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In this work, the solvent effect on the proton-transfer step (rate-determining) of the Morita\u2013Baylis\u2013Hillman (MBH) reaction in a protic medium was investigated through a combination of ab initio molecular dynamics, well-tempered metadynamics, and on-flow NMR kinetic experiments. The simulations reveal two competing proton-transfer pathways involving solvent-assisted and acid\u2013base mechanisms. These pathways have comparable free energy barriers and are driven mostly by the entropy and conformational preference of the zwitterionic intermediate. Conformational free energy surfaces, combined with NMR analysis, show that bulky substituents in the electrophilic partner may cause a steric effect that hinders proton-transfer accessibility and suppresses MBH adduct formation. These findings establish a direct relationship between conformation and proton-transfer reactivity, highlighting the importance of dynamically addressing the explicit solvation in the MBH reaction.<\/jats:p>","DOI":"10.1021\/acsphyschemau.6c00040","type":"journal-article","created":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T05:11:16Z","timestamp":1782277876000},"page":"1070-1082","source":"Crossref","is-referenced-by-count":0,"title":["Conformation-Driven Duality in the MBH Proton-Transfer\nMechanism: A Dynamic View of Solvent and Entropic Effects"],"prefix":"10.1021","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2712-9571","authenticated-orcid":true,"given":"Patrick R.","family":"Batista","sequence":"first","affiliation":[{"name":"University of Bonn , , Beringstr. 4+6 , ,","place":["Bonn, Germany, D-53115"]},{"name":"University of Campinas , , Monteiro Lobato, 270, Cidade Universita\u0301ria , , ,","place":["Campinas, Sa\u0303o Paulo, Brazil, 13083-862"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joa\u0303o","family":"Pedro B. da Silva","sequence":"additional","affiliation":[{"name":"University of Campinas , , Monteiro Lobato, 270, Cidade Universita\u0301ria , , ,","place":["Campinas, Sa\u0303o Paulo, Brazil, 13083-862"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dario","family":"Baum","sequence":"additional","affiliation":[{"name":"Vrije Universiteit Amsterdam , , De Boelelaan 1108 , ,","place":["Amsterdam, The Netherlands, 1081 HZ"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8843-7132","authenticated-orcid":true,"given":"Barbara","family":"Kirchner","sequence":"additional","affiliation":[{"name":"University of Bonn , , Beringstr. 4+6 , ,","place":["Bonn, Germany, D-53115"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1508-0694","authenticated-orcid":true,"given":"Cla\u0301udio F.","family":"Tormena","sequence":"additional","affiliation":[{"name":"University of Campinas , , Monteiro Lobato, 270, Cidade Universita\u0301ria , , ,","place":["Campinas, Sa\u0303o Paulo, Brazil, 13083-862"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,6,24]]},"reference":[{"key":"2026092310074899600_cit1","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1515\/zpch-1890-0607","article-title":"U\u0308ber\ndie Affinita\u0308tskoeffizienten der Alkylhaloide und der Amine","volume":"6U","author":"Menschutkin","year":"1890","journal-title":"Z. 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