A simple and universal method for the estimation of the intramolecular hydrogen bond (HB) energy (E(HB)) in hydroxycarbonyl aliphatic compounds is proposed by the application of the molecular tailoring approach (MTA) based on calculations at the second-order Møller-Plesset MP2 level. The calculation of EHB can be realized by the one optimization and three single point calculations of the energy for each compound with carbonyl and hydroxyl groups involved in HB. The intramolecular hydrogen bond energies estimated for 153 structures (of 102 compounds) ranged from 1.4 to 13.7 kcal/mol for systems without resonance-assisted hydrogen bonding (RAHB). To verify the method, we show the correlations of the energy (E(HB)) in six-, seven-, and eight-membered HB rings in the optimized multifunctional molecules with the usual geometry descriptors of hydrogen bonds. Moreover, topological parameters from the atoms in molecules (AIM) theory and the calculated infrared and proton NMR spectra are correlated. The effects of conjugation and π-electron delocalization, bifurcation, and cooperativity are discussed, along with the correlation between the strength and geometrical parameters of H bonding.

A method for the calculation of the intramolecular hydrogen bond (HB) energy (EHB) by molecular tailoring approach for hydroxycarbonyl aliphatic compounds has been used for compounds with resonance-assisted hydrogen bonding (RAHB). The intramolecular hydrogen bond energies estimated for 229 structures (of 186 compounds) range from 8.2 to 26.3 kcal/mol and show correlation with the geometry descriptors of hydrogen bonds, with the calculated frequencies as well as with topological parameters obtained from the atoms in molecules (AIM) theory. These correlations differ significantly from obtained formerly for saturated nonenolizable structures and prove the special character of the resonance-assisted hydrogen-bonded systems.

As a test for the applicability of the density functional theory to the system containing intramolecular hydrogen bonds, calculations were performed on propen-1,2,3-triol, the feasible intermediate in the epimerization of dihydroxyacetone and glyceraldehyde enantiomers. A comparison is made between results obtained by Becke's three parameter hybrid functional (for exchange) with gradient corrections provided by the LYP correlation functional (B3LYP) and those predicted at the ab initio Møller−Plesset second-order (MP2) level. The calculated minimum energy structures are in excellent agreement with respect to both energy and geometries of hydrogen-bonded structures. Earlier and recent studies suggest that, generally, the nonlocal B3LYP approximation leads to a very accurate overall description of intramolecular hydrogen-bonded systems. We propose a new, more efficient computational protocol, which may be useful in the study of the biologically important molecules at a level of accuracy usually only provided by traditional post-Hartree−Fock ab initio methods.

Intramolecular hydrogen bonding (HB) is one of the most studied noncovalent interactions of molecules. Many physical, spectral, and topological properties of compounds are under the influence of HB, and there are many parameters used to notice and to describe these changes. Hitherto, no general method of measurement of the energy of intramolecular hydrogen bond (EHB) has been put into effect. We propose the molecular tailoring approach (MTA) for EHB calculation, modified to apply it to Ar-O-H∙∙∙O=C systems. The method, based on quantum calculations, was checked earlier for hydroxycarbonyl-saturated compounds, and for structures with resonance-assisted hydrogen bonding (RAHB). For phenolic compounds, the accuracy, repeatability, and applicability of the method is now confirmed for nearly 140 structures. For each structure its aromaticity HOMA indices were calculated for the central (ipso) ring and for the quasiaromatic rings given by intramolecular HB. The comparison of calculated HB energies and values of estimated aromaticity indices allowed us to observe, in some substituted phenols and quinones, the phenomenon of transfer of aromaticity from the ipso-ring to the H-bonded ring via the effect of electron delocalization.

Among the conformers of the title compounds, all stable structures found reveal hydrogen bonding to an sp2 oxygen atom in five- or six-membered rings and usually cooperative effects. Nonlocal density functional calculations using different functionals prove the applicability of DFT to study geometries of systems containing intramolecular hydrogen bonds. The hydrogen bond parameters obtained applying the B3LYP approximation exhibit perfect agreement with those calculated at the MP2 level. The local gradient correction does not provide encouraging results.

Background: Molecular mechanics (MM) and quantum chemical (QM) calculations are widely applied and powerful tools for the stereochemical and conformational investigations of molecules. The same methods have been extensively used to probe the conformational profile of Taxol ( Figure 1) both in solution and at the β-tubulin protein binding site.

The molecular tailoring approach is recognized to be an efficient tool for quantifying the strength of the push-pull effect in the molecules with internal charge transfer.

The conformational properties of epothilone A have been analyzed in detail using electronic structure calculations to better understand the effect of intramolecular hydrogen bonding on the conformational energies of this highly potent anticancer molecule. Single-point second-order Møller-Plesset calculations done in vacuo at the MP2/6-31+G(d,p)//B3LYP/6-31+G(d,p) level yielded data on the relative stability of conformers that were more distinct than data obtained from the standard DFT model, although the structural trends are in fair agreement. We studied torsional profiles of both hydroxyl groups and sampled energies of the side chain and thiazole moiety rotamers within the whole set of all experimentally accessible conformers. The aldol hydrogen bonds, though relatively weak, generally contribute to the conformational profile, while dipole-dipole interactions, ester group puckering, transannular repulsions between hydrogen atoms, steric effects, and syn-pentane effects have a limited influence. A salient result of our calculations is the determination that the energy of the clustered exo conformer P01 lays 9.3 kcal/mol below that of the extended, experimental conformer P11, apparently due to the unconstrained, near linear 3-OH hydrogen bond to thiazole. Another finding to be noted is the corroboration of the remarkable ability of 3-OH to form transannular hydrogen bonding with the epoxide, which releases the conformational strain of the macroring and thus leads to extra stabilization energy within the endoW subset. Finally, we found that the general trend of the conformer populations of epothilone A obtained from conformational energies resembles those derived from experiments and can be used to interpret values of NMR vicinal coupling constants. The calculated geometries and energies provide essential data for further discussion of the mechanism of biological activity of epothilone A and might be of importance in the explanation of its ADME properties.