Basicity of pyrazole

The basicity of pyrazole and its relation with imidazole basicity (due both to enthalpy and entropy changes (77MI40403)) have been discussed on theoretical grounds (Section 4.04.1.2.1). The pK values of 90 pyrazoles have been determined by Gonzalez et al. (68BSF707,68BSF5009) and it is essentially his work that will be discussed below. A selection of pK values are shown in Table 28. The pK values for some other pyrazoles have been measured in connection with nitration studies (Section 4.04.2.1.4(ii)) (71JCS(B)2365). 

Theoretical studies of the basicity of pyrazoles, using the semiempirical approximations as well as the STO-3G and 4-31G methods have enhanced the understanding of the differences in basicity between the gas phase and the aqueous solution. To rationalize the relative gas-phase and solution basicity and acidity of pyrazole, it is necessary to take into account the lone pair/lone pair repulsion in the pyrazolate anion (6.5 kcal mol1), the adjacent NH/lone pair attraction in pyrazole (l.Okcal mol1) and the NH+/NH+ repulsion in the pyrazolium cation (6.5 kcal mol1). Solvation by water, and to a lesser extent by DMSO, modifies these values to the point that the position of the equilibria can be reversed. 

The pyrazole/pyridine-iV-oxide (which measures the HB acidity of the pyrazole NH) and the pyrazole/3,4-dinitrophenol (which measures the HB basicity of pyrazole N2 lone pair) equilibrium constants were determined for several N/f-pyrazoles in cyclohexane by UV spectroscopy <87CR(C)567>. The correlation between these equilibrium constants and the thermodynamic p s is excellent, allowing the indirect determination of p/f s of very lipophilic pyrazoles pATa of 1-(1-adamantyl)pyrazole = 3.12. The equilibrium constants, Afpj.o (in dm moF ) pertaining to equilibrium (AH -I- OPy AH - - OPy, AH = N/f-pyrazole, = pyridine iV-oxide) have been measured for pyrazole, 3(5)-methylpyrazole, 4-methylpyrazole, 3,5-dimethylpyrazole, 3,4,5-trimethylpyrazole, 4-bromopyrazole, and 3,5-dimethyl-4-bromopyrazole) <90JOC2230>. These values allow the determination of a 2 values (HB acidity parameter) it shows that pyrazole is as acidic as trifluoroethanol as far as HB acidity is concerned. 

Substituted isoxazoles, pyrazoles and isothiazoles can exist in two tautomeric forms (139, 140 Z = 0, N or S Table 37). Amino compounds exist as such as expected, and so do the hydroxy compounds under most conditions. The stability of the OH forms of these 3-hydroxy-l,2-azoles is explained by the weakened basicity of the ring nitrogen atom in the 2-position due to the adjacent heteroatom at the 1-position and the oxygen substituent at the 3-position. This concentration of electron-withdrawing groups near the basic nitrogen atom causes these compounds to exist mainly in the OH form. 

The basicities of the parent azole systems in water are shown in Table 1. When both heteroatoms are nitrogen, the mesomeric effect predominates when the heteroatoms are in the 1,3-positions, whereas the inductive effect predominates when they are in the 1,2-positions. The predominance of the mesomeric effect is illustrated by the pK value of imidazole (82 Z = NH), which is 7.0, whereas that of pyrazole (83 Z = NH) is 2.5 cf. pyridine, 5.2). An fV-methyl group is base-strengthening in imidazole, but base-weakening in pyrazole, probably because of steric hindrance to hydration. When the second heteroatom is oxygen or sulfur the inductive, base-weakening effect increases the pK of thiazole (82 Z = S) is 3.5 and that of isoxazole (83 Z = 0) is 1.3. 

Despite the weak basicity of isoxazoles, complexes of the parent methyl and phenyl derivatives with numerous metal ions such as copper, zinc, cobalt, etc. have been described (79AHC(25) 147). Many transition metal cations form complexes with Imidazoles the coordination number is four to six (70AHC(12)103). The chemistry of pyrazole complexes has been especially well studied and coordination compounds are known with thlazoles and 1,2,4-triazoles. Tetrazole anions also form good ligands for heavy metals (77AHC(21)323). 

The basicities of indazole (1.31), 1-methyl (0.42) and 2-methyl (2.02) derivatives and of eight other substituted indazoles have been measured (67BSF261 The effect of substituents in the 3-position is similar in pyrazoles and indazoles with Api values as follows Me, 0.80 and 0.86 Cl, -3.01 and -2.98 Br, -2.85 and -2.82, respectively. A nitro group in the homocycle has an expected base-weakening effect of -2 pK units, whether it is at the 5- or the 6-position. 

Another possibility is observed upon cyclization of hydrazides of pyrazole-carboxylic acids in the presence of CuCl in an inert atmosphere in DMF. When acetylenylcarboxylic acids are heated in the presence of CuCl in DMF, the orientation of the cycloaddition of the hydrazide group differs from that observed for cyclization in basic conditions. The cycloisomerization of hydrazides 78 in boiling DMF leads to the corresponding pyrazolopyridazines 79 in 60-71 % yields (Scheme 134 Table XXIX) (85IZV1367 85MI2). 

Generally, azolo-triazenes prepared from pyrazoles and triazoles are less toxic and more stable than the corresponding imidazo derivatives, probably because of the weaker basicity of the ring (69JMC545 70JPS1358). However, the most important role in this area is played by the... 

ICR has been used to determine the gas phase acidities of pyrrole (79JA6046), pyrazole (86JA), and imidazole (86JA), as well as the basicity of the compounds given in Table V (Section IV,A). 

Comparison of the intrinsic acidities and basicities of pyrrole (I), imidazole (4), and pyrazole (6), together with complementary information coming from the azine held, illustrate the main effects that control the acidity and the basicity of unsubstituted azoles (86JA3237). Particularly important are the role of electrostatic interactions between adjacent charged nitrogens (NH) and between adjacent lone pairs (N), as well as the aza electronegative effects. 

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