Infrared spectra and structures of protonated amantadine isomers: detection of ammonium and open-cage iminium ions

Abstract

The protonated form of amantadine (1-C₁₀H₁₅NH₂, Ama), the amino derivative of adamantane (C₁₀H₁₆, Ada), is a wide-spread antiviral and anti-Parkinsonian drug and plays a key role in many pharmaceutical processes. Recent studies reveal that the adamantyl cage (C₁₀H₁₅) of Ama can open upon ionization leading to distonic bicyclic iminium isomers, in addition to the canonical nascent Ama⁺ isomer. Herein, we study protonation of Ama using infrared photodissociation spectroscopy (IRPD) of Ar-tagged ions and density functional theory calculations to characterize cage and open-cage isomers of AmaH⁺ and the influence of the electron-donating NH₂ group on the cage-opening reaction potential. In addition to the canonical ammonium isomer (AmaH⁺(I)) with an intact adamantyl cage, we identify at least one slightly less stable protonated bicyclic iminium ion (AmaH⁺(II)). While the ammonium ion is generated by protonation of the basic NH₂ group, AmaH⁺(II) is formally formed by H addition to a distonic bicyclic iminium ion produced upon ionization of Ama and subsequent cage opening.