Enol acidity constants

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. 

An accurate value of the acidity constant of acetophenone enol (10.34 0.05) has recently been reported by Haspra et al. (1979) who used a straightforward method which consists in producing enol [66] by Norrish type 

II cleavage (flash photolysis) of butyrophenone [65] in weakly basic solution (41). The UV spectrum is typical of the enolate ion [67] and the UV 

Here is the enolate molar absorptivity at 310 nm and a is the overall enol + enolate concentration. 

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 

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Fig. 4 Determination of acetophenone enol acidity constant by flash spectroscopy. Enolate absorption (310 nm) as a function of pH (Haspra et al., 1979). (Reprinted by courtesy of Angewandte Chemie, Verlag Chemie, GmbH, Weinheim, Germany)...

From all this recent work, it appears that the problem of enol acidity constants is going to be solved, even though data are at present scarce. In particular, the method suggested by Haspra et al. (1979) is certainly very powerful. 

Some typical ketone to enolate acidity constants (water 25°C)... 

A study of the thermodynamics and pH-dependent kinetics of keto-enol/enolate interconversion of A-methylindoline-2-one and its 2-thione and 2-selone analogues in aqueous solution has allowed the estimation of the respective values for the carbon acid ionization constant (Qf), enol acidity constant (Qf) and keto-enol equilibrium constant (A e)- ... 

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). ... 

In 1978, we observed that flash photolysis of butyrophenone produced acetophenone enol as a transient intermediate, which allowed us to determine the acidity constant KE of the enol from the pH-rate profile (section pH Rate Profiles ) of its decay in aqueous base.4 That work was a sideline of studies aimed at the characterization of biradical intermediates in Norrish Type II reactions and we had no intentions to pursue it any further. Enter Jerry Kresge, who had previously determined the ketonization kinetics of several enols using fast thermal methods for their generation. He immediately realized the potential of the photochemical approach to study keto enol equilibria and quickly convinced us that this technique should be further exploited. We were more than happy to follow suit and to cooperate with this distinguished, inspiring, and enthusing chemist and his cherished wife Yvonne Chiang, who sadly passed away in 2008. Over the years, this collaboration developed into an intimate friendship of our families. This chapter is an account of what has been achieved. Several reviews in this area appeared in the years up to 1998.5 10... 

The pH-rate profiles of the enol of l-indene-3-carboxylic acid and of its ketene precursor, formed from either l-diazo-2( 1 //jnaphthalenone or 2-diazo-l(2//)naphthalenone by photochemical deazotization and Wolff rearrangement, are shown in Fig. 5.36 The first and second acidity constants of the diol, p = 1.9 and p aE = 8.3, are evident from the downward curvature of log (k /s-1) at these pH values. The photo-Wolff rearrangement of diazonaphthoquinones is the active principle of Novolak photoresists. 

The acidity constants of protonated ketones, pA %, are needed to determine the free energy of reaction associated with the rate constants ArG° = 2.3RT(pKe + pK ). Most ketones are very weak bases, pAT < 0, so that the acidity constant K b cannot be determined from the pi I rate profile in the range 1 < PH <13 (see Equation (11) and Fig. 3). The acidity constants of a few simple ketones were determined in highly concentrated acid solutions.19 Also, carbon protonation of the enols of carboxylates listed in Table 1 (entries cyclopentadienyl 1-carboxylate to phenylcyanoacetate) give the neutral carboxylic acids, the carbon acidities of which are known and are listed in the column headed pA . As can be seen from Fig. 10, the observed rate constants k, k for carbon protonation of these enols (8 data points marked by the symbol in Fig. 10) accurately follow the overall relationship that is defined mostly by the data points for k, and k f. We can thus reverse the process by assuming that the Marcus relationship determined above holds for the protonation of enols and use the experimental rate constants to estimate the acidity constants A e of ketones via the fitted Marcus relation, Equation (19). This procedure indicates, for example, that protonated 2,4-cyclohexadienone is less acidic than simple oxygen-protonated ketones, pA = —1.3. 

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. 

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. 

Most of these methods are unable to distinguish between enol and another fast-reacting species and, as stressed by Dubois and Barbier, results are highly dependent on the purity of the carbonyl compound. Another procedure which apparently does not suffer the same drawback was more recently suggested by Bell and Smith and was applied to cyclopentanone and cyclohexanone (Bell and Smith, 1966) and to acetophenone (Novak and Loudon, 1977) ketone solutions were pretreated with bromine and the enol content was measured by potentiometry after allowing the enol to form. This method was also used for determining the acidity constants of ends. 

When they are sufficiently low, the pAa (pA p values of carbonyl compounds (corresponding to enolate formation) in water can be obtained directly from pH measurements of partly neutralised compounds or by spectroscopic determination of the ratio of the ionised and unionised forms in weakly basic media. Indeed, most of the acidity constants of di- or tri-carbonyl compounds have been determined by these methods. However, such direct determinations are not valid for monocarbonyl compounds for which the pA values are known to be usually higher than that of water. For these very weak acids the competitive and acidity function approaches have been used, although both have serious limitations. 

The enol is less stable than the aldehyde and both lose a proton to give the same enolate ion. It follows that the enol is the more acidic. Make sure you understand this. Think of it this way the keto/enol equilibrium constant is small. 

A. Bagno, V. Lucchini and G. Scorrano, unpublished results cited in A. Bagno, G. Scorrano and R. A. More O Ferrall, Rev. Chem. Intermed., 7, 313 (1987). These authors list p H+ (acidity constants of carbonyl-oxygen-protonated conjugate acids) values for acetone, acetophenone, pinacolone and methyl benzoate. For the first three, the values were combined with keto-enol equilibrium constants to give the pK values shown in the Table. 

Because the system exists essentially completely as the thiol isomer, a carbon-acid acidity constant for ionization starting with the thio-keto form as the initial state, QJ, could not be measured, and a keto-enol equilibrium constant, ATe, could not be determined. A lower limit for can nevertheless be estimated on the assumption that 5% of the keto isomer would have produced a detectable signal in the H NMR spectrum of the enol form. Because no such signal was seen, must be greater than 20, which makes pK less than —1.3. The relationship = KeQJ then leads to > 1.1 x 10 M, pQ <2.1. 

The enantioselective total synthesis of 1 commences with the formation of the enamine of morpholine and cyclohexane-1,2-dione (6), which actually exists almost entirely in the enolic form. Constant removal of water shifts the equilibrium to the side of the product. 2-Siloxyaniline 7, " which can be easily prepared from 2-aminophe-nol, reacts with the morpholine enamine in an acid-catalyzed transamination to give enamine 8. 

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 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. 

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. 

Keto-enol-enolate rate and equilibrium constants have been reported for N-methylindoline-2-one (90), its 2-thione, and its 2-selone, i.e. a lactam, a thiolactam, and a selenolactam. As an example, the ketone tautomer of the thione has an acidity constant of 8.93, and that of its enoT is 4.05, giving a tautomerization constant, pACe. of 4.88. 

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