Enols, equilibrium with ketones

For simple carbonyl compounds, the equilibrium between an aldehyde or a ketone and its corresponding enol is usually so shifted towards the keto form that the amount of enol at equilibrium can neither be measured nor detected by spectroscopy. Nevertheless, as recently emphasised by Hart (1979), this does not mean that the enol cannot exist free, not in equilibrium with ketones and aldehydes. Several examples of kinetically stable enols in the gas phase or in aprotic solvents have been reported. Broadly speaking, it appears that enols have relatively large life-times when they are prepared in proton-free media [e.g. the half-life of acetone enol was reported to be 14 s in acetonitrile (Laroff and Fischer, 1973 Blank et al., 1975) and 200 s in the gas phase (MacMillan et al., 1964)]. These life-times are related to an enhanced intramolecular rearrangement, indicated by the very high energies of activation (85 kcal mol-1 for acetaldehyde-vinyl alcohol tautomerization) which have been calculated (Bouma et al., 1977 Klopman and Andreozzi, 1979) It has therefore been possible to determine most of the spectroscopic properties of simple enols [ H nmr,l3C nmr (CIDNP technique), IR and microwave spectra of vinyl alcohol... 

The ketone is added to a large excess of a strong base at low temperature, usually LDA in THF at -78 °C. The more acidic and less sterically hindered proton is removed in a kineti-cally controlled reaction. The equilibrium with a thermodynamically more stable enolate (generally the one which is more stabilized by substituents) is only reached very slowly (H.O. House, 1977), and the kinetic enolates may be trapped and isolated as silyl enol ethers (J.K. Rasmussen, 1977 H.O. House, 1969). If, on the other hand, a weak acid is added to the solution, e.g. an excess of the non-ionized ketone or a non-nucleophilic alcohol such as cert-butanol, then the tautomeric enolate is preferentially formed (stabilized mostly by hyperconjugation effects). The rate of approach to equilibrium is particularly slow with lithium as the counterion and much faster with potassium or sodium. 

In the preceding chapter you learned that nucleophilic addition to the carbonyl group IS one of the fundamental reaction types of organic chemistry In addition to its own reactivity a carbonyl group can affect the chemical properties of aldehydes and ketones m other ways Aldehydes and ketones having at least one hydrogen on a carbon next to the carbonyl are m equilibrium with their enol isomers... 

Enolization (Sections 18 4 through 18 6) Aldehydes and ke tones having at least one a hydro gen exist in equilibrium with their enol forms The rate at which equilibrium is achieved is in creased by acidic or basic cata lysts The enol content of simple aldehydes and ketones is quite small p diketones however are extensively enolized... 

Enols are in equilibrium with an isomeric aldehyde or ke tone but are normally much less stable than aldehydes and ketones... 

Aldehydes and ketones ( keto forms) normally exist in equilibrium with their enol tautomers. 

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... 

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). ... 

The equilibrium ratios of enolates for several ketone-enolate systems are also shown in Scheme 1.1. Equilibrium among the various enolates of a ketone can be established by the presence of an excess of ketone, which permits reversible proton transfer. Equilibration is also favored by the presence of dissociating additives such as HMPA. The composition of the equilibrium enolate mixture is usually more closely balanced than for kinetically controlled conditions. In general, the more highly substituted enolate is the preferred isomer, but if the alkyl groups are sufficiently branched as to interfere with solvation, there can be exceptions. This factor, along with CH3/CH3 steric repulsion, presumably accounts for the stability of the less-substituted enolate from 3-methyl-2-butanone (Entry 3). 

Still another possibility in the base-catalyzed reactions of carbonyl compounds is alkylation or similar reaction at the oxygen atom. This is the predominant reaction of phenoxide ion, of course, but for enolates with less resonance stabilization it is exceptional and requires special conditions. Even phenolates react at carbon when the reagent is carbon dioxide, but this may be due merely to the instability of the alternative carbonic half ester. The association of enolate ions with a proton is evidently not very different from the association with metallic cations. Although the equilibrium mixture is about 92 % ketone, the sodium derivative of acetoacetic ester reacts with acetic acid in cold petroleum ether to give the enol. The Perkin ring closure reaction, which depends on C-alkylation, gives the alternative O-alkylation only when it is applied to the synthesis of a four membered ring ... 

Tautomerization doesn t occur without an a-hydrogen. Most ketones do contain one or more a-hydrogen atoms, so they undergo tautomerization. These ketones exist in equilibrium with the enol form. In most cases, the ketone form predominates at equilibrium, but in a few cases the enol is particularly stable and it predominates. 

Griffiths and Gutsche (23) recently studied the interconversion of deuterated mandelaldehyde dimer and 2-hydroxyacetophenone in pyridine to obtain information concerning the glyceraldehyde-dihydroxy-acetone rearrangement. Their results support an enolization mechanism requiring a base and an acid catalyst. They found a deuterium isotope effect of ca. 1.3 for the transformation of the aldehyde to the ketone. When they corrected this for the apparently differing amounts of the aldehyde form in equilibrium with the proteo dimer and the deuterio dimer, they obtained a value of 3.9. By the Swain-Schaad equation (26) ... 

In fact, enolate anions add a proton at oxygen at least 1010 times faster than at carbon the proton also is removed from oxygen much faster than from carbon. Thus the enolate anion of 2-propanone is in rapid equilibrium with the enol, but is converted back and forth to the ketone only slowly (Equation 17-1). 

It is now common experimental practice to react ketones with lithium diisopropyl amide (LDA) in order to generate the enolate of the ketone. This methodology has largely replaced the older approach to enolates, which employed alkoxide bases to remove a proton alpha to the carbonyl group. Comparison of the equilibrium constants for these two acid-base reactions reveals why the LDA method is preferable. The use of the amide base leads to essentially complete conversion of die ketone to its enolate (Keq 1016). At equilibrium, there is virtually no... 

Rates of acid-catalysed enolization of isobutyrophenone and its ot-d analogue have been measured in H2O and D2O, by bromine scavenging.1403 Results include a solvent isotope effect, ku /kDi, of 0.56, and a substrate isotope effect, h/ d, of 6.2 (both for the enolization reaction). Combination of the data with that for ketonization in D2O140b gives the first isotope effect for the keto-enol equilibrium of a simple ketone e(H20)/ e(D20) = 0.92. The results are discussed in terms of the isotopic fiuctionation factors and the medium effect. 

A study of acid-catalysed enolization and carbon-acid ionization of isobutyrophenone has combined the solvent isotope effect k /kv = 0.56 and substrate isotope effect kH/kD = 6.2 determined for the enolization in H2O and D2O with literature information in order to estimate the solvent isotope effect on the enolization equilibrium, A e(H20)/A e(D20) = 0.92, and on the CH ionization of butyrophenone, kf (R20)/kK(D20) = 5.4.130 This is the first report of an isotope effect on AY forketo-enol equilibrium of a simple aldehyde or ketone. 

Hydronium ion catalytic coefficients for enolization and ketonization of simple aldehydes and ketones correlate with the enolization equilibrium constants pAE.48 The slopes of the two correlations are of opposite sign (-0.17 and 0.83, respectively), ketonization being considerably more sensitive to a change in the driving force. 

Ethers of the 1,2-benzisothiazole 1,1-dioxides (35 R = Et, Me3Si) have been shown to form 1,2-benzothiazepines 12 (R = Et, Mc Si) when treated with 1-diethylamino-l-propyne 37 <1996T3339>. These ethers 12 may be hydrolyzed to the ketone 13 (see also Section 13.07.2.1), which in the solid state is in equilibrium with the enol 12 (R = H) on the basis of infrared (IR) evidence (Scheme 3). In solution (CDCI3), only the keto form 13 was detectable by H nuclear magnetic resonance (NMR). 

Tributyltin enolates are useful radical mediators [47], although they generally exist in equilibrium with a-tributyltin ketones [48], Three-component coupling reactions proceed readily to give functionalized ketones in good to excellent yields, where an equilibrium shift to provide tin enolates operates efficiently (Scheme 6.28) [49]. Unlike the aforementioned case of allyltin-mediated reactions, acrolein is difficult to use in this reaction, since the Aldol reaction of the tin enolate with acrolein precedes the radical reaction. 

The concentration of the ketone enolate is higher than that of the aldehyde enolate. This is true under thermodynamic control as the stability of an enolate increases with its degree of substitution. It is also true under kinetic control since enolization is an acid-base equilibrium, the increased enolate concentration reflects the higher acidity of the ketone protons. 

Ketones that have hydrogen atoms on their a-carbon (the carbon next to the carbonyl group) are in rapid equilibrium with an isomeric structure known as an enol in which the a-hydrogen ends up on the oxygen instead of the carbon. The two isomeric forms are known as tautomers and the process of equilibrium is known as tautomerism (Following fig.). Generally the equilibrium favours the keto tautomer and the enol tautomer may only be present in very small quantities. 

Oxalic esters (for electronic reasons) and formic esters (because of their low steric hindrance) are reactive esters that can acylate ketone enolates formed with NaOR in equilibrium reactions. Formic esters acylate ketones to provide formyl ketones (for example, see Figure 13.61). It should be noted that under the reaction conditions the conjugate base of the active-methylene formyl ketone is formed. The neutral formyl ketone is regenerated upon acidic workup. 

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