Basicity of pyridazine

The basicity of the diazines is sharply reduced from that of pyridine (pAfa 5.2) the pKa of pyrazine is 0.4, pyrimidine is 1.1 and pyridazine is 2.1. The significantly higher basicity of pyridazine as compared to pyrazine, unexpected for mesomeric and inductive effects, is attributed to the lone pair-lone pair repulsion which is removed in the cation. 

The ionization constants of different mono- or polyalkylated pyridazines 4is g ow that the number and position of the alkyl groups affect the basicity of these compounds. Alkyl groups cause an increase in the basicity of pyridazine, due to inductive effects. Dipole moments have also been determined. The NMR spectrum of 3-methylpyridazine shows an ABX system in which —... 

The pH-independence of Tdhpz at Pt indicates that the driving force for coordination of the nitrogen heteroatom to the Pt surface is much larger than that for protonation even in molar acid. This behavior is in contrast to that of pyridine, where protonation of the nitrogen heteroatom in molar acid hinders N-coordination to the surface (H). Such a difference in chemisorption characteristics may be related to the fact that the basicity of the nitrogen heteroatom in pyridine (pKb =8.8) is much greater than that of the nitrogens in pyridazine (pKb = 11.8) (23.). ... 

The electroreductive hydrogenation of pyridazine-3-ones performed at the first wave, in acidic or basic medium, takes place at the 4,5-double bond. A further reduction of 4,5- dihydropyridazin-3-ones in basic media, affords the corresponding tetrahydro derivatives (Scheme 139) [252]. 

When a second nitrogen atom is introduced into the pyridine ring the basicity is reduced (pjRTa 5.23 for pyridine and 2.33 for pyridazine). The effect of the additional substituents on pKK depends on the position of the substituents (Table 3). An extensive set of pK values of pyridazine derivatives has been submitted to correlation analysis using the Hammett and the two Taft equations, which shows that the pKa values are most sensitive to the effect of a 2-substituent followed by the effects of 3- and 4-substituents. The interactions between nitrogen atom and 2-substituents represent over 70% of the inductive character. The composition of the effects of +M 4-substituents is significantly enriched in the resonance interactions, whereas -M 4-substituents interact with the nitrogen atom mainly by induction (77MI21201). 

It was established that the Pd(II) complexes of bmpa were more reactive than those of dien, and the aqua-complexes were much more reactive than the chloro-complexes. The most reactive nucleophile of the five-membered rings is triazole, while pyridazine is the most reactive six-membered ring nucleophile. This could be understood in terms of nitrogen donor atoms in the 1,2-positions rather than in other configurations. As noted earlier, 260 for a given complex, the reactivity is related to the basicity of the... 

Among diazines, pyridazine has a relatively high pK value (Table I). In general, the introduction of a second nitrogen in the pyridine ring diminishes considerably the basicity and this decrease is in accordance with the theoretical calculations of free valence indices of the nitrogen atoms. The relatively high pK of pyridazine has been attributed to resonance stabilization of the pyridazinium ion. 

Acyl-substituted imidazoles have distinctive UV and IR spectra, and can exist as hydrates in solution, e.g. imidazole-2-carbaldehyde. The aldehyde group is sufficiently electron withdrawing to assist nucleophilic displacement of an adjacent halogen atom. The normal aldehyde derivatives such as oximes, acetals and hydrazones can be formed, and the kinetics of oxime formation with the 4-carbaldehyde have been studied. The tautomeric ratio (zwitterion uncharged aldehyde form) of 1-substituted imidazole- and benzimidazole-2-aldoximes rises in parallel with an increase in basicity of the parent molecule (73CHE1074). These compounds have been shown by NMR studies to adopt the syn configuration. With hydrazine hydrate, imidazole-4,5-dicarbaldehydes give imidazo[4,5-d]pyridazines (208 Scheme 110). 

Examples of pyridazine synthesis from azines involve reaction between tetrafluoroformaldazine and perfluorosuccinyl fluoride in the presence of cesium fluoride to give a perfluoropyridazine, or via ketazine anions, as for acetophenone azine [Eq. (3)]. The azine from benzyl monohydrazone and ethyl acetoacetate or benzoylacetate is cyclized under basic conditions into the pyridazine 17. ... 

Relative rates have been determined for the competitive methylations and also acetylations of azines. Pyridazine reacts faster than pyridines in both reactions this is interpreted in terms of pair-pair electron repulsion and the a-effect. An additivity approach provides reasonable predictions of isomer ratios of quatemization products of pyridazine and other azines. Reinvestigation of the quatemization of various amino- and diamino-pyridazines with methyl iodide shows that both 1- and 2-methyl derivatives were usually formed. 3-Amino-6-chloropyridazine forms JV2-quateraary salts with a- and -halo esters and 1,4-dibromobutane, but with 1 -dibromo-ethane or 1,3-dibromopropane bicyclic products, are formed. Protonation and quatemization of l,4,S,6-tetrahydropyridazines takes place at position 1, this being the more basic nitrogen. ... 

Ionization constants of hydroxy- and mercaptopyridazines, ° of amino- and diaminopyridazines and their quaternization products,of methylsulfinylpyridazines," and of pyridazinium ylides have been recorded. The basicities of a series of pyridazines have been determined and correlated with substituent constants using the Hammett free-energy relationship. The magnetic susceptibility of pyridazine was measured, and the rate constant for the reaction of hydrogen atoms with pyridazine was determined. The experimental dipole moment, Kerr constant, and molar Cotton-Mouton constant, obtained at 298 K and 633 nm, are reported. The magnetic circular dichroism spectrum of pyridazine has been measured. ... 

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... 

The quaternization of (benzo)pyridazines by alkyl halides (these systems are not readily susceptible to arylation) was reviewed in CHEC-I <84CHEC-l(3B)l>. Monoquaternization of pyridazines occurs more readily than other diazines but less readily than pyridine, reflecting the intermediate basicity/nucleophilicity of pyridazine. Diquaternization of pyridazine can only be achieved with oxonium salts, particularly Me30 BF4 . As with protonation and A-oxidation, mixtures of products are often obtained on quaternization of unsymmetrical pyridazines and have been the subject of theoretical studies. A number of 2-(ribofuranosyl)-3(2//)-pyridazinones have been prepared by stannic chloride catalyzed alkylation of 3-(trimethylsilyloxy)pyridazines with protected 1-0-ace-tylribofuranose <83JHC369>. The quaternization behavior of phthalazines is similar to that of pyridazines, but with cinnolines alkylation usually occurs at N-2, unless there is a particularly bulky substituent at C-3. 

The gas and aqueous-phase basicities of pyrimidine are distinctly smaller by 3.4 and 1.1 pAi units, respectively, than those of pyridazine. A theoretical explanation has been proposed by considering important NH and lone pair electrostatic interactions that act from the 2-position. The proton-transfer equilibrium for the basicity comparison shows that the position of equilibrium is in the direction expected for the dominant effect to be the relief of the destabilization imparted by electrostatic repulsion between lone pair electrons, i.e., to the left in the equation (Equation (1)). Another significant contribution to AG° values is the field inductive effect of the electronegative aza substituent, which is less at the 3- than at the 2-position. This aza substituent effect destabilizes cations. Second-order attractive interactions between the lone pair electrons and the adjacent NH in the conjugate acid of pyridazine are also invoked. The attractive electrostatic interaction in the conjugate acid of pyridazine, and the predominant lone pair repulsion in pyridazine, are opposed by a favorable aza substituent effect. This accounts for the positive AG°(g) value. Solvation by water is expected to preferentially stabilize the neutral species or ion which is internally destabilized. The result is a smaller equilibrium shift in solution compared with the gas phase <86JA3237>. 

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