1. Mechanism

The acid catalyzed conversion of an enol to the keto form proceeds by a two-step mechanism in an aqueous acidic solution. For this, it is necessary that the alpha carbon atom (the carbon atom closest to the functional group) contains at least one hydrogen atom known as the alpha hydrogen atom. This alpha hydrogen atom must additionally be positioned such that it may line up parallel with the antibonding pi-orbital of the carbonyl group. The hyperconjugation of this bond with the C–H bond at the alpha carbon atom reduces the electron density of the C–H bond and weakens it, making the alpha hydrogen atom more acidic. When the alpha hydrogen atom is not aligned with the pi orbital, for example in the adamantanone or other polycyclic ketones, the enolization is impossible or very slow.^[1][2]

In the first step of the mechanism, the exposed electrons of the C=C double bond of the enol are donated to a hydronium ion (H₃O⁺). This addition follows Markovnikov's rule, thus the proton is added to the carbon atom with more attached hydrogen atoms. This is a concerted step with the oxygen atom in the hydroxyl group donating electrons to produce the eventual carbonyl group.

2. Erlenmeyer Rule

One of the early investigators into keto–enol tautomerism was Emil Erlenmeyer. His Erlenmeyer rule, developed in 1880, states that all alcohols in which the hydroxyl group is attached directly to a double-bonded carbon atom become aldehydes or ketones. This conversion occurs because the keto form is, in general, more stable than its enol tautomer. The keto form is therefore favored at equilibrium because it is the lower energy form.

3. Stereochemistry of Ketonization

If R¹ and R² (note equation at top of page) are different substituents, there is a new stereocenter formed at the alpha position when an enol converts to its keto form. Depending on the nature of the three R groups, the resulting products in this situation would be diastereomers or enantiomers.

4. Phenols

In certain aromatic compounds such as phenol, the enol is important due to the aromatic character of the enol but not the keto form. Melting the naphthalene derivative naphthalene-1,4-diol, which has the 1,4-diol as part of an aromatic ring, at 200 °C results in a 2:1 mixture with the diketo form (naphthalene-1,4-dione), where the ring with the oxygen atoms has become non-aromatic. Heating the diketo form in benzene at 120 °C for three days also affords a mixture (1:1 with first-order reaction kinetics). The diketo product is kinetically stable and reverts to the dienol in presence of a base. The diketo form can be obtained in a pure form by stirring the diketo form in trifluoroacetic acid and toluene (1:9 ratio) followed by recrystallisation from isopropyl ether.^[3]

When the enol form is complexed with chromium tricarbonyl, complete conversion to the keto form accelerates and occurs even at room temperature in benzene.

5. Significance in Biochemistry

Keto–enol tautomerism is important in several areas of biochemistry. The high phosphate-transfer potential of phosphoenolpyruvate results from the fact that the phosphorylated compound is "trapped" in the less thermodynamically favorable enol form, whereas after dephosphorylation it can assume the keto form. Rare enol tautomers of the bases guanine and thymine can lead to mutation because of their altered base-pairing properties.^[4]

5.2. DNA

Keto–enol and the analogous amino–imino tautomerism are among the primary causes of spontaneous mutations during DNA replication and repair. In deoxyribonucleic acids (DNA), the nucleotide bases are usually in the keto form, which is stabilized by the hydrogen bonding that holds together the two strands of the DNA double-helix. Single-stranded DNA exists transiently during replication, and there a rare shift to the enol form of thymine (T) or guanine (G) can occur. If the position of the enol base is replicated before it reverts to keto configuration, the result is incorporation of a mismatched base. For example, the tautomeric shift of keto-guanine to enol-guanine (G*) causes it to pair with thymine rather than its normal partner, cytosine. The tautomeric shift is transient and following reversion to the keto form the resulting mismatched nucleotide is usually detected and removed, but in cases of DNA damage or rapid replication, the mismatch may give rise to a permanent sequence change, a transition mutation.

The initial models of DNA constructed by James Watson and Francis Crick envisioned the bases to be in their enol tautomeric form until corrected by Jerry Donohue. This mistaken understanding delayed their solving the structure of DNA until corrected.^[5] As a consequence, though, they were the first to recognize the potential role of tautomerism in spontaneous mutation.