Abstract
Intramolecular hydrogen bond (IMHB) interactions have attracted considerable attention due to their central role in molecular structure, chemical reactivity, and interactions of biologically active molecules. Precise correlations of the strength of IMHB’s with experimental parameters are a key goal in order to model compounds for drug discovery. In this work, we carry out an experimental (NMR) and theoretical (DFT) study of the IMHB in a series of structurally similar o-carbonyl hydroquinones. Geometrical parameters, as well as Natural Bond Orbital (NBO) and Quantum Theory of Atoms in Molecules (QTAIM) parameters for IMHB were compared with experimental NMR data. Three DFT functionals were employed to calculated theoretical parameters: B3LYP, M06-2X, and ωB97XD. O…H distance is the most suitable geometrical parameter to distinguish among similar IMHBs. Second order stabilization energies ΔEij(2) from NBO analysis and hydrogen bond energy (EHB) obtained from QTAIM analysis also properly distinguishes the order in strength of the studied IMHB. ΔEij(2) from NBO give values for the IMHB below 30 kcal/mol, while EHB from QTAIM analysis give values above 30 kcal/mol. In all cases, the calculated parameters using ωB97XD give the best correlations with experimental 1H-NMR chemical shifts for the IMHB, with R2 values around 0.89. Although the results show that these parameters correctly reflect the strength of the IMHB, when the weakest one is removed from the analysis, arguing experimental considerations, correlations improve significantly to values around 0.95 for R2.
Highlights
Hydrogen bonding (HB) is generally described as a stabilizing electrostatic interaction with a partly covalent character
The implementation of Intramolecular hydrogen bond (IMHB) considerations in drug discovery programs requires experimental methodologies to assess the position of these equilibria, which are dependent on the strength of each IMBH [8]
We found that O . . . H distance is the most suitable geometrical parameter for distinguishing among IMHBs of similar strengths
Summary
Hydrogen bonding (HB) is generally described as a stabilizing electrostatic interaction with a partly covalent character. Some of the most direct experimental evidence of the HB formation is the deshielding of the hydrogen atom involved in the interaction, which is observed by NMR spectroscopy [1,2]. It is well known that intramolecular hydrogen bonding (IMBH) has a key role in determining the structure and properties of biologically-active molecules, and their study in model. The implementation of IMHB considerations in drug discovery programs requires experimental methodologies to assess the position of these equilibria, which are dependent on the strength of each IMBH [8]. The 1 H-NMR spectroscopy is the most common tool to measure the propensity of compounds to form IMHBs, up to now the throughput of NMR, and other traditional methods, is limited in obtaining structure–activity relationships (SAR)
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