Selective Formation of Ketals

Electrostatic potential map for protonated ketone B shows most positively-charged regions (in blue) and less positively-charged regions (in red). 

Ketones react with 1,2-ethanediol under acidic conditions to give cyclic ketals. 

The reaction proceeds by a multistep mechanism and normally is reversible. Therefore, we expect the reaction to be thermodynamically controlled. 

The following reaction provides an example of selective ketal formation. The product of the reaction is a single ketone-ketal with the formula CnHigOs. 

In order to predict the structure of the product, you must identify the factors that will tend to favor selective ketal formation. Consider selective carbonyl protonation first. Obtain energies and atomic charges, and display electrostatic potential maps of the alternative protonated ketones (protonated ketone A, protonated ketone B). Identify the more stable isomer. Compare geometries and draw whatever Lewis structures are needed to account for your data. Why is one isomer more stable than the other Is the more stable isomer also that in which the positive charge is better delocalized Will the more stable isomer undergo nucleophilic attack more or less easily than the other Explain. 

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Cyclic ketal formation may also be restricted by steric factors. It occurs most readily at the unhindered C<3> position, but C(ii) ketones are very resistant, while C 6) and C(i ) ketones, which are subject to moderate steric hindrance, show reduced reactivity which permits selective formation of ketals at C(3). Hemi-ketal formation appears to be a particularly sensitive indicator of steric and conformational interference [y]. Steroid ketones in acidified methanol display changes in the amplitudes of their o.r.d. curves corresponding to the establishment of ketone hemi-ketal equiUbria. Only at C s) is the hemi-ketal (7) more stable than the ketone, and the... 

The effect of the catalyst-steroid ratio has been studied for the p-toluene-sulphonic acid-catalyzed ketalization of androst-4-ene-3,17-dione. Selective formation of the 3-monoketal is observed with the use of an equimolar amount of ethylene glycol and a low ratio of catalyst to steroid. ... 

The saturated 3-ketone can also be protected as the ethylene ketal, which is prepared directly by reaction with ethylene glycol or by exchange dioxo-lanation. Selective formation of 3-ethylenedioxy compounds is also possible, but the former method is not particularly effective in the presence of 6-, 17- or 20-ketones. However, the exchange dioxolanation technique is more sensitive to steric effects and good selectivity at C-3 can be achieved in the presence of a 17-ketone, provided the reagent does not contain glycol. ... 

This is due to a rapid and selective transformation of aldehydes under these conditions to ketals or hemiketals, which are not reduced (Figure 3.7). The same type of situation permits the relatively rapid formation of ketals of unhindered ketones in the presence of HC(OEt)3, whereby the selective reduction of the most hindered ketone group of 3.13 is possible [GLl] (Figure 3.7). 

The methods described in the preceding section lead to smooth phosphorylation of all hydroxyl groups in inositol derivatives. Contrary to this exhaustive phosphorylation, the regioselective one is also quite useful, especially for the selective formation of the phosphoric diester functions at the C-l position in 1,2-diol derivatives of myo-inositol in the synthesis of phosphoinositides. These 1,2-diol derivatives are easily accessible because 1,2-cis-dihydroxyl groups of myo-inositol are easily protected by its ketalization in comparison with trans diols. The diol derivatives thus obtained comprise one equatorial and the other axial hydroxyl groups. Since the former is generally more reactive than the latter, several electrophiles were selectively introduced at the 1 position of the diols as shown in Scheme 2-5. However, phosphorylation at C-1 in a 1,2-diol was extraordinarily difficult when known procedures were used because migration of the phosphate function and cyclization occured with ease.- ... 

The regiochemical outcomes of Brpnsted acid-catalyzed reactimis of carbohydrate derivatives have been studied in detail, particularly in the context of the selective formation or hydrolysis of acetals and ketals [6, 7]. The group of Nagorny has added a new dimension to this strategy by employing chiral Br0nsted acids for the selective formation of mixed acetals and ketals from pyranoside-derived 1,2-diol... 

The selective formation of phenyl ethers from one hydroxy-group of a diol has been achieved with triphenylbismuth diacetate, Ph3Bi(OAc)2. Two new protecting groups suitable for 1,2- and 1,3-diols are shown in the ketal (39) and the t-butylsilylene derivative (40). ... 

Acetonide formation is the most commonly used protection for 1,2- and 1,3-diols. The acetonide has been used extensively in carbohydrate chemistiy to mask selectively the hydroxyls of the many different sugars. In preparing acetonides of triols, the 1,2-derivative is generally favored over the 1,3-derivative, but the extent to which the 1,2-acetonide is favored is dependent on stmcture. Note that the 1,2-selectivity for the ketal from 3-pentanone is better than that from acetone. ... 

Catechols can be protected as diethers or diesters by methods that have been described to protect phenols. However, formation of cyclic acetals and ketals (e.g., methylenedioxy, acetonide, cyclohexylidenedioxy, diphenylmethylenedioxy derivatives) or cyclic esters (e.g., borates or carbonates) selectively protects the two adjacent hydroxyl groups in the presence of isolated phenol groups. 

Thioketals are readily formed by acid-catalyzed reaction with ethane-dithiol. Selective thioketal formation is achieved at C-3 in the presence of a 6-ketone by carrying out the boron trifluoride catalyzed reaction in diluted medium. Selective protection of the 3-carbonyl group as a thioketal has been effected in high yield with A" -3,17-diketones, A" -3,20-diketones and A" -3,l 1,17-triones in acetic acid at room temperature in the presence of p-toluenesulfonic acid. In the case of thioketals the double bond remains in the 4,5-position. This result is attributed to the greater nucleophilicity of sulfur as compared to oxygen, which promotes closure of intermediate (66) to the protonated cyclic mercaptal (67) rather than elimination to the 3,5-diene [cf. ketal (70) via intermediates (68) and (69)]." " ... 

Unsubstituted 20-ketones undergo exchange dioxolanation nearly with the same ease as saturated 3-ketones although preferential ketalization at C-3 can be achieved under these conditions. " 20,20-Cycloethylenedioxy derivatives are readily prepared by acid-catalyzed reaction with ethylene glycol. The presence of a 12-ketone inhibits formation of 20-ketals. Selective removal of 20-ketals in the presence of a 3-ketal is effected with boron trifluoride at room temperature. Hemithioketals and thioketals " are obtained by conventional procedures. However, the 20-thioketal does not form under mild conditions (dilution technique). ... 

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