Equilibria keto-enol tautomerism

Enols are related to an aldehyde or a ketone by a proton transfer equilibrium known as keto-enol tautomerism (Tautomensm refers to an mterconversion between two struc tures that differ by the placement of an atom or a group)... 

Many nitrogen-containing compounds engage in a proton-transfer equilibrium that is analogous to keto-enol tautomerism ... 

Interestingly, the product actually isolated from alkyne hydration is not the vinylic alcohol, or enol (ene + ol), but is instead a ketone. Although the enol is an intermediate in the reaction, it immediately rearranges to a ketone by a process called keto-enol tautomerisni. The individual keto and enol forms are said to be tautomers, a word used to describe constitutional isomers that interconvert rapidly. With few exceptions, the keto-enol tautomeric equilibrium lies on the side of the ketone enols are almost never isolated. We ll look more closely... 

Carbonyl compounds are in a rapid equilibrium with called keto-enol tautomerism. Although enol tautomers to only a small extent at equilibrium and can t usually be they nevertheless contain a highly nucleophilic double electrophiles. For example, aldehydes and ketones are at the a position by reaction with Cl2, Br2, or I2 in Alpha bromination of carboxylic acids can be similarly... 

Like reaction rates, the effect of solvent polarity on equilibria may be rationalized by consideration of the relative polarities of the species on each side of the equilibrium. A polar solvent will therefore favour polar species. A good example is the keto-enol tautomerization of ethyl acetoacetate, in which the 1,3-dicarbonyl, or keto, form is more polar than the enol form, which is stabilized by an intramolecular H-bond. The equilibrium is shown in Scheme 1.3. In cyclohexane, the enol form is slightly more abundant. Increasing the polarity of the solvent moves the equilibrium towards the keto form [28], In this example, H-bonding solvents will compete with the intramolecular H-bond, destabilizing the enol form of the compound. 

Enolization and ketonization kinetics and equilibrium constants have been reported for phenylacetylpyridines (85a), and their enol tautomers (85b), together with estimates of the stability of a third type of tautomer, the zwitterion (85c). The latter provides a nitrogen protonation route for the keto-enol tautomerization. The two alternative acid-catalysed routes for enolization, i.e. O- versus Af-protonation, are assessed in terms of pK differences, and of equilibrium proton-activating factors which measure the C-H acidifying effects of the binding of a proton catalyst at oxygen or at nitrogen. 

A mechanistic study of acetophenone keto-enol tautomerism has been reported, and intramolecular and external factors determining the enol-enol equilibria in the cw-enol forms of 1,3-dicarbonyl compounds have been analysed. The effects of substituents, solvents, concentration, and temperature on the tautomerization of ethyl 3-oxobutyrate and its 2-alkyl derivatives have been studied, and the keto-enol tautomerism of mono-substituted phenylpyruvic acids has been investigated. Equilibrium constants have been measured for the keto-enol tautomers of 2-, 3- and 4-phenylacetylpyridines in aqueous solution. A procedure has been developed for the acylation of phosphoryl- and thiophosphoryl-acetonitriles under phase-transfer catalysis conditions, and the keto-enol tautomerism of the resulting phosphoryl(thiophosphoryl)-substituted acylacetonitriles has been studied. The equilibrium (388) (389) has been catalysed by acid, base and by iron(III). Whereas... 

The difference in conjugation between neutral molecules and their ion-radicals can also be traced for keto-enol tautomerism. As a rule, enols are usually less stable than ketones. Under the equilibrium conditions, enols exist only at a very low concentration. However, the situation becomes different in the corresponding cation-radicals, where gas-phase experiments have shown that enol cation-radicals are usually more stable than their keto tautomers. This is because enol cation-radicals profit from allylic resonance stabilization that is not available to ketones (Bednarek et al. 2001, references therein). 

Keto-enol-tautomerization is not resonance. The ketone and enol forms are different compounds that are in equilibrium. 

An investigation of keto-enol tautomerism for perfluorinated keto-enol systems was undertaken. N-methylpyrrolidone (NMP) catalyzes equilibration of the keto and enol forms, but if used in more than trace amounts, it drives the equilibrium strongly toward enol because of hydrogen bonding to the amide. The enol is much more thermodynamically stable than its ketone, and it was found that in mildly Lewis basic solvents, such as ether, THE, acetonitrile, and NMP, the enohzation equilibrium lies too far right to allow detection of ketone (Correa et al., 1994). 

Structural isomers existing in rapid equilibrium are tautomers and the equilibrium reaction is tautomerism. The above is a keto-enol tautomerism. 

Internal alkynes undergo acid-catalysed addition of water in the same way as alkenes, except that the product is an enol. Enols are unstable, and tautomer-ize readily to the more stable keto form. Thus, enols are always in equilibrium with their keto forms. This is an example of keto-enol tautomerism. 

Equilibrium and rate constants for the keto-enol tautomerization of 3-hydroxy-indoles and -pyrroles are collected in Table 32 (86TL3275). The pyrroles ketonize substantially (103-104 times) faster than their sulfur or oxygen analogues, and faster still than the benzo-fused systems, indole, benzofuran, and benzothiophene. The rate of ketonization of the hydroxy-thiophenes and -benzothiophenes in acetonitrile-water (9 1) is as follows 2-hydroxybenzo[b]thiophene > 2,5-dihydroxythiophene > 2-hydroxythiophene > 3-hydroxybenzo[/ Jthiophene > 3-hydroxythiophene. 3-Hydroxythiophene does not ketonize readily in the above solvent system, but in 1 1 acetonitrile-water, it ketonizes 6.5 times slower than 2-hydroxythiophene (87PAC1577). 

The potential of carbon-13 NMR in the analysis of keto-enol tautomerism has been demonstrated for 2,4-pentanedione (acetylacetone) and dimedone [293]. Quantitative evaluation of equilibrium concentrations is possible by application of the inverse gated decoupling technique illustrated in Fig. 2.23. 

The keto-enol tautomerism rates for oxaloacetate and zinc(II)-oxaloacetate have also been investigated using acetate buffer solutions.339,357 Thus for the equilibrium shown in equation (24) the value of fcf for the reaction oxacketI12 +OAc is 6.6x 10 3 M"1 s l, while for Zn(oxac)keto+ OAc , fcf= 25 M-1 s 1. The rate acceleration at 25 °C is ca. 4 x 103. Metal ion-promoted enolization is considered in detail in Section 61.4.20. 

Covey and Leussing330,357 have studied keto-enol tautomerism rates for oxaloacetate (oxac2-) and zinc(II) oxaloacetate complexes in acetate buffer solutions at 25 °C. Thus for the equilibrium oxacketo2 oxaceno,2- the value of fcf, the rate constant for the forward reaction, for the reaction oxacketo2 + OAc is 6.6 x 10 3 M-1 s 3 while for Zn(oxac)kcto) + OAc, kf is 25 M 1 s 1. The rate... 

The effects of cationic and zwitterionic micelles on the keto-enol tautomerism of 2-phenylacetyl-furan and -thiophene (73, X = O, S) have been studied in aqueous media.285 While the micelles perturb the equilibrium only slightly, the apparent acidity of one or other tautomer is increased, as the micelles have an affinity for the enolate. The systems also show lowered water rates at the minima of their pH-rate profiles, allowing an otherwise undetectable metal ion catalysis to be observed. 

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]. 

Another approach used in the empirical characterization of liquid polarity is the study of the outcome of a chemical reaction. Earle et al. [216] report a preliminary study of the keto-enol tautomerization of pentane-2,4-dione, and create an empirical correlation between the degree of tautomerization and the dielectric constant of molecular liquids. They then predict dielectric constants for a series of ILs based on the observed keto-enol equilibrium the values range from 40 to 50, slightly higher than those of short-chain alcohols. A more detailed study by Angelini et al. [217] considers the tautomerization of a nitroketone complex in a series of five imidazolium-based ILs. The results, parameterized as a linear free energy analysis of the behavior of the equilibrium constant, indicates an overall polarity comparable to that of acetonitrile, consistent with the partitioning and spectroscopic studies referenced above. 

The initial product has a hydroxy group attached to a carbon-carbon double bond. Compounds such as this are called enols (ene + ol) and are very labile—they cannot usually be isolated. Enols such as this spontaneously rearrange to the more stable ketone isomer. The ketone and the enol are termed tautomers. This reaction, which simply involves the movement of a proton and a double bond, is called a keto—enol tautomerization and is usually very fast. In most cases the ketone is much more stable, and the amount of enol present at equilibrium is not detectable by most methods. The mechanism for this tautomerization in acid is shown in Figure 11.6. The mercury-catalyzed hydration of alkynes is a good method for the preparation of ketones, as shown in the following example ... 

These molecules display keto-enol tautomerization as illustrated in Fig. 11. The open-form keto-acid salts and the closed-form butenolides exist in a pH-dependent equilibrium in solution, and at physiological pH both forms exists. In principle, the biological activity could reside in either or both forms. 

Keto-enol tautomerism equilibrium of ethyl acetoacetate at ca. 20°C. 

Enols tend to be unstable and isomerize to the ketone form. As shown next, this isomerization involves the shift of a proton and a double bond. The (boxed) hydroxyl proton is lost, and a proton is regained at the methyl position, while the pi bond shifts from the C = C position to the C=O position. This type of rapid equilibrium is called a tautomerism. The one shown is the keto-enol tautomerism, which is covered in more detail in Chapter 22. The keto form usually predominates. 

The keto-enol tautomerism is the equilibrium between these two tautomers. 

Equilibrium and rate constants for the keto-enol tautomerization of hydroxy heterocycles are summarized in Table 38 <1986TL3275>. The pyrroles ketonize (i.e., 226 — 230) substantially faster (103-104 times) than their sulfur or oxygen analogues, and still faster than the benzo-fused systems (indole, benzofuran, and benzothiophene). 

There is an equilibrium between the keto group (aldehyde or ketone) and the enol group that is known as keto-enol tautomerization. 

For acetone and the majority of cases in which this keto-enol tautomerism is possible, the keto form is far more stable and little if any enol can be detected. However, with j8-diketones and j8-ketoesters, such factors as intramolecular hydrogen bonding and conjugation increase the stability of the enol form and the equilibrium can be shifted significantly to the right. 

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