Other substituted azines

In amine-imine systems (83 84) the mobile proton can in principle be located at either of the two basic nitrogen sites in the anion (85). Since the canonical form with aromatic (benzenoid) structure is polar in the imine (84b) and non-polar in the amine (83a), the amine structure should be, and is favored, particularly in non-polar solvents. 

The tautomerism of a methyl group a or 7 to a ring nitrogen (86 87) is still less favorable than that of the amine simple valence and electronegativity considerations of the type employed above suggest much reduced aromaticity associated with the methylene tautomer (87). These tautomers are therefore present to only a very small extent at equilibrium. 

Benzo-fusion to a heterocyclic ring involved in tautomerism has the effect of steering the equilibrium in directions which tend to retain the full aromaticity of the benzene ring. Thus, while the 

3- hydroxyisoquinoline versus 3-isoquinolinone equilibrium (88 89) and that of the cinnoline derivatives (90 91) favor the oxo forms (89, 91), the proportion of hydroxy tautomers is considerably greater than in the corresponding unfused systems. By contrast the benzo-fusion in 2- and 

4- quinolinone and in 1-isoquinolinone has the effect of reducing the aromaticity of the heterocyclic ring, and consequently of lowering the proportion of the hydroxy tautomers. 

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The first generalization is illustrated by the behavior of the 2- and 4-vs. the 3-derivatives of pyridine, the second by the reactivity of 4- vs. 2-substituted pyridines, the third by the relation of 4- vs. 2-derivatives of pyrimidine, and the fourth by the appreciable reactivity of 3-substituted pyridines or 5-substituted pyrimidines compared to that of their benzene analogs. Various combinations of azine-nitrogens in other poly-azines supply further examples. Theoretical aspects of (1), (2) and (3) are discussed in Section II, B, 2. The effect involved in (4) is believed to be more the result of the inductive stabilization of an adjacent negative chaise in the transition state (cf. 251) than of the electron deficiency created in the ground state (cf. 252). The quantitative relation between inductive stabihzation and resonance stabilization is not precisely defined by available data. However, a... 

This section covers primary, secondary, tertiary, and quaternary aminopyrazines (both nuclear and extranuclear) but not (functionally substituted amino)pyrazines such as hydrazino-, hydroxyamino-, or azidopyrazines. General discussions have appeared on the spectra of 2-pyrazinamine,255 257 991 the proton-sponge properties of 2,3,5,6-tetra(pyridin-2-yl)pyrazine in relation to its fine structure,925 the fluorescene properties of 3,6-diamino-2,5-pyrazinedicarboxylic acid derivatives in relation to their fine structures,1646,1659 the basic properties of aminopyrazines and other such azines in relation to their electronic structures,412,928 and the fine structures of 3-amino-2-pyrazinecarboxylic acid1340 and l,4-diacetyl-2,3-diphenylpiperazine.559... 

A theoretical/NMR study of keto-enol tautomerism in 2-(2-methoxycarbony-lacetyl)pyrazine (277/278) and other similarly substituted azines has been undertaken the foregoing pyrazine exists in its enolic form (278) to the extent of 35% in deuterochloroform.411 l,4-Diacetyl-l,4-dihydropyrazine (279) gave the persistent radical cation (279) + on one-electron oxidation (cyclic voltammetry in MeCN— Bu4NC104).167... 

Other reactions such as the anodic cyanation or alkoxylation of electron-rich heterocycles such as pyrroles and indoles [85] or of electron-donating substituted azines [86] are important, but are not discussed in detail here, because this subject is well covered in electrochemistry textbooks. 

Dichloropyridazine, when briefly irradiated in acidified methanol, gives the pyridazines 269-273 as main products (Scheme 16) prolonged irradiation gives compounds 274-277 as main products. According to the proposed mechanism, 271 is transformed into 274 and 275 and finther to 276 and 277. Under similar reaction conditions other pyridazines also give y-lactones and succinates. In the same reaction medium pyrid-azine is transformed upon irradiation into its 4-methyl and 4,S-dimethyl derivative. Other substituted pyridazines undergo photoinduced methyla-tion in low yield. 

A large number of glycosulose l-(2-substituted) hydrazones have been prepared by Henseke and coworkers from the osazones by action of nitrous acid. These products, such as (89), were then treated with other substituted hydrazines, to give mixed osazones," or with hydrazine and other carbonyl reagents, to obtain ketazines and azines" hydrazone thiosemicarbazones, and hydrazone oximes. ... 

The quaternization of pyrazine compounds has not been extensively studied, and, therefore, a detailed discussion of the effect of substituents is not possible. Recently Cheeseman has shown, from spectroscopic evidence, that 2-amino- and 2-diethylamino-p3rrazine (50, Y = NH2 and NEt ) quatemize at N-4, although protonation occurs at position-1. Other substituted p3U azines from which quaternary salts of structure 51 are formed include 2-chloro- and 2-... 

The problem of the synthesis of highly substituted olefins from ketones according to this principle was solved by D.H.R. Barton. The ketones are first connected to azines by hydrazine and secondly treated with hydrogen sulfide to yield 1,3,4-thiadiazolidines. In this heterocycle the substituents of the prospective olefin are too far from each other to produce problems. Mild oxidation of the hydrazine nitrogens produces d -l,3,4-thiadiazolines. The decisive step of carbon-carbon bond formation is achieved in a thermal reaction a nitrogen molecule is cleaved off and the biradical formed recombines immediately since its two reactive centers are hold together by the sulfur atom. The thiirane (episulfide) can be finally desulfurized by phosphines or phosphites, and the desired olefin is formed. With very large substituents the 1,3,4-thiadiazolidines do not form with hydrazine. In such cases, however, direct thiadiazoline formation from thiones and diazo compounds is often possible, or a thermal reaction between alkylideneazinophosphoranes and thiones may be successful (D.H.R. Barton, 1972, 1974, 1975). 

It is quite reasonable to expect the bimolecular two-stage mechanism Sj Ar ) to predominate in most aromatic nucleophilic substitutions of activated substrates. However, only in rare instances is there adequate evidence to rule out the simultaneous occurrence or predominance of other mechanisms. The true significance of the alternative mechanisms in azines needs to be determined by trapping the intermediates or by applying modem separation and characterization methods to the identification of at least the major portion of the products, especially in kinetic studies. 

B. Activation by Azine-Nitrogen and Other Factors in THE Nucleophilic Substitution op Azines... 

Relative reactivity of ring-positions based on positional selectivity of polychloro-azines must be regarded with caution because of the unequal activating effects of the chlorine substituents on each other. Also, it should be emphasized that one cannot use the positional selectivity in di- and tri-substitutions to assess relative reactivity of different positions. In such substitutions, the reactivity is determined by a complex combination of activating and deactivating effects which are unequal at the ring-positions (cf. Sections II, E, 1, II, E, 2,c, and II,E,2,e). 

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