Cyclization of (1,2,4,5-tetrazin-3-yl)hydrazones to 3,7-dihydro-1,2,4-triazolo[4,3-b]-1,2,4,5-tetrazines

The intramolecular cyclization of (6-R-1,2,4,5-tetrazin-3-yl)hydrazones of ketones (R is 3,5-dimethylpyrazol-1-yl, 4-methylimidazol-1-yl, or 2-alkylidenehydrazino) giving rise to the previously unknown 3,7-dihydro-1,2,4-triazolo[4,3-b]-1,2,4,5-tetrazines, including spiro compounds, was studied. The reactivity and the yields of the reaction products depend on the structure of the alkylidene fragment and the nature of the substituent in the tetrazine ring.

     

Synthesis and Electrochemical Behavior of Electron‐Rich s‐Tetrazine and Triazolo‐tetrazine Nitrate Esters

We have prepared energetic nitrate ester derivatives of 1,2,4,5‐tetrazine and 1,2,4‐triazolo[4,3‐b]‐[1,2,4,5]‐tetrazine ring systems as model compounds to study the electrochemical behavior of tetrazines in the presence of explosive groups. The model compounds showed lower thermal stabilities relative to PETN (pentaerythritol tetranitrate), but slightly improved mechanical sensitivities. The presence of electron‐rich amine donors leads to a cathodic shift of the tetrazine redox potentials relative to those of previously reported tetrazine explosives. At these potentials, electron‐rich tetrazines with either covalently bound or co‐dissolved nitrate ester groups are irreversibly reduced. Effectively, changes in the electronic structure of tetrazines affect their electrochemical response to the presence of nitrate ester groups. Thus, it may be possible to develop tetrazine‐based electrochemical sensors for the detection of specific explosives and electrocatalysts for their disposal.     

N‐Oxide 1,2,4,5‐Tetrazine‐Based High‐Performance Energetic Materials

One route to high density and high performance energetic materials based on 1,2,4,5‐tetrazine is the introduction of 2,4‐di‐N‐oxide functionalities. Based on several examples and through theoretical analysis, the strategy of regioselective introduction of these moieties into 1,2,4,5‐tetrazines has been developed. Using this methodology, various new tetrazine structures containing the N‐oxide functionality were synthesized and fully characterized using IR, NMR, and mass spectroscopy, elemental analysis, and single‐crystal X‐ray analysis. Hydrogen peroxide (50 %) was used very effectively in lieu of the usual 90 % peroxide in this system to generate N‐oxide tetrazine compounds successfully. Comparison of the experimental densities of N‐oxide 1,2,4,5‐tetrazine compounds with their 1,2,4,5‐tetrazine precursors shows that introducing the N‐oxide functionality is a highly effective and feasible method to enhance the density of these materials. The heats of formation for all compounds were calculated with Gaussian 03 (revision D.01) and these values were combined with measured densities to calculate detonation pressures (P) and velocities (ν_D) of these energetic materials (Explo 5.0 v. 6.01). The new oxygen‐containing tetrazines exhibit high density, good thermal stability, acceptable oxygen balance, positive heat of formation, and excellent detonation properties, which, in some cases, are superior to those of 1,3,5‐tritnitrotoluene (TNT), 1,3,5‐trinitrotriazacyclohexane (RDX), and octahydro‐1,3,5,7‐tetranitro‐1,3,5,7‐tetrazocine (HMX).     

Azido and Tetrazolo 1,2,4,5‐Tetrazine N‐Oxides

This study presents the synthesis and characterization of the oxidation products of 3,6‐diazido‐1,2,4,5‐tetrazine ( 1 ) and 6‐amino‐[1,5‐b ]tetrazolo‐1,2,4,5‐tetrazine ( 2 ). 3,6‐Diazido‐1,2,4,5‐tetrazine‐1,4‐dioxide was produced from oxidation with peroxytrifluoroacetic acid, and more effectively using hypofluorous acid, and 2 can be oxidized to two different products, 6‐amino‐[1,5‐b]tetrazolo‐1,2,4,5‐tetrazine mono‐N‐oxide and di‐N‐oxide. These N‐oxide compounds display promising performance properties as energetic materials.     

Reaction of β‐cyano esters with hydrazine hydrate. Unexpected formation of dipyrrolo[1,2‐b:1′,2′‐e][1,2,4,5]tetrazine,a novel ring system

Some intermediates and by‐products of the title reaction, known to yield 6‐hydrazinopyridazine‐3‐one derivatives, were isolated or detected when the amount of hydrazine hydrate used to react with two model β‐cyano esters was reduced to less than two equivalents. N'‐(1‐amino‐4‐hydrazino‐4‐oxo‐2‐phenylbutyli‐dene)‐4‐hydrazino‐4‐oxo‐2‐phenylbutanehydrazonamide and 3,3,8,8‐tetramethyl‐2,3,7,8‐tetrahydro‐1H,6H‐dipyrrolo[1,2‐b:1′,2′‐e][1,2,4,5]tetrazine‐1,6‐dione were isolated as the terminal products of side‐reactions; they were unreactive to hydrazine. The latter compound is a derivative of a novel ring system. Mechanism of the reaction was proposed.     

Tetrazinodiheteroarene: ‘Charge-Transfer’-Komplexbildung mit Akzeptorverbindungen

Charge-Transfer Complexes of Tetrazinodiheteroarenes with Acceptor Compounds The formation of charge-transfer complexes and radical-ion pairs of donor compounds 1 – 6 with acceptor compounds 7 – 12 has been investigated by means of VIS/NIR-spectroscopic methods. The equilibrium constants K_CT up to 1100_M-1 for the donor/acceptor couple dipyrido[1,2-b:1,2′-e][1,2,4,5]tetrazine ( 2 )/ethylenetetracarbonitrile ( 11 ) and spectra of the CT complexes have been determined in 1,2-dichloroethane solution at 25°. Results are discussed in relation to known CT-complex properties and to voltammetric redox-potentials E_1/2.     

Synthesis and Self‐Assembly of Novel s‐Tetrazine‐Based Gelator

The design, synthesis and self‐assembly of new symmetrical 3,6‐bis(4‐(3,4,5‐tris(dodecyloxy)benzoate)phenyl)‐1,2,4,5‐tetrazine were described. The novel gelator, sym‐tetrazine, was prepared by addition reaction of 4‐cyanophenol with hydrazine monohydrate followed by oxidation reaction to afford the corresponding 3,6‐bis(4‐hydroxyphenyl)‐1,2,4,5‐tetrazine which was then subjected to esterification reaction with 3,4,5‐tris(dodecyloxy)benzoic acid. The chemical structure of the sym‐tetrazine gelator was confirmed by elemental analysis, fourier‐transform infrared spectroscopy (FT‐IR), and nuclear magnetic resonance (¹H‐ and ¹³C‐NMR) spectral measurements. It was confirmed to exhibit relatively strong gelation ability to produce supramolecular assemblies in several polar alcoholic organic solvents, such as butanol, octanol, and 1,6‐dihydroxyhexane. The π‐π stacking and van der Waals mediated self‐assembly of tetrazine‐based organogelator were studied by scanning electron microscopy images of the xerogel to reveal that the obtained organogel consists of fibrillar aggregates. Investigation of FT‐IR and concentration‐dependent ¹H‐NMR spectra confirm that the intermolecular van der Waals interactions and π‐π stacking were the key driving forces for self‐assembly during gelation process of s‐tetrazine molecules.     

Unusual fragmentation of fulvene endoperoxides with phenyliodosyl bis(trifluoroacetate) (PIFA)

Reaction of unsaturated fulvene endoperoxides with dimethyl 1,2,4,5‐tetrazine‐3,6‐dicarboxylate gave saturated fulvene endoperoxides containing the 1,2‐dihydropyridazine ring. Treatment of dihydropyridazine endoperoxides with water followed by phenyliodosyl bis(trifluoroacetate) oxidation provided acrylic acid derivatives and dimethyl pyridazine‐3,6‐dicarboxylate.     

Inverse electron demand diels‐alder reactions of psoralens. Synthesis and mass spectra of novel pyridazinocoumarins

Diels‐Alder reactions between the furan double bond of 8‐methoxypsoralen and 1,2,4,5‐tetrazine or 3,6‐bistrifluoromethyl‐1,2,4,5‐tetrazine were accompanied by the release of diatomic nitrogen and the opening of the furan ring to leave a 6‐pyridazinocoumarin. When 3,6‐bis(methoxycarbonyl)‐1,2,4,5‐tetrazine was used as diene with 8‐methoxy‐, 5‐methoxy‐ or 8‐hydroxypsoralen as substrate a previously unknown heterocyclic framework was created. Formation of the fourth ring was accompanied by conversion of the furan ring to a pyrone, presumably by intramolecular transestenfication with release of methanol. The characterization of the products of these reactions by exhaustive mass spectrometric analysis is discussed.     

“Azaphilic addition” of methyl lithium to 3,6-bisalkylthio-1,2,4,5-tetrazines: A remarkable dichotomy

A new type of “azaphilic addition” reaction of methyl lithium to 3,6-bisalkylthio-1,2,4,5-tetrazines has been discovered. Methyl lithium adds at the tetrazine nitrogen of 1 affording 4 while nitrogen nucleophiles displace tetrazine alkylthio groups at carbon affording 3 . The structures of the N-alkyl products were determined by ¹H- and ¹³C-nmr and uv experiments. Reversing the order of methyl lithium addition caused the formation of a bicyclic tetrazine 6 . Grignard reagents add in the same fashion as methyl lithium.     

Basicity of 3,6-diphenyl-1,2,4,5-tetrazine

We have determined the basicity of 3,6-diphenyl-1,2,4,5-tetrazine in aqueous solutions of sulfuric acid (pK_BH+ is –4.8). According to quantum chemical calculations done by the MNDO method and theab initio method in a 6-31G++ basis, the tetrazine ring is a nonpolar, highly aromatic system similar to benzene. The aromaticity of the tetrazine hererocycle decreases significantly upon protonation, which considerably destabilizes the protonated form.St. Petersburg State Technological Institute, St. Petersburg 198013, Russia, Translated from Khimiya Geterotsiklicheskikh Soedinenii, Vol. 34, No. 1, pp. 120–123, January, 1998.     

Insensitive Nitrogen‐Rich Materials Incorporating the Nitroguanidyl Functionality

A new class of nitroguanidyl‐functionalized nitrogen‐rich materials derived from 1,3,5‐triazine and 1,2,4,5‐tetrazine was synthesized through reactions between N‐nitroso‐N′‐alkylguanidines and the hydrazine derivatives of 1,3,5‐triazine or 1,2,4,5‐tetrazine. These compounds were fully characterized using multinuclear NMR and IR spectroscopies, elemental analysis, and differential scanning calorimetry (DSC). The heats of formation for all compounds were calculated with Gaussian 03 and then combined with experimental densities to determine the detonation pressures (P) and velocities (D_v) of the energetic materials. Interestingly, some of the compounds exhibit an energetic performance (P and D_v) comparable to that of RDX, thus holding promise for application as energetic materials.     

Metal‐Free Synthetic Approach to 3‐Monosubstituted Unsymmetrical 1,2,4,5‐Tetrazines Useful for Bioorthogonal Reactions

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.     

N,N'-bis(substituted phenyl)-1,2,4,5-benzenetetracarboxylic-1,2:4,5-diimides

The preparation of N,N'-bis(substituted phenyl)-1,2,4,5-benzenetetracarboxylic-1,2:4,5-di-imides by the reaction of 1,2,4,5-benzenetetracarboxylic-1,2:4,5-dianhydride ( 1 ) with aryl-amines and with aryl isocyanates is described. Correlations are made between the properties of these diimides and the nature and position of the substituents in the phenyl ring. The condensation of dianhydride 1 with diisocyanates yields polymers varying from soft elastomers to tough films, depending upon the amount of imide structure in the polymer chain.     

The Opening of 1,2‐Dithiolanes and 1,2‐Diselenolanes: Regioselectivity,Rearrangements, and Consequences for Poly(disulfide)s,Cellular Uptake and Pyruvate Dehydrogenase Complexes

The thiol‐mediated opening of 3‐alkyl‐1,2‐dithiolanes and diselenolanes is described. The thiolate nucleophile is shown to react specifically with the secondary chalcogen atom, against steric demand, probably because the primary chalcogen atom provides a better leaving group. Once released, this primary chalcogen atom reacts with the obtained secondary dichalcogenide to produce the constitutional isomer. Thiolate migration to the primary dichalcogenide equilibrates within ca. 20 ms at room temperature at a 3 : 2 ratio in favor of the secondary dichalcogenide. The clarification of this focused question is important for the understanding of multifunctional poly(disulfide)s obtained by ring opening disulfide exchange polymerization of 3‐alkyl‐1,2‐dithiolanes, to rationalize the cellular uptake mediated by 3‐alkyl‐1,2‐diselenolanes as molecular walkers and, perhaps, also of the mode of action of pyruvate dehydrogenase complexes. The isolation of ring‐opened diselenolanes is particularly intriguing because dominant selenophilicity disfavors ring opening strongly.     

Synthesis, Crystal Structure Analysis and DFT Calculation of 1-Benzoyl-3,6-diphenyl-1,4-dihydro-1,2,4,5-tetrazine

The new title compound, 1-benzoyl-3,6-diphenyl-1,4-dihydro-1,2,4,5-tetrazine (C21H16N4O, Mr = 340.38), has been prepared and its crystal structure can not be confirmed by the results of MS, elemental analysis, IR spectrum and 1H NMR spectrum, but determined by X-ray diffraction. The title compound crystallizes in an orthorhombic space group P212121 with a = 7.1100(19), b = 12.115(3), c = 19.884(6), V = 1712.7(8)3, Z = 4, Dc = 1.320 g/cm3, F(000) = 712, μ = 0.085 mm-1, MoKa radiation (λ = 0.71073), R = 0.0334 and wR = 0.0845 for 2254 observed reflections with I 2σ(I). X-ray diffraction analysis reveals that the central tetrazine adopts an unsymmetrical boat conformation. According to the bond lengths of tetrazine ring, the molecule should be 1,4-dihydro-1,2,4,5-tetrazine, rather than 1,2-dihydro-1,2,4,5-tetrazine. The crystal structure is stabilized mainly by intermolecular N–H···O hydrogen bonds.     

In Situ Synthesis of Alkenyl Tetrazines for Highly Fluorogenic Bioorthogonal Live‐Cell Imaging Probes

In spite of the wide application potential of 1,2,4,5‐tetrazines, particularly in live‐cell and in vivo imaging, a major limitation has been the lack of practical synthetic methods. Here we report the in situ synthesis of (E)‐3‐substituted 6‐alkenyl‐1,2,4,5‐tetrazine derivatives through an elimination–Heck cascade reaction. By using this strategy, we provide 24 examples of π‐conjugated tetrazine derivatives that can be conveniently prepared from tetrazine building blocks and related halides. These include tetrazine analogs of biological small molecules, highly conjugated buta‐1,3‐diene‐substituted tetrazines, and a diverse array of fluorescent probes suitable for live‐cell imaging. These highly conjugated probes show very strong fluorescence turn‐on (up to 400‐fold) when reacted with dienophiles such as cyclopropenes and trans‐cyclooctenes, and we demonstrate their application for live‐cell imaging. This work provides an efficient and practical synthetic methodology for tetrazine derivatives and will facilitate the application of conjugated tetrazines, particularly as fluorogenic probes for live‐cell imaging.     

Di­propyl 3,6‐di­phenyl‐1,2‐di­hydro‐1,2,4,5‐tetrazine‐1,2‐di­carboxyl­ate

The title compound, C₂₂H₂₄N₄O₄, was prepared from propyl chloro­formate and 3,6‐di­phenyl‐1,2‐di­hydro‐s‐tetrazine. This reaction yields the title compound rather than di­propyl 3,6‐di­phenyl‐1,4‐di­hydro‐s‐tetrazine‐1,4‐di­carboxyl­ate. The 2,3‐di­aza­buta­diene group in the central six‐membered ring is not planar; the C=N double‐bond length is 1.285 (2) Å, and the average N—N single‐bond length is 1.401 (3) Å, indicating a lack of conjugation. The ring has a twist conformation, in which adjacent N atoms lie 0.3268 (17) Å from the plane of the ring. The mol­ecule has twofold crystallographic symmetry.     

Asymmetric Ring Opening in a Tetrazine-Based Ligand Affords a Tetranuclear Opto-Magnetic Ytterbium Complex

We report the formation of a tetranuclear lanthanide cluster, [Yb₄(bpzch)₂(fod)₁₀] ( 1 ), which occurs from a serendipitous ring opening of the functionalised tetrazine bridging ligand, bpztz (3,6-dipyrazin-2-yl-1,2,4,5-tetrazine) upon reacting with Yb(fod)₃ (fod⁻=6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octandionate). Compound 1 was structurally elucidated via single-crystal X-ray crystallography and subsequently magnetically and spectroscopically characterised to analyse its magnetisation dynamics and its luminescence behaviour. Computational studies validate the observed M_J energy levels attained by spectroscopy and provides a clearer picture of the slow relaxation of the magnetisation dynamics and relaxation pathways. These studies demonstrate that 1 acts as a single-molecule magnet (SMM) under an applied magnetic field in which the relaxation occurs via a combination of Raman, direct, and quantum tunnelling processes, a behaviour further rationalised analysing the luminescent properties. This marks the first lanthanide-containing molecule that forms by means of an asymmetric tetrazine decomposition.     

Synthesis of the possible carcinogenic dihydrodiol and diol epoxide of phthalazine

Inverse-Diels-Alder reaction of dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate with benzene cis-diol gave dihydrodiol containing the 1,4-dihydropyridazine ring. Attempts at oxidation of the dihydropyridazine ring with PIFA and MnO₂ resulted in the formation of 5- and 5,6-dihydroxy-phthalazine derivatives. The oxidation of the dihydropyridazine ring was achieved by way of photooxygenation. The phthalazine type dihydrodiol is unstable and easily undergoes aromatization. The Diels-Alder reaction of tetrazine with cyclohexadiene acetonide and epoxy-ketal cyclohexene as a dienophile was investigated. These reactions led to the possible carcinogenic phthalazine type of dihydrodiol and diol epoxide where the hydroxyl groups are protected.