Structure and tautomerism of 4-substituted 3(5)-aminopyrazoles in solution and in the solid state: NMR study and Ab initio calculations

Emelina, E. E.; Петров, А. А.; Filyukov, D. V.

doi:10.1134/s1070428014030191

Cited by 8 publications

(13 citation statements)

References 27 publications

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“…Additionally, in the presence of electron-withdrawing substituents at C4 the ratio of tautomers was shown to invert, with dominance of the 5-amino form. These results were in agreement with experimental data also collected through solid-state and solution NMR spectroscopy [113]. Jarończyk et al performed a study at the MP2/6-311++G** level aiming at an evaluation of the structural differences between 3 and 5-aminopyrazoles and the distinct electronic contributions towards each system's stability [66].…”

Section: Theoretical Studiessupporting

confidence: 78%

“…Nevertheless, an increase in the electron donating nature of the substituent at the phenyl ring was shown to raise the fraction of the 5-amino tautomer [84]. A similar study was conducted by Emelina et al, through B3LYP/6-31G** calculations of total energies for 3-amino and 5-amino tautomers of 4-substituted 3(5)-aminopyrazoles (Scheme 10), in the gas phase and also in DMSO solution, by incorporation of the polarizable continuum model (PCM) [113]. This study clearly shows that the extrinsic factors to the nuclear aminopyrazole scaffold cannot be undermined, namely the environment and the electronic nature of the other ring-substituents.…”

Section: Theoretical Studiesmentioning

confidence: 68%

“…Depending on the chemotype targeted, several pathways may be thought by the organic chemist [13,15], but for the purpose of this work we will focus mainly on the preparation of pyrazole-fused six-membered heterocycles from coupling of 3(5)-aminopyrazoles with bifunctional reagents. In such terms, intramolecular cyclization relies on the participation of two of the nucleophilic positions from the aminopyrazole framework, one of them being the exocyclic amino moiety, which was shown to occupy the leading position in reactivity [18,107,113]. Aside from the exocyclic amino group, another nucleophilic element from the ring system is needed to promote ring closure.…”

Section: Intramolecular Cyclization Of 3(5)-aminopyrazolementioning

confidence: 99%

“…N-unsubstituted 3(5)-aminopyrazoles are tautomeric species possessing three N-nucleophilic sites, -NH 2 , N(H)1 and N2, which can readily participate in S N 2 reactions leading to N-endocyclic and N-exocyclic products, as depicted by the structures (a) and (b) of Scheme 14 [128]. In terms of electronic distribution, the major electron density is located at the exocyclic amino group, in both 3 and 5 tautomers, followed by the pyrrole-like nitrogen, the pyridine-like nitrogen and the 4-carbon [113]. Although literature reports state that 3(5)-aminopyrazoles are generally more stable as the 3-tautomer, intramolecular cyclization to yield pyrazolo[1,5-a]pyrimidines depends on the formation of the most reactive form, the 5-tautomer [128].…”

Section: Intramolecular Cyclization Of 3(5)-aminopyrazolementioning

confidence: 99%

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

2019

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Pyrazoles are known as versatile scaffolds in organic synthesis and medicinal chemistry, often used as starting materials for the preparation of more complex heterocyclic systems with relevance in the pharmaceutical field. Pyrazoles are also interesting compounds from a structural viewpoint, mainly because they exhibit tautomerism. This phenomenon may influence their reactivity, with possible impact on the synthetic strategies where pyrazoles take part, as well as on the biological activities of targets bearing a pyrazole moiety, since a change in structure translates into changes in properties. Investigations of the structure of pyrazoles that unravel the tautomeric and conformational preferences are therefore of upmost relevance. 3(5)-Aminopyrazoles are largely explored as precursors in the synthesis of condensed heterocyclic systems, namely pyrazolo[1,5-a]pyrimidines. However, the information available in the literature concerning the structure and chemistry of 3(5)-aminopyrazoles is scarce and disperse. We provide a revision of data on the present subject, based on investigations using theoretical and experimental methods, together with the applications of the compounds in synthesis. It is expected that the combined information will contribute to a deeper understanding of structure/reactivity relationships in this class of heterocycles, with a positive impact in the design of synthetic methods, where they take part.

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Section: Theoretical Studiessupporting

confidence: 78%

Section: Theoretical Studiesmentioning

confidence: 68%

Section: Intramolecular Cyclization Of 3(5)-aminopyrazolementioning

confidence: 99%

Section: Intramolecular Cyclization Of 3(5)-aminopyrazolementioning

confidence: 99%

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

2019

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“…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].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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A series of disubstituted 1H-pyrazoles with methyl (1), amino (2), and nitro (3) groups, as well as ester (a) or amide (b) groups in positions 3 and 5 was synthesized, and annular tautomerism was investigated using X-ray, theoretical calculations, NMR, and FT-IR methods. The X-ray experiment in the crystal state showed for the compounds with methyl (1a, 1b) and amino (2b) groups the tautomer with ester or amide groups at position 3 (tautomer 3), but for those with a nitro group (3b, 4), tautomer 5. Similar results were obtained in solution by NMR NOE experiments in CDCl3, DMSO-d6, and CD3OD solvents. However, tautomer equilibrium was observed for 2b in DMSO. The FT-IR spectra in chloroform and acetonitrile showed equilibria, which can be ascribed to conformational changes of the cis/trans arrangement of the ester/amide group and pyrazole ring. Theoretical analysis using the M06-2X/6-311++G(d,p) method (in vacuo, chloroform, acetonitrile, and water) and measurement of aromaticity (NICS) showed dependence on internal hydrogen bonds, the influence of the environment, and the effect of the substituent. These factors, pyrazole aromaticity and intra- and inter-molecular interactions, seem to have a considerable influence on the choice of tautomer.

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Direct demonstration of tautomeric nature of 4‐bromo‐3(5)‐methylpyrazoles

Aleksanyan

Hakobyan

Shahkhatuni

et al. 2022

Journal of Heterocyclic Chem

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Tautomerization is the key feature of pyrazoles, which is connected with the hydrogen transfer in pyrazoles between two nitrogens. It is scholarly accepted that tautomers of 3(5)-substituted pyrazole derivatives cannot be isolated as individual compounds with the exception of certain extreme conditions. Here using the fact that N-substitution suppresses tautomerization and allows their separation and isolation, the individual isomers of N-propanoates of 3(5)pyrazole were synthesized, isolated, and further modified several times without change of initial 3-or 5-methyl configuration. However, once the group attached to the nitrogen was removed, two individual isomers gained back their tautomeric properties and became the same mixture of tautomers, as expected. Close monitoring by NMR spectroscopy vividly demonstrates the loss and then reverting of tautomeric properties of 3(5)-pyrazole derivatives along the set of chemical transformations aimed at possible isolation of two tautomers. Failure to isolate them once again proves that the dynamic equilibrium of tautomers in solution is an inherent property of 3(5)-methylpyrazole.

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Structure and tautomerism of 4-substituted 3(5)-aminopyrazoles in solution and in the solid state: NMR study and Ab initio calculations

Cited by 8 publications

References 27 publications

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

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

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

Direct demonstration of tautomeric nature of 4‐bromo‐3(5)‐methylpyrazoles

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