Pyrazoles basicity

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). 

Azoles can form stable compounds in which metallic and metalloid atoms are linked to nitrogen. For example, pyrazoles and imidazoles Af-substituted by B, Si, P and Hg groups are made in this way. Imidazoles with a free NH group can be Af-trimethylsilylated and Af-cyanated (with cyanogen bromide). Imidazoles of low basicity can be Af-nitrated. 

Pyrazoles and imidazoles exist partly as anions (e.g. 108 and 109) in neutral and basic solution. Under these conditions they react with electrophilic reagents almost as readily as phenol, undergoing diazo coupling, nitrosation and Mannich reactions (note the increased reactivity of pyrrole anions over the neutral pyrrole species). 

Having its pyrazolic 4-position substituted, electrophilic attack on indazoles takes place in the 3-position and in the homocycle (the 5- and 7-positions). The condensation of a benzene ring results in a decrease of the aromaticity of the pyrazole moiety, as in naphthalene compared to benzene, and therefore basic ring cleavage is easier in indazoles than in pyrazoles (Section 4.04.2.1.7(v)). 

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). 

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. 

The creation of the N—N bond as the last step of the ring synthesis is common in indazoles and very rare in pyrazoles. In indazoles this method is well known (type B synthesis (67HC(22)l), for example, the dehydration of oximes (570) with acetic anhydride yields 1-acetylindazoles (571), and in basic medium the indazole 1-oxides (573) are formed from the nitro derivatives (572). 

Pyrazoles can be prepared by ring opening reactions of fused systems already containing the pyrazole nucleus. Thus several [5.5], [5.6] and [5.7] fused heterocycles have been opened to substituted pyrazoles, usually in basic medium. In general, the method has little preparative interest since another pyrazole derivative has usually been used to build the ring-fused system. However, due to the unexpected structures obtained, two publications are worthy of notice. 6//-Cyclopropa[5a,6a]pyrazolo[l,5-a]pyrimidine (638) was readily obtained from the corresponding pyrazolopyrimidine by the action of diazomethane at room temperature (Scheme 59) (81H(15)265). When (638) was treated with potassium hydroxide, the pyrazole (640) was formed, probably via the diazepine (639). 

Porphyrin, 5,10,15,20-tetraphenyl-, 4, 386 Porphyrin, vinyl-synthesis, 4, 278, 279 Porphyrin coenzymes in biochemical pathways, 1, 258-260 Porphyrinogen, mcso-tetraaryl-synthesis, 4, 230 Porphyrinogens, 4, 378, 394 pyrazoles, 5, 228 synthesis, 4, 231 Porphyrins, 4, 377-442 acetylation, 4, 395 aromatic ring current, 4, 385 basicity, 4, 400 biosynthesis, reviews, 1, 99... 

Optimum conditions for allylic alcohol formation ( 65% yield of olefin mixture) appear to be those originally described by Wharton, rather than strongly basic forcing conditions. The pyrazole (147) is a by-product. 

Draw a Lewis strueture for each molecule that shows the location of all nonbonding electrons. Examine electrostatic potential maps for both imidazole and pyrazole. Predict which is the more basic nitrogen in each molecule. What kind of orbital contains this nitrogen s nonbonding electrons What kind of orbital contains the other nitrogen s nonbonding electrons ... 

Which nitrogen in each molecule is more basic Compare energies of the alternative conjugate acids (Nprotonated imidazole, NH protonated imidazole, N protonated pyrazole and NH protonated pyrazole). Which compound, imidazole or pyrazole, is more basic Compare the energies of protonation (leading to the favored conjugate acid in each case). Rationalize your result. 

Pyrazole and [Os3(CO)io(AN)2] form two isomeric cluster complexes 90 and 91 (82IC634 84POL1175), corresponding to metallation of both basic nitrogen atoms (the major product having the symmetrical structure 90) and C,N-metallation... 

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). 

The ultraviolet spectra of compounds which may exist as either 1-substituted pyrazol-3-oncs (70, R — H) or 1-substituted 3-hydroxypy-razoles (71, R = H) do not allow distinction between the two possible forms, because their spectra and those of fixed derivatives of both types (70, R = Me and 71, R = Me) are too similar. The solid state infrared spectra of these compounds have been interpreted to support both the NH form (see reference 79a for a similar conclusion regarding indazoI-3-one) and the OH form. Basicity data have also been considered to indicate the predominance of the OH form. ... 

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