{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T19:26:17Z","timestamp":1774553177594,"version":"3.50.1"},"reference-count":49,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2019,7,19]],"date-time":"2019-07-19T00:00:00Z","timestamp":1563494400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/molecules24142632","type":"journal-article","created":{"date-parts":[[2019,7,22]],"date-time":"2019-07-22T02:55:37Z","timestamp":1563764137000},"page":"2632","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Annular Tautomerism of 3(5)-Disubstituted-1H-pyrazoles with Ester and Amide Groups"],"prefix":"10.3390","volume":"24","author":[{"given":"Anna","family":"Kusakiewicz-Dawid","sequence":"first","affiliation":[{"name":"Faculty of Chemistry, University of Opole, Oleska 48, 45-052 Opole, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Monika","family":"Porada","sequence":"additional","affiliation":[{"name":"Faculty of Chemistry, University of Opole, Oleska 48, 45-052 Opole, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"B\u0142a\u017cej","family":"Dziuk","sequence":"additional","affiliation":[{"name":"Faculty of Chemistry, University of Opole, Oleska 48, 45-052 Opole, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1686-5215","authenticated-orcid":false,"given":"Dawid","family":"Siod\u0142ak","sequence":"additional","affiliation":[{"name":"Faculty of Chemistry, University of Opole, Oleska 48, 45-052 Opole, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,7,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1039\/C0CE00621A","article-title":"Exceptions to the rule: New hydrogen-bonded networks from an old reliable","volume":"13","author":"Ugono","year":"2011","journal-title":"CrystEngComm"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2975","DOI":"10.1021\/acs.cgd.6b01478","article-title":"Five Multidimensional Co(II)-Complexes (Zero-Dimensional to Three-Dimensional) Derived from an Asymmetric 5-(Pyridin-3-yl)-1H-pyrazole-3-carboxylic Acid: Syntheses, Structures, and Magnetic Properties","volume":"17","author":"Li","year":"2017","journal-title":"Cryst. Growth Des."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1080\/00958972.2013.879983","article-title":"Synthesis, crystal structures, and luminescent properties of Pb(II) and Sr(II) coordination polymers constructed by 5-methyl-1H-pyrazole-3-carboxylic acid","volume":"67","author":"Cheng","year":"2014","journal-title":"J. Coord. Chem."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"588","DOI":"10.1080\/10601325.2013.784546","article-title":"Optoelectronic Properties and Electrochromic Device Application of Novel Pyrazole Based Conducting Polymers","volume":"50","author":"Camurlu","year":"2013","journal-title":"J. Macromol. Sci. A"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1016\/j.cej.2014.08.058","article-title":"Removal of heavy metal ions with the use of chelating polymers obtained by grafting pyridine\u2013pyrazole ligands onto polymethylhydrosiloxane","volume":"259","author":"Schroeder","year":"2015","journal-title":"Chem. Eng. J."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1021\/acs.cgd.7b01219","article-title":"A Three-Dimensional Copper Coordination Polymer Constructed by 3-Methyl-1H-pyrazole-4-carboxylic Acid with Higher Capacitance for Supercapacitors","volume":"18","author":"Yu","year":"2018","journal-title":"Cryst. Growth Des."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.eurpolymj.2016.04.017","article-title":"Fluorinated polymers based on pyrazole groups for fuel cell. Membranes","volume":"79","author":"Harit","year":"2016","journal-title":"Eur. Polym. J."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"5151","DOI":"10.1039\/C7NJ00835J","article-title":"Synthesis and structural diversity of d10 metal coordination polymers constructed from new semi-rigid bis(3-methyl-1H-pyrazole-4-carboxylic acid)alkane ligands","volume":"41","author":"Cheng","year":"2017","journal-title":"New J. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"5891","DOI":"10.1016\/j.bmc.2017.09.035","article-title":"Recently reported biological activities of pyrazole compounds","volume":"25","author":"Faria","year":"2017","journal-title":"Bioorg. Med. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1499","DOI":"10.1021\/acs.jmedchem.7b01261","article-title":"Discovery of 4-((7H-Pyrrolo [2,3-d]pyrimidin-4-yl)amino)-N-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrazole-3-carboxamide (FN-1501), an FLT3- and CDK-Kinase Inhibitor with Potentially High Efficiency against Acute Myelocytic Leukemia","volume":"61","author":"Wang","year":"2018","journal-title":"J. Med. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1016\/j.tetlet.2017.12.052","article-title":"Steric redirection of alkylation in 1H-pyrazole-3-carboxylate esters","volume":"59","author":"Wright","year":"2018","journal-title":"Tetrahedron Lett."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"842","DOI":"10.1039\/C4GC02028F","article-title":"\u201cOn water\u201d synthesis of N-unsubstituted pyrazoles: Semicarbazide hydrochloride as an alternative to hydrazine for preparation of pyrazole-3-carboxylate derivatives and 3,5-disubstituted pyrazoles","volume":"17","author":"Markovic","year":"2015","journal-title":"Green Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"7235","DOI":"10.1002\/ejoc.201501027","article-title":"New Life for Diazoacetonitrile (N2CHCN): In situ Generation and Practical Synthesis of CN-Pyrazoles","volume":"33","author":"Mykhailiuk","year":"2015","journal-title":"Eur. J. Org. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"6120","DOI":"10.1021\/ol502977a","article-title":"Synthesis of Functionalized Cyanopyrazoles via Magnesium Bases","volume":"16","author":"Dishington","year":"2014","journal-title":"Org. Lett."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"22351","DOI":"10.1039\/C8RA04576C","article-title":"Synthesis of 3-(5-amino-1H-1,2,4-triazol-3-yl) propanamides and their tautomerism","volume":"8","author":"Lim","year":"2018","journal-title":"RSC Adv."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3792","DOI":"10.1016\/j.tetlet.2018.09.018","article-title":"One-pot, microwave-assisted synthesis of polymethylene-bridged bis (1H-1,2,4-triazol-5(3)-amines) and their tautomerism","volume":"59","author":"Lim","year":"2018","journal-title":"Tetrahedron Lett."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2314","DOI":"10.1016\/j.tet.2019.03.003","article-title":"A new practical synthesis of 3-amino-substituted 5-aminopyrazoles and their tautomerism","volume":"75","author":"Lim","year":"2019","journal-title":"Tetrahedron"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"4138","DOI":"10.1016\/j.bmcl.2011.05.105","article-title":"Synthesis and anti-inflammatory activity of some novel 3-phenyl-N-[3-(4-phenylpiperazin-1yl)propyl]-1H-pyrazole-5-carboxamide derivatives","volume":"21","author":"Nagarapu","year":"2011","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1016\/j.bmcl.2015.12.007","article-title":"Novel thiol-based histone deacetylase inhibitors bearing 3-phenyl-1H-pyrazole-5-carboxamide scaffold as surface recognition motif: Design, synthesis and SAR study","volume":"26","author":"Wen","year":"2016","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"5624","DOI":"10.1016\/j.bmcl.2016.10.075","article-title":"Multiple biological activities and molecular docking studies of newly synthesized 3-(pyridin-4-yl)-1H-pyrazole-5-carboxamide chalcone hybrids","volume":"26","author":"Sribalan","year":"2016","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1016\/j.saa.2018.06.028","article-title":"Photophysical properties and biological evaluation of a Zinc (II)-5-methyl-1I-pyrazole Schiff base complex","volume":"204","author":"Ribeiro","year":"2018","journal-title":"Spectrochim. Acta A"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"5039","DOI":"10.1021\/jm401516c","article-title":"Opportunities and Challenges in Developing Stearoyl-Coenzyme A Desaturase-1 Inhibitors as Novel Therapeutics for Human Disease","volume":"57","author":"Zhang","year":"2014","journal-title":"J. Med. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"323","DOI":"10.5012\/bkcs.2008.29.2.323","article-title":"Discovery of Novel Transcription Factor Inhibitors Using a Pyrazole-based Small Molecule Library","volume":"29","author":"Ha","year":"2008","journal-title":"Bull. Korean Chem. Soc."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"4207","DOI":"10.1016\/j.bmcl.2009.05.108","article-title":"5-N,N-Disubstituted 5-aminopyrazole-3-carboxylic acids are highly potent agonists of GPR109b","volume":"19","author":"Tamura","year":"2009","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3614","DOI":"10.1021\/jo061918x","article-title":"Synthesis and Binding Studies of Alzheimer Ligands on Solid Suport","volume":"72","author":"Rzepecki","year":"2007","journal-title":"J. Org. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"5168","DOI":"10.1021\/jo0496603","article-title":"New heterocyclic \u03b2-sheet ligands with peptidic recognition elements","volume":"69","author":"Rzepecki","year":"2004","journal-title":"J. Org. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1603","DOI":"10.1039\/B401968G","article-title":"PEG-supported synthesis of pyrazole oligoamides with peptide \u03b2-sheet affinity","volume":"2","author":"Kemter","year":"2004","journal-title":"Org. Biomol. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3016","DOI":"10.1021\/ja045558b","article-title":"\u03b2-Sheet Ligands in Action: KLVFF Recognition by Aminopyrazole Hybrid Receptors in Water","volume":"127","author":"Rzepecki","year":"2005","journal-title":"J. Am. Chem. Soc."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1002\/psc.3018","article-title":"Pyrazole amino acids: Hydrogen bonding directed conformations of 3-amino-1H-pyrazole-5-carboxylic acid residue","volume":"23","author":"Porada","year":"2017","journal-title":"J. Pept. Sci."},{"key":"ref_30","first-page":"1737","article-title":"The Tautomerism of 3(5)-Phenylpyrazoles: An Experimental (1H, 13C, 15N NMR and X-Ray Crystallography) Study","volume":"2","author":"Cativiela","year":"1992","journal-title":"J. Chem. Soc. Perkin Trans."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1139\/v93-092","article-title":"A 13C NMR spectroscopy study of the structure of N-H pyrazoles and indazoles","volume":"71","author":"Lopez","year":"1993","journal-title":"Can. J. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"10783","DOI":"10.1016\/S0040-4020(97)00678-9","article-title":"Structure and tautomerism of 3(5)-amino-5(3)-arylpyrazoles in the solid state and in solution: An X-ray and NMR study","volume":"53","author":"Puello","year":"1997","journal-title":"Tetrahedron"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1002\/(SICI)1099-1395(199708)10:8<637::AID-POC930>3.0.CO;2-P","article-title":"Structure of 3-nitropyrazole in solution and in the solid state","volume":"10","author":"Jagerovic","year":"1997","journal-title":"J. Phys. Org. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1134\/S1070428014030191","article-title":"Structure and Tautomerism of 4-Substituted 3(5)-Aminopyrazoles in Solution and in the Solid State: NMR Study and Ab Initio Calculations","volume":"50","author":"Emelina","year":"2014","journal-title":"Russ. J. Org. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1002\/mrc.1481","article-title":"The tautomerism of 1H-pyrazole-3(5)-(N-tert-butyl)carboxamide in the solid state and in solution","volume":"43","author":"Claramunt","year":"2005","journal-title":"Magn. Reson. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1016\/j.molstruc.2015.07.055","article-title":"Synthesis, structure and biological activity of 3(5)-trifluoromethyl-1Hpyrazoles derived from hemicurcuminoids","volume":"1100","author":"Nieto","year":"2015","journal-title":"J. Mol. Sruct."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.theochem.2003.11.033","article-title":"Theoretical studies on tautomerism and IR spectra of pyrazole derivatives","volume":"673","author":"Dobrowolski","year":"2004","journal-title":"J. Mol. Struc. Theochem"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2861","DOI":"10.1039\/C4NJ02201G","article-title":"A theoretical study of the gas phase (proton affinity) and aqueous (pKa) basicity of a series of 150 pyrazoles","volume":"39","author":"Alkorta","year":"2015","journal-title":"New J. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1007\/s11224-015-0711-8","article-title":"DFT and experimental studies on structure and spectroscopic parameters of 3,6-diiodo-9-ethyl-9H-carbazole","volume":"27","author":"Kupka","year":"2016","journal-title":"Struct. Chem."},{"key":"ref_40","unstructured":"(2002). CrysAlis CCD, Oxford Diffraction Ltd."},{"key":"ref_41","unstructured":"(2002). CrysAlis RED, Oxford Diffraction Ltd."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1107\/S0108767307043930","article-title":"A short history of SHELX","volume":"64","author":"Sheldrick","year":"2008","journal-title":"Acta Cryst. A"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1107\/S2053229614024218","article-title":"New features added to the refinement program SHELXL since 2008 are described and explained","volume":"71","author":"Sheldrick","year":"2015","journal-title":"Acta. Cryst. C"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1107\/S0021889807067908","article-title":"Mercury CSD 2.0\u2013new features for the visualization and investigation of crystal structures","volume":"41","author":"Macrae","year":"2008","journal-title":"J. Appl. Crystallogr."},{"key":"ref_45","unstructured":"Frisch, M.J., Trucks, G.W., Schlegel, H.B., Scuseria, G.E., Robb, M.A., Cheeseman, J.R., Scalmani, G., Barone, V., Mennucci, B., and Petersson, G.A. (2009). Gaussian 09, Revision A.03, Gaussian, Inc."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1007\/s00214-007-0310-x","article-title":"The M06 suite of density functionals for main group thermochemistry, thermochemical kinetics, noncovalent interactions, excited states, and transition elements: Two new functionals and systematic testing of four M06-class functionals and 12 other functionals","volume":"120","author":"Zhao","year":"2008","journal-title":"Theor. Chem. Accounts"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"3397","DOI":"10.1039\/b704725h","article-title":"Double-hybrid density functionals with longrange dispersion corrections: Higher accuracy and extended applicability","volume":"9","author":"Schwabe","year":"2007","journal-title":"Phys. Chem. Chem. Phys."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"6317","DOI":"10.1021\/ja960582d","article-title":"Nucleus-Independent Chemical Shifts: A Simple and Efficient Aromaticity Probe","volume":"118","author":"Schleyer","year":"1996","journal-title":"J. Am. Chem. Soc."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1021\/jo051746o","article-title":"Nucleus-Independent Chemical Shifts (NICS): Distance Dependence and Revised Criteria for Aromaticity and Antiaromaticity","volume":"71","author":"Stanger","year":"2006","journal-title":"J. Org. Chem."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/24\/14\/2632\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:07:22Z","timestamp":1760188042000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/24\/14\/2632"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,7,19]]},"references-count":49,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2019,7]]}},"alternative-id":["molecules24142632"],"URL":"https:\/\/doi.org\/10.3390\/molecules24142632","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,7,19]]}}}