Heterocyclic compounds, aromatic tetrazines

A rich coordination chemistry of aromatic diazine (N-N), especially pyridazine and phthalazine related ligands has emerged over the last three decades,1-72 and recently open-chain diazine (N-N) coordination chemistry has been well developed, especially by Thompson and others.62-113 Many types of aromatic heterocyclic compounds contain a 1,2-diazine (N-N) moiety, e.g., pyridazine and its 3,6-disubstituted derivatives (Scheme 1, Type 1), phthalazine, condensed phthalazines and their substituted derivatives (Scheme 1, Type 2), and other compounds such as pyrazole, triazole, thiadiazole, tetrazole, indazole, 1,2,4-triazine, 1,2,4,5-tetrazine, and thiadiazepines. Alternatively, the 1,2-diazine (N-N) moiety also exists as an open-chain entity in some related compounds, e.g., A-substituted-amide hydrazonimidates (Scheme 1, Type 3), A-substituted-amide hydrazonidates (Scheme 1, Type 4), A-substituted hydrazides (Scheme 1, Type 5), A-substituted amidrazones (Scheme 1, Type 6), and A-sub-stituted hydrazidates (Scheme 1, Type 7). 

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). 

Simple uncharged six-membered aromatic heterocycles cannot contain a divalent heteroatom. The azines are numbered to indicate the relative positions of the nitrogen atoms. 1,2,3,4-Tetrazine, pentazine and hexazine are unknown, however, a number of fused 1,2,3,4-tetrazines, primarily A -oxides and A -aryl quaternary salts, are known, but of monocycUc compounds, only a few di-A -oxides have been prepared. Of the other systems, 1,2,3,5-tetrazine is unknown, although theoretically it could be moderately stable, but fused derivatives include the drug temozolomide (see 33.7). Derivatives of 1,3,5-triazine are very well known and available in large quantities, indeed they are amongst the oldest known heterocycles the trioxy-compound ( cyanuric acid ) was first prepared in 1776 by Scheele by the pyrolysis of uric acid. 

The MM3 force field has been extended by Allinger and co-workers to cover aromatic heterocycles of the pyridine and pyrrole types <93JA11906>. Structures (32 compounds), dipole moments (35 compounds), heats of formation (35 compounds), and vibrational spectra (11 compounds) were examined. The results are good for structure and fair for the other items resonance energies were reported for the series benzene (17.79 kcal mol ), pyridine (17.02 kcal mol ), pyridazine (14.35 kcal mol ), pyrazine (17.01 kcal mol ), pyrimidine (15.60 kcal mol ), 1,3,5-triazine (13.51 kcal mol ), and 1,2,4,5-tetrazine (17.72 kcal mol ). Finally, ab initio studies of the dipole polarizabilities of conjugated molecules have been reported in which monocyclic azines (pyridine, pyridazine, pyrimidine, pyrazine, 5-triazine, and 5-tetrazine) are compared <94JST(304)109>. 

Bond angles and bond lengths for the parent 1,2,4,5-tetrazine (7) <56AX510> and its diphenyl derivative (8) <72AX(B)739> are shown by the structures. The observed bond distances and angles are similar for the diphenyl and the parent compound. In both cases the heterocyclic ring is planar as expected for an aromatic system with electron delocalization. 

---