Microhydration of substituted diamondoid radical cations of biological relevance: infrared spectra of amantadine+-(H2O)n = 1–3 clusters

Abstract

Hydration of biomolecules and pharmaceutical compounds has a strong impact on their structure, reactivity, and function. Herein, we explore the microhydration structure around the radical cation of the widespread pharmaceutical drug amantadine (C₁₆H₁₅NH₂, Ama) by infrared photodissociation (IRPD) spectroscopy of mass-selected Ama⁺W_{n = 1–3} clusters (W = H₂O) recorded in the NH, CH, and OH stretch range of the cation ground electronic state. Analysis of the size-dependent frequency shifts by dispersion-corrected density functional theory calculations (B3LYP-D3/cc-pVTZ) provides detailed information about the acidity of the protons of the NH₂ group of Ama⁺ and the structure and strength of the NH⋯O and OH⋯O hydrogen bonds (H-bonds) of the hydration network. The preferred sequential cluster growth begins with hydration of the two acidic NH protons of the NH₂ group (n = 1–2) and continues with an extension of the H-bonded hydration network by forming an OH⋯O H-bond of the third W to one ligand in the first hydration subshell (n = 3), like in the W₂ dimer. For n = 2, a minor population corresponds to Ama⁺W₂ structures with a W₂ unit attached to Ama⁺via a NH⋯W₂ H-bond. Although the N–H proton donor bonds are progressively destabilized by gradual microhydration, no proton transfer to the W_n solvent cluster is observed in the investigated size range (n ≤ 3). Besides the microhydration structure, we also obtain a first impression of the structure and IR spectrum of bare Ama⁺, as well as the effects of both ionization and hydration on the structure of the adamantyl cage. Comparison of Ama⁺ with aliphatic and aromatic primary amine radical cations reveals differences in the acidity of the NH₂ group and the resulting interaction with W caused by substitution of the cycloalkyl cage.