Enolates stabilisation

Hagemann s ester (15) is ketone (13) with an activating group. It forms one enolate only (16, the anion being stabilised by both carbonyl groups) and it reacts at only one position with alkylating agents. 

Another feature that will serve to stabilise the enol, with respect to the keto, form is the possibility of strong, intramolecular hydrogen bonding, e.g. in MeCOCH2COMe (31) and MeC0CH2C02Et (23) ... 

Apart from any stabilisation effected with respect to the keto form, such intramolecular hydrogen-bonding will lead to a decrease in the polar character of the enol, and to a more compact, folded-up conformation of the molecule, compared with the more extended conformation of the keto form. This has the rather surprising result that where keto... 

Although the tautomeric ratios of the 4 species have not been measured directly, it is known that in aqueous solution the keto-N2H form dominates, while the keto-NlH form is only detectable in non-polar solvents. An analysis of experimental data concluded that in aqueous solution the stability (lowest free energy) is in the order keto-N2H > imino-N2H > enol-NlH > keto-NIH. In the gas phase, calculations predict that the keto-N2H form is the least stable. While solvation is found to favour this species, which is the most polar, this stabilisation is not enough to reverse the order of stability. It is thus clearly predicted that the keto-NIH tautomer is the most stable in... 

For example, the fluorination with [ F]F2 of diazepam, a 1,4-benzodiazepine (Scheme 18), gives the 3-fluoro derivative in up to 60% radiochemical yield [100]. The mechanism proposed is the electrophilic reaction of [ F]F2 with the enol form of the amide (stabilised by conjugation) yielding, after fluorine attachment and reformation of the carbonyl group, the a-fluoroketo derivative. 

The mechanism is illustrated in the simple case of the self-condensation of an aldehyde in the presence of base. Here the nucleophilic, mesomerically stabilised a-carbanion (the enolate ion) formed by the action of base, attacks the electrophilic carbonyl carbon of a second aldehyde molecule to form, after proton exchange with the solvent, the / -hydroxyaldehyde. 

Barbituric acid (83) may be regarded as 2,4,6-trihydroxypyrimidine, but in the crystalline state it exists as the triketo-form (95). In aqueous solution the compound is remarkedly acidic as the result of ionisation of the mono-enolic form (96) with the formation of a resonance stabilised anion (97). 

Figure 5-1. The formation of an enolate from the deprotonation of a ketone. The enolate is stabilised by interaction with the sodium cation.

The stabilisation of an enolate (intermediate or product) is also important in the decarboxylation reaction of /3-ketoacids. The decarboxylation of such compounds is facile, and is the key to the synthetic utility of ethyl acetoacetate and diethyl malonate. The mechanism of decarboxylation involves the formation of an enol (Fig. 5-21), and so is expected to be subject to metal ion control. 

However, if a further donor group is introduced, a chelate may be formed that does not involve the carboxylate group to be lost. In these cases, the decarboxylation is dramatically enhanced in the presence of metal ions. This is exactly the situation which pertains with oxalacetic acid, which undergoes a facile metal-promoted decarboxylation (Fig. 5-23). The rate of decarboxylation of oxalacetic acid is accelerated some ten thousand times in the presence of copper(n) salts. The metal ion is thought to play a variety of roles, including the stabilisation of the enolate that is produced after loss of carbon dioxide. 

The complex is additionally stabilised by co-ordination of the phenoxide, and possibly the carboxylate, to the metal ion, illustrating the utility of chelating ligands in the study of metal-directed reactivity. We saw in the previous section the ways in which a metal ion may perturb keto-enol equilibria in carbonyl derivatives, and similar effects are observed with imines. The metal ion allows facile interconversion of the isomeric imines. The first step of the reaction is thus the tautomerisation of 5.28 to 5.29 (Fig. 5-56). Finally, the metal ion may direct the hydrolysis of the new imine (5.29) which has been formed, to yield pyridoxamine (5.30) and the a-ketoacid (Fig. 5-57). 

The role of the metal ion may be purely conformational, acting to place the reactants in the correct spatial arrangement for cyclisation to occur, or it may play a more active role in stabilising the enol, enolate, imine or enamine intermediates. The prototypical example of such a reaction is shown in Fig. 6-18. The nickel(n) complex of a tetradentate macrocyclic ligand is the unexpected product of the reaction of [Ni(en)3]2+ with acetone. There are numerous possible mechanisms for the formation of the tetradentate macro-cyclic ligand and the exact mechanism is not known with any certainty. 

In chapter 21 we mentioned nitro compounds as promoters of conjugate addition they also stabilise anions strongly but do not usually act as electrophiles so that self-condensation is not found with nitro compounds. The nitro group is more than twice as good as a carbonyl group at stabilising an enolate anion. Nitromethane (p/ a 10) 1 has a lower pKa than malonates 4 (pKa 13). In fact it dissolves in aqueous NaOH as the enolate anion 3 formed in a way 2 that looks like enolate anion formation. 

Another good choice is the easily made fLketoester2 19 (compound 41 in chapter 19) as such stabilised enolate anions are not very basic. 

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