Computational Exploration of Ambiphilic Reactivity of Azides and Sustmann's Paradigmatic Parabola.

We examine the theoretical underpinnings of the seminal discoveries by Reiner Sustmann about the ambiphilic nature of Huisgen's phenyl azide cycloadditions. Density functional calculations with ωB97X-D and B2PLYP-D3 reproduce the experimental data and provide insights into ambiphilic control of reactivity. Distortion/interaction-activation strain and energy decomposition analyses show why Sustmann's use of dipolarophile ionization potential is such a powerful predictor of reactivity. We add to Sustmann's data set several modern distortion-accelerated dipolarophiles used in bioorthogonal chemistry to show how these fit into the orbital energy criteria that are often used to understand cycloaddition reactivity. We show why such a simple indicator of reactivity is a powerful predictor of reaction rates that are actually controlled by a combination of distortion energies, charge transfer, closed-shell repulsion, polarization, and electrostatic effects.