Diazines reactivity

Reactions of benzodiazines show no exceptional features compared with the simple diazines. Reactivity towards electrophiles is less than in quinoline and isoquinoline. If S Ar reactions take place, they lead to substitution of the benzene ring. As a rule, nucleophilic substitution of benzodiazines occur in the diazine ring, particularly if substituted by halogen. The quinazoline system displays C-4 regioselectivity, e.g. in the reactions of 2,4-dichloroquinazoline with amines or alcohols ... 

Chlorophthalazine is quite reactive to many basic nucleophiles but reacts sluggishly with aqueous or alcoholic alkali. In contrast, it is very rapidly hydrolyzed by warm, concentrated hydrochloric acid as are its diazine isomers. In hydrolysis with very dilute acid or with water, it forms some phthalazinone but mostly the self-con-densation product which hydrolyses to give 2-(l -phthalazinyl)-phthalazin-l-one (70% yield). Such self-condensations in diazanaph-thalenes and in monocyclic azines are always acid-catalyzed (Sections II, C and III,B). With methanolic methoxide, 1-chlorophthalazine (65°, few mins), its 7-methoxy analog (20°), and 1,6- and 1,7-dichlorophthalazines (20°) readily undergo mono-substitution. 

No kinetic data or semi-quantitative comparisons among themselves or with other diazines are available. The most reactive derivative is expected to be the 4-substituted-l,6-naphthyridine (425), with 2-substituted-1,6- and l-substituted-2,7-naphthyridines (426) somewhat less reactive, all three positions being activated by two ring-nitrogens by resonance. Other positions also activated in this way... 

Phenazine leucos until now are usually substituted at their 3 and 6 positions by amino groups due to the normal method of synthesis of the parent phenazine dyes. These types of leuco dyes are reactive. An alternative method of dye synthesis allows access to phenazine dyes with just one substituent at the 3-position.20 The resulting leuco dyes are called half diazine leucos. The loss of one exocyclic amino group leads to higher redox potential and results in less reactive leuco dyes, more useful in applications such as thermographic and photothermographic imaging, particularly Color Dry Silver. 

The chemistry of diazines remains an area of intense interest, both academic and industrial, with applications in many areas, from biomedical to materials science and electronics. They are versatile, having very varied reactivity, giving many opportunities for manipulation of substituents. Nucleophilic substitutions, electrophilic substitution in oxy and amino derivatives, organometallic and transition metal-catalysed coupling reactions are all subjects of substantial research effort. There are obvious similarities in reactivity of the three diazine systems but also many interesting and practically important, often subtle, differences. 

The main emphasis of this review will be on the synthetic and reactivity aspects of the three diazine systems and their benzo-derivatives, although some other interesting and significant applications will also be covered. Generally one or two representative examples of reactions or syntheses will be given and it is understood that further examples will usually be found in the original paper. However, this is flexible and generic reactions or products may be shown if this is considered more appropriate. 

Electron-deficient heteroaromatic systems such as 1,2,4-triazines and 1,2,4,5-tetrazines easily undergo inverse electron demand Diels-Alder (lEDDA) reactions. 1,2-Diazines are less reactive, but pyridazines and phthalazines with strong electron-withdrawing substituents are sufficiently reactive to react as electron-deficient diazadienes with electron-rich dienophiles. Several examples have been discussed in CHEC-II(1996) <1996CHEC-II(6)1>. This lEDDA reaction followed by a retro-Diels-Alder loss of N2 remains a very powerful tool for the synthesis of (poly)cyclic compounds. 

The reactivity of 1,8-naphthyridine (27) is greater than expected.61,79 Here, unlike the diazines, the two heteroatoms with their unshared electron pairs are in separate rings. After correction for the two kinetically equivalent reactive sites, the rate constant for 27 is nearly the same as that for pyridine and four times larger than that for quinoline. These results are surprising, especially when it is remembered that the diaza substrate is substantially less basic than the comparison compounds. Correcting for the diminished nucleophilicity expected to be associated with the lower basicity of 27 serves to make the reactivity comparisons even more striking.61... 

Alkyl halides react with diazines less readily than with pyridines. All the diazines are, nevertheless, more reactive toward methyl iodide than predicted by their pKa values and the Bronsted relationship. The significant although modest rate enhancements found are considered to arise from interactions between the two lone pairs on the nitrogen atoms this interaction is largest in pyridazine. Use of oxonium ions can convert the diazines into diquatemary salts. Quinoxalines and phenazines similarly yield diquatemary salts under forcing conditions. 

Diazines are considerably more reactive toward nucleophiles than pyridines and as the number of ring nitrogens increases the propensity for nucleophilic addition reactions increases still more. Many 1,2,4-triazines give addition products with various nucleophiles which are formally dihydrotriazines. 

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). 

Reactivity increases in the diazines as compared with pyridines. 3-Chloropyridazine (910) and 2-chloropyrazine, for example, undergo the usual nucleophilic replacements (cf. Section 3.2.3.10.6.ii) rather more readily than does 2-chloropyridine. 2-, 4- and 6-Halogen atoms in pyrimidines are easily displaced. The reactivity of halogens in pyridazine 1-oxides toward nucleophilic substitution is in the sequence 5 > 3 > 6 > 4. 

Pyridazine (1,2-diazine) (1) and its benzo analogs cinnoline (1,2-diazanaphthalene) or benzo[c]pyridazine (2) and phthalazine (benzo[rf]pyridazine) (3) have been known since the nineteenth century. Although the basic synthetic principles and reactivity were investigated in the early years, interest in these compounds was not very intense, compared with pyrimidines and their bicyclic analogs, as they were not found in nature. However, during the last three decades intensive research has been stimulated because many derivatives have found application as a result of their biological activity. 

Fig. 3. Reactivity effects in diazines and annelated pyridines 1, isoquinoline 2, quinoline 3, 1,10-phenanthroline 4, phthalazine 5, cinnoline 6, pyridazine 7. pyrimidine 8, pyrazine.

Preparation and Diels-Alder Reaction of a Reactive, Electron-Deficient Heterocyclic Azadiene Dimethyl 1,2,4,5-Tetrazine-3,S-Dicarboxylate. 1,2-Diazine and Pyrrole Introduction. 

Oxazine, azine and thiazine dyes are named for the characteristic heterocyclic ring systems 1,4-oxazine, 1,4-diazine, and 1,4-thiazine. The dyes are generally cationic (basic) or acid dyes. They also can be reduced to colorless forms, then oxidized back to the dye, as in vat dyeing. The dyes also have been used to a limited extent in disperse and fiber reactive applications. They are used as titration indicators and may be applied to acrylic fibers and leather. 

Other diazine moieties are also often incorporated into reactive dyes, e.g., 7 and 8 [22,23] N ... 

Formal replacement of a CH unit in pyridine 5.1 by a nitrogen atom leads to the series of three possible diazines, pyridazine 10.1, pyrimidine 10.2, and pyrazine 10.3. Like pyridine they are fully aromatic heterocycles. The effect of an additional nitrogen atom as compared to pyridine accentuates the essential features of pyridine chemistry. Electrophilic substitution is difficult in simple unactivated diazines because of both extensive protonation under strongly acidic conditions and the inherent lack of reactivity of the free base. Nucleophilic displacements are comparatively easier. 

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