How Bases Catalyze Diels‐Alder Reactions

We have quantum chemically studied the base‐catalyzed Diels‐Alder (DA) reaction between 3‐hydroxy‐2‐pyrone and N‐methylmaleimide using dispersion‐corrected density functional theory. The uncatalyzed reaction is slow and is preceded by the extrusion of CO(2) via a retro‐DA reaction. Base catalysis, for example, by triethylamine, lowers the reaction barrier up to 10 kcal mol(−1), causing the reaction to proceed smoothly at low temperature, which quenches the expulsion of CO(2), yielding efficient access to polyoxygenated natural compounds. Our activation strain analyses reveal that the base accelerates the DA reaction via two distinct electronic mechanisms: i) by the HOMO‐raising effect, which enhances the normal electron demand orbital interaction; and ii) by donating charge into 3‐hydroxy‐2‐pyrone which accumulates in its reactive region and promotes strongly stabilizing secondary electrostatic interactions with N‐methylmaleimide.