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 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.