Homoaromatics as intermediates in the substitution reactions of 1,2,4,5-tetrazines with ammonia and hydrazine

This thesis describes some nucleophilic substitution reactions between the red 1,2,4,5-tetrazines and hydrazine-hydrate or ammonia. Special attention was paid to the occurrence of the S _N (ANRORC) mechanism in these substitution reactions. This mechanism comprises a sequence of reactions, involving the A ddition of a N ucleophile to a heteroaromatic species, followed by a R ing- O pening and R ing C losure reaction to the substitution product.σ-Adducts, namely 6-hydrazino- and 6-amino-3-aryl(alkyl)-1,6-dihydro-1,2,4,5-tetrazines, are formed upon addition of hydrazine or ammonia to 3-aryl(alkyl)-1,2,4,5-tetrazines. This is accompanied by a change in colour from red to yellow. These adducts can be observed by NMR spectroscopy. ln heteroaromatics in liquid ammonia, an upfield shift (Δδ) of 4-5 ppm is usually measured for the hydrogen atom, attached to the carbon atom to which addition takes place. An extra ordinary large upfield shift is observed however upon addition to 1,2,4,5-tetrazines; Δδ= ~ 8.5 ppm in hydrazine and Δδ= ~ 8.7 ppm in liquid ammonia (at 230 K, chapters 4 and 6).The fact that 3-aryl(alkyl)-1,2,4,5-tetrazines are converted into the 6-amino compounds by oxidation of the intermediate in liquid ammonia (chapter 2), indicates that an intermediary 1,6-dihydro-6-amino structure must exist. ¹H NMR measurements at various temperatures of 1,6-dihydro-1,2,4,5-tetrazines as model compounds for these σ-adducts gave an explanation for the large up field shift (Δδ). 1,6-Dihydro-1,2,4,5-tetrazines and their conjugate acids and bases were found to be homoaromatic and they are present in the monohomotetrazole conformation. The hydrogens at the sp ³carbon atom have a different orientation towards the tetrazole ring. One (H ^A) is oriented above the aromatic ring, in the shielding regio; H ^Bis in the exo position, in the deshielding regio; thus resulting in a large difference in chemical shift. The homoaromatic species show a ring inversion. The kinetic parameters (ΔH, ΔS and ΔG) were determined by dynamic NMR measurements (chapter 3). Since a large substituent at C ₆ of the homotetrazole (e.g. methyl or ethyl) is found exclusively in the exo position, the hydrogen of the above mentioned a-adducts is oriented above the ring current of the tetrazole ring, resulting in a chemical shift at high field.The charge of the tetrazole ring exerts an influence through space on H ^A, H ^Bis hardly influenced. This became obvious from δH ^Ain ¹H NMR and J_CH Ain ¹³C NMR (chapters 3 and 4).The homoaromatic σ-adducts in liquid ammonia and even in hydrazine- hydrate/ methanol are anionic species, as was primarily proven by a ¹³C NMR study (chapters 4 and 6). The driving force for the deprotonation is probably the larger resonance stabilization of the homoaromatic anion with respect to the neutral homoaromatic species.
3-Alkyl(aryl)-1,2,4,5-tetrazines were found to undergo a Chichibabin hydrazination into 6-hydrazino-3-alkyl(aryl)-1,2,4,5-tetrazines on treatment with hydrazine-hydrate. The first step in this reaction sequence was the formation of a homoaromatic σ-adduct. Subsequently an open-chain intermediate was observed by NMR, on raising the temperature. Finally the hydrazino compound is formed by ring closure. This reaction sequence can be considered as an S _N (ANRORC) process. With ¹⁵N-labelled hydrazine, only part of the label was found to be built in the 1,2,4,5-tetrazine ring of the 6-hydrazino compounds. This is the first example of a reaction in which both the hydrazino compound with the ¹⁵N-label in the ring and with the ¹⁵N-label in the exocyclic hydrazino group are formed according to the S _N (ANRORC) mechanism (chapter 6).During the hydrazino-deamination and hydrazino-dehalogenation of 6-amino- and 6-halogeno-1,2,4,5-tetrazines only a part of the molecules was found to react according to the S _N (ANRORC) process. The other part followed the alternative S _N (AE), A ddition- E limination, pathway (chapters 5 and 6).The crystal structure of 6-ethyl-3-phenyl-1,6-dihydro-1,2,4,5-tetrazine was elucidated by X-ray structural analysis very recently. This analysis revealed that the molecule is in a boat-conformation. C ₆ points upwards with a dihedral angle of 49.3° and C ₃ with an angle of 26.7°. N ₁ was found to be sp ²hybridized and the N(1)-N(2), N(2)-N(3), C(3)-N(4) and N(4)-N(5) bond distances were found to be between single- en double bond length, in agreement with the expected electron delocalization. Therefore we came to the conclusion that the crystal structure agrees with the homoaromatic character of the compound (chapter 7).