Keto–enol tautomerism

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Keto–enol tautomerism.
Keto form (left); enol form (right).

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 an alpha hydrogen 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. 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 × 10−7). 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 (kH+/kD+ = 4.75, kH2O/kD2O = 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 ( kt ≈ 10−6 M/s), and the half life of the enol form can easily be increased to t1/2 = 42 minutes for first order hydrolysis kinetics.[1]

Mechanism[edit]

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 (the 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. 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.

Keto-enol.svg

Erlenmeyer rule[edit]

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 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.

Stereochemistry of ketonization[edit]

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, then diastereomers result in the ketonization process, as in Stereochemistry of ketonization of enols and enolates.

Phenols[edit]

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 1,4-dihydroxynaphthalene 2 at 200 °C results in a 2:1 mixture with the keto form 1. 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 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.[2]

Tetrahydronaphthalenedione.png

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

Significance in biochemistry[edit]

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.[3]

DNA[edit]

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 until corrected by Jerry Donohue. Their mistaken initial understanding prevented them from solving the structure of DNA until corrected.[4]

References[edit]

  1. ^ Investigations into the Chemistry of Thermodynamically Unstable Species. The Direct Polymerization of Vinyl Alcohol, the Enolic Tautomer of Acetaldehyde. Anna K. Cederstav and Bruce M. Novak. Journal of the American Chemical Society, 1994, Volume 116, Pages 4073–74. [1]
  2. ^ Rediscovery, Isolation, and Asymmetric Reduction of 1,2,3,4-Tetrahydronaphthalene-1,4-dione and Studies of Its [Cr(CO)3] Complex E. Peter Kündig, Alvaro Enríquez García, Thierry Lomberget, Gérald Bernardinelli Angewandte Chemie International Edition Volume 45, Issue 1 , Pages 98 – 101 2006 Abstract
  3. ^ Wang, W., H. W. Hellinga, et al. (2011). "Structural evidence for the rare tautomer hypothesis of spontaneous mutagenesis." Proceedings of the National Academy of Sciences 108(43): 17644-17648.
  4. ^ The Eighth Day of Creation. Judson, Horace Freeland. Simon & Schuster, NY:1979.