A Nexus between Theory and Experiment: Non‐Empirical Quantum Mechanical Computational Methodology Applied to Cucurbit[ n ]uril⋅Guest Binding Interactions

A training set of eleven X‐ray structures determined for biomimetic complexes between cucurbit[ n ]uril (CB[7 or 8]) hosts and adamantane‐/diamantane ammonium/aminium guests were studied with DFT‐D3 quantum mechanical computational methods to afford Δ G calcd binding energies. A novel feature of this work is that the fidelity of the BLYP‐D3/def2‐TZVPP choice of DFT functional was proven by comparison with more accurate methods. For the first time, the CB[ n ] ⋅ guest complex binding energy subcomponents [for example, Δ E dispersion , Δ E electrostatic , Δ G solvation , binding entropy (− T Δ S ), and induced fit E deformation(host) , E deformation(guest) ] were calculated. Only a few weeks of computation time per complex were required by using this protocol. The deformation (stiffness) and solvation properties (with emphasis on cavity desolvation) of cucurbit[ n ]uril ( n =5, 6, 7, 8) isolated host molecules were also explored by means of the DFT‐D3 method. A high ρ 2 =0.84 correlation coefficient between Δ G exptl and Δ G calcd was achieved without any scaling of the calculated terms (at 298 K). This linear dependence was utilized for Δ G calcd predictions of new complexes. The nature of binding, including the role of high energy water molecules, was also studied. The utility of introduction of tethered [‐(CH 2 ) n NH 3 ] + amino loops attached to N , N ‐dimethyl‐adamantane‐1‐amine and N , N , N ′, N ′‐tetramethyl diamantane‐4,9‐diamine skeletons (both from an experimental and a theoretical perspective) is presented here as a promising tool for the achievement of new ultra‐high binding guests to CB[7] hosts. Predictions of not yet measured equilibrium constants are presented herein.