Understanding the Retro-Cope Reaction of Linear Alkynes

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.