First Principles Investigation of Noncovalent Complexation: A [2.2.2]‐Cryptand Ion‐Binding Selectivity Study

A first principles methodology, aimed at understanding the roles of molecular conformation and energetics in host–guest binding interactions, is developed and tested on a system that pushes the practical limits of ab initio methods. The binding behavior between the 2.2.2]‐cryptand host (4,7,13,16,21,24‐hexaoxa‐1,10‐diaza‐bicyclo8.8.8]hexacosane) and alkali metal cations (Li⁺, Na⁺, and K⁺) in gas, water, methanol, and acetonitrile is characterized. Hartree–Fock and density functional theory methods are used in concert with crystallographic information to identify gas phase, energy‐minimized conformations. Gas phase free energies of binding, with vibrational contributions, are compared to solution‐state binding constants through relative binding selectivity analysis. Calculated relative binding free energies qualitatively correlated with solution state experiments only after gas phase metal desolvation is considered. The B3LYP exchange–correlation functional improves theoretical correlations with experimental relative binding free energies. The relevance of gas phase calculations towards understanding binding in condensed phases is discussed. Natural bond orbital methods highlights previously unidentified intramolecular and intermolecular M⁺(222) chemistries, such as an intramolecular n′_O→σ*_CH hydrogen bond.