Acidity enolates

Xenon difluoride [55], xenon difluoride complexed with dialkyl sulfides [59], and xenon difluoride intercalated with graphite [90] are all effective reagents for the fluonnalion of acids, enolates, or enols (Table 2)... 

P-Keto acid Enol form of ketone Ketone... 

A change in the pK of the molecule by elimination of the acidic enol function and inclusion of basic nitrogen leads to a marked change in biologic activity. That agent, chromonar (13) shows activity as a coronary vasodilator. Alkylation of ethyl acetoacetate with 2-chlorotriethylamine affords the substituted ketoester (10). Condensation with resorcinol in the presence of sulfuric acid affords directly the substituted coumarin (11). 

The Hell-Volhard-Zelinskii reaction is a bit more complex than it looks and actually involves substitution of an acid bromide enol rather than a carboxylic acid enol. The process begins with reaction of the carboxylic acid with PBr3 to form an acid bromide plus HBr (Section 21.4). The HBr then catalyzes enolization of the acid bromide, and the resultant enol reacts with Br2 in an cr-substitution reaction to give an cv-bromo acid bromide. Addition of water hydrolyzes the acid bromide in a nucleophilic acyl substitution reaction and yields the a-bromo carboxylic acid product. 

Substances determined acids, enols, imides, phenols, sulphonamides... 

Details of the interesting desmotropic phenomena exhibited by the hydroxyanthracenes are given by K. H. Meyer (Annalen, 1911, 379,37). Meso-hydroxy- and dihydroxyanthracene exist in two forms, a genuine, coloured acidic enol which fluoresces in solution and a colourless, neutral keto-ioxm. 

The divergent pathways arise from selective enolization. Thus, in media of lower acidity enolization occurs toward C-3, whereas in a stronger acid complete N-pro-tonation shifts the enolization toward C-l. The amino donor confers certain acceptor character C-l (although this is a captodative situation), but upon protonation it is converted into an acceptor and its adjacent carbon atom, a donor. 

Acidic enolic compounds (pyrazolidine-3,5-diones, oxicams)... 

With a pKA of 5.5 piroxicam is a weak acidic enol. The resonance stabilization of the anionic form is shown below. 

The dioxopyrazolines are also acidic because of their enolic group (4,4-disubstituted analogues are inactive) and a recent example azapropazone (apazone) (184) inhibits prostaglandin synthesis. Its pharmacological properties are like those of phenylbutazone and it is also uricosuric. Anti-inflammatory 1,2-benzothiazine 1,1-dioxides such as piroxicam (185 R = 2-pyridyl) also have an acidic enolic group whose anion can be stabilized by... 

Ascorbic acid (Vitamin C) is an example of a stable and quite acidic enol, or rather an enediol. It is a di-acid with pKa values of 4.17 and 11.57 ... 

Masked chiral a-hetero substituted carboxylic acid enolates have also shown utility in dia-stereoselective additions to nitroalkenes. For example, derivatives of a-hydroxycarboxylic acids, e.g. l,3-dioxolan-4-ones (187) a-amino acids, e.g. 1,3-imidazolidin-4-ones (188) and a-amino-fi-hydroxy-carboxylic acids, e.g. methyl 1,3-oxazolidin-4-carboxylates (189) and methyl l,3-oxazolin-4-carboxy-lates (190), have been employed.1S0a Further, diastereoselective additions of chiral (3-hydroxyesters (191), via the enediolates, to nitroalkenes (40) afford predominant anr/ -P-hydroxyesters (192 Scheme... 

The heteroatoms most commonly encountered by the organic chemist are oxygen, nitrogen and sulphur. The position of absorption of protons attached to these atoms is not normally sufficiently reliable for interpretative purposes, although there are exceptions to this general rule (e.g. carboxylic acids, enols,... 

The synthesis is very straightforward no bromination occurs on the ring as would be expected in the absence of a Lewis acid. Enols react with bromine without the need of any catalysis.3... 

In the presence of an electrophile, tautomerization of a substrate with a C=0 double bond to its enol only takes place when catalyzed by either a Bronsted- or a Lewis acid. The proton-catalyzed mechanism is shown for the ketone — enol conversion B — iso-B (Figure 12.4), the carboxylic acid —> enol conversion A — E (Figure 12.6), the carboxylic acid bromide — enol conversion E —> G (Figure 12.7) and the carboxylic acid ester — enol conversion diethyl-malonate —> E (Figure 12.9). Each of these enol formations is a two-step process consisting of the protonation to a carboxonium ion and the latter s deprotonation. The mechanism of a Lewis acid-catalyzed enolization is illustrated in Figure 12.5, exemplified by the ketone —> enol conversion A —> iso-A. Again, a protonation to a carboxonium ion and the latter s deprotonation are involved the Lewis acid-complexed ketone acts as a proton source (see below). 

Fig. 12.6. Bromination of malonic acids or alkylated mal-onic acids. The figure shows the mechanisms of the acid-catalyzed enolization (alkyl) malonic acid enol of (alkyl) malonic acid (E) and the actual bromination (E —> B).

It can be assumed that the small amount of piperidine in the reaction mixture is completely protonated by malonic acid because piperidine is more basic than pyridine. Hence, only the less basic pyridine is available for the formation of the malonic acid enolate D from free malonic acid and for the formation of the malonic acid dianion from the malonic acid mono-carboxylate C. The pKa value of malonic acid with regard to its C,H acidity should be close to the pKa value of malonic acid diethyl ester (p= 13.3). The pKa value of malonic acid monocarboxylate C with regard to its C,H acidity should be larger by at least a factor 10. Hence, the concentration of the malonic acid enolate D in the reaction mixture must be by many orders of magnitude higher than that of any malonic acid dianion. Due to the advantages associated with this enormous concentration D could be the actual nucleophile in Knoevenagel condensations. 

Fig. 13.56. Mechanism of the Knoevenagel condensations in Figure 13.55. The C,H( )-acidic reaction partneris malonicacidin the form of the malonic acid enolate D (malonic acid "monoanion"). The decarboxylation proceeds as a fragmentation of the pyridinium-substituted malonic acid carboxylate F to furnish the ,/Tunsaturated ester (G) and pyridine. This fragmentation resembles the decomposition of the sodium salts H of ,/Tdibrominated carboxylic acids to yield the a,/Tunsaturated bromides I and sodium bromide.

More recent examples of nucleophilic aromatic substitution reactions include the reactions of C6F6 with the superoxide ion, 02 to give F and, presumably, C6F502 278 and with the acetic acid enolate anion, as shown in Scheme 42, which also indicates how the anionic reagent was formed279. It should be noted that reaction of gas-phase F" with a suitably silylated precursor is one of the best and most specific reactions to prepare gas-phase anions280. 

Acetone has also an acidic character, as appears from the complete exchange of the hydrogen for deuterium in alkaline media (displacement of the equilibrium towards the side of the acid enol form). 

In the third pathway for the formation of 3-deoxyulosonic acids, enol pyruvate phosphate and an aldose phosphate are condensed, yielding orthophosphate and a 3-deoxyulosonic acid phosphate. In addition to formation of 3-deoxy-n-araInno-heptulosonic acid 7-phosphate, another example of this type of reaction is the formation of a 3-deoxyoctulosonic acid 8-phosphate (probably 3-deoxy-D-jfJMCo-octulosonic acid) from enolp3Tmvate phosphate and D-arabinose 5-phosphate. These reactions, unlike those involving pjrruvate, proceed completely to the right and have, so far, not been reversed. 

His main interests include organic chemistry, heterocyclic chemistry (quinolones, dihydropyr-idines, benzimidazoles, benzotriazoles, benzoselenadiazoles, bcnzothiadiazoles, glutaric acids, enol ethers), utilization of heterocyclic compounds in the organic synthesis, and molecular spectroscopy. 

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