Equilibria acetal formation

Other Reactions at the Carbonyl Carbon Atom.— Acetal formation from 3-oxo-steroids in anhydrous alcohols is far more effective than was previously realised. C.d. studies revealed almost quantitative conversion of 5a- or 5 -3-oxo-steroids in methanol into their 3,3-dimethoxy-derivatives, and ethanol or propan-2-ol also gave considerable proportions of the corresponding acetals. Contrary to earlier belief, even the hindered 2-oxo-group gave the 2,2-dimethoxy-derivative (73 % at equilibrium). Acetal formation was drastically reduced by traces of water, however, or by alkyl substitution adjacent to the oxo-group. 

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... 

The rates of both formation and hydrolysis of dimethyl acetals of -substituted benzaldehydes are substituent-dependent. Do you expect to increase or decrease with increasing electron-attracting capacity of the pam substituent Do you expect the Ahydroi to increase or decrease with the electron-attracting power of the substituent How do you expect K, the equilibrium constant for acetal formation, to vary with the nature of the substituent ... 

Because all the steps in acetal formation are reversible, the reaction can be driven either forward (from carbonyl compound to acetal) or backward (from acetal to carbonyl compound), depending on the conditions. The forward reaction is favored by conditions that remove water from the medium and thus drive the equilibrium to the right. In practice, this is often done by distilling off water as it forms. The reverse reaction is favored by treating the acetal with a large excess of aqueous acid to drive the equilibrium to the left. 

Such esterifications and acetal formations are achieved through enzyme catalyses. However, such reactions are relatively rare in aqueous conditions chemically. This is because the reversed reactions, hydrolysis, are much more favorable entropically. Kobayashi and co-workers found that the same surfactant (DBSA) that can catalyze the ether formation in water (5.2 above) can also catalyze the esterification and acetal formations reactions in water.52 Thus, various alkanecarboxylic acids can be converted to the esters with alcohols under the DBSA-catalyzed conditions in water (Eq. 5.6). Carboxylic acid with a longer alkyl chain afforded the corresponding ester better than one with a shorter chain at equilibrium. Selective esterification between two carboxylic acids with different alkyl chain lengths is therefore possible. 

Halide ions will also act as nucleophiles towards aldehydes under acid catalysis, but the resultant, for example, 1,1-hydroxychloro compound (35) is highly unstable, the equilibrium lying over in favour of starting material. With HC1 in solution in an alcohol, ROH, the equilibrium is more favourable, and 1,1-alkoxychloro compounds may be prepared, e.g. 1-chloro-l-methoxymethane (36, a-chloromethyl ether ) from CH20 and MeOH (cf. acetal formation, p. 209), provided the reaction mixture is neutralised before isolation is attempted ... 

Acetal formation is reversible (K for MeCHO/EtOH is 0-0125) but the position of equilibrium will be influenced by the relative proportions of R OH and H2O present. Preparative acetal formation is thus normally carried out in excess R OH with an anhydrous acid catalyst. The equilibrium may be shifted over to the right either by azeotropic distillation to remove H2O as it is formed, or by using excess acid catalyst (e.g. passing HCl gas continuously) to convert H2O into the non-nucleophilic H3O . Hydrolysis of an acetal back to the parent carbonyl compound may be effected readily with dilute acid. Acetals are, however, resistant to hydrolysis induced by bases—there is no proton that can be removed from an oxygen atom, cf. the base-induced hydrolysis of hydrates this results in acetals being very useful protecting groups for the C=0 function, which is itself very susceptible to the attack of bases (cf. p. 224). Such protection thus allows base-catalysed elimination of HBr from the acetal (27), followed by ready hydrolysis of the resultant unsatu-... 

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 ... 

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. 

S-Acetals are very readily hydrolyzed in the presence of soft metal ions and large rate accelerations e.g. ca. 106-fold compared with the proton) are found. In the case of S-acetals such as (136) only a small extent of pre-equilibrium complex formation occurs428 even with Hgu, but for substrates such as (137), 1 1 complex formation readily occurs with weaker binding metal ions such as Ag1. Kinetic terms reflecting binding of two Ag1 ions to the substrate (137) are detectable.429 Both A1 and A2-like schemes have been proposed for these S-acetal reactions and the topic was reviewed17 in 1977. 

In solution, DIB and carboxylic acids enter an equilibrium with formation of acetic acid and [bis(acyloxy)iodo]benzenes (Section 2.1). In some instances these need not be isolated upon irradiation of a mixture of DIB and an acid, a homolytic cleavage... 

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. 

Equilibrium of Acetal Formation Acetal formation is reversible, so the equilibrium constant controls the proportions of reactants and products that will result. For simple aldehydes, the equilibrium constants generally favor the acetal products. For example, the acid-catalyzed reaction of acetaldehyde with ethanol gives a good yield of the acetal. 

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). 

In fact, acetal formation is even more difficult than ester formation while the equilibrium constant for acid-catalysed formation of ester from carboxylic acid plus alcohol is usually about 1, for... 

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. 

Don t be confused by this statement Acetal formation and hydrolysis are invariably carried out under thermodynamic control—what we mean here is that the equilibrium constant for acetal hydrolysis, which is a measure of rate of hydrolysis divided by rate of formation, turns out to be small because the rate of formation is large. 

For a reversible reaction an increase in the acyl donor concentration results in higher product yields. In this case the chemical equilibrium is shifted towards synthesis. On the other hand, high concentrations of substrates may cause inhibition and the reaction is slowed down. For (R)-l-phenylethyl acetate formation the effect of the substrate vinyl acetate/l-phenylethanol molar ratio on the final conversion was studied. The results are presented on Figure 8.3. A higher yield of the enantiopure compound was achieved when raising the acyl donor molar concentration with respect to the alcohol concentration. A conversion of 49.9% was obtained at an acyl donor/alcohol molar ratio of 9/1. After 5 h of reaction at tested conditions a complete conversion of (R)-l-phenylethanol into the enantiopure (R)-l-phenylethyl acetate was attained. The enantiomeric excess for reactants (eeR) was 99.9%. 

Perhaps the most commonly encountered equilibrium reactions are those involving water as a reactant or product. Driving such equilibria by using excess water (e.g. hydrolysis reactions) is easy, but driving equilibria by removing water (e.g. in ester or acetal formation) can be more difficult. An excellent device for the continuous removal of water from a reaction mixture is the Dean-Stark trap (Fig. 9.27). 

Getting pure ethanol will be difficult. Ethanol is in the third distillation region, and no obvious means exist to cross the relevant distillation boundaries. A new entrainer might be added, as was the case for the previous example. However, since the ethanol is only going to be recycled to the reactor, the required purity specification might be questioned. What is the effect of small amounts of contaminants DEM and water in the recycled ethanol The acetal formation reaction is equilibrium-controlled, so there may be some deleterious effect of including products with a reactant. However, additional analysis indicated that the effect is small, and so the ethanol composition requirement was relaxed and the overhead composition recycled to the reactor directly as produced. 

The first line shows the normal mechanism for acetal formation and points out the by-product, a molecule of water. This w atcr is consumed in the hydrolysis of the ortho for mate (by an acetal n drolysis mechanism) to give a stable ordinary ester. The favourable second equilibrium pulls the Trst across to the right. 

Acetal formation is thermodynamically controlled so we need look only for the most stable possibi acetal. The one that is not formed is a ds-decalin - significantly less stable than the frans-decalir (12B) that is formed. The equatorial conformation of the phenyl group will decide its configuratior as aU the acetals are in equilibrium. 

We have not previously considered stereochemistry. Hemiacetal (and acetal) formation is thermodynamic control as aU the reactions are reversible. The dimer and trimer crystallize frc-liquid so the stereochemistry may be governed by the formation of the most stable p . compound or by the fact that the crystallization of the least soluble diastereoisomer removes the equilibrium and so more is formed. We can see some reasons why the diastereoisomer i might be the most stable. The as ring junction between the two five-membered rings is much m stable than the trans, the two acetyl groups may prefer to be trans to each other, and there ma. > H bond in the crystal. We cannot be sure of these reasons but they are explored more in Chap . ... 

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