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

Abstract

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 ΔG 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, ΔE , ΔE , ΔG , binding entropy (-TΔS), and induced fit E , E ] 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 =0.84 correlation coefficient between ΔG and ΔG was achieved without any scaling of the calculated terms (at 298 K). This linear dependence was utilized for ΔG 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 ) NH ] 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.

The Role of Packing, Dispersion, Electrostatics, and Solvation in High‐Affinity Complexes of Cucurbit[n]urils with Uncharged Polar Guests

“…[45] Moreover, the larger host-guest system formed by γ-cyclodextrin with dodecaborate clusters, is even bound more strongly and is more exothermic than that of the corresponding gold-standard β-cyclodextrin complexes with its optimally fitting adamantyl-or ferrocenyl-type guests. The special role of [46] ) or M2 (ref-B [47] , ref-C [11c] , ref-D [3] ) calculations. All energy values were referenced to 1 mol L À 1 .…”

Assessing the Recyclability of Supramolecularly Assembled Organocatalytic Species: A Theoretical Insight

“…The entropic penalty paid for the reconfiguration of all the translational, rotational and vibrational degrees of freedom of the guest when encapsulated into the cavity is somewhat antagonized by the entropic gain due to the dehydration of the negatively charged portals of CB[7] . Hostaš and co‐workers employed BLYP‐D3/def2‐TZVPP//BLYP‐D3/def2‐SVP level of theory for accurate calculation of potential energy . Our computational investigation suggests that DFT calculations at the same level of theory, employing aqueous implicit solvation (SMD) and corrected statistical thermodynamics, prove to be sufficiently accurate and reliable to describe the bonding and thermodynamics between CB[7] and neutral or monocationic adamantanyl guests responsible for the activation a single portal of the cucurbituril.…”

Piperine Encapsulation within Cucurbit[n]uril (n=6,7): A Combined Experimental and Density Functional Study

“…The computed binding energy was found to be higher for CB[7] than for CB[6] inclusion complex both in the gas and solution phases and follow the same trend of the experimental Gibbs free energy computed for the complexes. Furthermore, the gas phase binding energy is higher than the solution phase, as in the gas phase the cavities of the cucurbiturils have void spaces, while in the solution phase, solvent molecules fill the cavities and the existence of high energy water inside the cavity has been envisaged by theoretical and experimental methods ,…”

“…To understand the nature of the interaction between the guest and host cucurbiturils, several theoretical studies have been done . It has been suggested that the nature of interactions between the guest and host cucurbituril are dominated by (i) charge‐dipole interactions, when a cationic host is used (ii) hydrogen bonding interactions between the guest's hydrogen atoms with the carbonyl portal of the host (iii) hydrophobic interactions which exits at the concave cavity of the cucurbituril and (iv) hydrogen interactions between the hydrogen atoms of methylene unit of cucurbituril with guest molecules or an interplay of the above interactions .…”