Synthesis of Styrylbenzazole Photoswitches and Evaluation of their Photochemical Properties.

Styrylbenzazoles form a promising yet under-represented class of photoswitches that can perform a light-driven E-Z isomerization of the central alkene double bond without undergoing irreversible photocyclization, typical of the parent stilbene. In this work, we report the synthesis and photochemical study of 23 styrylbenzazole photoswitches. Their thermal stabilities, quantum yields, maximum absorption wavelengths and photostationary state (PSS) distributions can be tuned by changing the benzazole heterocycle and the substitution pattern on the aryl ring. In particular, we found that push-pull systems show large redshifts of the maximum absorption wavelengths and the highest quantum yields, whereas ortho-substituted styrylbenzazole photoswitches exhibit the most favorable PSS ratios. Taking advantage of both design principles, we produced 2,6-dimethyl-4-(dimethylamino)-styrylbenzothiazole, a thermally stable and efficient P-type photoswitch which displays negative photochromism upon irradiation with visible light up to 470 nm to obtain a near-quantitative isomerization with a very high quantum yield of 59%. Furthermore, 4-hydroxystyrylbenzothiazole was demonstrated to be a pH-sensitive switch which exhibits a 100 nm redshift upon deprotonation. Ortho-methylation of this switch improved the obtained PSS ratio in its deprotonated state from E:Z=53:47 to E:Z=18:82. We anticipate that this relatively unexplored class of photoswitches will form a valuable expansion of the current family of photoswitches.

Highly Efficient Oxindole-Based Molecular Photoswitches.

3-Benzylidene-indoline-2-ones play a prominent role in the pharmaceutical industry due to the diverse biomedical applications of oxindole heterocycles. Despite the extensive reports on their biological properties, these compounds have hardly been studied for their photochemical activity. Here, we present 3-benzylidene-indoline-2-ones as a promising class of photoswitches with high yields, robust photochemical switching with quantum yields reaching up to 50 % and potential for biological applications.

Directing Coupled Motion with Light: A Key Step Toward Machine-Like Function.

Molecular photoactuators can control shape and chemical or physical properties of the responsive system they are embedded in. These effects are usually mediated by supramolecular interactions and can be amplified to perform work at the micro- and macroscopic scale, for instance, in materials and biomimetic systems. While many studies focus on the observable outcome of these events, photoresponsive structures can also translate their conformational change to molecular components and perform work against random Brownian motion. Stereochemical cascades can amplify light-generated motion to a distant moiety of the same molecule or molecular assembly, via conformationally restricted stereogenic elements. Being able to control the conformation or motion of molecular systems remotely provides prospects for the design of the smallest machines imaginable. This Focus Review emphasizes the emergence of directed, coupled motion of remote functionalities triggered by light-powered switches and motors as a tool to control molecular topology and function.

IL-1 Receptor Antagonist Anakinra in the Treatment of COVID-19 Acute Respiratory Distress Syndrome: A Retrospective, Observational Study.

The IL-1 receptor antagonist, anakinra, may represent a therapeutic option for acute respiratory distress syndrome (ARDS) associated with coronavirus disease 2019 (COVID-19). In this study, COVID-19 ARDS patients admitted to the Azienda Socio Sanitaria Territoriale of Lecco, Italy, between March 5th to April 15th, 2020, and who had received anakinra off-label were retrospectively evaluated and compared with a cohort of matched controls who did not receive immunomodulatory treatment. The primary end point was survival at day 28. The population consisted of 112 patients (56 treated with anakinra and 56 controls). Survival at day 28 was obtained in 69 patients (61.6%) and was significantly higher in anakinra-treated patients than in the controls (75.0 versus 48.2%, p = 0.007). When stratified by continuous positive airway pressure support at baseline, anakinra-treated patients' survival was also significant compared with the controls (p = 0.008). Univariate analysis identified anakinra usage (odds ratio, 3.2; 95% confidence interval, 1.47-7.17) as a significant survival predictor. This was not supported by multivariate modeling. The rate of infectious-related adverse events was similar between groups. In conclusion, anakinra improved overall survival and invasive ventilation-free survival and was well tolerated in patients with ARDS associated with COVID-19.

Light-Fueled Transformations of a Dynamic Cage-Based Molecular System.

In a chemical equilibrium, the formation of high-energy species-in a closed system-is inefficient due to microscopic reversibility. Here, we demonstrate how this restriction can be circumvented by coupling a dynamic equilibrium to a light-induced E/Z isomerization of an azobenzene imine cage. The stable E-cage resists intermolecular imine exchange reactions that would "open" it. Upon switching, the strained Z-cage isomers undergo imine exchange spontaneously, thus opening the cage. Subsequent isomerization of the Z-open compounds yields a high-energy, kinetically trapped E-open species, which cannot be efficiently obtained from the initial E-cage, thus shifting an imine equilibrium energetically uphill in a closed system. Upon heating, the nucleophile is displaced back into solution and an opening/closing cycle is completed by regenerating the stable all-E-cage. Using this principle, a light-induced cage-to-cage transformation is performed by the addition of a ditopic aldehyde.

Stereodivergent Chirality Transfer by Noncovalent Control of Disulfide Bonds.

Controlling dynamic stereochemistry is an important challenge, as it is not only inherent to protein structure and function but often governs supramolecular systems and self-assembly. Typically, disulfide bonds exhibit stereodivergent behavior in proteins; however, how chiral information is transmitted to disulfide bonds remains unclear. Here, we report that hydrogen bonds are essential in the control of disulfide chirality and enable stereodivergent chirality transfer. The formation of S-S···H-N hydrogen bonds in solution can drive conformational adaption to allow intramolecular chirality transfer, while the formation of C=O···H-N hydrogen bonds results in supramolecular chirality transfer to form antiparallel helically self-assembled solid-state architectures. The dependence on the structural information encoded in the homochiral amino acid building blocks reveals the remarkable dynamic stereochemical space accessible through noncovalent chirality transmission.

Dynamic Control of a Multistate Chiral Supramolecular Polymer in Water.

Natural systems transfer chiral information across multiple length scales through dynamic supramolecular interaction to accomplish various functions. Inspired by nature, many exquisite artificial supramolecular systems have been developed, in which controlling the supramolecular chirality holds the key to completing specific tasks. However, to achieve precise and non-invasive control and modulation of chirality in these systems remains challenging. As a non-invasive stimulus, light can be used to remotely control the chirality with high spatiotemporal precision. In contrast to common molecular switches, a synthetic molecular motor can act as a multistate chiroptical switch with unidirectional rotation, offering major potential to regulate more complex functions. Here, we present a light-driven molecular motor-based supramolecular polymer, in which the intrinsic chirality is transferred to the nanofibers, and the rotation of molecular motors governs the chirality and morphology of the supramolecular polymer. The resulting supramolecular polymer also exhibits light-controlled multistate aggregation-induced emission. These findings present a photochemically tunable multistate dynamic supramolecular system in water and pave the way for developing molecular motor-driven chiroptical materials.

Photochemistry of para substituted benzanilides in solution: Preparative and mechanistic studies.

Preparative and mechanistic studies on the photochemical reaction of a series of p-substituted benzanilides in polar and nonpolar solvents have been carried out. The aim of this work is mainly focused to show whether the reaction solvent and the electronic effects of the substituents affect the product distribution, the chemical yields and the rate of formation of the 5-substituted-2-aminobenzophenone derivatives. Application of the Hammett linear free energy relationship (LFER) on the rate of formation of 2-aminobenzophenone derivatives, on the lower energy band of the UV-visible absorption spectra of the benzanilides and 5-substituted-2-aminobenzophenone derivatives allows a satisfactory quantification of the substituent effects. Furthermore, the solvent effect was also analyzed on the photoreaction by means of the Reichardt's solvent parameter (ET(30). Finally, (TD-) DFT calculations have been carried out to support the trends observed experimentally.

Aryl-Cl vs heteroatom-Si bond cleavage on the route to the photochemical generation of σ,π-heterodiradicals.

The photochemistry of aryl chlorides having a X-SiMe3 group (X = O, NR, S, SiMe2) tethered to the aromatic ring has been investigated in detail, with the aim to generate valuable Ï­,π-heterodiradicals. Two competitive pathways arising from the excited triplet state of the aromatics have been observed, namely heterolysis of the aryl-chlorine bond and homolysis of the X-silicon bond. The former path is found in chlorinated phenols and anilines, whereas the latter is exclusive in the case of silylated thiophenols and aryl silanes. A combined experimental/computational approach was pursued to explain such a photochemical behavior.Graphical abstract.

Generation of Alkyl Radicals: From the Tyranny of Tin to the Photon Democracy.

Alkyl radicals are key intermediates in organic synthesis. Their classic generation from alkyl halides has a severe drawback due to the employment of toxic tin hydrides to the point that "flight from the tyranny of tin" in radical processes was considered for a long time an unavoidable issue. This review summarizes the main alternative approaches for the generation of unstabilized alkyl radicals, using photons as traceless promoters. The recent development in photochemical and photocatalyzed processes enabled the discovery of a plethora of new alkyl radical precursors, opening the world of radical chemistry to a broader community, thus allowing a new era of photon democracy.

The Influence of Strain on the Rotation of an Artificial Molecular Motor.

In artificial small-molecule machines, molecular motors can be used to perform work on coupled systems by applying a mechanical load-such as strain-that allows for energy transduction. Here, we report how ring strain influences the rotation of a rotary molecular motor. Bridging the two halves of the motor with alkyl tethers of varying sizes yields macrocycles that constrain the motor's movement. Increasing the ring size by two methylene increments increases the mobility of the motor stepwise and allows for fine-tuning of strain in the system. Small macrocycles (8-14 methylene units) only undergo a photochemical E/Z isomerization. Larger macrocycles (16-22 methylene units) can perform a full rotational cycle, but thermal helix inversion is strongly dependent on the ring size. This study provides systematic and quantitative insight into the behavior of molecular motors under a mechanical load, paving the way for the development of complex coupled nanomachinery.

From Photoinduced Supramolecular Polymerization to Responsive Organogels.

Controlling supramolecular polymerization by external stimuli holds great potential toward the development of responsive soft materials and manipulating self-assembly at the nanoscale. Photochemical switching offers the prospect of regulating the structure and properties of systems in a noninvasive and reversible manner with spatial and temporal control. In addition, this approach will enhance our understanding of supramolecular polymerization mechanisms; however, the control of molecular assembly by light remains challenging. Here we present photoresponsive stiff-stilbene-based bis-urea monomers whose trans isomers readily form supramolecular polymers in a wide range of organic solvents, enabling fast light-triggered depolymerization-polymerization and reversible gel formation. Due to the stability of the cis isomers and the high photostationary states (PSS) of the cis-trans isomerization, precise control over supramolecular polymerization and in situ gelation could be achieved with short response times. A detailed study on the temperature-dependent and photoinduced supramolecular polymerization in organic solvents revealed a kinetically controlled nucleation-elongation mechanism. By application of a Volta phase plate to enhance the phase-contrast method in cryo-EM, unprecedented for nonaqueous solutions, uniform nanofibers were observed in organic solvents.

Ultrafast Photoclick Reaction for Selective 18F-Positron Emission Tomography Tracer Synthesis in Flow.

The development of very fast, clean, and selective methods for indirect labeling in PET tracer synthesis is an ongoing challenge. Here we present the development of an ultrafast photoclick method for the synthesis of short-lived 18F-PET tracers based on the photocycloaddition reaction of 9,10-phenanthrenequinones with electron-rich alkenes. The respective precursors are synthetically easily accessible and can be functionalized with various target groups. Using a flow photo-microreactor, the photoclick reaction can be performed in 60 s, and clinically relevant tracers for prostate cancer and bacterial infection imaging were prepared to demonstrate practicality of the method.

Predicting the substituent effects in the optical and electrochemical properties of N,N'-substituted isoindigos.

Isoindigo, the structural isomer of the well-known dye indigo, has seen a major revival recently because of the increasing interest of its use as a potential drug core structure and for the development of organic photovoltaic materials. Highly beneficial for diverse applications are its facile synthesis, straightforward functionalisation and the broad absorption band in the visible range. Moreover, its intrinsic electron deficiency renders isoindigo a promising acceptor structure in bulk heterojunction architectures. Here we present new insights into the substituent effects of N-functionalised isoindigos, developing a reliable and fast in silico screening approach of a library of compounds. Using experimental UV-Vis and electrochemical data increased the accuracy of the TD-DFT method employed. This procedure allowed us to accurately predict the optical and electrochemical properties of N-functionalised isoindigos and the elucidation of the relationship between substituent effects and electronic properties.

Computational Study of the Stability of Natural Amino Acid isomers.

The secular debate on the origin of life on our planet represents one of the open challenges for the scientific community. In this endeavour, chemistry has a pivotal role in disclosing novel scenarios that allow us to understand how the formation of simple organic molecules would be possible in the early primitive geological ages of Earth. Amino acids play a crucial role in biological processes. They are known to be formed in experiments simulating primitive conditions and were found in meteoric samples retrieved throughout the years. Understanding their formation is a key step for prebiotic chemistry. Following this reasoning, we performed a computational investigation over 100'000 structural isomers of natural amino acids. The results we have found suggest that natural amino acids are among the most thermodynamically stable structures and, therefore, one of the most probable ones to be synthesised among their possible isomers.

Phenylimino Indolinone: A Green-Light-Responsive T-Type Photoswitch Exhibiting Negative Photochromism.

Imines are photoaddressable motifs useful in the development of new generations of molecular switches, but their operation with low-energy photons and control over isomer stability remain challenging. Based on a computational design, we developed phenylimino indolinone (PIO), a green-light-addressable T-type photoswitch showing negative photochromism. The isomerization behavior of this photoactuator of the iminothioindoxyl (ITI) class was studied using time-resolved spectroscopies on time scales from femtoseconds to the steady state and by quantum-chemical analyses. The understanding of the isomerization properties and substituent effects governing these photoswitches opens new avenues for the development of novel T-type visible-light-addressable photoactuators based on C=N bonds.

Motorized Macrocycle: A Photo-responsive Host with Switchable and Stereoselective Guest Recognition.

Designing photo-responsive host-guest systems can provide versatile supramolecular tools for constructing smart systems and materials. We designed photo-responsive macrocyclic hosts, modulated by light-driven molecular rotary motors enabling switchable chiral guest recognition. The intramolecular cyclization of the two arms of a first-generation molecular motor with flexible oligoethylene glycol chains of different lengths resulted in crown-ether-like macrocycles with intrinsic motor function. The octaethylene glycol linkage enables the successful unidirectional rotation of molecular motors, simultaneously allowing the 1:1 host-guest interaction with ammonium salt guests. The binding affinity and stereoselectivity of the motorized macrocycle can be reversibly modulated, owing to the multi-state light-driven switching of geometry and helicity of the molecular motors. This approach provides an attractive strategy to construct stimuli-responsive host-guest systems and dynamic materials.

Photocatalytic Reductive Radical-Polar Crossover for a Base-Free Corey-Seebach Reaction.

A metal-free generation of carbanion nucleophiles is of prime importance in organic synthesis. Herein we report a photocatalytic approach to the Corey-Seebach reaction. The presented method operates under mild redox-neutral and base-free conditions giving the desired product with high functional group tolerance. The reaction is enabled by the combination of photo- and hydrogen atom transfer (HAT) catalysis. This catalytic merger allows a C-H to carbanion activation by the abstraction of a hydrogen atom followed by radical reduction. The generated nucleophilic intermediate is then capable of adding to carbonyl electrophiles. The obtained dithiane can be easily converted to the valuable α-hydroxy carbonyl in a subsequent step. The proposed reaction mechanism is supported by emission quenching, radical-radical homocoupling and deuterium labeling studies as well as by calculated redox-potentials and bond strengths.

Modulation of a Supramolecular Figure-of-Eight Strip Based on a Photoswitchable Stiff-Stilbene.

The preparation, assembly and dynamic properties of photoswitchable bisphosphine ligands based on the stiff-stilbene scaffold are reported. Directional bonding and coordination-induced assembly allow complexation of these ligands with palladium(II), resulting in the formation of discrete metallo-supramolecular entities. While the Z isomer forms a simple bidentate metallo-macrocycle, an intricate double helicate figure-of-eight dimer is observed with the E ligand. Topologically 3D complexes can thus be obtained from 2D ligands. Upon irradiation with UV light, isomerization of the ligands allows control of the architecture of the formed complexes, resulting in a light-triggered modulation of the supramolecular topology. Furthermore, a mechanistic investigation unveiled the dynamic nature of the helicate chirality, where a transmission of motion from the palladium centers yields an "eight-to-eight" inversion.

Direct Irradiation of Phenol and Para-Substituted Phenols with a Laser Pulse (266 nm) in Homogeneous and Micro-heterogeneous Media. A Time-Resolved Spectroscopy Study.

Direct irradiation of para-substituted phenols under N2 atmosphere in homogeneous (cyclohexane, acetonitrile, and methanol) and micellar (SDS) solution was investigated by means of time-resolved spectroscopy. After a laser pulse (266 nm), two transient species were formed, viz. the para-substituted phenol radical-cations and the corresponding phenoxy radicals. The radical-cations showed a broad absorption band located between 390 and 460 nm, while the phenoxy radicals showed two characteristic bands centered at 320 nm and 400-410 nm. The deprotonation rate constant of radical-cations (kH) of 105 s-1 and the reaction rate constant of the phenoxy radicals (kR) in the order of 109-1010 M-1·s-1 have been derived. The kH rate constants gave good linear Hammett correlation with positive slope indicating that electron-withdrawing substituents enhance the radical-cation acidity. The binding constants (Kb) of the para-substituted phenols with the surfactant were also measured, and NOESY experiments showed that phenols were located in the hydrophobic core of the micelle. Finally, computational calculations provided the predicted absorption spectra of the transients and nice linear correlations were obtained between the theoretical and experimental energy of the lower absorption band of these species.