Tetrazines atoms

Although all the rings in Figure 1 contain six tt-electrons, the accumulation of electronegative nitrogen atoms in the polyaza structures leads to hydrolytic as well as thermal instability. This is noticeable in pyrimidine, and marked in the triazines and tetrazine. Some stability can be conferred by appropriate substitution, as we shall outline later. 

The only ring system with a 0 3 nitrogen atom arrangement that has been studied in the past period is pyrrolo[2,l- /] [l,2,3,5]tetrazine, which was not synthesized earlier. The first synthesis was presented by Cirrincione et al. in two successive publications <1999S2082, 2003BMC2371>. The results are depicted in Scheme 36. 

Because of the clinical application of temozolomide 9a, the synthesis of a nC derivative 41 labeled at position 1 (i.e., the carbonyl carbon atom in the tetrazine ring) of these compounds has also been published (Scheme 13). 

Atomic charges have been calculated by semi-empirical method (AMI) for nitrogen atoms of two triazolo[4,3-A -[l,2,4,5]tetrazines in order to assess the site of alkylation of these compounds <2000ARK259>. The results are summarized in Table 1. 

Table 1 Calculated charges of nitrogen atoms in two triazolo[4,3-fa][1,2,4,5]tetrazine derivatives...

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>. 

We performed a series of theoretical studies on pump-probe diffraction patterns with a twofold objective the first aim is to evaluate the effect of electronic and vibrational excitation on electron diffraction patterns, compared to that of structural rearrangements that are the primary goal for observation in structural dynamics measurements. Secondly, we wish to explore to what extent electronic and vibrational probability density distributions are observable using the pump-probe electron diffraction methodology. Previously we have discussed the effect of electronic excitation in atomic systems,[3] and the observability of vibrational excitation in diatomic and triatomic systems.[4,5] We have now extended this work to the 8-atomic molecule s-tetrazine (C2H2N4). 

Some of these systems have been examined by X-ray analysis in the solid state.375a When a single conformation was found to exist in solution, this is reflected in the crystal structure, as for the saturated tricyclic derivative 480 in the e4 and the tetrabenzyl monocyclic 491 in the aeae conformation. The unsaturated tricyclic 479 crystallizes in the ae3 unsymmetrical form, which is the largest component of the solution equilibrium. However, the 1,4-dimethyl - 2,5-dibenzyl monocyclic derivative 486 crystallizes in the aeae conformation, which contributes only 33% to the solution equilibrium. 1,4-Dimethylhexahydro-l,2,4,5-tetrazine crystallizes with the N-methyl groups equatorial and the IV-hydrogen atoms axial.376... 

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. 

Position Pyridine Pyridazine 8 (,3Q (ppm, TMS) (Position of N atoms indicated) Pyrimidine Pyrazine 1,2,3-Triazine 1,2,4-Triazine 1,3,5-Triazine 1,2,4,5-Tetrazine... 

In the diazines, triazines and tetrazines, the effects of the additional nitrogen atom(s) are roughly additive. In Table 4 the positions of substituents in the common azine ring systems are listed in order of increasing reactivity. The limit is reached in 2-, 4- or 6-substituted 1,3,5-triazines for which the reactivity approximates to that in the corresponding carbonyl compound (559). 

Only about 20 compounds with the tetrahydro-l,2,3,4-tetrazine structure are known, but two X-ray crystallographic analyses have been reported. The structure of 1,4-dimethyl-l,4,5,6-tetrahydro-l,2,3,4-tetrazine 2-oxide (6) is a twisted boat conformation with non-planar terminal nitrogen atoms, which reflects the repulsion in the four-atom six-electron N—N=N—N system. The bond distances and angles are given in Figure 1 (78HCA1622). A similar study of dimethyl 2-phenyl-2,3,4,4a,5,6,7,8-octahydrobenzo-l,2,3,4-tetrazine-... 

When cyanamide was electrochemically oxidized at a platinum anode in 2M potassium hydroxide, and the anolyte was neutralized with hydrochloric acid or carbon dioxide, several products were isolated, and to three of these were assigned 1,2,3,5-tetrazine structures. These were the 4-amino-6-cyanamino- (27), 4-amino-6-cyanoguanidino- (28) and 4-ureido-6-cyanoguanidino-l,2,3,5-tetrazines (29) (76BCJ1339). The structures were consistent with the IR spectral data and elemental analyses, but it would be desirable to have unambiguous evidence on these compounds, particularly as their method of synthesis is not an obvious one for forming the connection of three adjacent nitrogen atoms. 

Another class of 1,2,4,5-tetrazine compounds which is well known and intensively studied is the stable radicals verdazyls (48), also called 1,2,4,5-tetrazin-1 (2H)-yls. Benzo derivatives of the 1,2,4,5-tetrazine system are not possible since in all cases the second ring has to be condensed to the 1,2,4,5-tetrazine ring either by two nitrogen atoms as in (49), or by one carbon and one nitrogen atom as in (50). 

Basic hydrolysis of 3-phenyl-l,2,4,5-tetrazine (81) led to the isolation of benzalazine (82) in 80% yield (71KGS708). In most other cases studied the isolated product was an aldehyde acylhydrazone (83), indicating that during the basic hydrolysis one carbon atom of the tetrazine ring is reduced from the acid oxidation level to an aldehyde level (78HC<33)1075, p. 1094). A mechanism for the reaction has been proposed by Libmann and Slack (56JCS2253). Benzalazine (82) was also isolated when 3-azido-6-phenyl-l,2,4,5-tetrazine (84) was hydrolyzed by base (71KGS711). 

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