Ketones acetal formation

The position of equilibrium is favorable for acetal formation from most aldehydes especially when excess alcohol is present as the reaction solvent For most ketones the position of equilibrium is unfavorable and other methods must be used for the prepara tion of acetals from ketones... 

Azirines react with alcohols in the presence of alkoxides to give alkoxyaziridines (67JA4456). Further treatment with alcohol and alkoxide results in the formation of amino ketone acetals. Alkoxyaziridines are not isolated in general from the acid-catalyzed addition of methanol to azirines. Azirines are also known to react with amines (66JOC1423). Frequently the initially produced adducts undergo subsequent transformations. 

X0 to hydroxy compounds. Lower temperatures favor ketone formation and sterically hindered carbonyls, such as 2-thienyl t-butyl ketone, are not reduced. The sensitivity of desulfurization to steric factors is evident by the failure to desulfurize 2,5-di-i-butyl-3-acetylthiophene. The carbonyl groups of both aldehydes and ketones can be protected by acetal formation, as particularly cyclic acetals are stable during desulfurization in methanol at room temperature. " The free aldehydes give primary alcohols on desulfurization. Another method to obtain only keto compounds is to oxidize the mixtures of ketone and secondary alcohol with CrOs after the desulfurization. - Through the desulfurization of 5,5 -diacetyl-2,2, 5, 2"-terthienyl (228), 2,15-hexadecandione (229) has been obtained, which... 

Acetal formation is similar to the hydration reaction discussed in Section 19.5. Like water, alcohols are weak nucleophiles that add to aldehydes and ketones only slowly under neutral conditions. Under acidic conditions, however, the reactivity of the carbonyl group is increased by protonation, so addition of an alcohol occurs rapidly. 

Mechanism of acid-catalyzed acetal formation by reaction of an aldehyde or ketone with an alcohol. 

The reaction of crotonaldehyde and methyl vinyl ketone with thiophenol in the presence of anhydrous hydrogen chloride effects conjugate addition of thiophenol as well as acetal formation. The resulting j3-phenylthio thioacetals are converted to 1-phenylthio-and 2-phenylthio-1,3-butadiene, respectively, upon reaction with 2 equivalents of copper(I) trifluoromethanesulfonate (Table I). The copper(I)-induced heterolysis of carbon-sulfur bonds has also been used to effect pinacol-type rearrangements of bis(phenyl-thio)methyl carbinols. Thus the addition of bis(phenyl-thio)methyllithium to ketones and aldehydes followed by copper(I)-induced rearrangement results in a one-carbon ring expansion or chain-insertion transformation which gives a-phenylthio ketones. Monothioketals of 1,4-diketones are cyclized to 2,5-disubstituted furans by the action of copper(I) trifluoromethanesulfonate. ... 

From the reactions presented in this section one can conclude that cyclic acetal formation via addition to a carbene intermediate is a general reaction for type I cleavage of cyclobutanones, tricyclic compounds, and certain bridged bicyclics as minor products. No acetal has been isolated from photolyses of cyclopentanones or cyclohexanones except for the special case of an a-sila ketone previously discussed. 

Birch reduction of the norgetrel intermediate 5 oil owed by hydrolysis of the enol ether gives the enone oxidation of the alcohol at 17 leads to dione 7. Fermentation of that intermediate in the presence of the mold PeniciIlium raistricky serves to introduce a hydroxyl group at the 15 position W. Acetal formation with neopentyl glycol affords the protected ketone which consists of a mixture of the A and A isomers (2 ) hindrance at position 17 ensures selective reaction of the 3 ketone. The... 

In a similar fashion to the formation of hydrate with water, aldehyde and ketone react with alcohol to form acetal and ketal, respectively. In the formation of an acetal, two molecules of alcohol add to the aldehyde, and one mole of water is eliminated. An alcohol, like water, is a poor nucleophile. Therefore, the acetal formation only occurs in the presence of anhydrous acid catalyst. Acetal or ketal formation is a reversible reaction, and the formation follows the same mechanism. The equilibrium lies towards the formation of acetal when an excess of alcohol is used. In hot aqueous acidic solution, acetals or ketals are hydrolysed back to the carbonyl compounds and alcohols. 

You will remember that acetal formation (frames 7-7 ) is a reversible reaction. It turns out that the equilibrium constant for acetal formation from a ketone is unfavourable ... 

Stage Synthesis of Mevalonate from Acetate The first stage in cholesterol biosynthesis leads to the intermediate mevalonate (Fig. 21-34). Two molecules of acetyl-CoA condense to form acetoacetyl-CoA, which condenses with a third molecule of acetyl-CoA to yield the six-carbon compound /3-hydroxy-/3-methylglu-taryl-CoA (HMG-CoA). These first two reactions are catalyzed by thiolase and HMG-CoA synthase, respectively. The cytosolic HMG-CoA synthase in this pathway is distinct from the mitochondrial isozyme that catalyzes HMG-CoA synthesis in ketone body formation (see Fig. 17-18). 

Resin-bound diols, amino alcohols, and dithiols, which reversibly form cyclic acetals with aldehydes and ketones, have been successfully used as linkers for carbonyl compounds (Entries 5-11, Table 3.40). Acetal formation on insoluble supports can be achieved by azeotropic removal of water (C6H6, TsOH, reflux [720]), whereas dithio-acetals can be prepared by acid-catalysis alone (BF3 OEt2 or TMSC1 CHCI3,0 °C, 2 h [721]). /V-Acylaminals such as R-CFI(OMe)NFI-CO-Pol have been prepared by treatment of resin-bound amides H2NCO-Pol with aldehydes in the presence of HC(OMe)3 and TFA [722],... 

In a situation where severe steric hindrance (e.g., 16,16-dimethyl-20-keto-pregnanes) prevents enol acetate formation, an alternate scheme has been devised. Condensation of ethyl oxalate at C-21 produces, after hydrolysis, the 21-glyoxylic acid this on treatment with acetic anhydride and a strong acid catalyst such as perchloric acid gives both A17(20)-enol lactone acetates. Epoxidation with peracid, and mild alkaline hydrolysis proceeds to give the 17a-hydroxy-20-ketone in a high overall yield.257... 

The position of equilibrium in acetal and hemiacetal formation is rather sensitive to steric hindrance. Large groups in either the aldehyde or the alcohol tend to make the reaction less favorable. Table 15-3 shows some typical conversions in acetal formation when 1 mole of aldehyde is allowed to come to equilibrium with 5 moles of alcohol. For ketones, the equilibria are still less favorable than for aldehydes, and to obtain reasonable conversion the water must be removed as it is formed. 

Aldehydes and ketones both may be reduced to alcohols by hydrogenation (see the alcohol dehydrogenation reaction, equation 5). Aldehydes may react with either water or alcohol to form aldehyde hydrates or hemiacetals, respectively (also see figure 7 for intramolecular hemiacetals formed by sugars). Reaction of an aldehyde with two molecules of alcohol leads to acetal formation. 

The reaction of a 1,2- or a 1,3-diol with an aldehyde or ketone under anhydrous conditions gives rise to a cyclic acetal. A discussion of this reaction is given in Section 5.10.3, p. 652, where some structural features for acetal formation and selectivity of removal are reviewed. Other instances of the value of this protective group are to be found in Expts 5.9 and 5.63 and in Section 5.8.8, p. 623. It should be pointed out that cyclic acetal formation is also an important procedure for the protection of the carbonyl group. 

In alcohol solution a carbonyl compound is in equilibrium with the acetal and hemiacetal forms. While for aldehydes these species are important, and sometimes predominate, for ketones they are usually present in smaller amounts. For this reason, most of the available data on equilibria deal with aldehydes, and only a few of them with ketones. Reports on acetal formation by Davis et al. (1975), Guthrie (1975), Machacek and Sterba (1976), Kavalek et al. (1976), Toullec and Alaya (1978) and Wiberg and Squires (1979), as well as ones on hemiacetal formation by Guthrie (1975) and Crampton (1975), have been published in the last few years. 

Experiments on the bromination of equilibrated ketone-acetal systems in methanol were also recently performed for substituted acetophenones (El-Alaoui, 1979 Toullec and El-Alaoui, 1979). Lyonium catalytic constants fit (57), but for most of the substituents the (fcA)m term is negligible and cannot be obtained with accuracy. However, the relative partial rates for the bromination of equilibrated ketone-acetal systems can be estimated. For a given water concentration, it was observed that the enol path is more important for 3-nitroacetophenone than for 4-methoxyacetophenone. In fact, the smaller the proportion of free ketone at equilibrium, the more the enol path is followed. From these results, it can be seen that the enol-ether path is predominant even if the acetal form is of minor importance. The proportions of the two competing routes must only depend on (i) the relative stabilities of the hydroxy-and alkyoxycarbenium ions, (ii) the relative reactivities of these two ions yielding enol and enol ether, respectively, and (iii) the ratio of alcohol and water concentrations which determines the relative concentrations of the ions at equilibrium. Since acetal formation is a dead-end in the mechanism, the amount of acetal has no bearing on the relative rates. Bromination, isotope exchange or another reaction can occur via the enol ether even in secondary and tertiary alcohols, i.e. when the acetal is not stable at all because of steric hindrance. 

Conversely, most acetals are hydrolyzed simply by shaking them with dilute acid in water. The large excess of water drives the equilibrium toward the ketone or aldehyde. The mechanism is simply the reverse of acetal formation. For example, cyclohexanone dimethyl acetal is quantitatively hydrolyzed to cyclohexanone by brief treatment with dilute aqueous acid. 

Cyclic Acetals Formation of an acetal using a diol as the alcohol gives a cyclic acetal. Cyclic acetals often have more favorable equilibrium constants, since there is a smaller entropy loss when two molecules (a ketone and a diol) condense than when three molecules (a ketone and two molecules of an alcohol) condense. Ethylene glycol is often used to make cyclic acetals its acetals are called ethylene acetals (or ethylene ketals). 

Selective Acetal Formation Because aldehydes form acetals more readily than ketones, we can protect an aldehyde selectively in the presence of a ketone. This selective protection leaves the ketone available for modification under neutral or basic conditions without disturbing the more reactive aldehyde group. The following example shows the reduction of a ketone in the presence of a more reactive aldehyde ... 

Just as protonated carbonyl groups are much more electrophilic than unprotonated ones, these oxonium ions are powerful electrophiles. They can react rapidly with a second molecule of alcohol to form new, stable compounds known as acetals. An oxonium ion was also an intermediate in the formation of hemiacetals in acid solution. Before reading any further, it would be worthwhile to write out the whole mechanism of acetal formation from aldehyde or ketone plus alcohol through the hemiacetal to the acetal, preferably without looking at the fragments of mechanism above, or the answer below. 

We have already mentioned that one of the factors that makes acyclic ftemiacetals unstable is the unfavourable decrease in entropy when two molecules of starting material (aldehyde or ketone plus alcohol) become one of product. The same is true for acetal formation, when three molecules of starting material (aldehyde or ketone plus 2 x alcohol) become two of product (acetal plus H2O). We can improve matters if we tie the two alcohol molecules together in a diol and make a cyclic acetal we discuss cyclic acetals in the next section. Alternatively, we can use an orthoester as a source of alcohol. Orthoesters can be viewed as the acetals of esters or as the triesters of the unknown orthoacids —the hydrates of carboxylic acids. They are hydrolysed by water, catalysed by acid, to ester + 2 x alcohol. 

Ketones or aldehydes can undergo acetal exchange with orthoesters. The mechanism starts off as if the orthoester is going to hydrolyse but the alcohol released adds to the ketone and acetal formation begins. The water produced is taken out of the equilibrium by hydrolysis of the orthoester. 

Mori et al. estimated, quantitatively by means of GC analysis, the effects of the functional groups at Cl 1, C17, and C20 on the 5(3/5a ratios of the resulting saturated ketones in the hydrogenation of twenty-five 3-oxo-4-ene steroids over a palladium black in i-PrOH, i-PrOH-HCl, AcOH, and AcOH-HCl at 25°C and atmospheric pressure.270 Isopropyl alcohol was used as the solvent, instead of ethanol, to avoid acetal formation.189 The results are summarized in Table 3.18. The effect of a substituent to increase the proportion of 5 3 isomer was defined as positive and the reverse effect as negative, on the basis of the results with the corresponding parent steroids without the substituent. The 5 3/5a ratio obtained in the hydrogenation of cholest-4-ene with a... 

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