Rationalizing the Strength of Hydrogen-Bonded Complexes. Ab Initio HF and DFT Studies

Abstract

A comparative study of the relative stabilities of 17 multiply hydrogen-bonded complexes has been carried out using ab initio Hartree−Fock and density functional methods at the HF/6-311(d,p) and B3LYP/6-311(d,p) levels, respectively. Predicted hydrogen-bond geometries, relative stabilities, solvent and structural effects, and electrostatic potential contours are discussed in conjunction with experimental data. The B3LYP method, which secures a better agreement of the optimized geometries with the available X-ray data, has also been applied to calculate the gas-phase free energies and enthalpies. The computations reveal that the frequently used incremental approach, which takes into consideration the primary and secondary electrostatic interactions, can often be deceptive in interpreting the stabilities of the multiply hydrogen-bonded dimers. The explanation that reduced entropy enhances the stability of dimers involving intramolecular hydrogen bonds in their monomeric parts compared to similar structures lacking such bonds has also been found to be misleading. A comparison of the calculated results with available experimental stabilities measured in CHCl3 solutions shows that water present in the solvent may cause dramatic changes in relative stabilities. Electrostatic potential contours calculated at the B3LYP/6-311(d,p) level provide a useful qualitative explanation of the stability differences in the investigated complexes.

Computational study of the thermodynamic stabilities of hydrogen-bonded complexes in solution

“…Use of large basis sets such as cc-pVTZ and spAug-ccpVTZ does not necessarily give good binding free energies of these complexes in solution compared to experimental values. Our current computations of the stabilities of these H-bonding complexes in the gas phase and solution with the Minnesota solvation model and functionals fully support an early HF and B3LYP/6-311G(d,p) study of similar H-bonded complexes without evaluation of solution-phase binding free energies in 2002 [55], which caused an interesting debate [60,61].…”

“…Molecular electrostatic potentials have been used to characterize the intermolecular interactions and activities of molecules [53][54][55][56]. The 5 kcal/mol more favorable interaction in 6-6 over 8-9 is clearly shown by the negative electrostatic potential contour plots at −20 kcal/mol (blue) and the potential maps on a 0.03 au (e/Bohr 3 ) surface (red refers to electron density-rich region) from M06-2X/ cc-pVDZ calculations in Fig.…”

Bindungsmechanismen in supramolekularen Komplexen

“…Dass noch erhebliche Probleme z. B. bei der Berechnung von einfachen Wasserstoffbrücken-Assoziaten bestehen, zeigen erhebliche Differenzen zu den experimentellen Daten bei einer neueren Arbeit über die Assoziation von Nucleobasen und ähnlichen Derivaten in Chloroform, [181] auch bei expliziter Berücksichtigung von Solvensmolekülen. Die Beschreibung von lokalisierbaren einzelnen Wechselwirkungen wird mithilfe von inversen Kraftkonstanten-("Compliance")-Matrizen verbessert.…”

It Is Important to Compute Intramolecular Hydrogen Bonding in Drug Design?

“…To treat complicated systems such as hydrogen bonding, the ab initio quantum chemistry method is an ideal approach since all electronic and steric effects are fully taken into account in such a treatment. Over the past decade, much work has been published on the ab initio study of hydrogen bonds [70,[294][295][296][297][298][299][300][301][302][303][304][305][306][307]. However, few ab initio calculations have been carried out on hydrogen bond systems that are directly related to medicinal chemistry in drug design.…”