{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T04:21:00Z","timestamp":1784521260709,"version":"3.55.0"},"reference-count":44,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2020,2,14]],"date-time":"2020-02-14T00:00:00Z","timestamp":1581638400000},"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>Nitroxides are broadly used as molecular probes and labels in biophysics, structural biology, and biomedical research. Resistance of a nitroxide group bearing an unpaired electron to chemical reduction with low-molecular-weight antioxidants and enzymatic systems is of critical importance for these applications. The redox properties of nitroxides are known to depend on the ring size (for cyclic nitroxides) and electronic and steric effects of the substituents. Here, two highly strained nitroxides, 5-(tert-butyl)-5-butyl-2,2-diethyl-3-hydroxypyrrolidin-1-oxyl (4) and 2-(tert-butyl)-2-butyl-5,5-diethyl-3,4-bis(hydroxymethyl)pyrrolidin-1-oxyl (5), were prepared via a reaction of the corresponding 2-tert-butyl-1-pyrroline 1-oxides with butyllithium. Thermal stability and kinetics of reduction of the new nitroxides by ascorbic acid were studied. Nitroxide 5 showed the highest resistance to reduction.<\/jats:p>","DOI":"10.3390\/molecules25040845","type":"journal-article","created":{"date-parts":[[2020,2,26]],"date-time":"2020-02-26T05:44:12Z","timestamp":1582695852000},"page":"845","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["2-Butyl-2-tert-butyl-5,5-diethylpyrrolidine-1-oxyls: Synthesis and Properties"],"prefix":"10.3390","volume":"25","author":[{"given":"Irina F.","family":"Zhurko","sequence":"first","affiliation":[{"name":"Novosibirsk Institute of Organic Chemistry, Siberian Branch of Russian Academy of Sciences, Academician Lavrentiev Ave. 9, Novosibirsk 630090, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3486-0335","authenticated-orcid":false,"given":"Sergey","family":"Dobrynin","sequence":"additional","affiliation":[{"name":"Novosibirsk Institute of Organic Chemistry, Siberian Branch of Russian Academy of Sciences, Academician Lavrentiev Ave. 9, Novosibirsk 630090, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Artem A.","family":"Gorodetskii","sequence":"additional","affiliation":[{"name":"Novosibirsk Institute of Organic Chemistry, Siberian Branch of Russian Academy of Sciences, Academician Lavrentiev Ave. 9, Novosibirsk 630090, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuri I.","family":"Glazachev","sequence":"additional","affiliation":[{"name":"Institute of Chemical Kinetics &amp; Combustion SB RAS, Institutskaya 3, Novosibirsk 630090, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2398-5271","authenticated-orcid":false,"given":"Tatyana V.","family":"Rybalova","sequence":"additional","affiliation":[{"name":"Novosibirsk Institute of Organic Chemistry, Siberian Branch of Russian Academy of Sciences, Academician Lavrentiev Ave. 9, Novosibirsk 630090, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1669-7864","authenticated-orcid":false,"given":"Elena I.","family":"Chernyak","sequence":"additional","affiliation":[{"name":"Novosibirsk Institute of Organic Chemistry, Siberian Branch of Russian Academy of Sciences, Academician Lavrentiev Ave. 9, Novosibirsk 630090, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nargiz","family":"Asanbaeva","sequence":"additional","affiliation":[{"name":"Novosibirsk Institute of Organic Chemistry, Siberian Branch of Russian Academy of Sciences, Academician Lavrentiev Ave. 9, Novosibirsk 630090, Russia"},{"name":"Novosibirsk State University, 2 Pirogova St., Novosibirsk 630090, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0057-383X","authenticated-orcid":false,"given":"Elena G.","family":"Bagryanskaya","sequence":"additional","affiliation":[{"name":"Novosibirsk Institute of Organic Chemistry, Siberian Branch of Russian Academy of Sciences, Academician Lavrentiev Ave. 9, Novosibirsk 630090, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6033-0368","authenticated-orcid":false,"given":"Igor A.","family":"Kirilyuk","sequence":"additional","affiliation":[{"name":"Novosibirsk Institute of Organic Chemistry, Siberian Branch of Russian Academy of Sciences, Academician Lavrentiev Ave. 9, Novosibirsk 630090, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,2,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1016\/j.sbi.2013.06.008","article-title":"Technological advances in site-directed spin labelling","volume":"23","author":"Hubbell","year":"2013","journal-title":"Curr. Opin. Struct. Biol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"5468","DOI":"10.1039\/C6OB00473C","article-title":"Site-directed spin labeling of proteins for distance measurements in vitro and in cells","volume":"14","author":"Roser","year":"2016","journal-title":"Org. Biomol. Chem."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1016\/bs.mie.2015.06.007","article-title":"Advanced EPR methods for studying conformational dynamics in nucleic acids","volume":"Volume 564","author":"Qin","year":"2015","journal-title":"Methods in Enzymology"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Babi\u0107, N., and Peyrot, F. (2019). Molecular Probes for Evaluation of Oxidative Stress by In Vivo EPR Spectroscopy and Imaging: State-of-the-Art and Limitations. Magnetochemistry, 5.","DOI":"10.3390\/magnetochemistry5010013"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1632","DOI":"10.1016\/j.freeradbiomed.2007.02.030","article-title":"The Chemistry and Biology of Nitroxide Compounds","volume":"42","author":"Soule","year":"2007","journal-title":"Free Radical Biol. Med."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Kokorin, A.I. (2012). In vivo Spectroscopy and Imaging of Nitroxide Probes. Nitroxides\u2013Theory, Experiment and Applications, InTech Publisher.","DOI":"10.5772\/2887"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1380","DOI":"10.1002\/ange.201710184","article-title":"A bioresistant nitroxide spin label for in-cell EPR spectroscopy: In vitro and in oocytes protein structural dynamics studies","volume":"130","author":"Karthikeyan","year":"2018","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.1002\/open.201900119","article-title":"gem-Diethyl pyrroline nitroxide spin labels: Synthesis, EPR characterization, rotamer libraries and biocompatibility","volume":"8","author":"Bleicken","year":"2019","journal-title":"ChemistryOpen"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"13938","DOI":"10.1021\/acs.analchem.8b03328","article-title":"In vivo extracellular pH mapping of tumors using electron paramagnetic resonance","volume":"90","author":"Komarov","year":"2018","journal-title":"Anal. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"13379","DOI":"10.1002\/anie.201506267","article-title":"Enzymatically shifting nitroxides for EPR spectroscopy and overhauser-enhanced magnetic resonance imaging","volume":"54","author":"Audran","year":"2015","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/0730-725X(85)90012-8","article-title":"Factors affecting nitroxide reduction in ascorbate solution and tissue homogenates","volume":"3","author":"Couet","year":"1985","journal-title":"Magn. Res. Imaging"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"9118","DOI":"10.1021\/acs.joc.5b01494","article-title":"The effect of sterical shielding on the redox properties of imidazoline and imidazolidine nitroxides","volume":"80","author":"Kirilyuk","year":"2015","journal-title":"J. Org. Chem."},{"key":"ref_13","first-page":"477","article-title":"Influence of structure on the reduction of nitroxide MRI contrast-enhancing agents by ascorbate","volume":"16","author":"Keana","year":"1984","journal-title":"Physiol. Chem. Phys. Med. NMR"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1002\/jps.2600800212","article-title":"Chemical and electrochemical reduction rates of cyclic nitroxides (nitroxyls)","volume":"80","author":"Morris","year":"1991","journal-title":"J. Pharm. Sci."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Marx, L., Chiarelli, R., Guiberteau, T., and Rassat, A. (2000). A comparative study of the reduction by ascorbate of 1, 1, 3, 3-tetraethylisoindolin-2-yloxyl and of 1, 1, 3, 3-tetramethylisoindolin-2-yloxyl. J. Chem. Soc., Perkin Trans. 1, 1181\u20131182.","DOI":"10.1039\/b001891k"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1025","DOI":"10.1039\/b400252k","article-title":"Synthesis of the tetraethyl substituted pH-sensitive nitroxides of imidazole series with enhanced stability towards reduction","volume":"2","author":"Kirilyuk","year":"2004","journal-title":"Org. Biomol. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1021\/jo101961m","article-title":"Structure\u2212 reactivity relationship of piperidine nitroxide: Electrochemical, ESR and computational studies","volume":"76","author":"Yamasaki","year":"2011","journal-title":"J. Org. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"5322","DOI":"10.1021\/ol302506f","article-title":"Synthesis and reduction kinetics of sterically Sshielded pyrrolidine nitroxides","volume":"14","author":"Paletta","year":"2012","journal-title":"Org. Lett."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"78","DOI":"10.3109\/10715762.2014.979409","article-title":"Sterically shielded spin labels for in-cell EPR spectroscopy: Analysis of stability in reducing environment","volume":"49","author":"Jagtap","year":"2015","journal-title":"Free Rad. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"5392","DOI":"10.1021\/acs.joc.8b00085","article-title":"Synthesis of 3,4-bis (hydroxymethyl)-2, 2, 5, 5-tetraethylpyrrolidin-1-oxyl via 1, 3-dipolar cycloaddition of azomethine ylide to activated alkene","volume":"83","author":"Dobrynin","year":"2018","journal-title":"J. Org. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"6579","DOI":"10.1002\/pola.23701","article-title":"Kinetic study of H-atom transfer in imidazoline-, imidazolidine-, and pyrrolidine-based alkoxyamines: Consequences for nitroxide-mediated polymerization","volume":"47","author":"Edeleva","year":"2009","journal-title":"J. Polym. Sci. Part A: Pol. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Nagura, K., Takemoto, Y., Yoshino, F., Bogdanov, A., Chumakova, N., Vorobiev, A.K., Imai, H., Matsuda, T., Shimono, S., and Kato, T. (2019). Magnetic mixed micelles composed of a non-ionic surfactant and nitroxide radicals containing a D-glucosamine unit: Preparation, stability, and biomedical application. Pharmaceutics, 11.","DOI":"10.3390\/pharmaceutics11010042"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"15713","DOI":"10.1002\/chem.201702785","article-title":"Preparation of robust metal-free magnetic nanoemulsions encapsulating low-molecular-weight nitroxide radicals and hydrophobic drugs directed toward MRI-visible targeted delivery","volume":"23","author":"Nagura","year":"2017","journal-title":"Chemistry"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"8898","DOI":"10.1021\/la5007296","article-title":"Nitroxide-loaded hexosomes provide MRI contrast in vivo","volume":"30","author":"Bye","year":"2014","journal-title":"Langmuir"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"997","DOI":"10.1007\/BF00472479","article-title":"Recyclization of enamino ketones that are imidazolidine derivatives to 1-pyrrolin-4-one 1-oxides","volume":"26","author":"Reznikov","year":"1990","journal-title":"Chem. Heterocycl. Compd."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2052","DOI":"10.1023\/B:RUCB.0000009651.51972.f5","article-title":"A new series of lipophilic pH-sensitive spin probes","volume":"52","author":"Reznikov","year":"2003","journal-title":"Russ. Chem. Bull."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"6044","DOI":"10.1021\/jo060787x","article-title":"Laser flash photolysis and CIDNP studies of steric effects on coupling rate constants of imidazolidine nitroxide with carbon-centered radicals, methyl isobutyrate-2-yl and tert-butyl propionate-2-yl","volume":"71","author":"Zubenko","year":"2006","journal-title":"J. Org. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1261","DOI":"10.1007\/BF00962395","article-title":"Oxidative dimerization of heterocyclic nitrones, derivatives of pyrroline and imidazoline","volume":"39","author":"Reznikov","year":"1990","journal-title":"Bull. Acad. Sci. USSR Div. Chem. Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1007\/BF02762749","article-title":"Investigation of conjugated dinitrones - derivatives of pyrroline oxide","volume":"38","author":"Rybalova","year":"1997","journal-title":"J. Struct. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1178","DOI":"10.1007\/s11172-005-0377-2","article-title":"Molecular ions of 3,3\u2032-bi(2-R-5,5-dimethyl-4-oxopyrrolinylidene) 1,1\u2032-dioxides","volume":"54","author":"Shundrin","year":"2005","journal-title":"Russ. Chem. Bull."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1007\/BF02499074","article-title":"Stable vinylnitroxyl radicals, pyrroline derivatives","volume":"49","author":"Reznikov","year":"2000","journal-title":"Russ. Chem. Bull."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"874","DOI":"10.1023\/A:1011319528481","article-title":"Synthesis and properties of monoimines of \u03b1-diketones, derivatives of 3-imidazoline nitroxides","volume":"50","author":"Reznikov","year":"2001","journal-title":"Rus. Chem. Bull."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1007\/BF00960664","article-title":"Reaction of 2-substituted 5,5-dimethyl-4-oxo-1-pyrroline-1-oxides with electrophilic reagents","volume":"39","author":"Reznikov","year":"1990","journal-title":"Rus. Chem. Bull."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1007\/BF00960663","article-title":"Reaction of 2-substituted 5,5-dimethyl-4-oxo-1-pyrroline-1-oxides with nucleophilic reagents and synthesis of nitroxyl radicals\u2014derivatives of pyrrolidine","volume":"39","author":"Reznikov","year":"1990","journal-title":"Bull. Acad. Sci. USSR, Div. Chem. Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1007\/s00723-010-0179-z","article-title":"EPR and quantum chemical studies of the pH-sensitive imidazoline and imidazolidine nitroxides with bulky substituents","volume":"39","author":"Bobko","year":"2010","journal-title":"Appl. Magn. Reson."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1016\/j.freeradbiomed.2006.11.007","article-title":"Reversible reduction of nitroxides to hydroxylamines: Roles for ascorbate and glutathione","volume":"42","author":"Bobko","year":"2007","journal-title":"Free Radic. Biol. Med."},{"key":"ref_37","unstructured":"Reichardt, C.H. (1990). Solvent Effects in Organic Chemistry, Wiley-VCH."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"6167","DOI":"10.1039\/C7OB01312D","article-title":"C-ON bond homolysis when too high polarity is detrimental","volume":"15","author":"Nkolo","year":"2017","journal-title":"Org. Biomol. Chem."},{"key":"ref_39","unstructured":"Dobrynin, S.A., Khoroshunova, Y.V., and Kirilyuk, I.A. (2020, February 14). Synthesis of 2,2,5,5-tetraethyl-3-carboxypyrrolidine 1-oxyl. 2019, RU. Patent No. 2 702 331. In russian. Available online: https:\/\/www1.fips.ru\/ofpstorage\/Doc\/IZPM\/RUNWC1\/000\/000\/002\/702\/331\/%D0%98%D0%97-02702331-00001\/document.pdf."},{"key":"ref_40","unstructured":"Sheldrick, G.M. (2008). SADABS, v. 2008\/1."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1107\/S2053229614024218","article-title":"Crystal structure refinement with SHELXL","volume":"71","author":"Sheldrick","year":"2015","journal-title":"Acta Cryst. Sect. C: Struct. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.jmr.2005.08.013","article-title":"EasySpin, a comprehensive software package for spectral simulation and analysis in EPR","volume":"178","author":"Stoll","year":"2006","journal-title":"J. Magn. Reson."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"3969","DOI":"10.1021\/jo00093a031","article-title":"Photolysis of a J-Azo perester, a bifunctional initiator. The fragmentation rate of a \u03b2-peroxy ester radical determined by the cyclopropylcarbinyl clock method","volume":"59","author":"Engel","year":"1994","journal-title":"J. Org. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"9763","DOI":"10.1021\/jo981372h","article-title":"Thermolysis of acylazo O-trimethylsilyl cyanohydrins: Azoalkanes yielding captodatively substituted radicals","volume":"63","author":"Billera","year":"1998","journal-title":"J. Org. Chem."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/25\/4\/845\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T08:57:52Z","timestamp":1760173072000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/25\/4\/845"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,2,14]]},"references-count":44,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2020,2]]}},"alternative-id":["molecules25040845"],"URL":"https:\/\/doi.org\/10.3390\/molecules25040845","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,2,14]]}}}