Enol titration

If the reaction between the enol and the electrophile proceeds extremely fast, the enol tautomer of a carbonyl or carboxyl compound might be consumed completely. The generation of enol becomes the rate-determining step. This situation occurs with the enol titration of ace-toacetic ester, (Figure 12.4). In this process, bromine is added to an equilibrium mixture of the ketone form (B) and the enol form (iso-B) of an acetoacetic ester. Bromine functionalizes the enol form via the intermediacy of the carboxonium ion E to form the bromoacetic ester D. The trick of conducting the enol titration is to capture the enol portion of a known amount of acetoacetic ester by adding exactly the equivalent amount of bromine. From the values for... 

Side Note 12.1. Enol Titration of Acetoacetic Ester... 

Enol titration Kinetic estimation1 Thermochemical approach Ah initio calculations Kinetic halogenation method ... 

Although ethereal solutions of methyl lithium may be prepared by the reaction of lithium wire with either methyl iodide or methyl bromide in ether solution, the molar equivalent of lithium iodide or lithium bromide formed in these reactions remains in solution and forms, in part, a complex with the methyllithium. Certain of the ethereal solutions of methyl 1ithium currently marketed by several suppliers including Alfa Products, Morton/Thiokol, Inc., Aldrich Chemical Company, and Lithium Corporation of America, Inc., have been prepared from methyl bromide and contain a full molar equivalent of lithium bromide. In several applications such as the use of methyllithium to prepare lithium dimethyl cuprate or the use of methyllithium in 1,2-dimethyoxyethane to prepare lithium enolates from enol acetates or triraethyl silyl enol ethers, the presence of this lithium salt interferes with the titration and use of methyllithium. There is also evidence which indicates that the stereochemistry observed during addition of methyllithium to carbonyl compounds may be influenced significantly by the presence of a lithium salt in the reaction solution. For these reasons it is often desirable to have ethereal solutions... 

Crystalline triose reductone has been shown (56) by titration with strong base and with iodine, to exist in solution, for practical purposes, entirely as the enol form. In addition, the fact that it reduces exactly three molar equivalents of periodate to give quantitative yields of formic acid and of carbon dioxide indicates that it is also oxidized entirely in this form. However, nothing is known of the rate of enolization of tartronic dialdehyde and the possibility therefore remains that part of it may be oxidized in the dialdehydo form. If this were the case, the results of periodate oxidations would be dependent on the ratio of the rate of enolization of tartronic dialdehyde to the rate of its oxidation by periodate, since the oxidation of triose reductone is, again, for practical purposes, instantaneous. 

It is, however, more likely that the discrepancies observed in the periodate oxidation of malonaldehyde concern mainly the hydroxylation step. In the mechanism proposed (5) for this reaction, it is the enol form of malonaldehyde which is hydroxylated. However, titrations of a solution of malonaldehyde, prepared by hydrolysis of an aqueous solution (33) of carefully distilled 1, 3, 3-tri-ethoxypropene (46, 47), both with strong base and with iodine, indicate that only about 80% of the enol form is present in the equilibrium solution. On the other hand, the thio-barbituric acid test (58, 59) gave consistently higher values for the malonaldehyde content of the solution. The fact that only about 80% of the enol form is present in the equilibrium solution is all the more important as it can be shown (56) by titration with strong base that the enolization is slow, and moreover does not seem to go to completion. 

Addition of Enolates and Azaenolates to, /i-l nsa titrated Carbonyl Compounds... 

Kimura and co-workers have synthesized a series of alkoxide complexes with the alcohol functionality as a pendent arm.447 674 737 A zinc complex of l-(4-bromophenacyl)-l, 4,7,10-tetraaza-cyclododecane was also synthesized by the same workers to mimic the active site of class II aldolases. The X-ray structure shows a six-coordinate zinc center with five donors from the ligand and a water molecule bound. The ketone is bound with a Zn—O distance of 2.159(3) A (Figure 12). Potentiometric titration indicated formation of a mixture of the hydroxide and the enolate. Enolate formation was also independently carried out by reaction with sodium methoxide, allowing full characterization.738... 

First of all, the mesomerism of HBI is rendered complex by the presence of several protonable groups actually, HBI might exist, depending on pH, under cationic, neutral, zwitterionic, anionic, and possibly enolic forms (Fig. 3a). The experimental p/sTa s of model analogs of HBI in aqueous solutions have been studied. Titration curves follow two macroscopic transitions at pH 1.8 and pH 8.2, each corresponding to a single proton release [69]. Comparison of theoretical... 

A plethora of weakly acidic pharmaceutical substances may be titrated effectively by making use of a suitable non-aqueous solvent with a sharp end-point. The wide spectrum of such organic compounds include anhydrides, acids, amino acids, acid halides, enols (viz., barbiturates), xanthines, sulphonamides, phenols, imides and lastly the organic salts of inorganic acids. 

Bis [(trifluoromethyl)thio] acetaldehyde (83a) has been prepared from an enam-ine precursor (84), although refluxing in aqueous ethanolic HCl is required to effect this reaction.The aldehyde is less stable than its enol tautomer (83b), and many reactions typical of aldehydes fail. For example, addition of aqueous silver nitrate immediately yields the silver salt of (83b), rather than giving precipitation of (elemental) silver. The (trifluoromethyl)thio substituent has pseudohalogenic character and, together with the hydroxy group, stabilizes the alkene tautomer in the manner of a push-pull alkene. The enol-aldehyde equilibrium mixture in acetonitrile shows an apparent of 2.6 when titrated with aqueous hydroxide. 

Methylene difluorocyclopropanes are relatively rare and their rearrangement chemistry has been reviewed recently [14]. In addition, electron deficient alkenes such as sesquiterpenoid methylene lactones may be competent substrates. Two crystal structures of compounds prepared in this way were reported recently [15,16]. Other relatively recent methods use dibromodifluoromethane, a relatively inexpensive and liquid precursor. Dolbier and co-workers described a simple zinc-mediated protocol [17], while Balcerzak and Jonczyk described a useful reproducible phase transfer catalysed procedure (Eq. 6) using bromo-form and dibromodifluoromethane [18]. The only problem here appears to be in separating cyclopropane products from alkene starting material (the authors recommend titration with bromine which is not particularly amenable for small scale use). Schlosser and co-workers have also described a mild ylide-based approach using dibromodifluoromethane [19] which reacts particularly well with highly nucleophilic alkenes such as enol ethers [20], and remarkably, with alkynes [21] to afford labile difluorocyclopropenes (Eq. 7). 

The quantitative determination of Enols can be made either using an esterification procedure with acetic anhydride (Ref 2, pp 455 59), or by direct titration in nonaqueous media (Ref 2 pp 461-62)... 

Ethyl 3-oxobutanoate exists at room temperature as an equilibrium mixture of keto and enol tautomers in the ratio of 92.5 to 7.5. The presence of enol can be shown by rapid titration with bromine, but is more evident from the proton nmr spectrum (Figure 18-6), which shows absorption of the hydroxyl, alkenyl, and methyl protons of the enol form, in addition to absorptions expected for the keto form ... 

In the following method a slight excess of an alcoholic solution of bromine is added to an alcoholic solution of the tautomeric mixture the excess of bromine is immediately removed by the addition of a few drops of alcoholic /3-naphthoI solution potassium iodide solution is next added, and the hydrogen iodide formed by interaction with the hydrogen bromide present reduces the bromo-ketone with liberation of free iodine, which is estimated by titration with standard thiosulphate (in absence of starch). One molecule of iodine = one molecule of enolic compound. For criticism of this method, see Ann. Rep., 1930, 100. 

This technique, called bromine titration method , was extensively used by K.H. Meyer in the early twentieth century.18 It was later extended to determine the enol content of simple ketones using faster flow methods combined with more sensitive potentiometric measurements of bromine uptake, but this technique sometimes produced apparent enol contents that were far too high, such as the enol content of acetone of 2.5 x 10 4% that is frequently quoted in older textbooks of organic chemistry. The excessive values so obtained have been attributed to the presence of small amounts of impurities reacting with bromine. 

Ascorbic acids reduce Fehling solution in the cold, and react with ferric chloride to produce the violet color typical of enolic compounds. They are readily oxidized reversibly to their primary oxidation products, 2,3-glycodiulosono-1,4-lactones (commonly known as dehydroascorbic acids 148, Scheme 16), by such mild oxidizing agents as aqueous iodine. Titration with such oxidants constitutes a quantitative method for distinguishing ascorbic acids from 2-glyculosonic acids. 

Fig. 12.4. Enot titration of acetoacetic acid ester. The mechanism of the acid-catalyzed B iso-B enolization and the mechanism of the electrophilic iso-B -> D bromina-tion is shown.

Acidity constants (p-Kjjj) of cyclopentanone and cyclohexanone enols have been determined by the halogen-titration method from the variations of the enol + enolate sum as a function of pH (Bell and Smith, 1966). However, since the values of the keto-enol equilibrium constants are questionable, these pflra-values (11.8 and 11.3, respectively) are doubtful as well, although they are in fair agreement with those expected. 

Potentiometric titration of free 11 in aqueous solution indicated no tendency for deprotonation of the active methylene group below pH 11. In the presence of Zn(II), however, a similar titration indicated a deprotonation corresponding to a piiQ of 8.41. With the assistance of spectroscopic data, this deprotonation was unambiguously assigned to the formation of a 3 1 equilibrium mixture of [Zn(ll)(OH)]+ and the enolate complex [Zn(12)]+. 

Care must be taken when interpreting ionization measurements since the enolic form of the ketone may also be present in the reaction solution. In aqueous solutions of 2-acetylcyclohexanone, for example, the enol is present to the extent of 29.2 % [82]. This can be measured by titrating the enol (EH) with bromine under conditions where the interconversion of ketone (KH) and enol and the reaction of ketone with bromine are slow. The measured overall dissociation constant of the ketone (K0) can be corrected to give the true ionization constant (Kk ) as in (66)... 

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