Keto-enol equilibrium constants

To indicate the importance of enolization, equilibrium constants for a number of substrates are shown in Table 10.1. These equilibrium constants are only approximate, and they do depend very much on the solvents employed. Nevertheless, we can see that the equilibrium constant K = [enol]/[keto] is very small for substrates like acetaldehyde, acetone, and cyclohexanone, with only a few molecules in every million existing in the enol form. However, in ethyl acetoac-etate, enol concentrations are measured in percentages, and in acetylacetone the equilibrium constant indicates the enol form can be distinctly favoured over the normal keto form. In hexane solution, only 8% of acetylacetone molecules remain in the keto form. 

The enol tautomers of many ketones and aldehydes, carboxylic acids, esters and amides, ketenes, as well as the keto tautomers of phenols have since all been generated by flash photolysis to determine the pH rate profiles for keto-enol interconversion. Equilibrium constants of enolization, KB, were determined accurately as the ratio of the rate constants of enolization, kE, and of ketonization, kK, Equation (1). 

It is of great interest to compare this last value with the keto-enol equilibrium constant obtained similarly for acetone = 0.35 x 10-8). Indeed, in many enzyme-catalysed reactions, aldolisation for example, enamine formation is not rate-limiting, and the rate is usually controlled by subsequent electrophilic additions. Consequently, the rate depends on enamine reactivity and on the enamine concentration at equilibrium. Therefore, if one wants to compare the two processes, via enol and via enamine, in order to explain why the enamine route is usually preferred, the difference in equilibrium constants for enol and enamine formation must be taken into account. Data on ketone to enol and ketone to enamine equilibrium constants show that the enamine and enol concentrations are of similar magnitude even for relatively small concentrations of primary amine. Thereafter, since the enamine is much more reactive than the enol for reactions with electrophilic reagents (in a ratio of 4-6 powers of ten for proton addition), it can be easily understood why the amine-catalysed pathway is energetically more favourable. 

The composition of a /3-dicarbonyl system is usually expressed as the molar percentage of the enol tautomer at equilibrium, rather than as the equilibrium constant K ([enol]/ [keto]). The amount of enol is influenced by a variety of factors ... 

Keto-enol equilibrium constants Keh = [enol form]/[keto form] were obtained from spectral data and from ratios of two polarographic waves of oxalacetic acid and its esters in acidic media (Table 3). 

Polar solvents shift the keto enol equilibrium toward the enol form (174b). Thus the NMR spectrum in DMSO of 2-phenyl-A-2-thiazoline-4-one is composed of three main signals +10.7 ppm (enolic proton). 7.7 ppm (aromatic protons), and 6.2 ppm (olefinic proton) associated with the enol form and a small signal associated with less than 10% of the keto form. In acetone, equal amounts of keto and enol forms were found (104). In general, a-methylene protons of keto forms appear at approximately 3.5 to 4.3 ppm as an AB spectra or a singlet (386, 419). A coupling constant, Jab - 15.5 Hz, has been reported for 2-[(S-carboxymethyl)thioimidyl]-A-2-thiazoline-4-one 175 (Scheme 92) (419). This high J b value could be of some help in the discussion on the structure of 178 (p. 423). 

For a review of keto-enol equilibrium constants, see Toullec, J. in Rappoport, Ref. 314, p. 

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... 

Spectral evidence" indicates an equilibrium between tetrahedral and octahedral Co" in iViV-dimethylacetamide and the equilibrium constant for [Co (tet)]/[Co (oct)] is reported at various temperatures. The complexes of acetylhydrazine (A), [CoA3]X2 (X = Cl or Br) and [Co(NCS)2A2]H20 and the tri-N-deuterio-analogue[Co(NCS)2(Ad3)2]D20 have been isolated and examined by i.r. Cationic complexes of JV-acyl hydrazines have been isolated with ligands in their keto-form, RCO-NH-NH2 however, the ligands also react in their enol form, RC(OH) = NNH2, forming neutral complexes (R = Me, Pr", Pr , or Ph). ... 

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). 

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... 

Table 8.6 Approximate Values of Keto-Enol Equilibrium Constants...

Keto-enol equilibrium constants for simple /i-dicarbonyl compounds, RCOCH2COX (R = X = Me R = Me, Ph for X = OEt) have been measured in water1423 by a micelle perturbation method previously reported for benzoylacetone142b (R = Ph, X = Me). The results have been combined with kinetic data for nitrosation by NO+, C1NO, BrNO, and SCNNO in all cases, reaction with the enol was found to be rate limiting. 

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 review starts with a discussion of the mechanism of keto-enol tautomerisation and with kinetic data. Included in this section are results on stereochemical aspects of enolisation (or enolate formation) and on regioselec-tivity when two enolisation sites are in competition. The next section is devoted to thermodynamic data (keto-enol equilibrium constants and acidity constants of the two tautomeric forms) which have greatly improved in quality over the last decade. The last two sections concern two processes closely related to enolisation, namely the formation of enol ethers in alcohols and that of enamines in the presence of primary and secondary amines. Indeed, over the last fifteen years, data have shown that enol-ether formation and enamine formation are two competitive and often more favourable routes for reactions which usually occur via enol or enolate. 

Standard enthalpies and entropies for the ketone to enol equilibrium have been determined from data obtained by the kinetic halogenation method (see Section 3) at 5, 15, 25 and 35°C. Since the keto-enol equilibrium constants depend on the absolute rate constant arbitrarily chosen for the diffusion-controlled halogen addition to the enol, only the differences in from one ketone to another must be considered... 

Recent data on the acidity constants of the conjugate acids of acetophenones (R. A. Cox et al., 1979 Azzaro et al., 1979) and on keto-enol equilibrium constants (Toullec and Dubois, 1976c Dubois et al., 1981) made it possible to calculate (z) the rate constants for the proton removal step k HiQ in (32)] and (it) the CH acidity constant (K H) of the hydroxycarbenium ion... 

In contrast to kinetic data, thermodynamic data on enol and enolate formation are far more scarce. This results from the usually very low enol and enolate stabilities which, at equilibrium, make it difficult to measure their proportions relative to the carbonyl compound. This section deals with available data on keto-enol equilibria as well as on acidity constants of the two tautomers. 

Comparison of keto-enol equilibrium constants obtained by various methods... 

Acidity constants (p-Kjjj) of cyclopentanone and cyclohexanone enols have been determined by the halogen-titration method from the variations of the enol + enolate sum as a function of pH (Bell and Smith, 1966). However, since the values of the keto-enol equilibrium constants are questionable, these pflra-values (11.8 and 11.3, respectively) are doubtful as well, although they are in fair agreement with those expected. 

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