Formation of Acetals and Ketals

Aldehydes and ketones react with two moles of an alcohol to give products called acetals and ketals. If one mole of an alcohol reacts with one mole of an aldehyde or ketone, the product is a hemiacetal or a hemiketal. 

Both acetals and ketals have two alkoxy groups (—OR ) attached to the same carbon atom. An acetal has a hydrogen atom and an alkyl group attached to the carbon atom, and a ketal has two alkyl groups attached. 

Cyclic hemiacetals and hemiketals also react with alcohols to produce cyclic acetals and cyclic ketals. We will see this reaction again when we consider carbohydrates in Chapter 24. 

The conversion of a hemiacetal to an acetal and the conversion of a hemiketal to a ketal are reversible in acid solution. Removing the water formed in the reaction or increasing the concentration of alcohol shifts the position of the equilibrium to the right, toward formation of an acetal or ketal. 

The benzyl groups can be removed by catalytic hydrogenolysis, using Pd/C catalyst [16]. A very simple, specific, and mild alternative method of removal uses ferric chloride in methylene chloride for 15-30 min at 20°C, and results in 70% yields [17]. Methyl ethers and esters are not removed by this procedure. 

Silyl ethers are formed with carbohydrate hydroxyl groups by reaction with chlorotrimethylsilane in pyridine with hexamethyldizilazane. Trimethylsilyl ethers are stable in neutral and basic condition but are hydrolyzed in aqueous acidic conditions [18]. The major uses of the silyl ethers is the formation of highly volatile carbohydrate derivatives that can be used in gas chromatography and gas chromatography/mass spectrometric analysis [19,20]. 

One of the best-known isopropylidene derivatives is diacetone glucose (1,2 5,6-di-O-isopropylidene D-glucofuranoside). It is prepared by the reaction of D-glu-cose in anhydrous acetone at 20°C with sulfuric acid or zinc chloride as catalysts [21] (reaction 4.20). The reaction of acetone has a preference for a cw-vicinal diol. 

When D-glucose forms the furanose ring, it has two such diols at positions 1 and 2, and 5 and 6 (reaction 4.20). This then is the acetone derivative of D-glucose that is formed. Diacetone D-glucose is easily crystallized from cyclohexane [21]. 

The isopropylidene groups can be removed by aqueous acid. When there are two isopropylidene groups, one of the groups is usually more easily removed than the 

In this section, consideration will be given to the actual processes of acetal- or ketal-formation and not to the more indirect methods by which acetals and ketals of the polyhydric alcohols may be synthesized from compounds (e.g. derivatives of the monosaccharides) containing preformed alkylidene or arylidene groupings. The condensation of a carbonyl compound with a glycol is facilitated by acidic catalysts, and, since the reaction is reversible, by dehydration. The catalysts most frequently employed are concentrated sulfuric, hydrochloric and hydro-bromic acids, gaseous hydrogen chloride, zinc chloride and cupric sulfate others are phosphorus pentoxide, sulfosalicylic acid, and anhydrous sodium sulfate. The formation of benzylidene compounds is promoted less efficiently by phosphorus pentoxide than by either concentrated sulfuric acid or concentrated hydrochloric acid 1 the reaction is assisted by chloro- and nitro-substituents on the aromatic nucleus, but hindered by methyl- and methoxy-groups.18 

In the absence of a catalyst, the reaction between a polyhydric alcohol and a carbonyl compound may proceed only as far as the formation of a semi-acetal 14 however, if water is removed as it is produced in the reaction mixture, the true acetal is obtained. For example, azeotropic distillation with a water-immiscible liquid, such as benzene, toluene or xylene, has been employed in the synthesis of butylidene, methylene and furfurylidene acetals.15 In the latter case, this technique is particularly useful because of the marked instability of furfuraldehyde under acidic conditions.15 

The nature of the condensation product derived from any given pair of reactants is frequently independent of the type of catalyst used, but this is not always the case. Haskins, Hann and Hudson, for example, demonstrated that at room temperature hydrogen chloride catalyzes the formation of a 2,3,4,5-dibenzylidene derivative of 1,6-dibenzoyl-dulcitol, 

The stability of an acetal or a ketal may depend on the catalyst employed in its synthesis. For this and other reasons, Fischer and Taube20 recommended the use of zinc chloride, rather than a mineral acid, as the catalyst in acetonation processes. Presumably the instability of the products prepared with the aid of strong acids is due to the difficulty of ensuring complete removal of the catalysts. 

When the carbonyl compound concerned in acetal-formation is appreciably volatile, it is often more convenient to use it in a polymeric form (e.g. paraformaldehyde,4 21 paraldehyde22). In such cases an acid is employed to catalyze both the regeneration of the monomer and the formation of the acetal. 

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See Section 60A (Protection of Aldehydes) and Section 180A (Protection of Ketones) for reactions involving formation of Acetals and Ketals. 

Sucrose is a disaccharide that is composed of a unit of glucose (acetal form) and a unit of fructose (ketal form) linked through C-1 of glucose and C-2 of fructose, i.e. a 1,2 link. In sucrose, neither glucose nor fructose can exist in open chain form because of the formation of acetal and ketal as shown below. As a result, sucrose is not a reducing sugar, and does now exhibit mutarotation. The specific rotation [a]D of sucrose is +66°. 

Reactions of Aldehydes and Ketones Aldehydes and ketones are central players in organic synthesis because of the wide variety of reactions they undergo. Likewise, their chemistry is important to biological systems. We will consider just two of the reactions involving these compounds oxidation/reduction and formation of acetals and ketals. 

SCHEME 2.19 Notable formations of acetals and ketals on pyranosides. 

The acid-catalysed formation of acetals and ketals of ascorbic acid is particularly useful for the. selective protection of the molecule whilst structural modification is being carried out. The 5,6-0-derivatives such as the isopropylidene ketal and benzylidene acetal are well known but, more recently, it has proved po.ssible to protect the C-2/C-3 positions selectively using particularly reactive aldehydes (Figure 4.14). This new development has paved the way for selective modification of the primary and secondary alcohol groupings on the ascorbic acid side chain. 

As for the diols, the symmetric compounds have found most uses for nonsymmetric diols, a versatile synthesis via silyl ketones using the SAMP/RAMP methodology has been developedl5. Both enantiomers of the simplest symmetric diol, 2,3-butanediol (11), are often used in asymmetric synthesis, mostly for the formation of acetals and ketals with carbonyl compounds and subsequent reactions with acidic catalysts (Section D. 1.1.2.2.), Grignard reagents (Section D. 1.3.1.4.) and other carbanions (Sections D. 1.5.1., D. 1.5.2.4.), and diastereoselective reductions (Section D.2.3.3.). Precursors of chiral alkenes for cycloprotonations (Section D.1.6.1.5.) and for chiral allenes (Section B.I.), and chiral haloboronic acids (Section D. 1.1.2.1.) are other applications. The free diol has been employed as a chiral ligand in molybdenum peroxo complexes used for enantioselective epoxidation of alkenes (Section D.4.5.2.2.). 

The equilibrium constants for addition of alcohols to carbonyl compounds to give hemiacetals or hemiketals show the same response to structural features as for the hydration reaction. Equilibrium constants for addition of methanol to acetaldehyde in both water and chloroform solution are near 0.8 M" The comparable value for addition of water is about 0.02 M The overall equilibrium constant for formation of the dimethyl acetal of acetaldehyde is 1.58 M . Because the position of the equilibrium does not strongly favor product, the formation of acetals and ketals must be carried out in such a way as to drive the reaction to completion. One approach is to use a dehydrating reagent or azeotropic distillation so that the water that is released is irreversibly removed from the system. 

Formation of Acetals and Ketals. The protection of carbonyl groups as acetals or ketals is a necessary requirement for the manipulation of many multifunctional molecules. Amberlyst 15 and Dowex 50 are excellent acidic catalysts for such transformations. When trlethyl orthoformate (eq 1) is used, enol ether formation from a,/3-unsaturated carbonyls can also occur. 

Formation of Acetals and Ketals under Alkaline Conditions... 

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