The 1,3‐Dipolar Cycloaddition: From Conception to Quantum Chemical Design

The 1,3‐dipolar cycloaddition (1,3‐DCA) reaction, conceptualized by Rolf Huisgen in 1960, has proven immensely useful in organic, material, and biological chemistry. The uncatalyzed, thermal transformation is generally sluggish and unselective, but the reactivity can be enhanced by means of metal catalysis or by the introduction of either predistortion or electronic tuning of the dipolarophile. These promoted reactions generally go with a much higher reactivity, selectivity, and yields, often at ambient temperatures. The rapid orthogonal reactivity and compatibility with aqueous and physiological conditions positions the 1,3‐DCA as an excellent bioorthogonal reaction. Quantum chemical calculations have been critical for providing an understanding of the physical factors that control the reactivity and selectivity of 1,3‐DCAs. In silico derived design principles have proven invaluable for the design of new dipolarophiles with tailored reactivity. This review discusses everything from the conception of the 1,3‐DCA all the way to the state‐of‐the‐art methods and models used for the quantum chemical design of novel (bioorthogonal) reagents.