2/24/2018 Keto–enol tautomerism - Wikipedia

Keto–enol tautomerism
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
Keto–enol tautomerism.
electrons; hence, the isomerism qualifies as
Keto form (left); enol form (right).
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]

Contents
Mechanism
Erlenmeyer rule
Stereochemistry of ketonization
Phenols
Significance in biochemistry
DNA
See also
References

Mechanism

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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 the alpha hydrogen. This alpha hydrogen 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 C–H bond at the alpha carbon
reduces the electron density of the C–H bond and weakens it, making the alpha hydrogen more acidic. When the alpha
hydrogen is not aligned with the pi orbital, for example in the adamantanone or other polycyclic ketones, the enolization is
impossible or very slow.[2][3]

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

Erlenmeyer rule
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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.

Stereochemistry of ketonization
See also: Stereochemistry of ketonization of enols and enolates

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.

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, where the ring with the oxygens 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 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.[4]

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
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.[5]

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 until corrected by Jerry Donohue. Their mistaken initial understanding
prevented them from solving the structure of DNA until corrected.[6]

See also
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Geminal diol, another form of ketones and aldehydes in water solutions

Regioselectivity

References
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] (http://pubs.acs.org.ezproxy1.library.arizona.edu/doi/abs/10.1021/ja0
0088a051)
2. Norlander, J.E.; Jindal, S.; Kitko, D. (1969). "Resistance of adamantanone to homoenolization". Journal of the
Chemical Society, Chemical Communications: 1136–1137. doi:10.1039/C29690001136 (https://doi.org/10.1039%2FC
29690001136).
3. Stothers, J.B.; Tan, C.T. (1974). "Adamantanone: stereochemistry of its homoenolization as shown by 2H nuclear
magnetic resonance". Journal of the Chemical Society, Chemical Communications (18): 378–379.
doi:10.1039/C39740000738 (https://doi.org/10.1039%2FC39740000738).
4. 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 (http://www3.interscience.wiley.com/
cgi-bin/abstract/112154960/ABSTRACT?CRETRY=1&SRETRY=0)
5. 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.
6. The Eighth Day of Creation. Judson, Horace Freeland. Simon & Schuster, NY:1979.

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