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Herein, we computationally investigate the reaction mechanism of 2\u2010methoxy\u20103\u2010\n                    <jats:italic>X<\/jats:italic>\n                    \u20105\u2010nitrothiophenes with pyrrolidine (where\n                    <jats:italic>X<\/jats:italic>\n                    \u2009=\u2009NO\n                    <jats:sub>2<\/jats:sub>\n                    , CN, SO\n                    <jats:sub>2<\/jats:sub>\n                    CH\n                    <jats:sub>3<\/jats:sub>\n                    , COCH\n                    <jats:sub>3<\/jats:sub>\n                    , CO\n                    <jats:sub>2<\/jats:sub>\n                    CH\n                    <jats:sub>3<\/jats:sub>\n                    , CONH\n                    <jats:sub>2<\/jats:sub>\n                    or H). This S\n                    <jats:sub>N<\/jats:sub>\n                    Ar reaction follows a stepwise pathway: initially, pyrrolidine adds to the\n                    <jats:italic>C2<\/jats:italic>\n                    position of the 2\u2010methoxy thiophene partner. Then, the release of methanol is triggered by a proton transfer from the newly formed ammonium intermediate to the methoxy group. With excess pyrrolidine, this proton transfer is catalyzed by an additional pyrrolidine molecule. We establish linear correlations between the experimental electrophilicity and the Gibbs free energy barrier, Parr electrophilicity (\u03c9), and molecular softness (S). Local reactivity descriptors for the\n                    <jats:italic>C2<\/jats:italic>\n                    position are generally non\u2010informative, except for the population of the C\uf8ffO bond basin, the\n                    <jats:italic>C2<\/jats:italic>\n                    population of the ELF\n                    <jats:sub>LUMO<\/jats:sub>\n                    function, and the condensed electrophilicity index \u03c9\n                    <jats:sup>+<\/jats:sup>\n                    (\n                    <jats:italic>C2<\/jats:italic>\n                    ). This theoretical approach provides a robust method to further predict electrophilicity parameters in versatile thiophene derivatives chemistry.\n                  <\/jats:p>","DOI":"10.1002\/jcc.70169","type":"journal-article","created":{"date-parts":[[2025,7,14]],"date-time":"2025-07-14T13:44:18Z","timestamp":1752500658000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Substituent Effect on the Nucleophilic Aromatic Substitution of Thiophenes With Pyrrolidine: Theoretical\u00a0Mechanistic and Reactivity Study"],"prefix":"10.1002","volume":"46","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-8779-1834","authenticated-orcid":false,"given":"Jean\u2010Thomas","family":"Pouzens","sequence":"first","affiliation":[{"name":"Universit\u00e9 Bourgogne Europe, CNRS, Institut de Chimie Mol\u00e9culaire de l\u2019Universit\u00e9 de Bourgogne (UMR 6302)  Dijon France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1268-7420","authenticated-orcid":false,"given":"Salma","family":"Souissi","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Bourgogne Europe, CNRS, Institut de Chimie Mol\u00e9culaire de l\u2019Universit\u00e9 de Bourgogne (UMR 6302)  Dijon France"},{"name":"Laboratoire de Chimie H\u00e9t\u00e9rocyclique, Produits Naturels et R\u00e9activit\u00e9 (LR11SE39), Facult\u00e9 des Sciences de Monastir Universit\u00e9 de Monastir  Monastir Tunisie"},{"name":"Universit\u00e9 de Lorraine\u2010CNRS  Vandoeuvre\u2010l\u00e8s\u2010Nancy Cedex France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-9562-8033","authenticated-orcid":false,"given":"Benjamin","family":"Ludwig","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Bourgogne Europe, CNRS, Institut de Chimie Mol\u00e9culaire de l\u2019Universit\u00e9 de Bourgogne (UMR 6302)  Dijon France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2019-6106","authenticated-orcid":false,"given":"Guillaume","family":"Le Breton","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Bourgogne Europe, CNRS, Institut de Chimie Mol\u00e9culaire de l\u2019Universit\u00e9 de Bourgogne (UMR 6302)  Dijon France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3606-0235","authenticated-orcid":false,"given":"Francesca","family":"Ingrosso","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Lorraine\u2010CNRS  Vandoeuvre\u2010l\u00e8s\u2010Nancy Cedex France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0923-4017","authenticated-orcid":false,"given":"Sahbi","family":"Ayachi","sequence":"additional","affiliation":[{"name":"Laboratory of Physico\u2010Chemistry of Materials (LR01ES19), Faculty of Sciences University of Monastir  Monastir Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2048-647X","authenticated-orcid":false,"given":"Jean\u2010Cyrille","family":"Hierso","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Bourgogne Europe, CNRS, Institut de Chimie Mol\u00e9culaire de l\u2019Universit\u00e9 de Bourgogne (UMR 6302)  Dijon France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3670-7828","authenticated-orcid":false,"given":"Taoufik","family":"Boubaker","sequence":"additional","affiliation":[{"name":"Laboratoire de Chimie H\u00e9t\u00e9rocyclique, Produits Naturels et R\u00e9activit\u00e9 (LR11SE39), Facult\u00e9 des Sciences de Monastir Universit\u00e9 de Monastir  Monastir Tunisie"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3114-2522","authenticated-orcid":false,"given":"Paul","family":"Fleurat\u2010Lessard","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Bourgogne Europe, CNRS, Institut de Chimie Mol\u00e9culaire de l\u2019Universit\u00e9 de Bourgogne (UMR 6302)  Dijon France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,7,14]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/jhet.3990"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioorg.2020.104026"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja801877k"},{"key":"e_1_2_8_5_1","first-page":"105","volume-title":"Advances in Heterocyclic Chemistry","author":"Scriven E. 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