Unveiling the Reaction Mechanism of Diels‐Alder Cycloadditions between 2,5‐Dimethylfuran and Ethylene Derivatives Using Topological Tools

The [4+2] Diels-Alder cycloaddition reaction between 2,5-DMF (1) and ethylene derivatives (2a-h) activated by electron-withdrawing groups has been studied at the density functional theory levels using a panoply of tools to unravel the reaction mechanisms. From the analysis of the reactivity indices, 2a-h behave as electrophiles while 1 as nucleophile, and the activation of the double bond of ethylene increases its electrophilicity, which is accompanied by an enhancement of the polarity of the reaction. The activation Gibbs free energy decreases linearly as a function of this increase of polarity, as estimated by the electrophilicity difference between the reactants. The difference of electrophilicity drives also the global electron density transfer at the transition state and the asynchronicity of the reaction, as evaluated by the difference of carbon-carbon bond lengths in the transition state. Then, Bonding Evolution Theory shows that the activation of the double bond of ethylene by an electron-withdrawing group changes the reaction mechanism from a one-step synchronous process to a one-step asynchronous process. Generally, the endo pathway is kinetically favored but, thermodynamically, it is the exo pathway. Finally, using the Distortion/Interaction-Activation Strain, it is shown that the endo/exo selectivity is mostly driven by the differences of interaction energies.