Tautomerism and Resonance.

Many simple organic compounds exist as mixtures of two or more rapidly interconvertible isomers or tautomeric forms. Tautomers can sometimes be separated one from the other at low temperatures where the rate of interconversion is low. The classic example is the oxo-enol (or keto-enol) equilibrium.

Although usually less stable than the oxo (keto) form, the enol is present in a small amount. It is formed readily from the oxo tautomer by virtue of the fact that hydrogen atoms attached to carbon atoms that are immediately adjacent to carbonyl (C=O) groups are remarkably acidic. Easy dissociation of a proton is a prerequisite for tautomerism. Since most hydrogen atoms bound to carbon atoms do not dissociate readily, tautomerism is unusual unless a carbonyl or other “activating group” is resent.
Since protons bound to oxygen and nitrogen atoms usually do dissociate readily, tautomerism also exists in amides and in ring systems containing O and N.



The tautomerism in is the counterpart of that in the oxo-enol transformation. However, the equilibrium constant for aqueous conditions favors form A very strongly. 2-Pyridone is tautomerized to 2-hydroxypyridine to a greater extent. Pyrimidines and purines can form a variety of tautomers. The existence of form D of is the basis for referring to uracil as dihydroxypyrimidine. However, the di-oxo tautomer A redominates. Pyridoxine (vitamin B6) exists in water largely as the dipolar ionic tautomer B but in methanol as the uncharged tautomer A. In a pair of tautomers, a hydrogen atom always moves from one position to another and the lengths and bond haracter of these bonds also change.
The equilibrium constant for a tautomeric interconversion is simply the ratio of the mole fractions of the two forms; for example, the ratio of enol to oxo forms of acetone12 in water at 25°C is 6.0 x 10–9, while that for isobutyraldehyde is 1.3 x 10–4. The ratio of 2-hydroxypyridine to 2-pyridone is about 10–3 in water but increases to 0.6 in a hydrocarbon solvent and to 2.5 in the vapor phase. The ratio of dipolar ion to uncharged pyridoxine is ∼4 at 25°C in water. The ratios of tautomers B, C, and D to the tautomer A of uracil are small, but it is ifficult to measure them quantitatively. These tautomeric ratios are defined for given overall states of rotonation. The constants are independent of pH but will change if the overall state f protonation of the molecule is changed. They may also be altered by changes in temperature or solvent or by binding to a protein or other molecule.
It is important to distinguish tautomerism from resonance, a term used to indicate that the properties of a given molecule cannot be represented by a single valence structure but can be represented as a hybrid of two or more structures in which all the nuclei remain in the same places. Only bonding electrons move to convert one resonance form into another. Examples are the enolate anion, which can be thought of as a hybrid of structures A and B, and the amide linkage, which can be represented by a similar pair of resonance forms.

A double-headed arrow is often used to indicate that two structures drawn are resonance structures rather than tautomers or other separable isomers.
Although they are distinctly different, tautomerism and resonance are related. Thus, the acidity of carbon-bound hydrogens in ketones, which allows formation of enol tautomers, results from the fact that the enolate anion produced by dissociation of one of these hydrogens is stabilized by resonance. Similarly, tautomerism in the imidazole group of the amino acid histidine is related to resonance in the imidazolium cation. Because of this resonance, if a proton approaches structure A of and becomes attached to the lefthand nitrogen atom (Nδ), the positive charge in the resulting intermediate is distributed over both nitrogen atoms. This makes the proton on Nε acidic, permitting it to dissociate to tautomer B.

Since Nσ has sometimes also been called N3, it is best not to use the numerical designations for the nitrogen atoms. The tautomeric ratio of B to A for histidine in
water has been estimated, using 15N- and 13C-NMR, as 5.0 when the α-amino group is protonated and as 2.5 when at high pH it is unprotonated. This tautomerism of the imidazole group is probably important to the function of many enzymes and other proteins; for example, if Nε of structure A is embedded in a protein, a proton approaching from the outside can induce the tautomerism shown with the release of a proton in the interior of the protein, perhaps at the active site of an enzyme. The form protonated on Nδ, which is the minor form in solution, predominates in some positions within proteins.