Tautomeric enol

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. 

Thus it has been possible to show that in the bromination of acetone, a process which has been found to be unimolecular, not the normal keto-form, but the tautomeric enol-form reacts. The enol-form is present, in equilibrium with the keto-form, in amount too small to be measured. As soon as this amount has reacted a further quantity is formed and the process is repeated. That the reaction is unimolecular follows from the fact that it is the rate of rearrangement (I) which is measured, whilst the reaction of the enol with bromine (II) takes place with immeasurable rapidity (Lapworth). 

The Mechanism of the Ethyl Acetoacetate Synthesis—Before the tautomerism of ethyl acetoacetate is discussed we must consider the mechanism of its formation, which for decades has been the subject of lively discussion and was conclusively explained only in recent years (Scheibler). It has been found that even the C=0-group of the simple carboxylic esters, although in other respects inferior in activity to the true carbonyl group, can be enolised by alkali metals. Thus ethyl acetate is converted by potassium into the potassium salt of the tautomeric enol with evolution of hydrogen ... 

An example where this abstraction from the carbonyl compound competes with photocycloaddition was discussed in the previous section (p. 312). In that case, 2-methylbenzophenone underwent intramolecular hydrogen abstraction, yielding the tautomeric enol,46 a process which completely inhibited the photocycloaddition reaction.37... 

NMR spectroscopy has also been a useful probe for the assignment of tautomeric structures. For example, compounds (20) and (21) can exist in the tautomeric enol forms (22) and (23), respectively. 1H NMR spectroscopy favors the keto form (20) over the enol form (22) and the enol form (23) over the amide form (21), in solution (78AHC(22)183). Few compounds with substituents capable of tautomeric existence are known or have been studied in all the series and therefore no specific predictions can be made regarding the predominance of one tautomer versus the other. 

The actual course of the reaction is complex. By the action of acids the sodium may be eliminated from the first product of the reaction and the flee ester obtained. This may exist in the tautomeric enol and keto forms (CH3 COH CH COOC2H5 and CH3 CO CH2 COOC2H5). 

The second type of reaction which is commonly associated with carbonyl compounds involves the generation of a nucleophilic enol or enolate ion. Although the conversion of a ketone to the tautomeric enol does not necessarily involve any other species, the generation of an enolate requires a base (Fig. 3-4). In this latter reaction, the putative nucleophile may act as a general base. 

Know the meaning of keto form, enol form, tautomers, tautomerism, enolate anion, a-hydrogen and a-carbon, aldol condensation, mixed aldol condensation. 

Carbonyl groups are not always present in their usual double-bond form, but also exist as the tautomeric enols or as hydrates upon addition of water, which was demonstrated by means of differently oxidized carbohydrate model compounds by NMR [ 102] (Scheme 6). A recent study revealed a much higher percentage of hydrated aldehyde groups compared to the pure acyclic form for all aldohexoses in water [44]. 

On the other hand, if only catalytic amounts of A1C13 are added, the acetyl group of the acetophenone is brominated. Under these conditions the carhonyl oxygen of a fraction of acetophenone can be complexed. The bulk of the substrate still contains uncomplexed carhonyl oxygen. It allows acetophenone to equilibrate with its tautomeric enol (for details see Figure 12.5). The enol is a better nucleophile than the aromatic ring because it is brominated elec-trophilically without intermediate loss of aromaticity. HBr is the stoichiometric by-product of this substitution. Just like the HC1 that is formed initially, it catalyzes the enolization of unreacted acetophenone and thus keeps the reaction going. 

Keto-Enol Tautomerism Enol Content of Carbonyl and Carboxyl Compounds... 

The bottom line complements Figure 12.1 by adding the >Ky values of representative ketones. The comparison of E G reveals the same substituent effects that are familiar from the analogous aldehydes A-C the enol content is increased by alkyl substituents in the on-position, and even more so by aryl substituents in the a-position. The ketone H in Figure 12.1, the nonexistent isophenol has by far the highest propensity to enolization of all the carbonyl compounds shown. The reason, of course, is that the tautomeric enol, phenol, is favored because of its aromaticity and thus particularly efficient C=C double bond stabilization. 

QT-Fimctionalizat ion of Carbonyl and Carboxyl Compounds via Tautomeric Enols... 

Selenium dioxide is able to a-oxygenate ketones via their enol tautomers. As is demonstrated in Figure 12.10 by the reaction of selenium dioxide with cyclohexanone, the actual electrophilic substitution product C is unstable. The latter contains selenium in the oxidation state +2 that takes the opportunity to transform into selenium in the oxidation state 0, i.e., elemental selenium, by way of the fragmentation reaction indicated. Thereby, the a-C O single bond of the primary product C is transformed into the a-C=0 double bond of the final product B (which, however, is largely present as the tautomeric enol A). 

Tautomeric enol and imino forms of bases occur only rarely, and can lead to mutations. It should be emphasized that in none of the above described mismatch base pairs is there any evidence for the existence of rare tautomeric forms. For the A-C pair, protonation at (adenine)N(l) appears more probable than the imino form (Fig. 20.6). However, conclusive evidence is still lacking because hydrogen atoms cannot be located at the attainable resolution of about 2 A. Moreover, in none of the crystal structures of the nucleosides and nucleotides or of the bases themselves is there any evidence of the enol-imino tautomers (Part II, Chaps. 15, 16, 17). 

Analysis of spectral data showed that products exist in the keto form 264 and not in the tautomeric enol form 265. This is indicated by the presence of a two-proton singlet for the methylene group of the thiophene ring at 3.69-3.92 ppm, and by an absorption band for a conjugated keto group in the IR spectra at 1620-1630cm 7 At the... 

Table 12. Oxidation potentials, Ep, of pora-substituted 2-aryl-propionaldehydes 88 and their tautomeric enols 89 in acetonitrile/DMSO [171] compared with calculated , 2 (89)- The enol content was taken from Ref. [187]...

The contrast between the behaviour of carbon acids and oxygen or nitrogen acids is perhaps most clearly seen for those substances, such as 13-diketones, which can exist in tautomeric enol or keto forms. The inter-relationships between these forms in acidic solution are shown in Fig. 10. Values of the rate coefficients found for the interconversion... 

The second modification is Umpolmg of the carbonyl group via conversion into the corresponding enol ethers or enols and subsequent oxidation to give the radical cations of enol ether and enol, respectively [192]. The oxidation potentials of these substrates are approximately 1 V (relative to the SCE) and thus oxidation is feasible even with moderately active oxidants or via anodic oxidation. Subsequent reactions of the enol radical cations and radical cations of enol ethers can result in a-substitution products (e.g. by running the reaction in the presence of nucleophiles) and re-formation of the carbonyl group (Scheme 47). Thus, the overall process corresponds to a-activation of carbonyl substrates via intermediate tautomeric enols (and sometimes also enolates) [193, 194]. 

Probably the aromatisation is due to the stabilisation of the tautomeric enolic form of 131 in the experimental conditions... 

Phenol undergoes a number of chemical reactions characteristic of alcohols however, it possesses a tautomeric enol structure that is weakly acidic. It will form salts with sodium hydroxide or potassium hydroxide, but not with their carbonates or bicarbonates. 

Although in this discussion the 4-arylazo-2-pyrazolin-5-ones have been written as 5-oxo compounds, it is likely that they exist largely in the tautomeric enol form.262... 

When an ester reacts with a ring-carbon atom in the presence of a Friedel-Crafts catalyst, a cyclic ketone (or its tautomeric enol) is usually formed (p. 378), but in boiling phosphorus oxychloride, the oxygen function may be replaced by a chlorine atom [2634]. A carboxylic acid may react with a suitably placed ring-carbon by heating with either PPA or phosphorus oxychloride [2127] phosphorus pentoxide in xylene is also effective [2347]. When an electron-rich ring such as that of pyrrole is available, heating with acetic anhydride for I h suffices [3913]. 

In reply to the objection that acetaldehyde and pyruvic acid are not so readily fermentable as dextrose, Neuberg suggests that the reaction takes place with one of their tautomeric (enolic) forms. 

---