Hoford Sabrina, Jan Julius, Johnston Jeffrey N, Dudding Travis
Department of Chemistry, Brock University, 1812 Sir Isaac Brock way, St. Catharines, Ontario L2S 3A1 (Canada).
Department of Chemistry and Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee 37235 (USA).
European J Org Chem. 2025 Feb 3;28(5). doi: 10.1002/ejoc.202401203. Epub 2025 Jan 2.
Fluorinated molecules are core to contemporary drug discovery programs and critical for advancing innovation in numerous fields. In merging these important chemical themes, fluorinated Diels-Alder cycloaddition products are a particularly attractive subset of compounds with significant utility. Herein, an in-depth computational and experimental study of fluorine substitution effects on dienophile partners in Diels-Alder reactions is reported. Of particular focus to this study is understanding the origin of reaction rate deceleration as a consequence of employing fluorinated dienophiles and the factors controlling vs. -selectivity. To unlock insight into this unique reactivity, density function theory calculations, distortion/interaction-activation strain models, energy decomposition analysis and natural bond orbital analysis, among other computational methods, were applied. In addition, the influence of oriented external-electric-field-effects (OEEFs) and local electric field effects were explored. To further probe this effect, experimental studies of charge-enhanced Diels-Alder reactivity with fluorinated dienophiles were conducted. Collectively, this work offers novel mechanistic understanding pertinent to Diels-Alder reactions of fluorinated dienophiles providing valuable fluorinated scaffolds.
氟化分子是当代药物发现计划的核心，对推动众多领域的创新至关重要。在融合这些重要的化学主题时，氟化狄尔斯-阿尔德环加成产物是一类特别有吸引力的化合物子集，具有重要用途。本文报道了对狄尔斯-阿尔德反应中亲双烯体伙伴上氟取代效应的深入计算和实验研究。本研究特别关注的是理解使用氟化亲双烯体导致反应速率减慢的原因以及控制对映选择性和非对映选择性的因素。为了深入了解这种独特的反应性，应用了密度泛函理论计算、畸变/相互作用-活化应变模型、能量分解分析和自然键轨道分析等多种计算方法。此外，还探索了定向外电场效应（OEEF）和局部电场效应的影响。为了进一步探究这种效应，进行了与氟化亲双烯体的电荷增强狄尔斯-阿尔德反应性的实验研究。总的来说，这项工作为氟化亲双烯体的狄尔斯-阿尔德反应提供了新的机理理解，提供了有价值的氟化支架。
