Hydration of neurotransmitters: a spectroscopic and computational study of ephedrine and its diastereoisomer pseudoephedrine

Abstract

Singly and multiply hydrated clusters of the two diastereoisomers, (1R,2S) ephedrine and (1S,2S) pseudoephedrine have been generated in a free-jet expansion and structurally assigned by comparing their mass-selected resonant two photon ionisation spectra, their partially resolved ultra-violet rotational band contours and/or their infra-red ion-dip spectra with the results of quantum chemical calculations. The singly hydrated clusters display two distinct types of structure; addition to the alcohol group, with water acting as the proton donor, or insertion of water into the intramolecular OH → N hydrogen bond of the monomer. In the doubly hydrated clusters, water dimer insertion structures are preferred. Hydration of ephedrine promotes relatively little change in its conformational landscape but dramatic changes are observed in the case of pseudoephedrine: the conformational landscapes of the two molecules are sensitive to the absolute configuration of their chiral centres. The sensitivity is attributed to a balance between a number of competing interactions including hydrogen bonding (both intra- and inter-molecular) and steric/non-bonded interactions (involving both the methyl groups of the side chain and the aromatic ring). The dramatic differences between ephedrine and pseudoephedrine mirror their differing biological activities.