Understanding the Retro‐Cope Elimination Reaction of Linear Alkynes

Abstract

The bioorthogonal retro‐Cope elimination reaction of linear alkynes R3C−C≡C−X (R3 = combinations of H, MeO, F; X = H, F, Cl, Br, I) with N,N‐dimethylhydroxylamine was quantum chemically investigated using relativistic density functional theory at ZORA‐BP86/TZ2P. This novel reaction can be tuned through judicious substitution of the alkyne at both the terminal and propargylic position to render second‐order kinetics that rival and out‐compete strain‐promoted variants. Activation strain and quantitative molecular orbital analyses reveal that, both upon terminal or propargylic substitution of propyne, the main effect of substituting H for X is a lowering of the propyne LUMO which stabilizes the HOMO–LUMO interactions and thus the transition state. In the case of terminal substitution with larger halogens (X = Cl, Br, I), a secondary effect interferes: steric repulsion with these larger halogens is absorbed into a longer forming C⋯N bond leading to a more asynchronous reaction accompanied by less (not more) steric Pauli repulsion.