Diazines protonation

Chemical shifts of pyridine and the diazines have been measured as a function of pH in aqueous solution and generally protonation at nitrogen results in deshielding of the carbon resonances by up to 10 p.p.m. (73T1145). The pH dependence follows classic titration curves whose inflexions yield pK values in good agreement with those obtained by other methods. 

For the diazine 52 there are three tautomeric forms conceivable. When R = C02Et, 53, the situation is complicated by the possibility of an additional pathway for tautomerism. The IR results for this system are in fact ambiguous, and the investigators mention the possibility of cooperative intermolecular proton transfer being responsible for broad bands in the spectrum (111). 

Interestingly, they are more basic than the unsubstituted diazine, and always protonate on a ring nitrogen. This allows resonance stabilization of the conjugate acid utilizing the lone pair of the amino substituent. It has been found that one can... 

The diazine is believed to be converted into a protonated free radical (68) by metallic silver in the presence of acid. The free radical then disproportionates to the diazine and... 

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. 

Interestingly, the second electronegative heteroatom reduces the capacity of the diazines to tolerate the positive charge resulting from protonation. Pyridazine 10.1 (pKa= 2.24), pyrimidine 10.2 (pAfa = 1.23), and pyrazine 10.3 (pA a = 0.51) are all far less basic than pyridine (pKa - 5.23). 

The total energies of the diazines and of their protonated forms have been calculated using the CNDO method. The data in the table show that differences between the total energies of the bases and their protonated forms correlate with the pKa of the base except in the case of pyridazine.67a... 

The monocyclic diazines, triazines, and tetrazines are all theoretically subject to electrophilic attack at one or more of their annular nitrogen atoms by protons alkylating, acylating, and aminating reagents and peracids. Coordination with metals could also be classified under this heading. 

Protonated 1,4-diazines are certainly more reactive toward nucleophilic reagents than the corresponding uncharged substrates. The formation of diadducts in reactions of protonated pyridopyrazines (63JCS5737 66JCS(C)999 75AG(E)354 79JHC301), pyrazino [2,3-h] pyrazine... 

Calculations have been made of the rr-electron distribution in the pyrazine ring by many methods (127-134) and the effects of protonation on the total electron densities have been calculated using the extended Hiickel theory (135). A good correlation was obtained between total carbon electron densities and both proton and carbon-13 chemical shifts. A recent molecular orbital study has been made of protonation in pyrazine (and other diazines) (135a). 

The reaction of nucleophilic radicals, under acidic conditions, with heterocycies containing an imine unit is by far the most important and synthetically useful radical substitution of heterocyclic compounds. Pyri-dines, quinolines, diazines, imidazoles, benzothiazoles and purines are amongst the systems that have been shown to react with a wide range of nucleophilic radicals, selectively at positions a and y to the nitrogen, with replacement of hydrogen. Acidic conditions are essential because A-protonation of the heterocycle... 

Diazine alkyl groups, with the exception of those at the 5-position of pyrimidine, can undergo condensation reactions that utilise a side-chain carbanion produced by removal of a proton. As in pyridine chemistry, formation of these anions is made possible by delocalisation of the charge onto one (or more) of the ring nitrogen atoms. 

The diazines, pyridazine (p/faH 2.3), pyrimidine (1.3), and pyrazine (0.65) are essentially mono-basic substances, and considerably weaker, as bases, than pyridine (5.2). This reduction in basicity is believed to be largely a consequence of destabilisation of the mono-protonated cations due to a combination of inductive and mesomeric withdrawal by the second nitrogen atom. Secondary effects, however, determine the order of basicity for the three systems repulsion between the lone pairs on the two adjacent nitrogen atoms in... 

The acidity and basicity, particularly of pyridazine derivatives, has been reviewed in CHEC-I <84CHEC-i(3B)i>. Pyridazine (pA, 2.3) is less basic than pyridine (pAa 5.2) but more basic than the other diazines (pyrimidine 1.3, pyrazine 0.6) perhaps because of repulsion between the adjacent nitrogen lone pairs. For comparison, the pAaS for proton gain by phthalazine and cinnoline are 3.5 and 2.3, respectively. Pyridazin-3(2//)-one is about as acidic as phenol with a pAa of 10.5, while the... 

Protonation of (benzo)pyridazines has been mentioned in Section 6.01.4.2 and was reviewed in CHEC-I <84CHEC-l(3B)l>. Pyridazine (pA 2.3) is more basic than the other diazines due to reduced lone pair lone pair repulsion on formation of the cation. There is no equivalent to the benzene-like... 

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