A theoretical study of the gas phase (proton affinity) and aqueous (pK_a) basicity of a series of 150 pyrazoles

Abstract

Experimental proton affinities and pKas covering a range of 208 kJ mol−1 and 10.3 pKa units, respectively, have been analyzed theoretically.

Revisiting the Structure and Chemistry of 3(5)-Substituted Pyrazoles

“…Additionally, according to the results of their MP2 calculations, the intramolecular prototropic annular tautomerism from the 3-amino to the 5-amino derivative was shown to involve an energy demand of 47.34 kcal/mol [43]. DFT 6-311++G(d,p) results attained by Marin-Luna et al sustained the previously reached conclusions, showing a prevalence of the 3-tautomer over the 5 one, both in the gas phase and in aqueous solution, although in this case a tendency towards a tautomeric equilibrium was noticed, marked by a decrease in percentage of the 3-amino tautomer and corresponding increase of its 5-amino counterpart, ascribed to the effect of solvent polarity [70].…”

“…Tautomerism in 3(5)-aminopyrazoles has to be carefully appraised by chemists, on account of the specificities inherent to this scaffold that impact in reactivity and synthesis. Several experimental [50,72,93,[109][110][111] and theoretical studies [43,60,64,70,72,84] were carried out, the majority focusing on the structural aspects and corroborating the general conclusions applicable to the pyrazole family.…”

“…Strong electron donating groups at C4 seem to promote a tautomeric equilibrium, with results showing an increase in the proportion of the 5-tautomer. In water, although for the majority of compounds under study the tautomeric preferences persisted, a tendency towards equilibrium, or even changes in ratio, was observed [70].…”

“…Marín-Luna et al studied the proton affinity and pKa values of a structurally diverse library of pyrazole derivatives and were also able to determine tautomeric ratios in the gas phase and in aqueous solution [70]. Theoretical (DFT) calculations on a library comprising 150 pyrazole derivatives, using the B3LYP functional and the 6-311++G(d,p) basis set, unraveled differences in tautomeric stability upon modifications in ring substituents.…”

Annular Tautomerism of 3(5)-Disubstituted-1H-pyrazoles with Ester and Amide Groups

“…The majority of the literature data is concerned with various 3(5)-substituted pyrazole compounds, investigated mostly using X-ray structure analysis and NMR spectroscopy, such as 3(5)-phenyl- and 5(3)-methyl-3(5)-phenylpyrazole [30], single aryl substituents [31], 3(5)-amino-5(3)-arylpyrazoles [32], 3-nitropyrazole [33], 3(5)-aminopyrazoles [34], 1 H -pyrazole-3-( N -tertbutyl)-carboxamide [35], or 3(5)-trifluoromethyl-1 H -pyrazoles [36]. Various monosubstituted pyrazoles were studied using theoretical methods on isolated molecules [37,38]. However, there is still insufficient data concerning 3(5)-substituted pyrazole with an amide or ester linkage.…”