Energetics of Formation and Fragmentation of Carbon-Centered Radicals α- to Nitrogen and Oxygen in N,N,O‑Trimethylhydroxylamine in Comparison to Trimethylamine and Dimethyl Ether: Implications for Medicinal and Synthetic Chemistry.

α-C-H bond dissociation energies (BDEs) have been computed for N,N,O-trimethylhydroxylamine, trimethylamine, and dimethyl ether, leading to the conclusion that there is no advantage to hydrogen abstraction from trisubstituted hydroxylamines over the corresponding tertiary amines and ethers. Additionally, the computed vertical ionization potential for s, trimethylamine, and dimethyl ether, leading to the conclusion that there is no advantage to hydrogen abstraction from trisubstituted hydroxylamines over the corresponding tertiary amines and ethers. Additionally, the computed vertical ionization potential for N,N,O-trimethylhydroxylamine is greater than that for either trimethylamine or dimethyl ether. Together with the established N-O BDEs of ∼50 kcal.mol-1, these findings argue strongly against common notions of trisubstituted hydroxylamines as inherently chemically or metabolically unstable and refute their designation as red flags or structural alerts in drug discovery campaigns. Subsequent to hydrogen abstraction α- to either nitrogen or oxygen, hydroxylamines undergo facile exothermic N-O bond cleavage to give either O- or N-centered radicals. It is this radical-induced cleavage of hydroxylamines that synthetic chemists exploit for N- and O-centered radical generation rather than any perceived weakness of the N-O bond in the unactivated hydroxylamines themselves.