Elucidating Fluorine Steering Effects in Diels‐Alder Reactions Interfaced with Charge‐Enhanced Reactivity

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.