Microhydrated clusters of a pharmaceutical drug: infrared spectra and structures of amantadineH(HO).

Solvation of pharmaceutical drugs has an important effect on their structure and function. Analysis of infrared photodissociation spectra of amantadineH(HO) clusters in the sensitive OH, NH, and CH stretch range by quantum chemical calculations (B3LYP-D3/cc-pVTZ) provides a first impression of the interaction of this pharmaceutically active cation with water at the molecular level. The size-dependent frequency shifts reveal detailed information about the acidity of the protons of the NH group of N-protonated amantadineH (AmaH) and the strength of the NH⋯O and OH⋯O hydrogen bonds (H-bonds) of the hydration network. The preferred cluster growth begins with sequential hydration of the NH group by NH⋯O ionic H-bonds ( = 1-3), followed by the extension of the solvent network through OH⋯O H-bonds. However, smaller populations of cluster isomers with an H-bonded solvent network and free N-H bonds are already observed for ≥ 2, indicating the subtle competition between noncooperative ion hydration and cooperative H-bonding. Interestingly, cyclic water ring structures are identified for ≥ 3, each with two NH⋯O and two OH⋯O H-bonds. Despite the increasing destabilization of the N-H proton donor bonds upon gradual hydration, no proton transfer to the (HO) solvent cluster is observed up to = 4. In addition to ammonium cluster ions, a small population of microhydrated iminium isomers is also detected, which is substantially lower for the hydrophilic HO than for the hydrophobic Ar environment.