Biochemistry - The Chemical Reactions of Living Cells Volume 1 - D. Metzler 1980

The Molecules We Are Made Of
Principles of Small Molecule Architecture
Tautomerism

Many simple Organic compounds exist as mixtures of two or more isomers, or tautomeric forms, that rapidly interconvert. Tautomers can, at least in principle, be separated at low temperatures where the interconversion is hindered.

A classic example of this phenomenon is the keto-enol equilibrium.

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Although the enol form is generally less stable than the keto form, it is invariably present in the system, albeit in small amounts. The enol is readily formed from the keto tautomer because the hydrogen atoms attached to the carbon adjacent to the carbonyl group (C = O) exhibit pronounced acidic properties. One of the primary driving forces behind tautomerism is the presence of an easily dissociable proton. However, hydrogen atoms bonded to carbon typically dissociate poorly, which is why tautomerism arises only in the presence of a carbonyl or some other "activating group".

As a rule, protons attached to oxygen or nitrogen atoms dissociate readily, predisposing tautomerism in amides and ring systems containing O and N atoms [Equations (2-2) through (2-5)].

The tautomerism described by Equation (2-2) is closely related to the keto-enol interconversion. Form B is occasionally found in Peptides. Pyridoxine [Equation (2-3)] exists predominantly as the zwitterionic tautomer B in aqueous solution, whereas in methanol it adopts the uncharged tautomer A. Pyrimidines [Equation (2-4)] and Purines [Equation (2-5)] are capable of forming multiple tautomers. The existence of form D [Equation (2-4)] led to uracil also being referred to as dioxypyrimidine (although the diketo tautomer A clearly predominates here). In any tautomeric pair, a hydrogen atom shifts from one position to another, accompanied by Changes in the lengths and nature of other bonds.

The Equilibrium Constant for a tautomeric transition is equal to The ratio of the mole fractions of the two forms. For example, for the enol and keto forms of acetone in Water, this ratio is ~2∙10^-6 [8]; for the zwitterionic and uncharged forms of pyridoxine [Equation (2-3)] at 25 °C, it is ~4 [9]. The relative Abundance of uracil tautomers B, C, and D compared to tautomer A is presumably small, though quantitative measurements are difficult in this case [10, 11]. Tautomeric ratios (determined for fully protonated forms) are independent of pH, but vary with Temperature and solvent, and are extremely sensitive to the binding of tautomers to protein or other molecules.