Ionization constants, pKa and tautomerism

Pyridazines with a hydroxy group at an a- or y-position to a ring nitrogen atom, i.e. 3-and 4-hydroxypyridazines (4) and (5), exist predominantly in the oxo form. This conclusion is based on spectroscopic evidence from UV spectra of unsubstituted compounds and their A-methyl and O-methyl derivatives in alkaline, neutral and acidic solutions. In some instances, as for example for 6-oxo-l,6-dihydropyridazine-3-carboxamide, there is also evidence from X-ray analysis 54AX199, 63AX318). Maleic hydrazide and substituted maleic hydrazides exist in the monohydroxymonooxo form (6). 

Similarly, 3- and 4-hydroxycinnolines and their derivatives exist predominantly in the 0X0 forms (7) and (8), as supported by both pjSTa values and UV spectral data. The oxo forms for 3-hydroxycinnolines have been further supported by IR data 76MI21200 . Phthalazin-4-ones exist in the oxo form and phthalic hydrazide in the monohydroxymonooxo 

Compound Proton gain Proton loss first second  

Pyridazine-3(2//)-thiones exist in the thione form (14), as is evident from an X-ray structure analysis of pyridazine-3(2//)-thione. 6-Mercaptopyridazine-3(2//)-thione is predominantly in the monothiolmonothione form (15) in aqueous solution and in the solid state, 6-hydroxypyridazine-3(2//)-thiones are in the hydroxythione form (16) and 6-aminopyridazine-3(2//)-thiones exist in the aminothione form (17) for further details see (73HC(28)755). Cinnoline-4(l//)-thiones and phthalazine-l(2//)-thione have been shown on the basis of UV data and ionization constants to exist in the thione forms. 

Both 3- and 4-aminopyridazines exist in the amino form 4-aminocinnoline was formerly claimed to be anomalous and to be best represented in the imino form (18), while 4-alkylamino-3-phenylcinnolines are in the amino form. There seems no doubt, however, that amino forms predominate in both the 3- and 4-aminocinnoline series (71JCS(B)2344). 

When a second nitrogen atom is introduced into the pyridine ring the basicity is reduced (P a5. 23 for pyridine and 2.33 for pyridazine). The effect of the additional substituents on pjRTa depends on the position of the substituents (Table 3). An extensive set of pjRT, values of pyridazine derivatives has been submitted to correlation analysis using the Hammett and the two Taft equations, which shows that the pjRTa 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). 

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From the pKa values, the following sequence of 2-substituted 4-thiazolidinones with respect to the degree of acidity are 5 > 2 > 3.186 The opening of the thiazolidinone ring leads to an increase in acidity, but does not affect the activity sequence of the substituents.186 The acidity of a series of substituted 5-benzylidene-2,4-thiazoIidinediones has been investigated the entropy, enthalpy, and free energy of ionization have been calculated.187 Potentiometric determination of the tautomeric equilibrium constants of various 4-thiazolidinones has been reported.188... 

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