Enol tautomers Enolate anions

Carbanions derived from carbonyl compoimds are often referred to as etiolates. This name is derived from the enol tautomer of carbonyl compounds. The resonance-stabilized enolate anion is the conjugate base of both the keto and enol forms of carbonyl... 

Rate and equilibrium constant measurements for the enolization of 3-phenylcoumaran-2-one (82) in aqueous dioxane indicate an enol content of ca 0.1%, a pKg, of 8.9 (6.0 for the enol tautomer), and a fairly symmetrical transition state for enolate anion formation the Brpnsted Pb = 0.52 Below pH 5, enolization is independent of pH, occurring via O-protonation of the enolate. 

Of the two resonance forms of the enolate anion, that with the charge on the electronegative oxygen will be preferred over that with charge on the carbon. Note the distinct difference between resonance as shown here, a redistribution of electrons, and tautomerism, as described above. Tautomers are isomers in equilibrium and have the atoms arranged differently. 

The Mannich reaction is best discussed via an example. A mixture of dimethylamine, formaldehyde and acetone under mild acidic conditions gives N,N-dimethyl-4-aminobutan-2-one. This is a two-stage process, beginning with the formation of an iminium cation from the amine and the more reactive of the two carbonyl compounds, in this case the aldehyde. This iminium cation then acts as the electrophile for addition of the nucleophile acetone. Now it would be nice if we could use the enolate anion as the nucleophile, as in the other reactions we have looked at, but under the mild acidic conditions we cannot have an anion, and the nucleophile must be portrayed as the enol tautomer of acetone. The addition is then unspectacular, and, after loss of a proton from the carbonyl, we are left with the product. 

Hydroxycoumarin can be considered as an enol tautomer of a 1,3-dicarbonyl compound conjugation with the aromatic ring favours the enol tautomer. This now exposes its potential as a nucleophile. Whilst we may begin to consider enolate anion chemistry, no strong base is required and we may formulate a mechanism in which the enol acts as the nucleophile, in a simple aldol reaction with formaldehyde. Dehydration follows and produces an unsaturated ketone, which then becomes the electrophile in a Michael reaction (see Section 10.10). The nucleophile is a second molecule of 4-hydroxycoumarin. 

Suelter90 has classified enzymes that are activated by monovalent cations into two groups. One involves the catalysis of phosphoryl-transfer reactions and the other a variety of elimination and/or hydrolytic reactions in which a keto-enol tautomer can be invoked as an intermediate. The M+ cation is then required to stabilize the enolate anion. It is still not possible to verify this hypothesis, but it seems unlikely in view of the comments above. 

The alternative situation where k- zero order in [X], and the clear disparitybetween stoichiometric coefficients and reaction orders demands the existence of an intermediate. The situation occurs in acid- and base-catalysed reactions of ketones with reactive electrophiles (e.g. X = CI2, Br2 or I2), which are usually zero order in the electrophilic reagent, unless concentrations of the electrophiles are extremely low [19]. The intermediate reacting with the electrophile may be the enol tautomer of the ketone or its enolate anion, formed catalytically from the ketone. 

Aldehydes or ketones with an a-hydrogen exist as an equilibrium mixture of keto (H-Ca-C=0) and enol (Ca=C-OH) tautomers. The keto form usually predominates. An a-hydrogen is weakly acidic and can be removed by a base to produce a resonance-stabilized enolate anion. Deuterium exchange of a-hydrogens provides experimental evidence for ends as reaction intermediates. 

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

Addition of a proton to the oxygen of the enolate anion produces the enol tautomer. 

The oxazoliumcarboxylic acid (147) is easily decarboxylated via the ylide (148) the neutral compound (149) is much more stable due to the low equilibrium concentration of the zwitterionic tautomer (150 Scheme 7). Oxazolium salts lacking substituents at the 2-position react with dialkyl acylphosphonates in the presence of triethylamine to give mixtures of l,4-oxazin-3-ones and 2-azetidinones the reaction (see Scheme 8) proceeds by electrophilic attack of the phosphonate on an oxazolium ylide, e.g. (151), followed by insertion of oxygen into the carbon-phosphorus bond, ring-opening, and formation of the enolate anion (152) which can cyclize in two alternative ways with expulsion of the phosphonate group. 

The relationship between the delocalized imidazole anion and imidazole itself is rather like that between an enolate anion and an enol. It will come as no surprise that imidazole tautomerizes rapidly at room temperature in solution. For the parent compound the two tautomers are the same, but with unsymmetrical imidazoles the tautomerism is more interesting. We will explore this question alongside electrophilic aromatic substitution of imidazoles. 

However, it seems more reasonable to reserve this name for the true nucleophilic adduct 40 and to refer to 41 and 42 as ring-opened tautomers of this pseudobase. More basic aqueous solutions of this cation are orange-pink (Amax = 490 nm), and this is ascribed204,210,214 to the presence of the enolate anion 43 derived from 41 or 42. Griot et al.201 claim the isolation of the true pseudobase 40 from highly basic solutions. 

There are numerous base-solvent combinations that are capable of quantitatively converting even weakly acidic simple ketones into their enolate anions. However, in order to avoid aldol condensation and unwanted equilibration of enolates of unsymmetrical ketones during enolate formation, it is best to choose conditions under which the ketone, the base and the metal enolate are soluble. Likewise, solutions should be produced when indirect methods of enolate formation are employed. While certain metal cations such as Hg form a-metallated ketones, most of the metal cations in Groups 1, II and III exist as 0-metallated tautomers. - For organotin derivatives both the 0-metallated and C-metallated forms probably exist in equilibrium. ... 

Enol stannyl ethers have recently been used as synthetic equivalents of enolate anions. However, or-ganotin enol ethers usually exist as mixtures of C- and (7-metallated species, irrespective of the methods of preparation. Nevertheless, the two tautomers (71) and (72) often show similar reactivity and can be considered collectively as tin enolates . 

In a basic solution, hydroxide ion removes a proton from the a-carbon of the keto tautomer. The anion that is formed has two resonance contributors a carbanion and an enolate ion. The enolate ion contributes more to the resonance hybrid because the negative charge is better accommodated by oxygen than by carbon. Protonation on oxygen forms the enol tautomer, whereas protonation on the a-carbon reforms the keto tautomer. 

Within the series of 4-hydroxy-1,2-benzothiazine carboxamides represented by the general structure shown below, optimum activity was observed when Ri was a methyl substituent. The carboxamide substituent, R, generally is an aryl or heteroaryl substituent, because alkyl substituents are less active. Oxicams are acidic compounds, with pKa values in the range of four to six. N-heterocyclic carboxamides generally are more acidic than the corresponding N-aryl carboxamides, and this enhanced acidity was attributed (69) to stabilization of the enolate anion by the pyridine nitrogen atom, as illustrated in tautomer A and additional stabilization by tautomer B ... 

MA, a three carbon dialdehyde, can experience a number of configurational modifications as discussed by Kwon and Watts (6). Enolization of the diketo form may take place. The enolic tautomer may further undergo molecular rearrangement into its open cis-, open trans-, or chelated forms. At pH 3 or lower, MA is chelated and exists as 3 hydroxy-acrolein above pH 6.5 MA is completely dissociated and exists as an enolate anion. Between pH 3 and 6.5, MA is an equilibrium mixture of enolate anion and chelated forms. MA (also malondialdehyde), is one of the main secondary products of lipid oxidation. It forms a pink color by condensing with 2 moles of TBA (7). 

A second type of oxygen-chelated complex that can be formed with acetylacetone is the simple Lewis acid-base adduct. In these complexes acetylacetone does not lose its acidic proton to form an enolate anion, but rather as the neutral molecule in the keto tautomer donates electrons from the oxygens of each carbonyl to an acceptor or acidic species. Examples of this type of complex are the six-coordinate adducts formed between typically strong Lewis adds as tin tetrachloride or titanium... 

Resonance and tautomerism are closely related. Thus the acidity of carbon-bound hydrogen in ketones, which allows formation of enol tautomers, is a direct result of the fact that the enolate anion produced by dissociation of one of these hydrogen atoms is stabilized by resonance. Similarly, tautomerism in the imidazole group of histidines is related to resonance in the imidazolium cations. 

Suelter has summarized the enzymes catalysed by monovalent cations and has suggested that the data from the various reactions are consistent with a unique interaction of metal with the enzyme and substrate to form a functional ternary complex. While this complex cannot yet be uniquely defined, the pattern of activation suggests that (i) phosphorylation of a carboxy-group or enolate anion, (ii) elimination reactions resulting in a keto-enol tautomer, and (iii) other reactions in which a keto-enol tautomer can be considered as an intermediate, are all candidates for activation by a monovalent cation. 

The a-proton of a ketone or aldehyde is a weak acid and can be removed by a strong base to give a resonance-stabilized enolate anion. Deprotonation may occur via the enol tautomer. The a-proton of an aldehyde is slightly more acidic than that of a ketone. 

---