Vinylazaarenes as dienophiles in Lewis acid-promoted Diels–Alder reactions

Described are the first examples of Lewis acid-promoted Diels–Alder reactions of vinylpyridines and other vinylazaarenes with unactivated dienes. Cyclohexyl-appended azaarenes constitute a class of substructures of rising prominence in drug discovery. Despite this, thermal variants of the vinylazaarene Diels–Alder reaction are rare and have not been adopted for synthesis, and Lewis acid-promoted variants are virtually unexplored. The presented work addresses this gap and in the process furnishes increased scope, dramatically higher yields, improved regioselectivity, and high levels of diastereoselectivity compared to prior thermal examples. These reactions provide scalable access to druglike scaffolds not readily available through other methods. More broadly, these studies establish a useful new class of dienophiles that, based on preliminary mechanistic studies, should be amenable to conventional strategies for enantioselective catalysis.

Vinyl-substituted azaarenes are rare and challenging substrates as dienophiles in Diels–Alder reactions; by employing Lewis acid activation, high yielding and highly selective cycloadditions with unactivated dienes are enabled.     

Extended phenothiazines: synthesis,photophysical and redox properties,and efficient photocatalytic oxidative coupling of amines

Herein we successfully developed a ring-fusion approach to extend the conjugation length of phenothiazines and synthesized a series of novel extended phenothiazines 1–5. The intriguing π-conjugation length-dependent photophysical and redox properties of 1–5, and their photocatalytic performance towards visible-light-driven oxidative coupling reactions of amines were systematically investigated. The results indicated that this series of extended phenothiazines exhibited continuous red shifts of light absorption with increasing numbers of fused rings. As compared with the conventional phenothiazine (PTZ), all the extended phenothiazines displayed reversible redox behavior and maintained a strong excited-state reduction potential as well. Consequently, 3, 4 and 5 with longer effective conjugation lengths could efficiently catalyze the oxidative coupling of amines to imines under visible-light irradiation; by comparison, the shorter 1, 2 and PTZ could only catalyze such reactions in the presence of UV light. Moreover, 3 showed superior catalytic performance which can result in better yields within a shorter reaction time, and in a broad substrate scope. Finally, a direct and efficient conversion of amines to imines under sunlight in an air atmosphere was successfully realized. We believe that our study including the new phenothiazine modification methodology and the newly developed extended phenothiazine-based photocatalysts will open up a new way to develop novel phenothiazine-based materials for optoelectronic and catalytic applications.

Herein, we successfully developed a ring-fusion approach to extend the conjugation length of phenothiazines that were demonstrated to be efficient photocatalysts for visible-light-driven oxidative coupling reactions of amines under an air atmosphere.     

Visible light activated BINOL-derived chiroptical switches based on boron integrated hydrazone complexes

Chiral optical switches, which use light to control chirality in a reversible manner, offer unique properties and fascinating prospects in the areas of molecular switching and responsive systems, new photochromic materials and molecular data processing and storage. Herein, we report visible light responsive chiroptical switches based on tetrahedral boron coordination towards an easily accessible hydrazone ligand and optically pure BINOL. Upon instalment of a non-planar dibenzo[a,d]-cycloheptene moiety in the hydrazone ligand''s lower half, the enantiopure boron complex shows major chiroptical changes in the CD read-out after visible light irradiation. The thermal isomerization barrier in these chiroptical switching systems showed to be easily adjustable by the introduction of substituents onto the olefinic bond of the cycloheptene ring, giving profound control over their thermal stability. The control over their thermal stability in combination with excellent reversibility, photochemical properties and overall robustness of the complexes makes these BINOL-derived chiroptical switches attractive candidates for usage in advanced applications, e.g. photonic materials and nanotechnology.

Chiroptical switches, which use light to control chirality in a reversible manner, offer unique properties and fascinating prospects in the areas of molecular responsive systems, new photochromic materials and molecular data processing and storage.     

Structure–function relationships in aryl diazirines reveal optimal design features to maximize C–H insertion

Diazirine reagents allow for the ready generation of carbenes upon photochemical, thermal, or electrical stimulation. Because carbenes formed in this way can undergo rapid insertion into any nearby C–H, O–H or N–H bond, molecules that encode diazirine functions have emerged as privileged tools in applications ranging from biological target identification and proteomics through to polymer crosslinking and adhesion. Here we use a combination of experimental and computational methods to complete the first comprehensive survey of diazirine structure–function relationships, with a particular focus on thermal activation methods. We reveal a striking ability to vary the activation energy and activation temperature of aryl diazirines through the rational manipulation of electronic properties. Significantly, we show that electron-rich diazirines have greatly enhanced efficacy toward C–H insertion, under both thermal and photochemical activation conditions. We expect these results to lead to significant improvements in diazirine-based chemical probes and polymer crosslinkers.

Electron-rich aryl diazirines have lower activation temperatures and a longer λ_max than electron-poor analogues, and undergo C–H insertion up to ten-fold more efficiently—suggesting improved performance for biological probes and polymer crosslinkers.     

Local detection of pH-induced disaggregation of biocompatible micelles by fluorescence switch ON

Fluorogenic nanoparticles (NPs) able to sense different physiological environments and respond with disaggregation and fluorescence switching OFF/ON are powerful tools in nanomedicine as they can combine diagnostics with therapeutic action. pH-responsive NPs are particularly interesting as they can differentiate cancer tissues from healthy ones, they can drive selective intracellular drug release and they can act as pH biosensors. Controlled polymerization techniques are the basis of such materials as they provide solid routes towards the synthesis of pH-responsive block copolymers that are able to assemble/disassemble following protonation/deprotonation. Ring opening metathesis polymerization (ROMP), in particular, has been recently exploited for the development of experimental nanomedicines owing to the efficient direct polymerization of both natural and synthetic functionalities. Here, we capitalize on these features and provide synthetic routes for the design of pH-responsive fluorogenic micelles via the assembly of ROMP block-copolymers. While detailed photophysical characterization validates the pH response, a proof of concept experiment in a model cancer cell line confirmed the activity of the biocompatible micelles in relevant biological environments, therefore pointing out the potential of this approach in the development of novel nano-theranostic agents.

pH-responsive micelles disassembly, upon acidification during lysosomal uptake, leads to fluorescence switch ON. These nanoparticles are promising candidates for the design of novel stimuli-responsive drug delivery systems.     

Catalytic intramolecular aminoarylation of unactivated alkenes with aryl sulfonamides

Arylethylamines are abundant motifs in myriad natural products and pharmaceuticals, so efficient methods to synthesize them are valuable in drug discovery. In this work, we disclose an intramolecular alkene aminoarylation cascade that exploits the electrophilicity of a nitrogen-centered radical to form a C–N bond, then repurposes the nitrogen atom''s sulfonyl activating group as a traceless linker to form a subsequent C–C bond. This photoredox catalysis protocol enables the preparation of densely substituted arylethylamines from commercially abundant aryl sulfonamides and unactivated alkenes under mild conditions. Reaction optimization, scope, mechanism, and synthetic applications are discussed.

A photochemical assembly of cyclic arylethylamines occurs by cascade radical annulation and desulfonylative rearrangement in N-acyl sulfonamides. This aminoarylation is made possible through judicious design intended to thwart undesired reactivity.     

Adsorptive separation using self-assembly on graphite: from nanoscale to bulk processes

Adsorptive separation is a promising lower-energy alternative for traditional industrial separation processes. While carbon-based materials have a long history in adsorptive removal of organic contaminants from solution or gas mixtures, separation using an adsorption/desorption protocol is rarely considered. The main drawbacks are the limited control in bulk adsorption experiments, as often all organic molecules are adsorbed, and lack of desorption methods to retrieve the adsorbed molecules. Using high-resolution on-surface characterization with scanning tunneling microscopy (STM), an increased understanding of the on-surface adsorption behavior under different conditions was obtained. The insight obtained from the nanoscale experiments was used to develop a highly selective separation method using adsorption and desorption on graphite, which was tested for the separation of quinonoid zwitterions. These experiments on adsorptive separation using self-assembly on graphite show its potential and demonstrate the advantage of combining surface characterization techniques with bulk experiments to exploit different possible applications of carbon-based materials.

Insights from high-resolution on-surface characterization techniques are used to improve the control over adsorption and desorption on graphite in bulk adsorptive separation processes.     

Ligand-redox assisted nickel catalysis toward stereoselective synthesis of (n+1)-membered cycloalkanes from 1,n-diols with methyl ketones

A well-defined, bench-stable nickel catalyst is presented here, that can facilitate double alkylation of a methyl ketone to realize a wide variety of cycloalkanes. The performance of the catalyst depends on the ligand redox process comprising an azo-hydrazo couple. The source of the bis electrophile in this double alkylation is a 1,n-diol, so that (n+1)-membered cycloalkanes can be furnished in a stereoselective manner. The reaction follows a cascade of dehydrogenation/hydrogenation reactions and adopts a borrowing hydrogen (BH) method. A thorough mechanistic analysis including the interception of key radical intermediates and DFT calculations supports the ligand radical-mediated dehydrogenation and hydrogenation reactions, which is quite rare in BH chemistry. In particular, this radical-promoted hydrogenation is distinctly different from conventional hydrogenations involving a metal hydride and complementary to the ubiquitous two-electron driven dehydrogenation/hydrogenation reactions.

A homogeneous nickel catalyst is described that forms (n+1)-membered cycloalkane rings from ketones and 1,n-diols following a radical-promoted pathway.     

Hypervalent iodine promoted the synthesis of cycloheptatrienes and cyclopropanes

A new strategy is reported for intramolecular Buchner-type reactions using PIDA as a promotor. Traditionally, the Buchner reaction is achieved via Rh-carbenoids derived from Rh^II catalysts with diazo compounds. Herein, the first metal-free Buchner-type reaction to construct highly strained cycloheptatriene- and cyclopropane-fused lactams is presented. The advantage of these transformations is in their mild reaction conditions, simple operation, broad functional group compatibility and rapid synthetic protocol. In addition, scaled-up experiments and a series of follow-up synthetic procedures were performed to clarify the flexibility and practicability of this method. DFT calculations were carried out to clarify the mechanism.

A new strategy is reported for intramolecular Buchner-type reactions using PIDA as a promotor.     

An experimental approach probing the conformational transitions and energy landscape of antibodies: a glimmer of hope for reviving lost therapeutic candidates using ionic liquid

Understanding protein folding in different environmental conditions is fundamentally important for predicting protein structures and developing innovative antibody formulations. While the thermodynamics and kinetics of folding and unfolding have been extensively studied by computational methods, experimental methods for determining antibody conformational transition pathways are lacking. Motivated to fill this gap, we prepared a series of unique formulations containing a high concentration of a chimeric immunoglobin G4 (IgG4) antibody with different excipients in the presence and absence of the ionic liquid (IL) choline dihydrogen phosphate. We determined the effects of different excipients and IL on protein thermal and structural stability by performing variable temperature circular dichroism and bio-layer interferometry analyses. To further rationalise the observations of conformational changes with temperature, we carried out molecular dynamics simulations on a single antibody binding fragment from IgG4 in the different formulations, at low and high temperatures. We developed a methodology to study the conformational transitions and associated thermodynamics of biomolecules, and we showed IL-induced conformational transitions. We showed that the increased propensity for conformational change was driven by preferential binding of the dihydrogen phosphate anion to the antibody fragment. Finally, we found that a formulation containing IL with sugar, amino acids and surfactant is a promising candidate for stabilising proteins against conformational destabilisation and aggregation. We hope that ultimately, we can help in the quest to understand the molecular basis of the stability of antibodies and protein misfolding phenomena and offer new candidate formulations with the potential to revive lost therapeutic candidates.

Probing the energy landscape and thermodynamics of biomolecules for drug design.     

Predicting reaction conditions from limited data through active transfer learning

Transfer and active learning have the potential to accelerate the development of new chemical reactions, using prior data and new experiments to inform models that adapt to the target area of interest. This article shows how specifically tuned machine learning models, based on random forest classifiers, can expand the applicability of Pd-catalyzed cross-coupling reactions to types of nucleophiles unknown to the model. First, model transfer is shown to be effective when reaction mechanisms and substrates are closely related, even when models are trained on relatively small numbers of data points. Then, a model simplification scheme is tested and found to provide comparative predictivity on reactions of new nucleophiles that include unseen reagent combinations. Lastly, for a challenging target where model transfer only provides a modest benefit over random selection, an active transfer learning strategy is introduced to improve model predictions. Simple models, composed of a small number of decision trees with limited depths, are crucial for securing generalizability, interpretability, and performance of active transfer learning.

Transfer learning is combined with active learning to discover synthetic reaction conditions in a small-data regime. This strategy is tested on cross-coupling reactions from a high-throughput experimentation dataset and shows promising results.     

Cobalt-catalyzed chemoselective dehydrogenation through radical translocation under visible light

The transformations that allow the direct removal of hydrogen from their corresponding saturated counterparts by the dehydrogenative strategy are a dream reaction that has remained largely underexplored. In this report, a straightforward and robust cobaloxime-catalyzed photochemical dehydrogenation strategy via intramolecular HAT is described for the first time. The reaction proceeds through an intramolecular radical translocation followed by the cobalt assisted dehydrogenation without needing any other external photosensitizers, noble-metals or oxidants. With this approach, a series of valuable unsaturated compounds such as α,β-unsaturated amides, enamides and allylic and homoallylic sulfonamides were obtained in moderate to excellent yields with good chemo- and regioselectivities, and the synthetic versatility was demonstrated by a range of transformations. And mechanistic studies of the method are discussed.

The dehydrogenative reactions proceeded through selective 1,n-hydrogen atom transfer (n = 5–7) for remote C–H activation by cobaloxime catalysis.     

Electrochemically switchable polymerization from surface-anchored molecular catalysts

Redox-switchable polymerizations of lactide and epoxides were extended to the solid state by anchoring an iron-based polymerization catalyst to TiO₂ nanoparticles. The reactivity of the molecular complexes and their redox-switching characteristics were maintained in the solid-state. These properties resulted in surface-initiated polymerization reactions that produced polymer brushes whose chemical composition is dictated by the oxidation state of the iron-based complex. Depositing the catalyst-functionalized TiO₂ nanoparticles on fluorine-doped tin oxide resulted in an electrically addressable surface that could be used to demonstrate spatial control in redox-switchable polymerization reactions. By using a substrate that contained two electrically isolated domains wherein one domain was exposed to an oxidizing potential, patterns of surface-bound polyesters and polyethers were accessible through sequential application of lactide and cyclohexene oxide. The differentially functionalized surfaces demonstrated distinct physical properties that illustrated the promise for using the method to pattern surfaces with multiple, chemically distinct polymer brushes.

Patterns of multiple polymer brushes on surfaces are obtained through application of an electrical potential to a surface functionalized with redox-switchable polymerization catalysts.     

Controlling cyclization pathways in palladium(ii)-catalyzed intramolecular alkene hydro-functionalization via substrate directivity

We report a series of palladium(ii)-catalyzed, intramolecular alkene hydrofunctionalization reactions with carbon, nitrogen, and oxygen nucleophiles to form five- and six-membered carbo- and heterocycles. In these reactions, the presence of a proximal bidentate directing group controls the cyclization pathway, dictating the ring size that is generated, even in cases that are disfavored based on Baldwin''s rules and in cases where there is an inherent preference for an alternative pathway. DFT studies shed light on the origins of pathway selectivity in these processes.

We report a series of palladium(ii)-catalyzed, intramolecular alkene hydrofunctionalization reactions with carbon, nitrogen, and oxygen nucleophiles to form five- and six-membered carbo- and heterocycles.     

By-design molecular architectures via alkyne metathesis

Shape-persistent purely organic molecular architectures have attracted tremendous research interest in the past few decades. Dynamic Covalent Chemistry (DCvC), which deals with reversible covalent bond formation reactions, has emerged as an efficient synthetic approach for constructing these well-defined molecular architectures. Among various dynamic linkages, the formation of ethynylene linkages through dynamic alkyne metathesis is of particular interest due to their high chemical stability, linearity, and rigidity. In this review, we focus on the synthetic strategies of discrete molecular architectures (e.g., macrocycles, molecular cages) containing ethynylene linkages using alkyne metathesis as the key step, and their applications. We will introduce the history and challenges in the synthesis of those architectures via alkyne metathesis, the development of alkyne metathesis catalysts, the reported novel macrocycle structures, molecular cage structures, and their applications. In the end, we offer an outlook of this field and remaining challenges.

The recent synthesis of novel shape-persistent 2D and 3D molecular architectures via alkyne metathesis is reviewed and the critical role of catalysts is also highlighted.     

The dioxasilepanyl group as a versatile organometallic unit: studies on stability,reactivity, and utility

Organic synthesis is performed based on precise choices of functional groups and reactions employed. In a multistep synthesis, an ideal functional group should be compatible with various reaction conditions and unaltered until it is subjected to a selective conversion. The current study was set out to search for a silicon functionality that meets these criteria. Here we have established a new silicon-based synthetic methodology centred on a bulky 7-membered dialkoxysilyl group (2,4,4,7,7-pentamethyl-1,3,2-dioxasilepan-2-yl) that uniquely has both stability and on-demand reactivity. The exceptional stability of this functional group was corroborated by both experimental and computational studies which demonstrated that key factors for its stability were a 7-membered structure and steric hindrance. In turn, the dioxasilepanyl group was found to become reactive and to be easily transformed in the presence of appropriate activators. Combined with the development of easy and robust methods to introduce the dioxasilepanyl group onto aryl rings, these findings have allowed a shorter and more efficient synthesis of a bioactive molecule, thus demonstrating the potential utility of the easily accessible dioxasilepanyl group in organic synthesis.

A bulky 7-membered dioxasilepanyl group has been established as a new organometallic unit for multistep organic syntheses.     

Excited-state palladium-catalysed reductive alkylation of imines: scope and mechanism

Palladium catalysis induced by visible-light irradiation is a promising tool for promoting unusual chemical transformations. We describe the development of excited-state palladium-catalyzed reductive alkylation of imines with alkyl bromides. The new methodology shows broad functional group tolerance and can additionally be applied in the direct three-component reaction of aldehydes, anilines, and alkyl bromides to give the alkyl amines under mild reaction conditions. Time-resolved photoluminescence experiments allowed the determination of the excited-state reaction kinetics and indicate that the reaction is proceeding via the inner-sphere electron transfer mechanism.

Palladium catalysis induced by visible-light irradiation is a promising tool for promoting unusual chemical reactivity. Here, the hybrid alkyl radical/Pd(i) species generated is used to promote the reductive alkylation of imines.     

A visible-light mediated ring opening reaction of alkylidenecyclopropanes for the generation of homopropargyl radicals

Classical cyclopropylcarbinyl radical clock reactions have been widely applied to conduct mechanistic studies for probing radical processes for a long time; however, alkylidenecyclopropanes, which have a similar molecular structure to methylcyclopropanes, surprisingly have not yet attracted researcher''s attention for similar ring opening radical clock processes. In recent years, photocatalytic NHPI ester activation chemistry has witnessed significant blooming developments and provided new synthetic routes for cross-coupling reactions. Herein, we wish to report a non-classical ring opening radical clock reaction using innovative NHPI esters bearing alkylidenecyclopropanes upon photoredox catalysis, providing a brand-new synthetic approach for the direct preparation of a variety of alkynyl derivatives. The potential synthetic utility of this protocol is demonstrated in the diverse transformations and facile synthesis of bioactive molecules or their derivatives and medicinal substances.

A non-classical ring opening radical clock reaction using the innovative NHPI esters bearing alkylidenecyclopropanes upon photoredox catalysis has been demonstrated, providing a brand-new synthetic approach to access a variety of alkynyl derivatives.     

Controlling hydrogel properties by tuning non-covalent interactions in a charge complementary multicomponent system

Mixing small molecule gelators is a promising route to prepare useful and exciting materials that cannot be accessed from any of the individual components. Here, we describe pH-triggered hydrogelation by mixing of two non-gelling amphiphiles. The intermolecular interactions among the molecules can be tuned either by controlling the degree of ionization of the components or by a preparative pathway, which enables us to control material properties such as gel strength, gel stiffness, thermal stability, and an unusual shrinking/swelling behaviour.

The properties of a charge complementary multicomponent gel can be tuned either by pH change or by varying the preparative pathway.     

Direct visible-light-induced synthesis of P-stereogenic phosphine oxides under air conditions

Over the past two decades, visible-light-induced transformations have been regarded as being among the most environmentally benign and powerful strategies for constructing complex molecules and diverse synthetic building blocks in organic synthesis. However, the development of efficient photochemical processes for assembling enantiomerically pure molecules remains a significant challenge. Herein, we describe a simple and efficient visible-light-induced C–P bond forming reaction for the synthesis of P-chiral heteroaryl phosphine oxides in moderate to high yields with excellent ee values (97–99% ee). Even in the absence of transition metal or photoredox catalysts, a variety of P-chiral heteroaryl phosphine oxides, including chiral diphosphine oxide 41, have been directly obtained under air conditions. Density functional theory (DFT) calculations have shown that the reaction involves intersystem crossing and single electron transfer to give a diradical intermediate under visible light irradiation.

We describe a simple and efficient visible-light-induced C–P bond forming reaction for the synthesis of P-chiral heteroaryl phosphine oxides in moderate to high yields with excellent ee values (97–99% ee).