Interactions of N-hydroxyamphetamine with an iron porphyrin: A unique intramolecular H-bond probed by DFT calculations

Hydroxylamine (NH2OH) and its N-substituted derivatives (RNHOH) are important biological intermediates in the global N cycle. Heme plays a central role in the binding and activation of these hydroxylamines. We report the crystal structures of N-hydroxyamphetamine (AmphNHOH) in complex with Fe and Co heme models. We demonstrate a previously unrecognized internal H-bond interaction between a hydroxylamine RNHO–H group and a porphyrin N-atom. We utilize density functional theoretical (DFT) calculations to show that the conformations with the internal H-bond represent global minima along the potential energy surfaces for both the Fe and Co heme models. A natural bond orbital (NBO) analysis reveals a donor π (porN=C) to acceptor σ* (O-H) interaction of 3.04 kcal/mol for Fe, accounting for 11% of the total heme–AmphNHOH interaction energy. Our DFT calculations with the parent Fe–NH2OH suggests that the presence of internal H-bonds between hydroxylamine (R/H)NHOH moieties and heme N-atoms may be more common than previously recognized. Crystal structures of N-hydroxyamphetamine (AmphNHOH) in complex with Fe and Co heme models demonstrate an internal H-bond interaction between the AmphNHO–H group and a porphyrin N-atom. Calculations and natural bond orbital analyses reveal a donor π (porN=C) to acceptor σ* (O-H) interaction that weakens the AmphNHO–H bond. [Display omitted] •The first crystal structures of heme model-hydroxyamphetamine adducts have been obtained.•A unique internal H-bond between the hydroxylamine and porphyrin is established.•Computational calculations reveal a weakening of the ligand NHO-H bond due to the H-bond.