The Challenging Conformational Landscape of Cysteamine···H₂O Revealed by the Strong Interplay of Rotational Spectroscopy and Quantum Chemical Calculations

A 1:1 molecular complex of cysteamine with water is shown to adopt a cage-like structure where cysteamine accepts a relatively strong hydrogen bond from water while also engaging in two additional weaker interactions (SH···O_w and CH···O_w). Experimental and theoretical approaches confirm this conformer as the global minimum on the potential energy surface. Fitting of key structural parameters to experimentally determined moments of inertia yields consistent and accurate results for rotational and ¹⁴N nuclear quadrupole coupling constants which are shown to be challenging to calculate using <i>ab initio</i> methods. Comprehensive analysis of the intermolecular interactions and a thorough comparison with the properties of aminoethanol-water is presented, utilizing independent gradient models based on Hirshfeld partition, quantum theory of atoms-in-molecules, and symmetry-adapted perturbation theory approaches. As expected, the OH group of aminoethanol is a stronger hydrogen bond donor than the SH group in cysteamine, while the CH···O_w interaction is a key determining factor of the conformational landscape in both cysteamine-water and aminoethanol-water complexes. The results show very clearly that the synergy between theoretical calculations and experimental results is not only desirable but mandatory to get the right answers in such complex conformational surfaces. The results are also clear benchmarks for the accuracy of different theoretical methods in assessing the structures and energy order of the conformations.