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Polymer-based aqueous redox flow batteries (RFBs) are attracting increasing attention as a promising next-generation energy storage technology due to their potential for low cost and environmental friendliness. The search for new redox-active organic compounds for incorporation into polymer materials is ongoing, with anolyte-type compounds in high demand. In response to this need, we have synthesized and tested a range of new water-soluble redox-active s-tetrazine derivatives, including both low molecular weight compounds and polymers with different architectures. S-tetrazines are some of the smallest organic molecules that can undergo a reversible two-electron reduction in protic media, making them a promising candidate for anolyte applications. We have successfully modified linear polyacrylic acid and poly(N-isopropylacrylamide-co-acrylic acid) microgels with pendent 1,2,4,5-tetrazine groups. Electrochemical testing has shown that the new tetrazine-containing monomers and, importantly, the water-soluble redox polymers, both linear and microgel, demonstrate the chemical reversibility of the reduction process in an aqueous solution containing acetate buffer. This expands the range of water-soluble anodic materials suitable for water-based organic RFBs. The reduction potential value can be adjusted by changing the substituents in the tetrazine core. It is also worth noting that the choice of electrode material plays an important role in the kinetics of the tetrazine reaction: the use of carbon electrodes is particularly beneficial. [ABSTRACT FROM AUTHOR]

Bioorthogonal reactions that enable switching molecular functions by breaking chemical bonds have gained prominence, with the tetrazine‐mediated cleavage of trans‐cyclooctene caged compounds (click‐to‐release) being particularly noteworthy for its high versatility, biocompatibility, and fast reaction rates. Despite several recent advances, the development of highly reactive tetrazines enabling quantitative elimination from trans‐cyclooctene linkers remains challenging. In this study, we present the synthesis and application of sulfo‐tetrazines, a class of derivatives featuring phenolic hydroxyl groups with increased acidity constants (pKa). This unique property leads to accelerated elimination and complete release of the caged molecules within minutes. Moreover, the inclusion of sulfonate groups provides a valuable synthetic handle, enabling further derivatization into sulfonamides, modified with diverse substituents. Significantly, we demonstrate the utility of sulfo‐tetrazines in efficiently activating fluorogenic compounds and prodrugs in living cells, offering exciting prospects for their application in bioorthogonal chemistry. [ABSTRACT FROM AUTHOR]

Bioorthogonal bond‐cleavage reactions have emerged as a powerful tool for precise spatiotemporal control of (bio)molecular function in the biological context. Among these chemistries, the tetrazine‐triggered elimination of cleavable trans‐cyclooctenes (click‐to‐release) stands out due to high reaction rates, versatility, and selectivity. Despite an increasing understanding of the underlying mechanisms, application of this reaction remains limited by the cumulative performance trade‐offs (i.e., click kinetics, release kinetics, release yield) of existing tools. Efficient release has been restricted to tetrazine scaffolds with comparatively low click reactivity, while highly reactive aryl‐tetrazines give only minimal release. By introducing hydroxyl groups onto phenyl‐ and pyridyl‐tetrazine scaffolds, we have developed a new class of ‘bioorthogonal scissors’ with unique chemical performance. We demonstrate that hydroxyaryl‐tetrazines achieve near‐quantitative release upon accelerated click reaction with cleavable trans‐cyclooctenes, as exemplified by click‐triggered activation of a caged prodrug, intramitochondrial cleavage of a fluorogenic probe (turn‐on) in live cells, and rapid intracellular bioorthogonal disassembly (turn‐off) of a ligand‐dye conjugate. [ABSTRACT FROM AUTHOR]

This article provides an overview of the field of bioorthogonal chemistry and its advancements at Radboud University. Bioorthogonal chemistry involves conducting chemical reactions within a biological environment with high selectivity and compatibility. Radboud University has made significant contributions to this field, including the development of strained alkynes and the synthesis of bioorthogonal tools such as BCN and TCO. These tools have been applied in various areas such as chemical biology and materials science. The article also highlights the interdisciplinary nature of research at Radboud University and the importance of synthetic availability in bioorthogonal reagents. The text specifically discusses the use of VBAs in bioorthogonal chemistry, particularly in the IEDDA reaction with tetrazines. The authors found that introducing boronic acid substituents on linear alkenes improved their reactivity in the IEDDA reaction. They also observed that the reactivity of VBAs varied depending on the coordinating substituent on the tetrazine. The authors explored the potential of VBAs in click-to-release chemistry, protein modification, and drug delivery applications. The article emphasizes the collaborative efforts and interdisciplinary approach necessary for advancing bioorthogonal chemistry. [Extracted from the article]

The review is devoted to the key achievements of the Laboratory of Chemistry of Nitro Compounds at the Zelinsky Institute of Organic Chemistry of the Russian Academy of Sciences since its founding by Academician of the Russian Academy of Sciences V. A. Tartakovsky in 1971. The main attention is paid to the structural factors affecting the stability of polynitrogen-oxygen systems (PNO systems), design rules for new stabilized PNO systems, and new synthetic methods towards such systems. The synthesis of dinitramide salts, 1,2,3,4-tetrazine 1,3-dioxides, nitro-NNO-azoxy compounds, and other new classes of PNO systems is considered in detail. The advances in synthesis of new types of N-nitroamines are also considered. [ABSTRACT FROM AUTHOR]

Cyclic peptides offer many advantages compared to their linear counterparts, including prolonged stability within the biological environment and enhanced binding affinity. Typically, peptides are cyclized by forming an amide bond, either on‐resin or in solution, through extensive use of orthogonal protecting groups or chemoselective ligation strategies, respectively. Here, we show that the chemoselective tetrazine‐thiol exchange is a powerful tool for rapid in situ cyclization of peptides without the need for additional activation reagents or extensive protecting group reshuffling. The reaction between N‐terminal sulfide‐bearing unsymmetric tetrazines and internal cysteines occurs spontaneously within a mildly acidic environment (pH 6.5) and is of traceless nature. The rapidly available unsymmetric sulfide tetrazine building blocks can be incorporated on resin using standard solid‐phase peptide synthesis protocols and are orthogonal to trifluoroacetic acid cleavage conditions. The cyclized peptides display high stability, even when incubated with a large excess of free thiols. Due to its traceless and mild nature, we expect that the tetrazine‐thiol exchange will be of high value for the in situ formation of cyclic peptide libraries, thus being applicable in drug discovery and development. [ABSTRACT FROM AUTHOR]

Since the first report that 1,2,4,5‐tetrazines undergo a bioorthogonal reaction with dienophiles in the form of an inverse electron‐demand Diels‐Alder reaction, the demand for high‐yielding synthetic approaches towards them grew steadily. Despite this significant interest, tetrazines were predominantly accessed via the Pinner synthesis or other Pinner‐like reactions, significantly limiting available substrates. In particular, the synthesis of unsymmetrically substituted s‐tetrazines for the selective conjugation to another species presented a major challenge. To tackle these challenges, new and innovative high‐yielding transformations have been developed to widen the scope of accessible symmetric and unsymmetric tetrazines. For instance, Ni(II), Zn(II), and sulphur‐catalysed reactions between two nitriles and hydrazine were developed, which provide access to a wide range of (un‐)symmetric aryl s‐tetrazines. Also, amidines and orthoesters give tetrazines with alkyl substituents, whereas the usage of CH2Cl2 yields valuable H‐monosubstituted tetrazines. Methods using thiocarbohydrazides, terminal fluoroolefins, oxetane esters, or tosyl hydrazones are among the recent additions. Due to the high interest in tetrazine click‐chemistry approaches, some of which reach beyond inverse electron‐demand Diels‐Alder reactions, we expect this overview of synthetic routes to aid the exploration for further applications of tetrazines. Ultimately, we hope to provide a guide for chemists and chemical biologists for accessing functional s‐tetrazines. [ABSTRACT FROM AUTHOR]

Multicomponent reactions are of utmost importance at generating a unique, wide, and complex chemical space. Herein we describe a novel multicomponent approach based on the combination of the isonitrile‐tetrazine (4+1) cycloaddition and the Ugi four‐component reaction to generate pyrazole amide derivatives. The scope of the reaction as well as mechanistic insights governing the 4H‐pyrazol‐4‐imine tautomerization are provided. This multicomponent process provides access to a new chemical space of pyrazole amide derivatives and offers a tool for peptide modification and stapling. [ABSTRACT FROM AUTHOR]

1,2,4,5-Tetrazines are increasingly used as reactants in bioorthogonal chemistry due to their high reactivity in Diels--Alder reactions with various dienophiles. Substituents in the 3- and 6-positions of the tetrazine scaffold are known to have a significant impact on the rate of cycloadditions; this is commonly explained on the basis of frontier molecular orbital theory. In contrast, we show that reactivity differences between commonly used classes of tetrazines are not controlled by frontier molecular orbital interactions. In particular, we demonstrate that mono-substituted tetrazines show high reactivity due to decreased Pauli repulsion, which leads to a more asynchronous approach associated with reduced distortion energy. This follows the recent Vermeeren--Hamlin--Bickelhaupt model of reactivity increase in asymmetric Diels--Alder reactions. In addition, we reveal that ethylene is not a good model compound for other alkenes in Diels--Alder reactions. [ABSTRACT FROM AUTHOR]

In this synthetic procedure, a seven‐step protocol for the preparation of monosubstituted 3‐bromo‐1,2,4,5‐tetrazine is presented. The procedure features efficient transformations and purification methods starting from commercially readily available starting materials and affords the title compound on a gram scale with 13 % overall yield in reliable purity (>97 %). Detailed experimental procedures, supported by images and additional notes, allow the preparation of a valuable advanced building block, enabling further applications in bioconjugation, protein labelling, bio‐orthogonal chemistry, heterocycle syntheses, high energy materials, and drug release, among others. [ABSTRACT FROM AUTHOR]

Immobilizing matrix plays a crucial role in anchoring the receptors of target biomolecules and enhancing the sensing capability of biosensor. Howbeit, the immobilization platforms that induce stable molecular interactions with the receptors without the need for harsh reaction conditions (covalent bonding) are rare. Herein, we report the design, development and application of novel semiconducting one-dimensional (1D) tetrazine polymers (TTz, PhTTz, PhAlkTz) as immobilizing matrices for electronic biosensing of carcinoembryonic antigen (CEA), a cancer biomarker. The polymers are fully loaded with electron-deficient tetrazine units (nitrogen-rich), which develop strong hydrogen bonding (H-bonding) interactions and effectively immobilize the bioreceptor (anti-CEA). The sensor comprises reduced graphene oxide (rGO) as the base conducting layer and tetrazine polymers as immobilizing matrices for the CEA antibodies. The rGO/TTz/anti-CEA, rGO/PhTTz/anti-CEA, rGO/PhAlkTz/anti-CEA sensors exhibited 3.5 to 34.16 µA, 2.2 to 34.89 µA, 1.1 to 39.27 µA responses, respectively, for 1 pg/ml to 200 ng/ml of CEA. The sensors' (TTz, PhTTz, and PhAlkTz) sensitivities, selectivities and stabilities are found to be better than that of previously reported partially tetrazine loaded polymer (PhPTz). The study discloses the presence of H-bonding in tetrazine units is highly critical for superior sensing. The concept of utilizing N-rich tetrazine units in the immobilizing platforms can be generalized to several other hetero-atom based systems and polymers. Thus, a wide variety of novel immobilizing substrates can be developed to realize superior sensing performance. [ABSTRACT FROM AUTHOR]

The straightforward access to a new class of aza‐polyaromatics is reported. Starting from readily available fluorinated s‐tetrazine, a cyclization process with azide leads to the formation of an unprecedented tetrazo[1,2‐b]indazole or a bis‐tetrazo[1,2‐b]indazole (cis and trans conformers). Based on the new nitrogen core, further N‐directed palladium‐catalyzed ortho‐C−H bond functionalization allows the introduction of halides or acetates. The physicochemical properties of these compounds were studied by a joint experimental/theoretical approach. The tetrazo[1,2‐b]indazoles display solid‐state π‐stacking, low reduction potential, absorption in the visible range up to the near‐infrared, and intense fluorescence, depending on the molecular structure. [ABSTRACT FROM AUTHOR]

An optimized synthetic protocol toward the assembly of Kuhn verdazyls based on an azo coupling of arenediazonium salts with readily available hydrazones followed by the base-mediated cyclization of in situ formed formazans with formalin was developed. The scope and limitations of the presented method were revealed. Some new mechanistic insights on the formation of Kuhn verdazyls were also conducted. It was found that in contradiction with previously assumed hypotheses, the synthesis of verdazyls was accomplished via an intermediate formation of verdazylium cations which were in situ reduced to leucoverdazyls. The latter underwent deprotonation under basic conditions to generate corresponding anions which coproportionate with verdazylium cations to furnish the formation of Kuhn verdazyls. The spectroscopic and electrochemical behavior of the synthesized verdazyls was also studied. Overall, our results may serve as a reliable basis for further investigation in the chemistry and applications of verdazyls. [ABSTRACT FROM AUTHOR]

This paper presents the data of research studies on the mechanisms, kinetics and thermodynamics of decomposition of three high-energy compounds: [1,2,4]triazolo[4,3-b][1,2,4,5]tetrazine-3,6-diamine (TTDA), 3-amino-6-hydrazino[1,2,4]triazolo[4,3-b][1,2,4,5]tetrazine (TTGA) and 3,6-dinitroamino[1,2,4]triazolo[4,3-b][1,2,4,5]tetrazine (DNTT). The points of change of the reaction mechanisms under thermal effects with different intensities from 0.1 to 2000 s−1 have been established. The values of activation and induction energies for the limiting stages of decomposition have been obtained. The formation of nanostructured carbon nitride (α-C3N4) in condensed decomposition products, cyanogen (C2N2) and hydrogen cyanide (HCN) in gaseous products have been shown. Concentration-energy diagrams for the reaction products have been compiled. The parameters of heat resistance and thermal safety proved to be: 349.5 °C and 358.2 °C for TTDA; 190.3 °C and 198.0 °C for TTGA; 113.4 °C and 114.1 °C for DNTT. The energy and thermodynamic properties have also been estimated. This work found the activation energy of the decomposition process to be 129.0 kJ/mol for TTDA, 212.2 kJ/mol for TTGA and 292.2 kJ/mol for DNTT. The average induction energy of the catalytic process (Ecat) for TTGA was established to be 21 kJ/mol, and for DNTT-1500–1700 kJ/mol. The induction energy of the inhibition process (Eing) of TTDA was estimated to be 800–1400 kJ/mol. [ABSTRACT FROM AUTHOR]

The molecules possessing triazine and tetrazine moieties belong to a special class of heterocyclic compounds. Both triazines and tetrazines are building blocks and have provided a new dimension to the design of biologically important organic molecules. Several of their derivatives with fine-tuned electronic properties have been identified as multifunctional, adaptable, switchable, remarkably antifungal, anticancer, antiviral, antitumor, cardiotonic, anti-HIV, analgesic, anti-protozoal, etc. The objective of this review is to comprehensively describe the recent developments in synthesis, coordination properties, and various applications of triazine and tetrazine molecules. The rich literature demonstrates various synthetic routes for a variety of triazines and tetrazines through microwave-assisted, solid-phase, metal-based, [4+2] cycloaddition, and multicomponent one-pot reactions. Synthetic approaches contain linear, angular, and fused triazine and tetrazine heterocycles through a combinatorial method. Notably, the triazines and tetrazines undergo a variety of organic transformations, including electrophilic addition, coupling, nucleophilic displacement, and intramolecular cyclization. The mechanistic aspects of these heterocycles are discussed in a detailed way. The bioorthogonal application of these polyazines with various strained alkenes and alkynes provides a new prospect for investigations in chemical biology. This review systematically encapsulates the recent developments and challenges in the synthesis and possible potential applications of various triazine and tetrazine systems. [ABSTRACT FROM AUTHOR]

The synthesis of cyclopentadiene derivatives via the domino reaction of norbornadienes with dimethyl 1,2,4,5‐tetrazine‐3,6‐dicarboxylate, followed a retro‐Diels‐Alder reaction, was reported by Dalkılıç few years ago (Tetrahedron 2015;71 : 1966). In some cases, the formation of an unexpected dihydropyridazine (DHP) was observed, and explained by a 1,3‐hydrogen shift. A density functional theory study is herein reported giving insights into the proposed mechanisms with different substituents on norbornadiene. Based on the kinetic and thermodynamic data, the retro‐Diels‐Alder reaction is confirmed to explain the formation of cyclopentadienes plus pyridazines. The intramolecular 1,3‐hydrogen shift mechanism was not sufficient to explain the exclusive formation of two DHPs. Thus, an alternative mechanism involving a stepwise tautomerisation is being reported for formation of DHPs. [ABSTRACT FROM AUTHOR]

trans‐Cyclooctenes (TCOs) are essential partners in the fastest known bioorthogonal reactions, but current synthetic methods are limited by poor diastereoselectivity. Especially hard to access are hydrophilic TCOs with favorable physicochemical properties for live cell or in vivo experiments. Described is a new class of TCOs, "a‐TCOs", prepared in high yield by stereocontrolled 1,2‐additions of nucleophiles to trans‐cyclooct‐4‐enone, which itself was prepared on a large scale in two steps from 1,5‐cyclooctadiene. Computational transition‐state models rationalize the diastereoselectivity of 1,2‐additions to deliver a‐TCO products, which were also shown to be more reactive than standard TCOs and less hydrophobic than even a trans‐oxocene analogue. Illustrating the favorable physicochemical properties of a‐TCOs, a fluorescent TAMRA derivative in live HeLa cells was shown to be cell‐permeable through intracellular Diels–Alder chemistry and to wash out more rapidly than other TCOs. [ABSTRACT FROM AUTHOR]

The inverse electron-demand Diels-Alder (IEDDA or DAinv) reaction is an emerging bioorthogonal ligation reaction that finds application in all areas of chemistry and chemical biology. In this review we highlight its application in metabolic glycoengineering (MGE). MGE is a versatile tool to introduce unnatural sugar derivatives that are modified with a chemical reporter group into cellular glycans. The IEDDA reaction can then be used to modify the chemical reporter group allowing, for instance, the visualization or isolation of glycoconjugates. During the last years, many different sugar derivatives as well as reporter groups have been published. These probes are summarized, and their chemical and biological properties are discussed. Furthermore, we discuss examples of MGE and subsequent IEDDA reaction that highlight its suitability for application within living systems.

Due to the interest in, and diverse applications of, 1,2,4,5-tetrazines and 1,3,4-thiadiazoles, individually and, more recently, in combination, a series of novel 1,2,4,5-tetrazine derivatives conjugated directly or via a 1,4-phenylene linker with a 1,3,4-thiadiazole core, were synthesized. A six-step reaction sequence, involving the Pinner reaction and oxidation under mild conditions, was used. This approach worked well for both symmetrical and unsymmetrical arrangements. Their luminescence properties were examined and are reported. The obtained compounds may have a number of great applications potential. [ABSTRACT FROM AUTHOR]

Since tetrazines are important tools to the field of bioorthogonal chemistry, there is a need for new approaches to synthesize unsymmetrical and 3‐monosubstituted tetrazines. Described here is a general, one‐pot method for converting (3‐methyloxetan‐3‐yl)methyl carboxylic esters into 3‐thiomethyltetrazines. These versatile intermediates were applied to the synthesis of unsymmetrical tetrazines through Pd‐catalyzed cross‐coupling and in the first catalytic thioether reduction to access monosubstituted tetrazines. This method enables the development of new tetrazine compounds possessing a favorable combination of kinetics, small size, and hydrophilicity. It was applied to a broad range of aliphatic and aromatic ester precursors and to the synthesis of heterocycles including BODIPY fluorophores and biotin. In addition, a series of tetrazine probes for monoacylglycerol lipase (MAGL) were synthesized and the most reactive one was applied to the labeling of endogenous MAGL in live cells. [ABSTRACT FROM AUTHOR]

Fluorescent probes that light‐up upon reaction with complementary bioorthogonal reagents are superior tools for no‐wash fluorogenic bioimaging applications. In this work, a thorough study is presented on a set of seventeen structurally diverse coumarin–tetrazine probes that produce fluorescent dyes with exceptional turn‐on ratios when reacted with trans‐cyclooctene (TCO) and bicyclononyne (BCN) dienophiles. In general, formation of the fully aromatic pyridazine‐containing dyes resulting from the reaction with BCN was found superior in terms of fluorogenicity. However, evaluation of the probes in cellular imaging experiments revealed that other factors, such as reaction kinetics and good cell permeability, prevail over the fluorescence turn‐on properties. The best compound identified in this study showed excellent performance in live cell‐labeling experiments and enabled no‐wash fluorogenic imaging on a timescale of seconds. [ABSTRACT FROM AUTHOR]

Rapid analysis of single and scant cell populations is essential in modern diagnostics, yet existing methods are often limited and slow. Herein, we describe an ultra‐fast, highly efficient cycling method for the analysis of single cells based on unique linkers for tetrazine (Tz)/trans‐cyclooctene (TCO)‐mediated quenching. Surprisingly, the quenching reaction rates were more than 3 orders of magnitude faster (t1/2 <1 s) than predicted. This allowed multi‐cycle staining and immune cell profiling within an hour, leveraging the accelerated kinetics to open new diagnostic possibilities for rapid cellular analyses. [ABSTRACT FROM AUTHOR]

Recent developments in fluorescence microscopy call for novel small‐molecule‐based labels with multiple functionalities to satisfy different experimental requirements. A current limitation in the advancement of live‐cell single‐molecule localization microscopy is the high excitation power required to induce blinking. This is in marked contrast to the minimal phototoxicity required in live‐cell experiments. At the same time, quality of super‐resolution imaging depends on high label specificity, making removal of excess dye essential. Approaching both hurdles, we present the design and synthesis of a small‐molecule label comprising both fluorogenic and self‐blinking features. Bioorthogonal click chemistry ensures fast and highly selective attachment onto a variety of biomolecular targets. Along with spectroscopic characterization, we demonstrate that the probe improves quality and conditions for regular and single‐molecule localization microscopy on live‐cell samples. [ABSTRACT FROM AUTHOR]

A new organocatalytic and environmentally friendly aerobic oxidative‐catalyzed nitroso‐Diels‐Alder (NDA) reaction of N‐arylhydroxylamines with dienecarbamates has been developed. 3,6‐Bis(2,2,2‐trifluoroethoxy)‐s‐tetrazine was found to be an effective catalyst to selectively oxidize various N‐arylhydroxylamines in the presence of molecular oxygen, but in the absence of photostimulation, as a terminal oxidant. In addition, active catalytic species can be generated in situ from commercially available 3,6‐dichlorotetrazine. [ABSTRACT FROM AUTHOR]

A series of 6-alkoxy-3-aryl-[1,2,4]triazolo[4,3- b ][1,2,4,5] tetrazine derivatives is synthesized and evaluated for their antitumor activities. These compounds exhibit potent antiproliferative activities against A549, Bewo, and MCF-7 cells. Molecular docking is performed to study the inhibitor–c-Met kinase interactions, and the results show that 6-ethoxyl-3-phenylethyl-[1,2,4]triazolo[4,3- b ][1,2,4,5] tetrazine is potently bound to c-Met kinase with two hydrogen bonds and one π–π interaction. Based on these preliminary results, it is thought that compound 6-ethoxyl-3-phenylethyl-[1,2,4]triazolo[4,3- b ][1,2,4,5] tetrazine with potent inhibitory activity may be a potential anticancer agent. [ABSTRACT FROM AUTHOR]

Fluorogenic bioorthogonal reactions enable visualization of biomolecules with excellent signal‐to‐noise ratio. A bicyclononyne−tetrazine ligation that produces fluorescent pyridazine products has been developed. In stark contrast to previous approaches, the formation of the dye is an inherent result of the chemical reaction and no additional fluorophores are needed in the reagents. The crucial structural elements that determine dye formation are electron‐donating groups present in the starting tetrazine unit. The newly formed pyridazine fluorophores show interesting photophysical properties the fluorescence intensity increase in the reaction can reach an excellent 900‐fold. Model imaging experiments demonstrate the application potential of this new fluorogenic bioorthogonal reaction. [ABSTRACT FROM AUTHOR]

This account presents the synthesis and the characterization of triazine-tetrazine nitrogen heterocyclic compounds. Some compounds were characterized by NMR and IR spectroscopy, mass spectrometry, differential scanning calorimetry (DSC), and single-crystal X-ray diffraction. The physical and chemical properties were obtained by EXPLO5 v6.01, gas pycnometer, BAM Fallhammer, BAM Friction tester, and several detonation tests. The results show that the new metal-free polyazido compound 3,6-bis-[2-(4,6-diazido-1,3,5-triazin-2-yl)-diazenyl]-1,2,4,5-tetrazine (4) with high heat of formation (2820 kJ mol–1 /6130.2 kJ kg–1) and excellent detonation velocity and pressure (D = 8602 m s–1 , P = 29.4 GPa) could be used as ingredient in secondary explosives. 3,6-Bis-[2-(4,6-diazido-1,3,5-triazin-2-yl)-hydrazinyl]-1,2,4,5-tetrazine (3) can detonate research department explosive (RDX, cyclonite) as a primer (Δf H m = 2114 kJ mol–1 /4555.2 kJ kg–1 , D = 8365 m s–1 , P = 26.8 GPa), whose initiation capacity is comparable to that of the traditional primary explosive Pb(N3)2. Therefore, the metal-free compound 3 can potentially replace lead-based-primary explosives, which would be advantageous for the environment. 1 Introduction 2 Strategies to Form High-Nitrogen Compounds with High Heat of Formation 3 Metal-Free Strategies to Prepare Primary Explosives 4 Concluding Remarks [ABSTRACT FROM AUTHOR]

We have synthesized the first example of a heptazine molecule bearing three arms, each of them functionalized by a tetrazine at the end. This new original molecule is redox active and fluorescent, benefiting from the energy transfer between the strongly absorbing heptazine core and the emitting tetrazine units. This molecule has been used to functionalize reduced graphene oxide by an easy process resulting in a material able to store charges by a dual faradaic and capacitive mechanism. [Display omitted] [ABSTRACT FROM AUTHOR]

A novel and unexpected convenient one‐pot synthesis of 1,2,3,4‐thiatriazoles has been discovered while investigating the classical tetrazine "Pinner synthesis". The synthetic route starts from commercially‐available nitrile derivatives and gives good to high yields (51–80 %) with no need to isolate any thioacylating agents. The crucial impact of the solvent on the outcome of the modified "Pinner synthesis" is moreover examined and discussed. Using this new synthetic route, a novel donor‐acceptor thiatriazole derivative has been prepared, which exhibits prominent thermally‐activated delayed fluorescence (TADF) in both solution and film. The photoluminescence quantum yield (PLQY) in methylcyclohexane (MCH) and Zeonex (a cyclo olefin polymer) in oxygen‐free conditions were determined to be 76 and 99 %, respectively. This work provides an efficient and practical synthetic approach to functionalized 1,2,3,4‐thiatriazole derivatives, and will noticeably facilitate the application of 1,2,3,4‐thiatriazole as an electron acceptor in organic electronics. One‐stop shop: A novel and unexpected convenient one‐pot synthesis of 1,2,3,4‐thiatriazoles has been discovered meanwhile investigating on the classical tetrazine "Pinner synthesis". The synthetic route starts from commercially‐available nitrile derivatives and gives good to high yields (51–80 %) with no need to isolate any thioacylating agents. Using this new synthetic route a novel donor‐acceptor thiatriazole derivative has been prepared which exhibits prominent thermally activated delayed fluorescence (TADF). [ABSTRACT FROM AUTHOR]

A new and versatile method to prepare Ag nanoparticles on functionalized graphene sheets is described. In a first step, pyridine‐pyridazine units are introduced on graphene sheets by cycloaddition reaction with a tetrazine derivative. Then the material is coated on an electrode and electrodeposition is carried out to generate silver nanoparticles in a one‐step electroreduction process. The applied potential signal is shown to influence the size and dispersity of the particles in the composite. While larger particles are active in improving sensitivity of Surface‐Enhanced Raman Spectroscopy, smaller ones can be efficiently used in electrocatalysis, like for oxygen reduction. Both effects are demonstrated to highlight the versatility of the applications of these easily prepared nanocomposites. Silver nanoparticles decorated graphene sheets are synthesized in a simple two‐step process : first pyridine‐pyridazine are introduced at the graphene surface by inverse Diels‐Alder reaction. Then electroreduction in presence of silver nitrate leads to nanoparticles. Application to SERS and electrocatalysis according to nanoparticle size are demonstrated. [ABSTRACT FROM AUTHOR]

A number of di-, tri-, and tetraazido-substituted azines as potential energetic dispersing agents of solid propellants for ramjet engines have been studied. The enthalpy of combustion and the enthalpy of formation of several azides (2,4,6-triazidopyrimidine, 2,4,6-triazidopyridine, 3,4,5-triazidopyridine-2,6-dicarbonitrile, and 3,4,5,6-tetraazidopyridine-2-carbonitrile) were experimentally determined. Eleven azides were compared with HMX in terms of the enthalpy of combustion in oxygen to CO2 and water (in the case of the presence of hydrogen in the component), as well as in terms of the temperature of the products of adiabatic conversion of the investigated components due to the high enthalpy of formation in the absence of an external oxidizer and the amount of gases released in this process. The enthalpy of combustion of all the investigated azides burned in air was found to be significantly higher than that of HMX, and for seven of the azides studied, the combustion temperature is significantly higher. As regards the gas release volume (24–31 mol/kg), the azides are inferior to HMX (41.9 mol/kg). Based on the combination of properties, the investigated azides can be considered as promising dispersing agents of solid propellants for ramjet engines. [ABSTRACT FROM AUTHOR]

Abstract: A facile, efficient and metal‐free synthetic approach to 3‐monosubstituted unsymmetrical 1,2,4,5‐tetrazines is presented. Dichloromethane (DCM) is for the first time recognized as a novel reagent in the synthetic chemistry of tetrazines. Using this novel approach 11 3‐aryl/alkyl 1,2,4,5‐tetrazines were prepared in excellent yields (up to 75 %). The mechanism of this new reaction, including the role of DCM in the tetrazine ring formation, has been investigated by 13C labeling of DCM, and is also presented and discussed as well as the photophysical and electrochemical properties. [ABSTRACT FROM AUTHOR]

Abstract: The bioorthogonal cleavage of allylic carbamates from trans‐cyclooctene (TCO) upon reaction with tetrazine is widely used to release amines. We disclose herein that this reaction can also cleave TCO esters, carbonates, and surprisingly, ethers. Mechanistic studies demonstrated that the elimination is mainly governed by the formation of the rapidly eliminating 1,4‐dihydropyridazine tautomer, and less by the nature of the leaving group. In contrast to the widely used p‐aminobenzyloxy linker, which affords cleavage of aromatic but not of aliphatic ethers, the aromatic, benzylic, and aliphatic TCO ethers were cleaved as efficiently as the carbamate, carbonate, and esters. Bioorthogonal ether release was demonstrated by the rapid uncaging of TCO‐masked tyrosine in serum, followed by oxidation by tyrosinase. Finally, tyrosine uncaging was used to chemically control cell growth in tyrosine‐free medium. [ABSTRACT FROM AUTHOR]

The fast and biocompatible ligation of 1,2,4,5-tetrazines with strained alkenes has found numerous applications in biomedical sciences. The reactivity of a 1,2,4,5-tetrazine can generally be tuned by changing its electronic properties by varying the substituents in the 3- and/or 6-position. An increased reactivity of such bioorthogonal probes upon conjugation or attachment to a target molecule has not previously been described. Such an approach would be beneficial, as it would minimize the impact of residual tetrazine reagents and/or impurities. Herein, we describe such a 'kinetic turn-on' of 1,2,4,5-tetrazines upon conjugation. On the basis of the significant increase in reactivity following N-acylation predicted by quantum chemical calculations, we prepared 3-aminotetrazines and their corresponding acetylated derivatives. An investigation of the reaction kinetics indeed revealed a remarkable increase in reactivity upon acylation. [ABSTRACT FROM AUTHOR]

A novel series of 3,6-bis(4-hdroxyphenyl)-1,2,4,5-tetrazine alkanoate esters were synthesized and their mesogenic properties were studied using differential scanning calorimetry (DSC) and polarizing optical microscopy (POM). The impact of changing the tail-core linkage from alkyl or alkoxy to ester is profound. Compared to the alkyl or alkoxy linkages, the ester linkage reduced mesogenic properties. Short-tailed compounds are non mesogenic (4a-4e), while long-tailed compounds (4f-4r) exhibit nematic phases. Unlike the alkyl or alkoxy tail series, none of the 18 presented esters in this series exhibits a smectic phase. [ABSTRACT FROM AUTHOR]

We describe the synthesis and the structural characterization of new H₂L(CF₃CO₂)₂ (1) and H₂L(Ph₂PO₄)₂ (2) compounds containing the diprotonated form (H₂L2+) of the tetrazine-based molecule 3,6-di(pyridin-4-yl)-1,2,4,5-tetrazine. X-ray diffraction (XRD) analysis of single crystals of these compounds showed that H₂L2+ displays similar binding properties toward both anions when salt bridge interactions are taken into account. Nevertheless, the different shapes, sizes and functionalities of trifluoroacetate and diphenyl phosphate anions define quite different organization patterns leading to the peculiar crystal lattices of 1 and 2. These three-dimensional (3D) architectures are self-assembled by a variety of non-covalent forces, among which prominent roles are played by fluorine-π (in 1) and anion-π (in 2) interactions. [ABSTRACT FROM AUTHOR]

Abstract: Fluorogenic bioorthogonal reactions enable visualization of biomolecules under native conditions with excellent signal‐to‐noise ratio. Here, we present the design and synthesis of conformationally‐strained aziridine‐fused trans‐cyclooctene (aza‐TCO) dienophiles, which lead to the formation of fluorescent products in tetrazine ligations without the need for attachment of an extra fluorophore moiety. The presented aza‐TCOs adopt the highly strained “half‐chair” conformation, which was predicted computationally and confirmed by NMR measurements and X‐ray crystallography. Kinetic studies revealed that the aza‐TCOs belong to the most reactive dienophiles known to date. The potential of the newly developed aza‐TCO probes for bioimaging applications is demonstrated by protein labeling experiments, imaging of cellular glycoconjugates and peptidoglycan imaging of live bacteria. [ABSTRACT FROM AUTHOR]

The reactions of CuX 2 · n H 2 O (X = ClO 4 , BF 4 ), Cu turnings and 3,6-bis(2-pyridyl)-1,2,4,5-tetrazine (bptz) with excess 1,5-cyclooctadiene (cod) in Me 2 CO under C 2 H 4 afforded dinuclear Cu(I)-bptz/η 2 ,η 2 -cod-X complexes {( 1 ) and ( 4 )} and dinuclear Cu(I)-2,5-H 2 bptz/η 2 ,η 2 -cod-X complexes {( 2 ) and ( 5 )}. In complexes 1 and 4 , each Cu(I) atom is coordinated by two chelate N atoms of bptz and two C C bonds of η 2 ,η 2 -cod in the distorted tetrahedral geometry to produce a transoid dinuclear structure. It should be noted that the redox state of the central tetrazine ring is electrochemically neutral. In complexes 2 and 5 , each Cu(I) atom is coordinated by two chelate N atoms of 2,5-H 2 bptz and two C C bonds of η 2 ,η 2 -cod in the distorted tetrahedral geometry to afford a transoid dinuclear structure in the 2,5-dihydro form. In contrast, the reactions of Cu(BF 4 ) 2 · n H 2 O, Cu turnings and bptz with excess 2,5-norbornadiene (nbd) in MeEtCO under C 2 H 4 afforded Cu(I)-2,5-H 2 bptz/η 2 -nbd-BF 4 complex ( 6 ). Each Cu(I) atom is coordinated by two chelate N atoms in bptz and one C C bond in η 2 -nbd to form a transoid dinuclear structure in the 2,5-dihydro form. These facts show that the flexible cod can preferentially produce a Cu(I)-cyclodiene complex in the η 2 ,η 2 -mode (complexes 1 , 2 , 4 and 5 ) while the rigid nbd can produce a Cu(I)-cyclodiene complex in the η 2 -mode (complex 6 ). Furthermore, the reaction of Cu(NO 3 ) 2 ·3H 2 O, Cu turnings and bptz with excess nbd in Me 2 CO under C 2 H 4 afforded tetranuclear Cu(I)-4,5-H 2 bptz-NO 3 complex ( 7 ) containing a unique anionic [Cu 2 (nbd)(NO 3 ) 4 ] 2− moiety. In the cationic [Cu 4 (4,5-H 2 bptz) 4 ] 4+ moiety, four Cu(I) atoms are bridged by four 4,5-H 2 bptz ligands to form a [4 × 4] grid-like tetranuclear structure with two 4,5-H 2 bptz ligands lying above the Cu 4 mean plane and two lying below. In the anionic [Cu 2 (nbd)(NO 3 ) 4 ] 2− moiety, the two Cu atoms are bridged by one nbd ligand in the μ 2 -η 2 ,η 2 -mode. [ABSTRACT FROM AUTHOR]

New tetrazine derivatives were prepared and their electrochemical properties as well as their reactivity in the inverse demand Diels−Alder (DAinv) reaction were investigated. DFT calculations were performed to calculate the energy and electronic distribution in the frontier molecular orbitals. In particular, the reactivity of these tetrazine derivatives has been compared with that of the already known dichlorotetrazine. A comparison of the gathered data allows a rough correlation to be established between the reactivity and the electron-withdrawing character of the substituent, but only a closer examination of the involved orbitals can enable an accurate prediction of the DAinv reactivity of the investigated compounds. [ABSTRACT FROM AUTHOR]