Keto–enol tautomerism

Keto-enol tautomerism.
Left the keto form; right the enol.

In organic chemistry, keto-enol tautomerism refers to a chemical equilibrium between a keto form (a ketone or an aldehyde) and an enol (an alcohol). The enol and keto forms are said to be tautomers of each other. The interconversion of the two forms involves the movement of a proton and the shifting of bonding electrons; hence, the isomerism qualifies as tautomerism.

A compound containing a carbonyl group (C=O) is normally in rapid equilibrium with an enol tautomer, which contains a pair of doubly bonded carbon atoms adjacent to a hydroxyl (−OH) group, C=C-OH. The keto form predominates at equilibrium for most ketones. Nonetheless, the enol form is important for some reactions. Furthermore, the deprotonated intermediate in the interconversion of the two forms, referred to as an enolate anion, is important in carbonyl chemistry, in large part because it is a strong nucleophile.

Normally, the keto-enol tautomerization chemical equilibrium is highly thermodynamically driven, and at room temperature the equilibrium heavily favors the formation of the keto form. A classic example for favoring the keto form can be seen in the equilibrium between vinyl alcohol and acetaldehyde (K = [enol]/[keto] ≈ 3 x10⁻⁷). However, it is reported that in the case of vinyl alcohol, formation of a stabilized enol form can be accomplished by controlling the water concentration in the system and utilizing the kinetic favorability of the deuterium produced kinetic isotope effect (k_H⁺/k_D⁺ = 4.75, k_H2O/k_D2O = 12). Deuterium stabilization can be accomplished through hydrolysis of a ketene precursor in the presence of a slight stoichiometric excess of heavy water (D₂O). Studies show that the tautomerization process is significantly inhibited at ambient temperatures ( k_t ≈ 10⁻⁶ M/s), and the half life of the enol form can easily be increased to t_1/2 = 42 minutes for first order hydrolysis kinetics.

Mechanism

The conversion of an acid catalyzed 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(carbon closest to functional group) contains at least one hydrogen atom known as alpha hydrogen.This atom is removed from the alpha carbon and bonds to the oxygen of the carbonyl carbon to form the enol tautomer. The existence of hydrogen atom at alpha carbon is necessary but not sufficient condition for enolization to occur. In order to be acidic the alpha hydrogen should be positioned such that may line up parallel with antibonding pi-orbital of the carbonyl group. The hyperconjugation of this bond with C-H bond at alpha carbon reduces the electron density out of C-H bond and weakens it. Thus the alpha hydrogen becomes acidic. When this requirement is not enforced, for example in the adamantanone or other polycyclic ketones, the enolization is impossible or very slow. (J. E. Ordlander et al., Resistance of Adamantanone to Homoenolization, 1969), (J.B. Stothers and C.T. Tan,Adamantanone: Stereochemistry of its Homoenolization as shown by 2H Nuclear Magnetic Resonance, 1974)

First, 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 with more hydrogens. This is a concerted step with the oxygen in the hydroxyl group donating electrons to produce the eventual carbonyl group.

Second, the oxygen in a water molecule donates electrons to the hydrogen in the hydroxyl group, thus relieving the positive charge on the electronegative oxygen atom.The keto form is more stable in single carbonyl carbon containing compounds as the carbon-oxygen pi bond is stronger and hence more stable than the carbon-carbon pi bond.

Erlenmeyer rule

One of the early investigators into keto-enol tautomerism was Richard August Carl 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 occurs because the keto form is, in general, more stable than its enol tautomer. As the lower energy form, the keto form is favored at equilibrium.

Stereochemistry of Ketonization

If R1 and R2 (note equation at top of page) are different substituents, the conversion of the enol to the keto tautomer affords enantiomers. On the other hand, if additionally R1 or R2 has a stereogenic center, the diastereomers result in the ketonization process, as in Stereochemistry of ketonization of enols and enolates.

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 stable 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 .

In certain aromatic compounds such as phenols, the enol is important due to the aromatic character of the enol but not the keto form. Melting the naphthalene derivative 1,4-dihydroxynaphthalene 1 at 200 °C results in a 2:1 mixture with the keto form 2. Heating the keto form in benzene at 120°C for three days also affords a mixture (1:1 with first-order reaction kinetics). The keto product is kinetically stable and reverts back to the enol in presence of a base. The keto form can be obtained in a pure form by stirring the keto form in trifluoroacetic acid and toluene (1:9 ratio) followed recrystallisation from isopropyl ether.

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

Probable Error

The reaction of Dihydroxynapthalene with Chromium Trioxide gives 1,4-Naphthoquinone and not the saturated 1,4-Dione. This oxidation is unrelated to the equilibrium under discussion. When the enol form is complexed with chromium tricarbonyl, complete conversion to the keto form accelerates and occurs even at room temperature in benzene. Please check this and correct it if I am right.

DNA

In deoxyribonucleic acids(DNA), the nucleotide bases are in keto form. However, James Watson and Francis Crick first believed them to be in the enol tautomeric form, delaying the solution of the structure for several months.