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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 (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.^[1]

1 Mechanism
2 Erlenmeyer rule
3 Stereochemistry of ketonization
4 Phenols
5 Significance in biochemistry
- 5.1 DNA
6 References

Mechanism[edit source | edit]

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 (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.

Erlenmeyer rule[edit source | 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 source | 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 source | 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]

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 source | 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 source | 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 source | edit]

^ 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]
^ 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
^ 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.
^ The Eighth Day of Creation. Judson, Horace Freeland. Simon & Schuster, NY:1979.

English Journal

Mapping the Kinetic and Thermodynamic Landscape of Formaldehyde Oligomerization under Neutral Conditions.

Kua J, Avila JE, Lee CG, Smith WD.Author information Department of Chemistry and Biochemistry, University of San Diego , 5998 Alcala Park, San Diego, California 92110, United States.AbstractDensity functional theory calculations, including Poisson-Boltzmann implicit solvent and free energy corrections, are applied to study the thermodynamic and kinetic free energy landscape of formaldehyde oligomerization up to the C4 species in aqueous solution at pH 7. Oligomerization via C-O bond formation leads to linear polyoxymethylene (POM) species, which are the most kinetically accessible oligomers and are marginally thermodynamically favored over their oxane ring counterparts. On the other hand, C-C bond formation via aldol reactions leads to sugars that are thermodynamically much more stable in free energy than POM species; however, the barrier to dimerization is very high. Once this initial barrier is traversed, subsequent addition of monomers to generate trimers and tetramers is kinetically more feasible. In the aldol reaction, enolization of the oligomers provides the lowest energy pathway to larger oligomers. Our study provides a baseline free energy map for further study of oligomerization reactions under catalytic conditions, and we discuss how this will lead to a better understanding of complex reaction mixtures with multiple intermediates and products.
The journal of physical chemistry. A.J Phys Chem A.2013 Nov 27;117(47):12658-67. doi: 10.1021/jp4098292. Epub 2013 Nov 18.
Density functional theory calculations, including Poisson-Boltzmann implicit solvent and free energy corrections, are applied to study the thermodynamic and kinetic free energy landscape of formaldehyde oligomerization up to the C4 species in aqueous solution at pH 7. Oligomerization via C-O bond fo
PMID 24191666

Tautomeric effect of hydrazone Schiff bases in tetranuclear Cu(ii) complexes: magnetism and catalytic activity towards mild hydrocarboxylation of alkanes.

Sutradhar M, Kirillova MV, Guedes da Silva MF, Liu CM, Pombeiro AJ.Author information Centro de Química Estrutural, Complexo I, Instituto Superior Técnico, University of Lisbon, Av. Rovisco Pais, 1049-001 Lisboa, Portugal. pombeiro@ist.utl.pt.AbstractThree new tetranuclear copper(ii) complexes [Cu(HL(1))]4·4EtOH (·4EtOH), [Cu(HL(2))]4 () and [Cu(H2L(3))]4(NO3)4·2H2O (·2H2O) have been synthesized using three different hydrazone Schiff base ligands derived from the condensation of the aromatic acid hydrazides 2-hydroxybenzo-, 2-aminobenzo- or benzo-hydrazide, with 2,3-dihydroxybenzaldehyde. Complexes and have been characterized by single crystal X-ray diffraction analysis. The coordinating behaviour of the ligand depends on the nature of the ortho substituent present in the hydrazide moiety. The ligands bearing a strong electron donating group (by resonance) in the ortho position undergo complexation via enolization and deprotonation, whereas the absence of such an effect leads to complexation via the keto form, and two different types of tetranuclear Cu(ii) clusters, viz. open-cubane and cubane, are obtained. Variable temperature magnetic susceptibility measurements of complexes and have been carried out to examine the nature of magnetic interaction between the Cu(ii) centres. All the three complexes () act as good catalyst precursors towards mild hydrocarboxylation of linear and cyclic alkanes into carboxylic acids in water-acetonitrile medium.
Dalton transactions (Cambridge, England : 2003).Dalton Trans.2013 Nov 12;42(47):16578-87. doi: 10.1039/c3dt52453a.
Three new tetranuclear copper(ii) complexes [Cu(HL(1))]4·4EtOH (·4EtOH), [Cu(HL(2))]4 () and [Cu(H2L(3))]4(NO3)4·2H2O (·2H2O) have been synthesized using three different hydrazone Schiff base ligands derived from the condensation of the aromatic acid hydrazides 2-hydroxybenzo-, 2-aminobenzo- or
PMID 24068161

Cytotoxicity of 1,4-diamino-2-butanone, a putrescine analogue, to RKO cells: mechanism and redox imbalance.

Soares CO, Boiani M, Marnett LJ, Bechara EJ.Author information Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, SP, Brazil.Abstractα-Aminocarbonyl metabolites (e.g., 5-aminolevulinic acid and aminoacetone) and the wide spectrum microbicide 1,4-diamino-2-butanone (DAB) have been shown to exhibit pro-oxidant properties. In vitro, these compounds undergo phosphate-catalyzed enolization at physiological pH and subsequent superoxide radical-propagated aerobic oxidation, yielding a reactive α-oxoaldehyde and H2O2. DAB cytotoxicity to pathogenic microorganisms has been attributed to the inhibition of polyamine biosynthesis. However, the role played in cell death by reactive DAB oxidation products is still poorly understood. This work aims to clarify the mechanism of DAB-promoted pro-oxidant action on mammalian cells. DAB (0.05-10 mM) treatment of RKO cells derived from human colon carcinoma led to a decrease in cell viability (IC50 ca. 0.3 mM DAB, 24 h incubation). Pre-addition of either catalase (5 μM) or aminoguanidine (20 mM) was observed to partially inhibit the toxic effects of DAB to the cells, while N-acetyl-L-cysteine (NAC, 5 mM) or reduced glutathione (GSH, 5 mM) provided almost complete protection against DAB. Changes in redox balance and stress response pathways were indicated by the increased expression of HO-1, NQO1 and xCT. Moreover, the observation of caspase 3 and PARP cleavage products is consistent with DAB-triggered apoptosis in RKO cells, which was corroborated by the partial protection afforded by the pan-caspase inhibitor z-VAD-FMK. Finally, DAB treatment disrupted the cell cycle in response to increased p53 and activation of ATM. Altogether, these data support the hypothesis that DAB exerts cytotoxicity via a mechanism involving not only polyamine biosynthesis but also by DAB oxidation products.
Free radical research.Free Radic Res.2013 Sep;47(9):672-82. doi: 10.3109/10715762.2013.814126. Epub 2013 Jul 8.
α-Aminocarbonyl metabolites (e.g., 5-aminolevulinic acid and aminoacetone) and the wide spectrum microbicide 1,4-diamino-2-butanone (DAB) have been shown to exhibit pro-oxidant properties. In vitro, these compounds undergo phosphate-catalyzed enolization at physiological pH and subsequent superoxid
PMID 23758064

Japanese Journal

One-Pot Synthesis of Phenol Derivatives by the Novel Intramolecular Alder–Rickert Reaction : Effects of Aryl Substituent at the 3-Position of Cyclohexenone Derivatives on Reactivity

Kinbara Atsushi,Yamagishi Takehiro,Fujishige Takeshi [他],Miyaoka Hiroaki
Chemical and Pharmaceutical Bulletin 61(7), 768-775, 2013
… We examined In(OTf)3-catalyzed enolization and intramolecular Alder–Rickert reactions of cyclohexenone derivatives. …
NAID 130003360800

水晶振動子を用いたマロン酸のエノール化反応速度定数の決定

吉本稔,松永大志,愛澤秀信,黒澤茂
分析化学 = Japan analyst 61(10), 863-867, 2012-10-05
NAID 10030877543

水晶振動子を用いたマロン酸のエノール化反応速度定数の決定

吉本稔,松永大志,愛澤秀信 [他],黒澤茂
分析化学 61(10), 863-867, 2012
… That process involves an enolization reaction of MA as a rate-limiting reaction. … This new finding led us to a determination of the reaction rate constant for the enolization reaction of MA due to the QCM measurement. …
NAID 130001886963