Addressing the Importance of Non-Covalent Interactions in the Selectivity of Diels–Alder Reactions under Pressure: a Theoretical Study

In this work, we propose a detailed analysis of the effect of pressure on a prototype Diels–Alder reaction, namely the one occurring between diphenylfulvene and maleimide, recently experimentally explored under ball-milling conditions. Our results are in good agreement with the experimental findings in predicting the endo-product as the major isomer under kinetic control. An analysis of the non-covalent interactions (NCI) allowed to clarify the origin of this selectivity, which is attributed to a loss of symmetry in the transition state leading to the exo-product, caused by steric repulsion between the maleimide carbonyl group and one of the phenyl rings of the diphenylfulvene, not totally compensated by a weak hydrogen-bond interaction between these two groups. Activation strain model (ASM) analysis shows that the selectivity originates from the balance between distortion and interaction energies. Interestingly, our calculations predict that an inversion in selectivity towards the exo-product can be envisaged at high pressures. Under compression, interaction stabilization increases more rapidly for the exo-pathway but is accompanied by a larger distortion penalty; the selectivity inversion occurs when interaction stabilization outweighs the additional distortion energy. The NCI and ASM analyses are thus complementary, providing, respectively, structural and energetic interpretations of the pressure-dependent selectivity. This finding opens new perspectives on the effect of mechanical constraints on reactivity and suggests a possible route towards an exo-selective Diels–Alder reaction.