We present a novel copper-catalyzed method for aniline cross-couplings promoted by a 6-hydroxy picolinhydrazide ligand. The method achieves room-temperature reactivity with aryl bromides, enabled by a methanol/ethanol solvent mixture and a mild, functional group-compatible base, with catalyst loadings as low as 0.5 mol %. The use of industrially preferred solvents and base, as well as the high catalytic activity, offers a significant advancement in the practicality and scalability of industrial processes. Furthermore, the approach extends to the cross-coupling of aryl chlorides under elevated temperatures and demonstrates compatibility with additional nucleophile classes.

Transition metal-catalyzed cross-coupling reactions are essential in modern organic synthesis, facilitating the rapid creation of complex molecular structures. Traditionally, these reactions rely heavily on conventional bases, with only a few exceptions reported. Recently, we developed adaptive dynamic homogeneous catalysis (AD-HoC), a method that enables C(sp2)-S cross-couplings without needing traditional ligands, bases, or additives. Given the growing demand for protocols compatible with acidic conditions in metal-catalyzed cross-couplings, we revisited AD-HoC to pioneer acid-facilitated transition metal-catalyzed thioetherification. Our method enables the swift synthesis of thioethers using nickel and visible light, with a substoichiometric amount of Br & oslash;nsted acid acting as an enabler. NMR kinetic studies indicate that in the absence of acid, the system displays an induction period characteristic of autocatalysis. Introducing the acid as a simple additive eliminates this induction period and significantly accelerates the reaction. Moreover, the protocol has been successfully scaled to gram-level synthesis using continuous flow technology, achieving productivities of over 100 g per hour in a commercially available lab-scale photoreactor. This highlights the method's robustness and scalability, making it a powerful tool for large-scale applications.

Lichtschaltbare unnatürliche Aminosäuren (lsUAs) spielen eine entscheidende Rolle bei der Entwicklung von lichtsensitiven Enzymen, was erhebliches Potenzial für vielfältige Anwendungen wie Biotherapie und Biokatalyse birgt. Neben einer nahezu quantitativen lichtinduzierten Schaltung bestimmen vor allem das Interaktionspotenzial mit dem Enzym, die thermische Stabilität und die effektive Belichtungswellenlänge den Erfolg und die Eignung einer lsUA für eine bestimmte Anwendung. Um eine hohe Vielseitigkeit im aktuell verfügbaren Repertoire zu etablieren, wurden sechs lsUAs auf Basis von Azobenzol, Arylazopyrazol, Arylazothiazol, Hemithioindigo und Spiropyran entworfen und synthetisiert. Die resultierenden lsUAs weisen ein erweitertes Interaktionspotenzial auf, das auf ihre Fähigkeit zur Ausbildung von Wasserstoffbrückenbindungen, ionischen Wechselwirkungen und Metallionenkoordination zurückzuführen ist. Darüber hinaus zeigen die lsUAs unterschiedliche photochemische Eigenschaften, wobei vier von ihnen ausschließlich mit sichtbarem Licht reversibel zwischen den Isomeren schalten. Für fünf der sechs lsUAs konnten jeweils orthogonale Aminoacyl‐tRNA‐Synthetasen identifiziert werden, die den co‐translationalen Einbau in ein Protein ermöglichen. Zusätzlich dazu wurden die Wechselwirkungen zwischen der Synthetase und der lsUA computergestützt analysiert. Schließlich wurde das photochemische Verhalten der fünf lsUAs in einem enzymatischen Modellsystem validiert, wobei deren Eignung zur lichtgesteuerten Regulation enzymatischer Aktivität bestätigt werden konnte. Die Ergebnisse zeigen die signifikante Erweiterung des lsUA‐Repertoires und demonstrieren dessen Anwendbarkeit für die gezielte Modulation enzymatischer Aktivität.

An in‐depth mechanistic study for the photogeneration of free diazoalkanes from N ‐tosylhydrazone precursors by combining observations from synthesis with spectroscopic and theoretical methods is presented. The N ‐tosylhydrazones have been previously established as donors for alkyl diazo species upon light irradiation, but exact mechanistic details of this photodissociation have remained elusive. Investigations of cyclohexane tosylhydrazone (CyNNTsH) by time‐resolved FTIR spectroscopy proved the role of the deprotonated CyNNTs − as the light‐harvesting species and revealed an intricate dependency of the thermal lifetime of the resulting diazoalkane on the deprotonating base. Computational studies including multiple approaches and levels of theory as well as rigorous benchmarking elucidated the dissociation mechanism via an allowed charge transfer state, a resulting destabilization of the dissociating bond, and a fast change of electronic character of the S 1 . These insights allow to suggest specific reaction conditions for photolabile or previously incompatible reaction partners thus paving way towards photo‐orthogonal synthetic strategies.

Azobenzene is a widely recognized tool for achieving artificial spatiotemporal control of enzyme activity through the use of light. Photocontrol reversibility is typically based on photostationary states with varying E and Z isomer compositions attained through irradiation at specific wavelengths. Here, we report an alternative mechanism for azobenzene based enzyme regulation, discovered through simultaneous irradiation with two wavelengths. Using two engineered variants of imidazole glycerol phosphate synthase, in which azobenzene was incorporated as an unnatural amino acid to enable reversible control under monochromatic irradiation, we uncovered unique behavior under dichromatic irradiation. Notably, a distinct spectroscopic signal from the azobenzene moiety emerged during simultaneous irradiation at 365:420 nm, inducing the establishment of a second photostationary state, and vanished upon return to the dark. Intriguingly, dichromatic irradiation triggered a reproducible 2-fold increase in catalytic activity and an instantaneous return to baseline activity in the dark for one variant. We could exclude sample heating as cause of this effect, as the other variant and the wild-type enzyme maintained their baseline activity under the same conditions. Remarkably, we could directly correlate this alternative photocontrol with the formation of the second photostationary state. Finally, we demonstrate that photocontrol with dichromatic irradiation appears to be successful in positions with conformational importance for catalysis. These findings reveal an unexplored avenue for azobenzene photoswitching, offering an alternative approach to photocontrol with potential applications in the sequential regulation of multiple enzymes, especially when combined with monochromatic irradiation strategies.

Nitroarenes are indispensable building blocks in organic chemistry and are embedded in numerous pharmaceuticals. However, their direct C–H functionalization via alkylation is hindered by the strongly electron-withdrawing nature of the nitro group and its tendency to intercept radical species generated under photochemical or other reaction conditions. Here, we report a photocatalytic strategy for the direct C–H alkylation of nitroarenes using readily available carboxylic acids as alkyl radical precursors. This transformation proceeds under mild, visible-light irradiation conditions, exhibits broad functional group tolerance, and is compatible with both aromatic and aliphatic carboxylic acids. Mechanistic studies indicate a decarboxylative radical addition pathway initiated by photoexcitation of an organic photocatalyst. This method enables late-stage functionalization of complex molecules and provides a modular platform for sequential C–H diversification, thereby expanding the synthetic utility of nitroarenes for medicinal chemistry applications.

Photoredox catalysis, which enables both electron and hydrogen atom transfer, has become a powerful tool for activating chemical bonds and synthesizing complex molecules under mild conditions. Typically, photocatalysts are optimized either for oxidative or reductive reactions within a limited redox window (less than 3.1 V) and for hydrogen atom transfer (HAT) reactions, with few frameworks capable of mediating both pathways for high redox-demanding reactions (covering more than a 5 V redox window) without requiring special conditions. Herein, we report the use of quinones as multifunctional scaffolds in light-driven redox transformations, offering access to a redox window of approximately 5 V using visible light. The quinone scaffold's versatility facilitates a wide range of radical and ionic processes under both oxidative and reductive conditions, in addition to enabling HAT reactions. By keeping the parameters, i. e. the reaction partners, constant, such transformations can be carried out under just two reaction conditions. Oxidative transformations and HAT reactions occur under ambient air, while activation of the chromophore for reductive transformations can be achieved using an inorganic base (Cs2CO3) via a simple acid-base deprotonation event. This dual capability highlights the potential of quinones as scaffolds to extend their utility in photoredox catalysis.

Iodanyl radical catalysis represents a frontier in hypervalent iodine catalysis, offering unique reactivity distinct from those of traditional I(I)/I(III) and I(III)/I(V) systems. This study presents an innovative photocatalytic strategy for generating and harnessing iodanyl radicals through an efficient I(I)/I(II) catalytic cycle. Using visible-light photocatalysis to convert aryl iodides, we achieve precise control over the formation of iodanyl radical intermediates under redox-neutral conditions. The developed system exhibits versatility, particularly in the activation of alcohols as hydrogen atom transfer catalysts. We show the power of this iodanyl radical catalysis in challenging C-H bond functionalizations, including the activation of light hydrocarbons such as methane, ethane, and propane. Mechanistic investigations reveal the crucial role of iodanyl species in facilitating HAT processes. This work expands the scope of hypervalent iodine chemistry and provides a valuable tool for synthetic organic chemistry, opening avenues for previously challenging transformations.

Pyridine N-oxides are reported as neutral ligands in cerium photocatalysis. By using those neutral ligands, photoactive Ce(IV)-species are generated, which show an extensive bathochromic shift compared to previously employed cerium-based complexes. This allows the effective utilization of green light in the redox-neutral CH-hydrazination of small molecules under very mild photocatalytic conditions.

Lactam rings are essential structural motifs in organic chemistry, widely present in natural products and clinically important drugs, such as antibiotics and antiepileptics. Existing methods for synthesizing N-functionalized lactams often require harsh conditions, toxic reagents, or complex catalytic systems. Here, we report a mild and efficient photochemical approach for generating N-centered radicals, enabling straightforward N-heteroarylation of lactams. This versatile method enables the synthesis of a range of N-(het)arylated lactams and is effective even in aqueous media, facilitating the functionalization of biomolecules. Furthermore, the photochemical reaction is easily scalable under continuous flow conditions, making it highly suitable for large-scale applications.

Benzoate anions coordinate to cerium ions. Excitation of such complexes by light leads to homolytic oxygen-cerium bond cleavage through ligand-to-metal charge transfer (LMCT). This process results in the reduction of the metal ion and the oxidation of the ligand via a single-electron transfer event. The resulting benzoic acid radical can serve as a potent hydro-gen atom abstractor, facilitating the activation of carbon atoms via C-H activation. This study investigated the scope of other oxo-anions and other ligands on cerium(IV) ions that undergo synthetically useful LMCT processes. As a model reaction, the nucleophilic carbon-centred radical from C-H abstraction in alkyl esters was reacted with phthalimide derivatives.

Anthraquinone sulfonates are water‐soluble and cost‐effective photocatalysts that have been attracting increasing interest due to their unique features. Their sulfonate groups unlock the application of the photoactive anthraquinone core in aqueous solution. Moreover, these readily available catalysts can engage with substrates through different activation modes, such as hydrogen atom transfer and proton‐coupled electron transfer events. However, to date, their reactivity has not been fully explored and further applications are expected to emerge. Herein, the existing synthetic applications are outlined and the future perspectives are discussed.

Iron, mostly as Fe2+ or Fe3+ bound in oxides, is the second most common element in the Earth's crust after aluminium. Salts of the d-block metal are cheap and commercially available and have already been used in organic chemistry in many preparative examples for the C-H functionalization of different classes of starting materials. The literature revealed that like copper or cerium, iron can undergo ligand-to-metal charge transfer processes. Different (anionic) ligands of different sizes can be added in various stoichiometries to commercial Fe(ii)/Fe(iii) salts leading to a unique orientation of the ligands around the metal centre. The resulting complexes are often coloured and can be excited by UV or visible light initiating a metal-ligand bond homolysis in which the metal part gets reduced, and the ligand loses one electron to form highly reactive radical species that can abstract hydrogen atoms or in the case of halide radicals add to double or triple bonds in a suitable substrate. In most of the literature-known procedures, the photoreaction proceeds in organic (polar protic/aprotic) solvents and the reaction medium hardly competes against the ligands (such as alcoholates or halides) for free coordination sites on the metal centre. However, in pure water, unlike other solvents (polar-protic or polar-aprotic), the iron cations get fully solvated and result in aquo-complexes due to the exclusive attachment of water molecules to a metal species, such as in sulphate, nitrate, and perchlorate salts. They possess a general stoichiometry of [M(H2O)n]z+ and have been known for a long time in inorganic and environmental chemistry showing unique and useful characteristics that will be exemplified in this review. Fully hydrated! - Iron photocatalysis tests the waters.

Photocatalytic reactions involving a reductive radical-polar crossover (RRPCO) generate intermediates with carbanionic reactivity. Many of these proposed intermediates resemble highly reactive organometallic compounds. However, conditions of their formation are generally not tolerated by their isolated organometallic versions and often a different reactivity is observed. Our investigations on their nature and reactivity under commonly used photocatalytic conditions demonstrate that these intermediates are indeed best described as free, superbasic carbanions capable of deprotonating common polar solvents usually assumed to be inert such as acetonitrile, dimethylformamide, and dimethylsulfoxide. Their basicity not only towards solvents but also towards electrophiles, such as aldehydes, ketones, and esters, is comparable to the reactivity of isolated carbanions in the gas-phase. Previously unsuccessful transformations thought to result from a lack of reactivity are explained by their high reactivity towards the solvent and weakly acidic protons of reaction partners. An intuitive explanation for the mode of action of photocatalytically generated carbanions is provided, which enables methods to verify reaction mechanisms proposed to involve an RRPCO step and to identify the reasons for the limitations of current methods.

A convenient and versatile approach to important 1-azaspirocyclic systems relevant to medicinal chemistry and natural products is reported herein. The main strategy relies on a reductive decarboxylative cyclization of redox-active esters which can be rapidly assembled from abundant cyclic azaacids and tailored acceptor sidechains, with a focus on alkyne acceptors enabling the generation of useful exo-alkene moieties. Diastereoconvergent variants were studied and could be achieved either through remote stereocontrol or conformational restriction in bicyclic carbamate substrates. Two sets of metal-free photocatalytic conditions employing inexpensive eosin Y were disclosed and studied experimentally to highlight key mechanistic divergences.

Herein, we report a mild photocatalytic redox-neutral dehydration of aryl-1,2-ethanediols forming the respective methyl ketones. In the proposed mechanistic cycle an initial hydrogen atom abstraction (HAT) is followed by a 1,2-spin center shift (SCS) as key steps. Interestingly, Eosin Y was found to act as a pre-catalyst dissociating into a catalytically active mixture under irradiation. To the best of our knowledge, this exemplifies the first synthetic utilization of Eosin Y degradation products. As a result, our reaction can be realized with a single organic photocatalyst and releases water as a sole by-product.

Cyclic adenosine monophosphate (cAMP) is one of the most prominent molecules involved in intracellular signaling. As a second messenger, it regulates a plethora of biochemical processes that are essential to keep a cell alive and orchestrates physiological responses to external stimuli. Ever since its discovery, great efforts have been made to elucidate all the molecular mechanisms involved in cAMP-mediated signaling cascades. However, experimental evidence suggests that cAMP-mediated signal transduction is much more complex than previously assumed. For new insights, it is crucial to study the real-time dynamics and reversibility of the cAMP-related signaling mechanisms, which often remain disguised by classic pharmacological assays or modulators of cAMP signaling. By chemically attaching a photoswitchable moiety to cAMP, we got control over the biological activity of the molecule through visible light of different wavelengths. Combined with label-free electric cell-substrate impedance sensing (ECIS), the dynamic response of living cells treated with photochromic cAMP has been monitored in real-time while the cAMP-mediated signaling cascade is reversibly switched on and off by visible light with high temporal resolution.

A static external electric field (EEF) is for the first time successfully applied to enhance the photocatalytic activity of graphene oxide (GO) photocatalysts functionalized by either zinc porphyrins or perylene diimide. The applied 4 kV EEF increases the reaction rate of the hybrid-assisted photodestruction of a model organic pollutant, 1,5-dihydroxynaphthalene (DHN), in water by 2.2-2.3 times in a contactless transparent static electric cell. A control material presenting zinc porphyrins on the non-polarizable MoS2 nanosheets does not change its activity in EEF. Ultrafast time-resolved photoluminescence spectroscopy, photoluminescent hydroxyl radical probing, and the GC-MS analysis of the supernatant solutions are used to confirm no effect of EEF on photochemical properties of the porphyrins as well as on the pathway of photodestruction of DHN. The DFT calculations show that the dielectric properties and polarizability of GO play a key role in the EEF-induced enhancement of photocatalysis due to the decrease in electron energy facilitating its transfer from GO into water or substrate. Our finding may provide a basis for an affordable alternative for conventional electrophotocatalysis schemes to advance this field towards more effective green-chemistry technologies and to encourage the rational design of new carbon-based photocatalysts, which can be applied for EEF-facilitated photocatalysis.

Isotonitazene belongs to a potent class of mu-opioid receptor (mu OR) ligands, known as nitazenes. The lack of knowledge surrounding this agonist and others in its class has sparked thorough re-investigations. To aid in these investigations, the purportedly covalent yet underexplored nitazene BIT was biochemically re-evaluated in this work, along with a newly synthesized analogue, Iso-BIT. Moreover, in the pursuit of understanding the mechanism, function and interactions of the mu OR, this study involved developing photoswitchable nitazene derivatives as potential probe molecules. Converting known ligands into azo-containing photoswitchable derivatives offers the opportunity to modulate ligand structure with light, allowing for photocontrol of compound activity. While photocontrol of mu OR activity could not be entirely achieved, photophysical evaluation of these 2-benzimidazole azo-arenes revealed a novel photoswitch scaffold that responds to visible light. Furthermore, azo-containing 2 e and 3 e emerged as promising nitazene derivatives that were able to form an exceptionally high fraction of covalent-ligand receptor complexes with wild-type mu OR at physiological pH. Potent synthetic opioids, nitazenes, were converted into photoswitchable derivatives and derivatives containing an isothiocyanate functionality for covalent interaction with the mu-opioid receptor. Photophysical analysis of the resulting 2-benzimidazole azo-arenes revealed a novel photoswitch scaffold that responds to visible light. Importantly, ligands in this series were able to effectively localize and covalently bind to the target receptor at physiological pH. image

Herein we unveil a visible-light-driven transition-metal-free 1,3-bromodifluoroallylation of [1.1.1]propellane. This reactivity is harnessed through organophotocatalysis, providing practical synthetic pathways to 1-brominated-3-gem-difluoroallylic bicyclo[1.1.1]pentane derivatives, particularly derived from readily available α-trifluoromethylalkenes and inexpensive KBr salts utilized as precursors for bromine radicals. Mechanistic investigations reveal that bromide anions quench the excited state of the photocatalyst, leading to the formation of bromine radicals, which react in a strain-release radical addition process rather than hydrogen atom abstraction with [1.1.1]propellane.