Keto and Enol Tautomers

The keto and enol forms of carbonyl compounds are constitutional isomers, but of a special type. Because they are easily interconverted in the presence of traces of acids and bases, chemists use a special term to describe this type of constimtional isomerism. 

Under most circumstances, we encounter keto-enol tautomers in a state of equilibrium. (The surfaces of ordinary laboratory glassware are able to catalyze the interconversion and establish the equilibrium.) For simple monocarbonyl compounds such as acetone and acetaldehyde, the amount of the enol form present at equilibrium is very small. In acetone it is much less than 1% in acetaldehyde the enol concentration is too small to be detected. The greater stability of the following keto forms of monocarbonyl compounds can be related to the greater strength of the carbon-oxygen tt bond compared to the carbon-carbon tt bond (—364 versus —250 kJ moU )  

Keto-enol tautomers are not resonance structures. They are constitutional isomers in equilibrium (generally favoring the keto form). 

TIM (Triose Phosphate Isomerase) Recycles Carbon via an Enol in WileyPLUS for more information relating to this chapter s opener about an important energy-yielding biochemical process. 

In compounds whose molecules have two carbonyl groups separated by one carbon atom (called j8-dicarbonyl compounds), the amount of enol present at equilibrium is far higher. For example, pentane-2,4-dione exists in the enol form to an extent of 76%  

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If the refractivity of the pure tautomeric constituents is known, the composition of the equilibrium mixture can be determined. This method has been used to study, for example, the keto and enol tautomers of ethyl acetoacetate. So far it has not been applied to heterocyclic compounds in this series the isolation of the pure... 

Hydroxythianaphthene has been isolated in tw o forms,and it has been suggested that these may be the individual keto and enol tautomers. A reinvestigation of this system using modem techniques would be welcome. 

The keto/enol equilibrium (15) has been a spur to much research. In the absence of catalysts the equilibrium is established slowly and is very sensitive to a variety of influences, both internal, such as the nature of a- and P-substituents, and external, such as temperature and solvent. The discovery that the equilibrium was established sufficiently slowly to permit both keto and enol tautomers to be observed by H-nmr spectroscopy allowed these several influences to be easily investigated (see Kol tsov and Kheifets, 1971, for a review of the early work, and Emsley, 1984, for later work). 

The carbonyl stretching frequency of both the keto and enol tautomers can be recognized in the vibrational spectrum of pentane-2,4-dione. The enol has v(C=0) at 1618cm" , generally the dominant peak in the spectrum and more intense than the in- and out-of-phase v(C=0) stretching modes of the keto form, which are found at 1727 and 1707 cm" , respectively. These are identified by their Raman counterparts at 1719 cm" (polarized) and 1697 cm" (depolarized) (Ernstbrunner, 1970). The ratio of absorbances of the enol and the out-of-phase keto bands in the ir was used as an early method of analysis of the keto/enol equilibrium in different solvents (Le Fevre and Welsh, 1949). 

Problem 17.7 (a) Write the structural formulas for the stable keto and enol tautomers of ethyl acetoacetate. (b) Why is this enol much more stable than that of a simple ketone (c) How can the enol be chemically detected ... 

Ethyl 3-oxobutanoate exists at room temperature as an equilibrium mixture of keto and enol tautomers in the ratio of 92.5 to 7.5. The presence of enol can be shown by rapid titration with bromine, but is more evident from the proton nmr spectrum (Figure 18-6), which shows absorption of the hydroxyl, alkenyl, and methyl protons of the enol form, in addition to absorptions expected for the keto form ... 

Kinetic and thermodynamic measurements show that 2-phenylacetylthiophene (92a) has a low enol content K = 3.55 x 10 7 (or )K = 6.45).136 The keto and enol tautomers have pKa values of 14.60 and 8.15, respectively. Relative to a phenyl or furanyl substituent at the carbonyl carbon, the thiophene increases the acidity of the enol tautomer, but stabilizes the ketone, probably via the resonance contribution (92b). Thus 2-thiophenyl stabilizes the enolate by electron attraction, but the ketone by donation. Effects of micelles on the equilibria are also reported. 

Tautomerism is an extremely solvent-dependent chemical process which affects the chemical properties of molecules. A well known example is the keto-enol equilibrium of (3-diketones, in which the enol form is the most populated species in apolar solvents, whereas the keto species is the most stable tautomer in aqueous solution [70], Another classical example is the solvent influence on the keto-enol tautomerism of 4-pyridone, where the population ratio between the keto and enol tautomers changes by a factor of 104 upon its transfer from the gas phase to an aqueous solution [71]. 

The program is reported to carry out simple Hiickel molecular orbital calculations to determine the relative sensitivity of aromatic carbon atoms to oxidation and the relative stability of keto and enol tautomers. Klopman et al. (1999) have reported that for polycyclic aromatic hydrocarbons, adequate reactivity is an essential but not sufficient condition for enzyme catalyzed reaction. The accessibility of the reactive site (i.e., the absence of steric hindrance) was also found to be important. Genetic algorithms have been used to optimize the performance of the biotransformation dictionary by treating the initial priority scores set by expert assessment as adjustable parameters (Klopman et al., 1997). 

Tautomerism is used to describe the rapid interconversion of two different isomeric forms (tautomers). In this case the keto and enol tautomers of a ketone. The keto tautomer is by far the dominat species for a ketone and the enol tautomer is generally present in only very small amounts (typically 0.0001 per cent). Therefore,... 

Electron transmission spectroscopy results bB3LYP/D95V+(D) except for G which is estimated from trends CDFT (B3LYP/6-311+G(2df,p)) destimated from stable valence anion complexes, e.g.., U(Ar)- ebest estimates from DFT basis set dependence study (vide infra). Thymine from ref. [88], note these values are likely too positive by 0.15 eV fEstimate of keto tautomer from enol tautomer experimental value (—0.46eV) plus calculated difference in energy between keto and enol tautomers (0.28 eV) ref. [94],... 

The proton chemical environments are quite different for the keto and enol tautomers, and the interconversion rate constants ki and k i between these forms are small enough... 

The product from Step 1 (2.0 g) was dissolved in 50 ml toluene, triethylamine (8.87 mmol) added, then refluxed 2 hours. Thereafter, the mixture was cooled, diluted with 50 ml toluene, washed once with 100 ml 1M HCl, 3 times with 50 ml water, and concentrated. The residue was purified by flash chromatography using hexane/EtOAc, 10 1, and the product isolated in 30% yield as a mixture of keto and enol tautomers. An orange resin was obtained which, according to NMR, contained approximately 30% (E)-5-[3-(4-fluorophenyl)-l-isopropyl-lH-indol-2-yl]-3-oxopent-4-enoic acid methyl ester. 

Recall from Chapter 11 that the keto and enol tautomers of a carbonyl compound are in equilibrium, but the keto form is lower in energy, so it is highly favored in most cases. 

Cucinotta et studied the equilibrium between the keto and enol tautomers of acetone, cf. Fig. 5, both in vacuum and in an aqueous solution. They used parameter-free, electronic-structure calculations for a periodically repeated supercell (see section IIB) with the Car-Parrinello approach (see, e.g., ref. 1). In static calculations for solely the acetone molecule they found a total-energy difference between the enol and keto forms of 11.8 kcal/mol. The barrier between the two forms was found to be around 58 kcal/mol (Fig. 5). 

Fig. 5 Schematic representation of the keto and enol tautomers of acetone. Open circles, closed circles, and closed triangles mark hydrogen, carbon, and oxygen atoms, respectively. 

Compare the energies of 2-butanone and its enol using Spartan View. Which tautomer is lower in energy, and by how much Repeat the comparison for keto and enol tautomers of 2,4-pentanedione and 2,4-cydohexadienone. Why does the keto-eiiol preference change ... 

Aldehydes and ketones can often exist in two tautomeric forms which differ in the position of an (x-hydrogen atom. The keto and enol tautomers are in dynamic equilibrium with each other. For acetone (propanone), which only contains about 10 % of the enol, the structures are ... 

Whereas keto and enol tautomers can be isolated only in the crystalline form and when in solution or melted pass rapidly one into the other, 2-hydroxy-1-phenyl-1-propanone CH3CH(OH)COC6H5 and l-hydroxy-l-phenyl-2-pro-panone CH3COCH(OH)C6H5 have not merely been isolated in pure form but also their different chemical properties have been demonstrated. Their interconversion is catalysed by alkali. 

A ketone and an enol differ only in the location of a double bond and a hydrogen. Such isomers are called tautomers ( taw-toe-mers ). The ketone and enol are called keto-enol tautomers. Interconversion of the tautomers is called tautomerization. We will examine the mechanism of this reaction in Chapter 19. For now, the important thing to remember is that the keto and enol tautomers come to equilibrium in solution, and the keto tautomer, because it is usually much more stable than the enol tautomer, predominates at equilibrium. 

Now that we know that a hydrogen on a carbon adjacent to a carbonyl carbon is somewhat acidic, we can understand why keto and enol tautomers interconvert as we first saw in Chapter 6. Keto-enol interconversion is also called keto-enol tautomer-ization or enolization. The interconversion of the tautomers can be catalyzed by either acids or bases. 

Z = Pr 0 or Et2N = Et2N or (CH2)n, n = 4-6) the latter exist as mixtures of keto and enol tautomers, the latter as ( ) plus (Z) mixtures. Also, carbanions from non-functionalized alkylphosphonic esters react with the reagent (178) to give (179) which may be hydrolysed to the (2,3-dioxoalkyl)phos-phonates (180). ... 

Since the preparation of acetylacetone and similar /J-dicarbonyl compounds in the latter half of the nineteenth century, organic chemists have had considerable interest in their properties and reactions. The best known phenomenon of -dicarbonyls is their participation in tautomeric equilibria where an apparently pure compound is actually a mixture of two substances having keto and enol structures. Early studies with / -dicarbonyls revealed that these compounds exhibited chemical properties indicative of both the dicarbonyl and unsaturated hydroxy ketone structures. In an unsuccessful attempt to explain this anomalous behavior Laar (7) in 1885 coined the word tautomerism" which has survived to the present. By the turn of the century it was generally held that the dichotomous properties of -dicarbonyls resulted from the pure compound existing as a mixture of both keto and enol tautomers. Since... 

Reaction of levoglucosenone with amides of a-nitrocarboxylic acids resulted in the formation of the tetrahydropyridones 77 and with acetoacetic acid amides, mixtures of the keto and enol tautomers were obtained [137]. 

When the 1,3-indanedione 1-phenylhydrazone (89) was subjected to a double Mannich reaction using benzylamine or methylamine and formaldehyde in the presence of a small amount of acetic acid, it afforded (60-65% yield) the indano-1,2,4-triazepines (90) (Scheme 14) <90ZN(B)80>. The NMR spectra indicate that (90) existed in solution as mixtures of keto and enol tautomers. Similarly,... 

Fig. 2.7 shows the calculated free energy differences between the keto and enol tautomers along with the available experimental values. In H2O the free energy of the keto form was calculated to be lower than that of the enol by —1.37 kcal/mol, which is in good agreement with the experiment, —1.18 kcal/mol. For DMSO solution the stability of the two tautomers became comparable to each other, 0.14 kcal/mol, as in the experiment. The free energies were also very close in CCI4, which is... 

Similar results have been obtained by Pearson and Anderson for the formation of mono(acetylacetonato)copper(ii) in water and methanol. Both the keto and enol tautomers of acac react with Cu + at rates which are much less than expected for normal substitution. The second-order rate constant for the reaction of the enol form is the same in water and methanol (2 x 10 lmol s" ), as expected for a mechanism in which the rate-determining step is the sterically difficult closure of the six-membered ring. For the reaction between the Cu" ion and the keto form of acac, the slow step is thought to be the metal-ion-catalysed proton transfer from the weakly-bound keto tautomer. This suggestion is supported by the increase in rate constant of two orders of magnitude on changing from water (121 mol s ) to methanol (13001 mol s ) and the results of deuterium isotope substitution studies. 

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