An NMR Method for the Quantitative Assessment of Intramolecular Hydrogen Bonding; Application to Physicochemical, Environmental, and Biochemical Properties

Abstract

ABSTRACT:1 H NMR chemical shifts have been obtained in the solvents deuterochloroform and dimethyl sulfoxide. The difference in the chemical shifts of an OH or NH group in these two solvents, Δδ = δ(DMSO) − δ(CDCl 3 ), can be converted into the hydrogen bond acidity, A, of the group using the equation A = 0.0065 + 0.133Δδ. The NMR A value, A NMR , can be used as a quantitative assessment of intramolecular hydrogen bonding. We list values of Δδ and A NMR for 55 compounds containing an OH group and 60 compounds with an NH group. For the hydroxy compounds, if A > 0.5 then the OH group is not part of an intramolecular hydrogen bond, but if A < 0.1 then the OH group forms part of an intramolecular hydrogen bond. For NH compounds, if A > 0.16 the NH group is not part of an intramolecular hydrogen bond, and if A < 0.05 the NH group is part of an intramolecular hydrogen bond. No comparison compounds are needed, and the method is extremely simple. We further show how it is possible to relate intramolecular hydrogen bonding to the actual effect on values of a number of physicochemical, environmental, and biochemical properties. ■ INTRODUCTION Shalaeva et al.1 have recently shown that the presence of an intramolecular hydrogen bond (intraHB) in a molecule can considerably alter the properties of a molecule. These include properties relevant to drug design such as solubility, permeability, and partition. It is therefore important to be able to identify molecules that possess intraHBs and, if possible, to assess the effect of an intraHB on the molecular properties. Testa and co-workers 2−5 were the first to show that the effect of intraHBs could be observed in water−solvent partition coefficients (as log P) and particularly in differences between partition coefficients in water−octanol and water−aprotic solvent systems. They set out differences in log P for water− octanol and water−heptane partitions (eq 1) and showed that intraHBs greatly reduce the value of Δ(log P) oct−hept . They also observed similar effects due to intraHBs in other water−octanol and water−solvent systems.4,5 Leo 6 used octanol and chloroform as the two solvent systems in order to calculate the hydrogen bond acidity of a solute, and Feng et al. 7 used dibutyl ether and cyclohexane as the solvent systems to calculate solute hydrogen bond acidity.

Is there an intramolecular hydrogen bond in 2-halophenols? A theoretical and spectroscopic investigation

“…We have reported results for a large number of hydroxylic solutes 15,16 where the A(NMR) values agreed very well with those obtained by the general method. In these reports, we did not compare the two methods for the 2-halophenols, as we were concerned about the concentration dependence of the OH chemical shifts in chloroform.…”

Synthesis of a coumarin derivative of resorcin[4]arene with solvent-controlled chirality

“…NMR method is a very simple method of assessing the presence of an intramolecular hydrogen bond in a molecule. 35 The difference in the chemical shis of an OH or NH group in two solvents, Dd Based on the 1D-and 2D-NMR spectra run in chloroform and DMSO, we postulated the formation of "out" conformer of compound (1), the dynamics of which were controlled by the solvent's proton-donor-acceptor properties and temperature. In chloroform, a solvent devoid of proton-donor-acceptor properties, an intramolecular hydrogen bond stiffened "out"conformer of coumarin derivative of resorcin [4]arene was formed at room temperature (Scheme 3).…”

Studies on the hydrogen bond acidity, and other descriptors and properties for hydroxyflavones and hydroxyisoflavones

“…(1) and (2). These were then used to assess intramolecular hydrogen bonding, as set out in some detail before [17]. The hydroxy group at positions 6, 7, 3′ and 4′ in flavone functions as a strong hydrogen-bond acid, just like phenol itself with A = 0.60, but internal hydrogen bonding of the 3-hydroxy group with the flavone carbonyl group and internal hydrogen bonding of the 2′-hydroxy group with the flavone ether group reduces the hydrogen bond acidity.…”