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.