Acidity of pyrazole

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. 

Pyrazoles are much weaker bases than imidazoles, but can be precipitated as picrates. The conjugate acid of pyrazole has a p value of 2.52. The difference is due to the fact that the positive charge in the pyrazolium ion is less delocalized than in the imidazolium ion (see p 166) ... 

R.W. Taft, E Anvia, M. Taagepera, J. Catalan, and J. Elguero, Electrostatic proximity effects in the relative basicities and acidities of pyrazole, imidazole, pyridazine, and pyrimidine, J. Am. Chan. Soc. 108 (1986), pp. 3237-3239. 

Thekinetics of nitration in sulphuric acid of both pyrazole and imidazole have been studied. Data have already been quoted (tables 8.1, 8.3) to support the view that the nitration of both of these compounds at C(4)... 

Methylpyrazole has been investigated as a possible treatment for alcoholism. The stmcture—activity relationship (SAR) associated with a series of pyrazoles has been examined ia a 1992 study (51). These compounds were designed as nonprostanoid prostacyclin mimetics to inhibit human platelet aggregation. In this study, 3,4,5-triphenylpyrazole was linked to a number of alkanoic acids, esters, and amides. From the many compounds synthesized, triphenyl-IJT-pyrazole-l-nonanoic acid (80) was found to be the most efficacious candidate (IC g = 0.4 //M). 

Table 36 summarizes the known annular tautomerism data for azoles. The tautomeric preferences of substituted pyrazoles and imidazoles can be rationalized in terms of the differential substituent effect on the acidity of the two NFI groups in the conjugate acid, e.g. in (138 EWS = electron-withdrawing substituent) the 2-NFI is more acidic than 1-NFI and hence for the neutral form the 3-substituted pyrazole is the more stable. 

Free valences and localization energies have been calculated for a series of pyrazoles (neutral molecules and conjugate acids) for homolytic substitution. In all the compounds the site with the lowest localization energy has the Wghest free valence index. This parallel between the two indices of reactivity is maintained in pyrazole, 1-methylpyrazole and their conjugate acids, but not in 1-phenylpyrazole and its conjugate acid. For the three compounds examined experimentally, (32), (33) and (35) (Section 4.04.2.1.8(ii)), only the predictions for (33) are in agreement with the experimental results. 

The mean chemical shifts of A- unsubstituted pyrazoles have been used to determine the tautomeric equilibrium constant, but the method often leads to erroneous conclusions (76AHC(Sl)l) unless the equilibrium has been slowed down sufficiently to observe the signals of individual tautomers (Section 4.04.1.5.1). When acetone is used as solvent it is necessary to bear in mind the possibility (depending on the acidity of the pyrazole and the temperature) of observing the signals of the 1 1 adduct (55) whose formation is thermodynamically favoured by lowering the solution temperature (79MI40407). A similar phenomenon is observed when SO2 is used as solvent. 

Pyrazole and its C-methyl derivatives acting as 2-monohaptopyrazoles in a neutral or slightly acidic medium give M(HPz) X, complexes where M is a transition metal, X is the counterion and m is the valence of the transition metal, usually 2. The number of pyrazole molecules, n, for a given metal depends on the nature of X and on the steric effects of the pyrazole substituents, especially those at position 3. Complexes of 3(5)-methylpyrazole with salts of a number of divalent metals involve the less hindered tautomer, the 5-methylpyrazole (209). With pyrazole and 4- or 5-monosubstituted pyrazoles M(HPz)6X2... 

Surprisingly, there are very few examples of successful fV-oxidation of pyrazoles. Simple fV-alkylpyrazoles generally do not react with peracids (B-76MI40402,77JCS(P1)672). The only two positive results are the peracetic acid (hydrogen peroxide in acetic acid) transformation of 1-methylpyrazoIe into 1-methylpyrazole 2-oxide (268) in moderate yield and the peroxy-trifluoroacetic acid (90% hydrogen peroxide in trifluoroacetic acid) transformation of 5-amino-l-methylpyrazoIe into l-methyl-5-nitropyrazoIe 2-oxide (269). 

In the preceding parts of Section 4.04.2.1.3 the electrophilic attack on pyrazolic nitrogen with the concomitant formation of different classes of N—R bond has been examined N—H (iv, v), N—metal (vi), N—C(sp ) (vii, viii, xi), N—C(sp ) (be, x, xi), N—SO2R (x), N—halogen (xii), N—O (xiii) and N—-N (xiv). In this last part the reaction with other Lewis acids leading to the formation of pyrazole N—metalloid bonds will be discussed, and the study of their reactivity will be dealt with in Section 4.04.2.3.lO(viii). 

The mechanism of the reaction is now well known due to a series of kinetic studies by Katritzky et al. (Table 31). The nature, free base or conjugate acid, of the substrate depends on the substituents in the pyrazole ring and on the acidity of the nitrating mixture. 

The difference in the susceptibility of the 3- and 4-positions in the free-base form of pyrazole towards nitration is a relatively small factor in favour of the 4-position ca. 1 log unit). Doubtless for the more usual nitration via the conjugate acid the difference is considerably greater. 

Potassium t-butoxide in t-butyl alcohol requires powerful electron-attracting substituents at C-4 to effect ring opening of pyrazoles but sodamide does not (Scheme 26) (B-76MI40402). As the key to the transformation is the generation of the anion, similar results were obtained by heating some pyrazole-3-carboxylic acids with quinoline. 

The important synthesis of pyrazoles and pyrazolines from aldazines and ketazines belongs to this subsection. Formic acid has often been used to carry out the cyclization (66AHQ6)347) and N-formyl-A -pyrazolines are obtained. The proposed mechanism (70BSF4119) involves the electrocyclic ring closure of the intermediate (587) to the pyrazoline (588 R = H) which subsequently partially isomerizes to the more stable trans isomer (589 R = H) (Section 4.04.2.2.2(vi)). Both isomers are formylated in the final step (R = CHO). 

A solventless synthesis of pyrazoles, a green chemistry approach, has been described where an equimolar amount of the diketone and the hydrazine are mixed in a mortar with a drop of sulfuric acid and ground up. After an appropriate length of time ( 1 h) the product is purified to provide clean products. Even acyl pyrazoles 42 were obtained under the solvent-less reaction conditions in good yields. 

Hydrazone 56a was heated for 6 h under reflux in ethanol containing a catalytic amount of hydrochloric acid to afford a mixture of pyrazol-3-one 57a (15%), pyrazole 58a (29%), and hydrazone 59a (49%). The cyclization of hydrazone 56b was much more sluggish. Under similar reaction conditions 5 days was required to give a mixture of pyrazol-3-one 57b (40%), pyrazole 58b (11%), and hydrazone 59b (20%) (80JHC1413) (Scheme 18). 

In an altogether different type of approach, the hydrazone is formed in situ as a lithium salt. Wilson et al. (80JHC389) described this approach in the one-pot synthesis of 5-aryl-2-phenylpyrazol-3-ones 72a-f from the corresponding hydrazones 65a-f (Scheme 20). The latter were obtained by condensing ketones 64a-f with phenylhydrazine. Treatment of hydrazones 65a-f with n-butyllithium in dry THF, followed by the addition of half a molar equivalent of diethyl carbonate 67 and then quenching the reaction mixture with hydrochloric acid, produced pyrazol-3-ones 72a-f, along with products 71. The yields of the products 72 are in the range 22-97%. Four intermediates—66a-f, 68a-f, 69a-f, and 70a-f— were proposed for this reaction. 

The reaction of pyrazole acetic acids 269a-c with two equivalents of bromine in water gave the corresponding monobromopyrazol-3-ones 270a-c. When acids 269d,e were reacted with three equivalents of bromine, the respective dibromo-pyrazol-3-ones 271d,e were isolated (98JPR437) (Scheme 66). 

The pA"a values of 49 derivatives of pyrazol-3-one were measured by poten-tiometric titration and their H NMR spectra were recorded in DMSO- fe- The experimental acidity order correlates for structurally similar compounds as do substituent constants and HMO electron densities (76JPR555). 

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). 

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