The Diels–Alder reaction is a useful tool for generating functionalized chiral molecules through the concerted cycloaddition of dienes and dienophiles leading to six-membered rings. Traditionally, the selective predictions of the products rely heavily on consideration of the secondary orbital interactions that stabilize the endo pathway. However, there remain some basic examples defying this notion and produce the exo-isomer as major product. Here we systematically evaluated of the structural features driving exo selectivity in thermal normal-electron-demand Diels–Alder reactions. Substitution at the Cβ position and the size and electronegativity of the electron-withdrawing group of the dienophile are contributing factors. Experimental and computational studies both point toward the steric and electrostatic forces between the substituents in both the diene and the dienophile that increase the likelihood of the exo pathway. For these substrates, the dominance of the endo pathway is reduced by transition state distortions and poor structural alignments of the reacting partners. We also noted the tilt of the dienophile with respect to the diene causing steric strain on the functionalities at the more advanced bond forming carbon-carbon position of the endo transition state. Insights into such factors may benefit synthetic planning and asserting control over this important named reaction.

Exo-exclusive stereoselectivity for simple, terminal-substituted dienes and dienophiles may be achieved under thermal conditions through a delicate control of substituent identities.