Azines, monocyclic

Table 1 H Chemical Shifts of the Simple Monocyclic Azines cf. benzene, S 7.24) (b-73NMR>...

Table 10 UV Absorption Bands of the Simple Monocyclic Azines ...

III. Monocyclic Azines. Relative Reactivity of Rings and Ring-Positions 262... 

B. Monocyclic Azines. Behavior of Simple Derivatives with... 

Conclusions and predictions concerning the reactivity of monocyclic azines are derived from three sources a) the kinetic data of Section III, A, 2, (6) qualitative or semi-quantitative comparisons in preparative organic chemistry (Section III,B), and (c) theoretical considerations presented in Section II, B. Reactivity can be described by four generalizations ... 

The following sequence of reactivity of monocyclic azines toward nucleophiles includes a number of postulated relations based on analogy and on theoretical considerations ... 

Statements in the hterature on the reactivity of the ring-positions in monocyclic azines are conflicting. Reactivity is said to be greater at the position ortho (or alpha) than at the position para (or gamma) to an azine nitrogen 2-> 4-position in pyridine and pyrimidine and 3-> 5-position in as-triazine. By others, the... 

The reactivity of 2- and 4-halopyridines toward a variety of nucleophiles is far greater than that of the 3-halo isomers (274), which are nevertheless appreciably activated. The 4-position (cf. 271) is more reactive than the 2-position (cf. 272), except when the specific factors described in Sections II, B and III, A and also below, produce an increase in the reactivity at the 2-position. Pyridine derivatives are the least reactive of the monocyclic azines (cf. Scheme I, p. 266). 

In bicyclic azines, as in the monocyclic azines already discussed, the faster of two nucleophilic substitutions proceeds via the transition state which has the lower free energy (with respect to the reactants) due to the stabilizing effects of resonance, hydrogen bonding, or electrostatic attractions. Different nucleophiles and different leaving... 

Three comparisons of para vs. ortho activation by an additional ring-nitrogen are possible from the available data and all show the former to be more effective, as found for the nitronaphthalenes above and for monocyclic azines (Section III). In piperidino-dechlorination of chloroquinazolines (Table XV, lines 3 and 4), the 4-isomer (405) reacts 6,500-fold faster than the 2-chloro compound (400) due entirely to a 4.1 kcal decrease in the dS being the same for both. However,... 

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. 

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. 

Monocyclic azines are very weak rr-donors and behave mostly as n-donors on interaction with electrophiles. However, ir-donor character is significantly increased in their benzo-derivatives. For instance, acridine forms with chloranil a highly colored 1 1 molecular complex. Perimidine is one of the strongest heterocyclic ir-donors which gives deeply colored molecular complexes with a variety of organic electron acceptors. On the other hand, the rr-acceptor ability of perimidine is moderate. 

Substrate Ji-deficiency is, apparently, a critical factor. Thus, dibromovinyl derivatives of monocyclic azines, e.g. pyrimidine 92, pyrazine 93 and quinoline 94 are not subjected to this reaction (01H2139). On the contrary, lumazines 95 and pyrimidopyridazines 97 form the corresponding thiophenes 96 and 98 (Scheme 29) (03RCB1403, 05JHC413). 

This chapter is concerned with the electrophilic substitution of pyridaz-ine, pyrimidine, pyrazine, and their derivatives. Aspects of this topic have been reviewed previously [72AHC( 14)99 74AHC(16)1] and the general chemistry of the monocyclic azines has been surveyed in Comprehensive Organic Chemistry, Vol. 4 (1979) and Comprehensive Heterocyclic Chemistry, Vol. 3 (1984). 

Although nitrogen atoms lower the energies of all MOs, the energy gap between HOMO and LUMO (A) (Table 2) does not change greatly among the monocyclic azines, and this is reflected in the similarity of their tz tz absorption... 

Table 5 1H NMR chemical shifts of the simple monocyclic azines (cf. benzene, <5 = 7.24) ...

Table 19 UV absorption bands of the simple monocyclic azines...

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