Equilibrium constants of enolization

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). 

Rate constants for the reverse tautomerization reaction can be measured by thermal halogenation of ketones or isotope exchange reactions. Combination of the rate constants of ketonization, A , and enolization, kK, provides accurate equilibrium constants of enolization, K k> /kK. The acidity constants of ketones, K, and of the corresponding enols, Kf, are related to the enolization constant Kti by a thermodynamic cycle, pl E = pKf—pK (Scheme 5.21). 

The concentration of the enolic form can be estimated from the area enclosed below the kinetic curve in Fig. 5 and then the equilibrium constant of enolization could be measured ... 

The amount of enol present at equilibrium the enol content is quite small for sim pie aldehydes and ketones The equilibrium constants for enolization as shown by the following examples are much less than 1... 

Other compounds with reactive methylene and methyl groups are completely analogous to the nitroalkanes. Compounds with ketonic carbonyl groups are the most important. Their simplest representatives, formaldehyde and acetone, were considered for many decades to be unreactive with diazonium ions until Allan and Podstata (1960) demonstrated that acetone does react. Its reactivity is much lower, however, than that of 2-nitropropane, as seen from the extremely low enolization equilibrium constant of acetone ( E = 0.9 x 10-7, Guthrie and Cullimore, 1979 Guthrie, 1979) and its low CH acidity (pK = 19.1 0.5, Guthrie et al., 1982). ... 

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. 

Thus the approach to equilibrium always follows a first-order rate law, Equation (14), with the pH-dependent rate constant kobs = kE + kK. Figure 1 shows the concentration changes in time starting from a 1m solution of pure enol (full line) and of pure ketone (dashed line). The individual, unidirectional rate constants kE and kK can be determined as follows For most ketones the equilibrium enol concentration is quite small, i.e., tE = cE(oo)/ ck(oo)<<1. Hence kE kK [Equation (1)], so that enol ketonization is practically irreversible and kE may be neglected, kobskK. The rate constant of enolization kE, on the other hand, is equal to the observed rate constant of reactions for which enolization is rate-determining, such as ketone bromination (Scheme 2). 

Finally, concordant results have been obtained from a kinetic study of the iodination of acetophenone and acetone at very low iodine concentration (Verny-Doussin, 1979). The procedure used is similar to that followed for the determination of equilibrium constants for enol formation by the kinetic-halogenation method, i.e. second-order rate constants were measured under conditions such that halogen additions to enol and enolate are rate-limiting (43). Under these conditions, the experimental kn-values can be expressed by... 

Recently, the present author (Toullec and Verny-Doussin, 1980) obtained a concordant value for the equilibrium constant of (65 L = H) for [83, n — 3] from kinetic data on amine-catalysed iodination of acetone at low iodine concentrations. The principle of this determination is similar to that described for estimation of the keto-enol equilibrium constants by the kinetic halogenation method (see p. 48). At low iodine concentrations ( 10-6 mol dm-3), the enamine pathway is preferred [see (61)] and iodination of the enamine is rate-limiting. Rate measurements, in a pH range in which only the monoprotonated and diprotonated forms of the diamine exist, made it possible to determine the second-order rate constants k u which include the equilibrium constants, for interconversion of the ketone and protonated enamine... 

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 ... 

The first attempt to introduce an empirical relationship between an equilibrium constant and solvent polarity was made in 1914 by K. H. Meyer [24]. Studying the solvent-dependent keto-enol tautomerism of 1,3-dicarbonyl compounds, he found a proportionality between the equilibrium constants of various tautomeric compounds in the same set of different solvents cf. Table 4-2 in Section 4.3.1). He therefore split the tautomeric equilibrium constant Ky into two independent factors according to Eq. (7-9). 

E is the so-called enol constant and measures the enolization capability of the diketo form ( = 1 for ethyl acetoacetate by definition). Thus, the so-called desmotropic constant L is a measure of the enoHzation power of the solvent. By definition, the values of L are equal to the equilibrium constants of ethyl acetoacetate E = 1), determined in different solvents [24]. This desmotropic constant seems to be the first empirical solvent parameter. It describes the relative solvation power of a solvent for diketo and enol forms of 1,3-dicarbonyl compounds. It was measured only for a few solvents and was soon forgotten. 

The carbonyl (pX a ) and enol (p/sTa ) acidity and associated equilibrium constant of a variety of structurally related carbonyl-containing compounds are given in Table 3. 

Let us remember that the energy difference between phenol 26 and both keto isomers 27 and 28 amount to 73 and 69kJmoH, respectively (Figure 31). The contribution of entropy is small, amounting to AS = —9 and —1 Jmol K , for both ketonization reactions, respectively, and this also leads to an estimate for the equilibrium constant of the enolization, ranging from —12 to —13, of the same order of magnitude as... 

One of the most important applications of the quantum theory of molecules in condensed media is the prediction of their chemical reactivity. It is often necessary to predict the rate or equilibrium constant of a chemical reaction in different organic and inorganic media. However, in most cases the theoretical calculations have been limited to the aqueous solutions. Therefore, it would be important to study the applicability of the solvation theories in different dielectric media. An appropriate reaction for such study is the tautomeric equilibrium between acetylacetone (1) and its enol form (2)... 

The rate-determining step always corresponds to protonation or deprotonation of a carbon atom, while equilibration of oxygen acids with their conjugate bases is established rapidly. This fact can be used to determine the acidity constants of enols, ynols and ynamines by flash photolysis, Kf, either kinetically, from downward bends in the pH rate profiles indicating a pre-equilibrium, or from the changes of the transient absorption in solutions of different pH (spectrographic titration). Such studies have provided some remarkable benchmark numbers, such as the acidity constant of phenylynol (pKf < 2.1),476 phenylynamine (pKf < 18.0)477 and its pentafluoro derivative (pKf = 10.3),478 and of the carbon acid 2,4-cyclohexadienone, pKf = —2.9 475 The enolization constant of 2,4-cyclohexadienone is pKE = 12.7. 

Table 6.12. Equilibrium Constants for Enolization of Some Carbonyl Compounds...

Enamines are the nitrogen analogues of enols but their formation from imines is thermodynamically more favourable than enol formation from ketones (Table 1). The equilibrium constant for enol formation is ca. 10 compared with a value of 10 for enamine formation. However, at pH 7 half of the imine exists as the iminium ion and the proportion of enamine present is 10 -fold greater than the proportion of enolate anion. In general, this implies that loss of an electrophile from... 

Equilibrium constants for enolization, 706, 727 for hydration of aldehydes and ketones, 663 table... 

In the acetone enolization reaction the rate-determining step is the first one, namely the transfer of the proton from the acid to the acetone. By a principle which has already been discussed (p. 365) the rate-constant k for the reaction in presence of an acid HA, shows a parallelism with the equilibrium constant of the reaction... 

Carboxylic acids and esters contain far less enol than aldehydes and ketones. So little enol is present that it is difficult to measure, and the 10 values for the enolization equilibrium constants of acetic acid and methyl acetate given in Table 20.2 are only approximate. The main reason for the decreased tendency of carboxylic acids and esters to enolize appears to be the stabilization of the carbonyl group of the keto form by electron release from the alkoxy oxygen. 

Equilibrium constants for enolization of some carbonyl compounds... 

The results from the calculation of the equilibrium constants of keto-enol tautomerism for some aliphatic ketones in CCl are given in Table 7. The data for acetylacetone and 2-naphthylmethylketone are not presented in the table because in the former case the rate of reaching the equilibrium is commensurable with the rate of ozone consumption and in the latter case the ozone reacts with the double bonds in the naphthyl ring. The equilibrium constants do not differ from those found within the temperature range of 21°C to 3°C and agrees with data from the literature [59-62],... 

TABLE 7 Equilibrium constants of keto-enol tautomerism of some ketones in CCl solution at 21°C determined by titration with ozone. 

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