Tetrazines aromaticity

Complexes of anions with electron-deficient r-tetrazine aromatic rings and other binding units have been studied and compared using both high-level MP2/6-311-l-G ab initio and molecular interaction potential with and without polarization and molecular electrostatic potential calculations, in order to explore the physical nature of the interactions <2003CPL(370)7>. 

The isomeric pyridazino[4,5-6]azepine 19 is obtained directly during the decomplexation of the [4 + 2] adduct 17 formed from tricarbonyl(ethyl +17/-azepine-l-carboxylate)iron and 1,2,4,5-tetrazine-3,6-dicarboxylate, with trimethylamine A-oxide.113 Surprisingly, decomplexation of adduct 17 with tetrachloro-l,2-benzoquinone yields only the dihydro derivative 18 (71 %), aromatization of which is achieved in high yield with trimethylamine A-oxide in refluxing benzene. 

The reaction of dimethyl-1,2,4,5-tetrazine-3,6-dicarboxylate 353 with aromatic amines gave (82CB683) pyrazolo[3,4-e][l,2,4]triazines 354 (Scheme 75). 

Regarding the series of hetero aromatic pentacyclic compounds with three heteroatoms, an accelerated synthesis of 3,5-disubstituted 4-amino-1,2,4-triazoles 66 under microwave irradiation has been reported by thermic rearrangement of dihydro-1,2,4,5 tetrazine 65 (Scheme 22). This product was obtained by reaction of aromatic nitriles with hydrazine under microwave irradiation [53]. The main limitation of the method is that exclusively symmetrically 3,5-disubstituted (aromatic) triazoles can be obtained. 

Elimination of nitrogen from D-A adducts of certain heteroaromatic rings has been useful in syntheses of substituted aromatic compounds.315 Pyrazines, triazines, and tetrazines react with electron-rich dienophiles in inverse electron demand cycloadditions. The adducts then aromatize with loss of nitrogen and a dienophile substituent.316... 

The hydrazination of aza-aromatics, using sodium hydrazide, has been reported, but no detailed mechanism was given (64AG206). On treatment of 3-i -l,2,4,5-tetrazines R = CH3, C2H5, C6H5) with 3 equiv of... 

The reaction of aromatic amines with tetrazine (151) gave either 1,2,4-triazoles (154) or pyrazolo[4,3-e]-l,2,4-triazines (155), depending on the substituents. While aniline, p-toluidine, p-anisidine and p-chloroaniline afford 155, the bromo and p-nitro derivatives give 154. Intermediates 152 and 153 were postulated (Scheme 22) (82CB683). 

Only those compounds which do not have tautomeric aromatic triazole structures will be considered here, the others having been treated as triazoles. The triazolines are unstable and have been subjected to little study. Compounds which are disubstituted at the C(3) or C(5) atom are more stable than the mono- or unsubstituted analogues. The equilibrium has been observed by NMR spectroscopy between the six-membered tetrazine (75) and the triazolinethione (76) via the open-chain form, thus mirroring monosaccharide equilibria (Scheme 12) <90TL3927>. 

Dihydro-l,2,4-tetrazine 49 reacts with trimethylaluminium to produce mono 5 a and diketones 50b depending upon the reaction conditions. Borohydride reduction of 50a gives alcohol 50c. Aromatization of 50a-c by exposure to nitrous gases affords tetrazines 51a-c which have proved to be very good electron-defficient heteroatomic azadienes for inverse electron demand Diels-Alder chemistry. Numerous examples are described with symmetric and nonsymmetric electron rich dienophiies <98JOC10063>. 

The inverse electron demand Diels-Alder [4- -2]-cycloaddition of imidazoles to electron-poor dienes to yield imidazo[4,5-i pyridazines, reported in CHEC-II(1996), has been further developed. It was reported that the reaction of267 with tetrazines 268 was fruitless. However, 267 reacted with excess of 268 to yield aromatic 271 along with 1,4-dihydrotetrazine 270. Most likely, 271 arose from dehydrogenation of first-formed 269 by an extra equivalent of 268 <2001T5497> (Scheme 18). 

In the simulations presented here, we assume that a pump laser excites the molecule to either the vibrationless, or specific vibrational levels of the Si electronic state. The diffraction pattern is measured by scattering the electron beam off the excited molecules on a time scale shorter than the rotational motion of the molecules, i.e. on a time scale less than about 10 ps. The diffraction pattern is measured in the plane perpendicular to the electron beam. The diffraction patterns shown here are for an excitation laser polarization parallel to the detector plane, and perpendicular to the electron beam. Since the electronic transition dipole moment of s-tetrazine is perpendicular to the aromatic ring, this pump-pulse polarization selects preferentially those molecules that are aligned with the aromatic plane parallel to the electron beam. 

Deprotonation from the azonium group leaves a lone pair of electrons on the nitrogen atom, and a neutral aza substituent. The known parent monocyclic azines (see Scheme la) include all the possible diazines and triazines, but only one tetrazine, the 1,2,4,5-isomer. Some 1,2,3,5-tetrazines have been reported, but only when heavily substituted or fused. Some aromatic bicyclic 1,2,3,4-tetrazines have been prepared (see Section 4.4.8.2.3) as well as reduced 1,2,3,4-tetrazines (see CHEC 2.21). No pentazines are known. All attempts to prepare hexazine also failed though several claims about fixation of the latter in a matrix have appeared. 

Van der Waals complexes of C2v symmetry between 1,2,4,5-tetrazine and a number of light gases (He, Ar, H2) have been observed and characterized by laser spectroscopic studies of free supersonic jet expansion of the tetrazine in the carrier gas (84CHEC-(3)53l). In these complexes, one equivalent of noble gas sits on top of the aromatic TT-system of the heterocycle. 1,2,4,5-Tetrazine, its 3-methyl, and 3,6-dimethyl derivative as well as aminotetrazine have all been used as heterocycles with noble gases, water, HC1, benzene, and acetylene, playing the role of the second partner. 

Tetrazines react with alkenes to give bicycles (403) which lose nitrogen to give the 4,5-dihydropyridazine (404). This can either tautomerize to a 1,4-dihydropyridazine, be oxidized to the aromatic pyridazine, or undergo a second Diels-Alder reaction to give (405). Many heterocycles can act as the dienophiles in such reactions for example thiophene gives (406). The reaction is also used to trap unstable compounds, for example, 2-phenylbenzazete (407) as compound (408). 

Oxidation of 1,2-bishydrazones (494) is now known to give triazoles (495) and not dihydro-1,2,3,4-tetrazines. Possibly the latter are intermediates but are aromatized by ring contraction. 

Dihydropyridazines (117) result from Diels-Alder addition of. v-tetrazines (115) with electron-rich alkenes (e.g. 116). Frequently the products aromatize, as in (117) — (118) (see also Section 3.2.1.10.2.iv). 

The five-membered ring systems can also behave as electron-rich dienophiles in [n4 + 2] reactions. Indole and 1,2,4,5-tetrazines yield indolopyridazines (262) via [ 4 + 2] cycloaddition followed by extrusion of nitrogen and aromatization, whilst the dihydro adduct,... 

Dihydro-, tetrahydro- and hexahydro-1,2,4,5-tetrazines are less coloured than the aromatic 1,2,4,5-tetrazines. In most cases these substances are yellow, yellow-orange or colourless. Most dihydro-1,2,4,5-tetrazines have two absorption maxima but their positions depend on the substituents on the ring, and on the pattern of hydrogenation. Bands in the visible (ca. 430 nm e 400-600) are found with the 1,6-dihydro compounds (42) 1,4-dihydrotetrazines (41) absorb at somewhat shorter wavelength (ca. 300 nm, e 100) in ethanol (72HCA1404). 

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