**5. Hydrogen Bond Energy**

Hydrogen bond energies and the less well-defined hydrogen bond strength is clearly very important for molecular properties [65]. One way of getting a qualitative idea is the monitor isotope effects in solvents of different polarity. Sigala et al. [42] found no difference in going to water (see Section 4) and also for the pegylated usnic acid the isotope effects were similar in CDCl3 and in a mixture of water and DMSO [48].

Two-bond deuterium isotope effects on 13C chemical shifts may also be related to electron densities at bond critical points [66] (Figure 26). The latter are related to hydrogen bond energies.

**Figure 26.** Two-bond deuterium isotope effects on 13C chemical shifts vs. electron density at bond critical points. Reprinted from Ref. [67].

A quantitative approach was proposed by Reuben [68], who correlated two-bond deuterium isotope effects with hydrogen bond energies of intramolecular hydrogen bonds. Recently, this was tested in *o*-hydroxybenzaldehydes (Figure 27) [67]. The hydrogen bond energies were calculated by the hb and our method. This method was originally formulated by Cuma, Scheiner and Kar [69]. Another example is found in 5-acyl rhodanines and thiorhodanines with bulky acyl groups [70] again with a very good correlation.

Two-bond deuterium isotope effects are clearly a way of estimating hydrogen bond energies in cases in which the theoretical methods are less suited.

**Figure 27.** Plot of hydrogen bond energies vs. two-bond deuterium isotope effect on 13C chemical shifts of *o*-hydroxyacyl aromatics. Plot of 'hb and out' hydrogen bond energies in kcal/mol. calculated either with MP2/6-311++G(d,p) or with B3LYP/6-311++G(d,p) vs. observed two-bond deuterium isotope effect (TBDIE) on 13C chemical shifts in ppm. Top correlation line is B3LYP, bottom one is MP2. The observed TBDIE for gossypol is marked with the vertical blue line. Reprinted from Ref. [67].
