Hydrogen bonds are a key feature of chemical structure and reactivity. Recently there has been much interest in a special class of hydrogen bonds called "strong" or "low-barrier" and characterized by great strength, short distances, a low or vanishing barrier to hydrogen transfer, and distinctive features in the NMR spectrum. Although the energy of an ordinary hydrogen bond is ca 5 kcal mol-1, the strength of these hydrogen bonds may be > or = 10 kcal mol-1. The properties of these hydrogen bonds have been investigated by many experimental techniques, as well as by calculation and by correlations among those properties. Although it has been proposed that strong, short, low-barrier hydrogen bonds are important in enzymatic reactions, it is concluded that the evidence for them in small molecules and in biomolecules is inconclusive.

No abstract

In a symmetric hydrogen bond (H-bond), the hydrogen atom is perfectly centered between the two donor atoms. The energy diagram for hydrogen motion is thus a single-well potential, rather than the double-well potential of a more typical H-bond, in which the hydrogen is covalently bonded to one atom and H-bonded to the other. Examples of symmetric H-bonds are often found in crystal structures, and they exhibit the distinctive feature of unusually short length: for example, the O-O distance in symmetric OHO H-bonds is found to be less than 2.5 Å. In comparison, the O-O distance in a typical asymmetric H-bond, such as ROH···OR(2), ranges from about 2.7 to 3.0 Å. In this Account, we briefly review and update our use of the method of isotopic perturbation to search for a symmetric, centered, or single-well-potential H-bond in solution. Such low-barrier H-bonds are thought to be unusually strong, owing perhaps to the resonance stabilization of two identical resonance forms [A-H···B ↔ A···H-B]. This presumptive bond strength has been invoked to explain some enzyme-catalyzed reactions. Yet in solution, a wide variety of OHO, OHN, and NHN H-bonds have all been found to be asymmetric, in double-well potentials. Examples include the monoanion of (±)-2,3-di-tert-butylsuccinic acid and a protonated tetramethylnaphthalenediamine, even though these two ions are often considered prototypes of species with strong H-bonds. In fact, all of the purported examples of strong, symmetric H-bonds have been found to exist in solution as pairs of asymmetric tautomers, in contrast to their symmetry in some crystals. The asymmetry can be attributed to the disorder of the local solvation environment, which leads to an equilibrium among solvatomers (that is, isomers that differ in solvation). If the disorder of the local environment is sufficient to break symmetry, then symmetry itself is not sufficient to stabilize the H-bond, and symmetric H-bonds do not have an enhanced stability or an unusual strength. Nor are short H-bonds unusually strong. We discuss previous evidence for "short, strong, low-barrier" H-bonds and show it to be based on ambiguous comparisons. The role of such H-bonds in enzyme-catalyzed reactions is then ascribed not to any unusual strength of the H-bond itself but to relief of "strain."

The Problem For many years biochemists have been studying proton exchange (eq 1) in amides, peptides, and proteins (l).1 They observed that protons buried in the RCONHR' + H20 ^RCONHR' + HOH (1)interior of a protein are slow to exchange. By measuring rates, they could count the number of buried protons, information also available by X-ray diffraction. They could also learn about the dynamics of protein motion-how those buried protons escape into solvent Scheme I MeO NH2

The nuclear magnetic resonance method of isotopic perturbation can distinguish between single- and double-well potentials in intramolecularly hydrogen-bonded monoanions of dicarboxylic acids. These are classic cases of a "strong," symmetric hydrogen bond in the crystal. The observed carbon-13 isotope shifts induced by the substitution of oxygen-18 demonstrate that these monoanions exist as a single symmetric structure in a nonpolar solvent but as two equilibrating tautomers in aqueous solution. The change is attributed to the disorder of the aqueous environment. These are simple counterexamples to the hope that the crystal structure reveals the actual molecular structure in aqueous solution.