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 endo‐ vs. exo‐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.

中文翻译：

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阐明与电荷增强反应性相互作用的 Diels-Alder 反应中的氟转向效应


氟化分子是当代药物发现计划的核心，对于推动众多领域的创新至关重要。在合并这些重要的化学主题时，氟化 Diels-Alder 环加成产物是一个特别有吸引力的化合物子集，具有重要的实用性。在此，报道了氟取代对 Diels-Alder 反应中亲二烯烃配偶体影响的深入计算和实验研究。本研究的特别重点是了解由于使用含氟嗜二烯试剂而导致的反应速率减速的起源以及控制内选择性与外显选择性的因素。为了深入了解这种独特的反应性，应用了密度函数理论计算、失真/相互作用-激活应变模型、能量分解分析和自然键轨道分析等计算方法。此外，还探讨了定向外电场效应 （OEEFs） 和局部电场效应的影响。为了进一步探索这种效应，对电荷增强的 Diels-Alder 与含氟嗜二烯试剂的反应性进行了实验研究。总的来说，这项工作提供了与氟化亲二烯体的 Diels-Alder 反应相关的新机理理解，提供了有价值的氟化支架。