate as a novel HAT catalyst allowed for the selective generation of the sulfur-centered radical, so that the N-benzyl selectivity was achieved by overriding the inherent N-methyl and/or N-methylene selectivity under SET catalysis conditions. While visible light-driven α-C-H functionalization of amines has mostly been demonstrated with aniline derivatives and tetrahydroisoquinolines (THIQs), our method is applicable to a variety of primary, secondary and tertiary benzylamines for efficient N-benzylic C-H arylation. Functional group tolerance was high, and various 1,1-diarylmethylamines, including an α,α,α-trisubstituted amine, were obtained in good to excellent yield (up to 98%). Importantly, the reaction is applicable to late-stage functionalization of pharmaceuticals.

C-Alkylation of N-alkylamides with styrenes in air and scale-up using a microwave flow reactor.

C-Alkylation of N-alkylamides with styrenes is reported, proceeding in ambient air/moisture to give arylbutanamides and pharmaceutically-relevant scaffolds in excellent mass balance. Various amide and styrene derivatives were tolerated, rapidly affording molecular complexity in a single step; thus highlighting the future utility of this transformation in the synthetic chemistry toolbox. Reaction scalability (up to 65 g h-1 product) was demonstrated using a Microwave Flow reactor, as the first example of a C-alkylation reaction using styrenes in continuous flow.