Enolization and isomerization

In common with other aldehydes or ketones that have hydrogen on the a-carbon, enoMzation is possible (see Section 10.1), especially when sugars are treated with base. The additional presence of a hydroxyl 

Removal of the a-hydrogen in o-glucose leads to enolization (we have omitted the enolate anion in the mechanism). Reversal of this process allows epimerization at C-2, since the enol function is planar, and a proton can be acquired from either face, giving D-mannose as well as o-glucose. Alternatively, we can get isomerization to o-fmctose. This is because the intermediate enol is actually an enediol restoration of the carbonyl function can, therefore, provide either a C-1 carbonyl or a C-2 carbonyl. The equilibrium mixture using dilute aqueous sodium hydroxide at room temperature consists mainly of o-glucose and o-fructose, with smaller amounts of D-mannose. The same mixture would be obtained 

Note that harsher conditions may lead to further changes, e.g. epimerization at C-3 in fmctose, plus isomerization, or even reverse aldol reactions (see Section 10.3). In general, basic conditions must be employed with care if isomerizations are to be avoided. To preserve stereochemistry, it is usual to ensure that free carbonyl groups are converted to acetals or ketals (glycosides, see Section 12.4) before basic reagents are used. Isomerization of sugars via enediol intermediates features prominently in the glycolytic pathway of intermediary metabolism (see Box 10.1). 

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Laurene differs in stereochemical configuration from the observed product at the carbon a to the methylene group. Since this position is a to the carbonyl group in the precursor to laurene, enolization and isomerization must have occurred during the reaction. 

Organotin radicals, and some related species, add to the carbonyl oxygen of cyclopropyl ketones 1 to produce a,a-disubstituted cyclopropylmethyl radicals. j -Scission, followed by hydrogen transfer with the organotin hydride, yields a mixture of enolates and isomeric a-stannyl ketones. Although the enolates can be isolated, they are usually hydrolyzed in situ with methanol to give the corresponding ketones 3. 

The choice of the chiral proton source, cation(s), (chiral) base, auxiliaries and temperature dramatically changes the enantiomeric excess of (/ )- or (S)-a-damascone (11) on protonation of the enolate and isomerization of the intermediate ketone156. 

Caramelization of sucrose requires a temperature of about 200°C. Reactions involved in the caramelization of sucrose include mutarotation, enolization and isomerization, dehydration and fragmentation, anhydride formation, and polymerization. The extent to which the reaction occurs depends upon pH, temperature, and heating time. Sucrose, held at 160°C as a melt, will hydrolyze to glucose and fructose anhydride. The production of water and organic acids such as acetic, formic, and pyruvic during sucrose caramelization will enhance the hydrolysis. Hydrolytic products, glucose and fructose, are reactants in the formation of caramel and volatile flavor compounds... 

Under mild acid conditions (viz., pH 5-6 at 0-60 C) reducing sugars ionize and mu-tarotate, at lower pH (v/z., down to pH 3 or 4) and at higher temperatures viz., up to ca. 100°C) enolization and isomerization occurs. In acid solution enolization is initiated by direct protonation of the carbonyl group (see Figure 2). In fact, acids are far less effective enolization catalysts than alkalies and as a consequence D-glucose and D-fructose in aqueous solution show maximum stability between pH 3 and 4 e.g., McDonald, 1950). 

Interestingly enough, both protons at C-11 are exchanged quite readily in 12-keto steroids. In these compounds C-11 is the only possible enolization site where the axial (/3) proton is probably expelled first. During ketonization, the deuteron attack is more likely to occur from the less hindered a-side. By this sequence the proton which was originally at the lla-equato-rial position becomes axial and readily available for expulsion in the next enolization step. Thus, isomerization of the C-11 hydrogens may be an important reason for the facile exchange at this position. (For a more detailed discussion of the mechanism of enolization and ketonization reactions, see ref 114.)... 

Recently, Grubbs138 demonstrated that olefin isomerization of allyl-lic ethers and alcohols is catalyzed by Ru(II)(H20)6(tos)2 (tos = p-toluenesulfonate) in aqueous medium. The olefin migration products, enols, and enol ethers thus generated are unstable and are hydrolyzed instantly to yield the corresponding carbonyl compounds (Eq. 3.34). 

Recently, we have demonstrated another sort of homogeneous sonocatalysis in the sonochemical oxidation of alkenes by O2. Upon sonication of alkenes under O2 in the presence of Mo(C0) , 1-enols and epoxides are formed in one to one ratios. Radical trapping and kinetic studies suggest a mechanism involving initial allylic C-H bond cleavage (caused by the cavitational collapse), and subsequent well-known autoxidation and epoxidation steps. The following scheme is consistent with our observations. In the case of alkene isomerization, it is the catalyst which is being sonochemical activated. In the case of alkene oxidation, however, it is the substrate which is activated. 

It will be seen that the enediolic system can theoretically be written in the isomeric 2-keto (II) or 3-keto (III) forms and these in turn are seen to be derived from the 2-keto and the 3-keto acids IV and V, respectively (compare with benzoin which reacts with iodine in an analogous fashion to L-ascorbic acid). Consequently the synthesis of L-ascorbic acid and of its analogs has consisted in devising methods for the formation of 2-keto or 3-keto hydroxy acids followed by their enolization and lactonization. Four main methods are available for the synthesis of analogs of L-ascorbic acid containing the characteristic five-membered unsaturated enediolic ring. 

If hydrogen gas is added to the reaction mixture of J, and 11 the hydrogenolysis reaction of thorium-to-carbon sigma bonds (J-1 22) allows interception of species 13 and thus, catalytic hydrogenation of the inserted carbon monoxide functionality. At 35 C under 0.75 atm initial H2 pressure with [JJ =9.0 x 10" M and [ 1JJ = 6.5 x 10" M, hydrogenation and isomerization are competitive and both the enolate and the alkoxide reduction product 14 are produced (eq.(13)). Under these conditions, turnover fre-... 

Upon r-BuOK treatment, 147 undergoes Dieckmann-type cyclization, and subsequent enolization affords compound 148 at 60% yield. Compound 148 is then converted to 149 through benyloxymethyl lithium addition. Successive deprotection and isomerization converts compound 149 to 150 for further functionalization (Scheme 7-44). 

The mechanism of the coupling reaction has been very exhaustively studied. Summarising first what has already been mentioned, it must be noted that the reaction is not confined to the aromatic series, for diazo-compounds condense also with enols and with the very closely related aliphatic aci-nitro-compounds. The final products of these reactions are not azo-compounds, but the isomeric hydrazones formed from them by rearrangement. 

Molybdenum complexes A (Figure 3.46) react efficiently with terminal and internal alkenes in toluene (e.g. 500 eq. Z-2-pentene are metathesized in 2 min at 25 °C 20 eq. of styrene in 2 h at 25 °C). These catalysts also oligomerize 2,4-hexadiene [808] and 1,5-hexadiene [809] and promote RCM of enol ethers. Isomerization of alkenes by catalysts A is a potential catalytic side-reaction [810-812]. 

There is a distinct relationship between keto-enol tautomerism and the iminium-enamine interconversion it can be seen from the above scheme that enamines are actually nitrogen analogues of enols. Their chemical properties reflect this relationship. It also leads us to another reason why enamine formation is a property of secondary amines, whereas primary amines give imines with aldehydes and ketones (see Section 7.7.1). Enamines from primary amines would undergo rapid conversion into the more stable imine tautomers (compare enol and keto tautomers) this isomerization cannot occur with enamines from secondary amines, and such enamines are, therefore, stable. 

As was pointed out in Part A, Section 7.3, under many conditions halogenation is faster than enolization. When this is true, the position of substitution in unsymmetrical ketones is governed by the relative rates of formation of the isomeric enols. In general, mixtures are formed with unsymmetrical ketones. The presence of a halogen substituent decreases the rate of acid-catalyzed enolization and therefore retards the introduction of a second halogen at the same site. Monohalogenation can therefore usually be carried out satisfactorily. A preparatively useful procedure for monohalogenation of ketones involves reaction with cupric chloride or cupric bromide.81 82 83 84 85 86... 

Unexpected reaction products were obtained when compound 206 was treated with diazomethane. After initial methylation of the enol, ring opening and isomerization of the secondary amine to the imine follows, furnishing compound 207 in good yield (Equation 69) <2002JOC6971>. 

From the base-catalyzed degradation of D-fructose (pH 8.0), Shaw and coworkers147 identified 18 compounds, none of which was (a) isomeric with the starting material, or (b) a simple dehydration product. Among the products, the hydroxy-2-butanones and 1-hydroxy-2-propanone (acetol) were shown to participate in forming the carbo-cyclic products identified, but the mechanism of their formation was not elucidated. Several furan derivatives were isolated, but no lactic acid was isolated. In a similar study but with weak acid,41 most of the products were formed by a combination of enolization and dehydration steps, with little fragmentation. 

Chapter 13. Enzymatic Addition, Elimination, Condensation, and Isomerization Roles for Enolate and Carbocation Intermediates... 

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