Computational insights into the inverse electron-demand Diels-Alder reaction of norbornenes with 1,2,4,5-tetrazines: norbornene substituents' effects on the reaction rate.

The study of the reaction rates and mechanism of click chemistry reactions still remains an interesting challenge in organic chemistry. In this regard, the inverse electron demand Diels-Alder (IEDDA) reaction represents a promising metal-free alternative with enhanced reaction rates compared to other reactions of the click chemistry toolbox. Among the different types of dienophiles used in the IEDDA reactions, norbornenes have been widely used given their high stability and fast reaction rates. The inverse electron-demand Diels Alder reaction of 3,6-dipyridin-2-yl-1,2,4,5-tetrazine with a series of norbornene derivatives was studied with quantum mechanical calculations at the M06-2X/6-311+G(d,p) level of theory. The theoretical predictions were confirmed with the experimental data and analyzed with the use of the distortion/interaction model. The obtained results will help in obtaining a better understanding of the factors that affect the relative cycloaddition rates of norbornenes with tetrazines, which are crucial for selectively tuning their efficacy.