The Acetalation Reaction

The oxonium ion 3 reacts rapidly with the nearest hydroxyl group to give the first (or kinetic) product, which may, however, subsequently rearrange to give the thermodynamically most stable product(s). Thus, the reaction may be divided into a kinetic and a thermodynamic phase, and the product(s) of each of these may differ considerably from each other. Whether or not the products isolated are true equilibrium products depends on the stage at which the reaction was terminated, and on such factors as the solubility and the temperature. 

These principles are clearly illustrated by reference to the reaction between glycerol and benzaldehyde in /V,/V-dimethylformamide in the presence of p-toluenesulfonic acid.9 The reaction may conveniently be monitored by n.m.r. spectroscopy, which reveals that the cis- and tram-1,3-dioxolanes (5 and 7, respectively) are formed first. These are then slowly converted into the 1,3-dioxanes (6 and 8), which preponderate in the equilibrium mixture. The final ratios for the acetals 6,8,5, and 7 are 1.8 1.8 1.2 1.0. It may be noted that initial ring-closure of the intermediate oxocarbonium ion (9) affords a five-membered more readily than a six-membered ring. The large differences in entropy between the 1,3-dioxanes and the 1,3-dioxolanes imply that the product composition is temperature-dependent. At low temperatures, the formation of 1,3-dioxanes is favored. 

Newer synthetic procedures now enable the chemist to impose a considerable degree of kinetic control on the products of the reaction. Thus, good yields of acetals have been obtained from trans (eq-eq), vicinal-diol groupings on pyranoid rings such acetals are rare if conventional procedures are used. Furthermore, the dominance of kinetic control frequently leads to good yields of diastereoisomers. These aspects will be discussed in more detail in succeeding Sections. 

One of the essential factors governing the products of acetalation is the disposition of available hydroxyl groupings of the conceivable products obtained at equilibrium, the relative free-energies of the isomers will be decisive. This, in turn, will involve a consideration of ring strain, nonbonded interactions, and repulsions. 

for example, immediately evident from an inspection of the data that O-isopropylidene derivatives of cis-1,2-diols are formed more readily than those of trans-1,2-diols. This is attributed to the facts that acetal formation at the cts-diol requires less distortion, and subsequent strain, of either the five- or six-membered rings. In fact, there does not appear to be any recorded case of a 1,3-dioxolane acetal trans-fused to a five-membered ring. 

---

Based on the above-mentioned stereochemistry of the allylation reactions, nucleophiles have been classified into Nu (overall retention group) and Nu (overall inversion group) by the following experiments with the cyclic exo- and ent/n-acetales 12 and 13[25], No Pd-catalyzed reaction takes place with the exo-allylic acetate 12, because attack of Pd(0) from the rear side to form Tr-allyl-palladium is sterically difficult. On the other hand, smooth 7r-allylpalladium complex formation should take place with the endo-sWyWc acetate 13. The Nu -type nucleophiles must attack the 7r-allylic ligand from the endo side 14, namely tram to the exo-oriented Pd, but this is difficult. On the other hand, the attack of the Nu -type nucleophiles is directed to the Pd. and subsequent reductive elimination affords the exo products 15. Thus the allylation reaction of 13 takes place with the Nu nucleophiles (PhZnCl, formate, indenide anion) and no reaction with Nu nucleophiles (malonate. secondary amines, LiP(S)Ph2, cyclopentadienide anion). 

As these acetals could be converted into the 4,6-O-ethylidene derivatives on treatment with acid, it was reasoned that use of a cyclic vinyl ether, namely, 3,4-dihydro-2H-pyran, might prevent this second process, thus leading to a more useful method of selective acetalation.338 An equimolar reaction with methyl a-D-glu-copyranoside for 4 days in N,N-dimethylformamide led to utilization of 88% of the glycoside, and the 6-(tetrahydropyran-2-yl) ether constituted —85% of the crude reaction-product. In contrast to the steric control apparent in this instance, reaction of 3,4-dihydro-2H-pyran with the axial and equatorial hydroxyl groups in dl-1,4,5,6-tetra-O-acetyl-mi/o-inositol was completely unselective,339 a fact that has been rationalized310 in terms of the probable mechanism of these reactions. 

Important in this quite general strategy is that, for practically all instances, die reaction is under thermodynamic control, and the control of the stoichiometry is extremely difficult It follows that only the more stable acetals are produced (see Sec. H.B) and usually multiacetals are obtained if several hydroxyl groups are available within die same molecule. This has been a major concern in acetalation reactions in neutral conditions. For instance, use of copper(II)sulfate either in acetone alone or in N, N-dunethylformamide without any additional catalyst leads to acetals with structures that differ from those resulting from reactions in the presence of an acid The reaction depends on the temperature [31] however, the strict neutrality of a medium in which copper(II)sulfate and polyols are interacting can be questioned. 

Hphe molecular mechanism of acid hydrolysis of glycosides is rather well understood today, much confusion being resolved now by the achievements of conformational analysis of carbohydrates (1,2). With regard to the three consecutive steps of reaction (cf. Figure 1)—Le., the formation of a conjugate acid by protonation of either one of the acetalic... 

With the heterogeneous hydrolysis of polysaccharides like cellulose, these general considerations are valid, too, of course, but the rate of cleavage is slowed down by one or two orders of magnitude by the limited accessibility of the acetalic O atoms. The rate of reaction depends largely on the physical structure of the original samples and on the state... 

For a five-membered dioxolane ring, the regioselectivity depends on the stereochemistry of the benzylidene acetalic carbon atom. For example, treatment of the methyl endo 2,3-0-benzylidene protected rhamnoside with LiAlILi-AlClj gave a 2-0-benzyl derivative, but the same reaction with the 2-exo isomer yielded mainly the 3-0-benzyl derivative.32... 

Further investigations on the field of oxidative bond cleavage even made single bonds accessible. Thus, biaryls 10 and 11 were similarly obtained by electrooxidation of 9,10-dihydrophenanthrene. Moreover, the cleaving reaction of benzylic carbons was also exploited in the synthesis p-tert-butylbenzaldehyde dimethyl acetale (3) starting from l,2-di-(p-ferf-butylphenyl)ethane (4, 1,2-DPTE) (Fig. 5.8) (Zollinger et al. 2004b). 

Application of the Wittig reaction in the carbohydrate field is accompanied by certain difficulties. A correct choice of the initial sugar components is the main problem, owing to the basicity of phosphoranes and, especially, to the drastically basic conditions employed with phosphonium ylides (2a). It is not surprising, therefore, that protected (acetalated and aeetylated) aldehydo sugars and resonance-stabilized phosphoranes were used at first,3-5 although partially protected, and even unprotected, aldoses were shown to be amenable to the reaction with various resonance-stabilized phosphoranes, thanks to the presence of the carbonyl form in the mobile equilibrium. The latter reactions, however, are extremely complicated (see Section IV, p. 284). 

The mechanism of the acetalation of D-fructose has not been studied so comprehensively as that of L-sorbose. The former reaction appears to be much less complex, but there are many features common to the two reactions. Comparative studies of the acetalation of D-fructose by various aldehydes and ketones have not been reported, although such researches would be a fruitful source of needed and valuable information. 

NBS is an effective catalyst for the acetalation of alcohols under mild conditions 4 4 aldehydes are converted to 1,1-diacetates by reaction of acetic anhydride with NBS as a catalyst. ... 

In some cases the addition of electrophilic alkenes, such as 4-allyl-1,2-dimethoxybenzene, to the reaction mixture can improve the outcome of the reaction, particularly when run in the presence of thioglycosides, by scavenging a by-product of the reaction, phenylsulfenyl tritlate. Non-carbohydrate thioacetal sulfoxides also undergo similar acetalation reactions when treated with Tf20 (eq71).i ... 

Another important modification of poly(vinyl acetate) is its derivatization with aldehydes to poly(vinyl acetal)s [269]. This can be accomplished by first hydrolyzing the poly(vinyl acetate) to poly(vinyl alcohol) and then carrying out a subsequent acetalation reaction with an aldehyde and a strong mineral acid in water. Alternatively, poly(vinyl acetate) can be converted in a single one-pot reaction with acetic acid as a solvent directly to the poly(vinyl acetal) by reaction with water, an aldehyde, and a mineral acid catalyst. 

Another common method for the synthesis of polyacetals involves trans-acetalation reactions of diols with acetylenic compounds [14] or vinyl ethers [15], The reaction of bis(chloromethyl) ether with diols in the presence of pyridine to give polyacetals is not recommended since bis(chloromethyl) ether is considered highly carcinogenic [16]. 

This unwanted phenomenon can be minimized by conducting the acetalation under milder conditions—brief reaction in dilute solution at low temperatures [23],... 

Cyclic Acetals. One of the most significant developments in the chemistry of sucrose was the synthesis of cycHc acetals which, despite many attempts, were not synthesized until 1974. The first synthesis of 4,6-0-benzyhdenesucrose was achieved from the reaction of sucrose with a, a-dibromotoluene in pyridine (29). Since then, many new acetalating reagents have been used to give a variety of sucrose acetals, generally by transacetalation reactions. 

Acetalation. As polyhydroxy compounds, carbohydrates react with aldehydes and ketones to form cycHc acetals (1,13). Examples are the reaction of D-glucose with acetone and a protic or Lewis acid catalyst to form l,2 5,6-di-0-isoprop5lidene-a-D-glucofuranose [582-52-5] and its reaction with benzaldehyde to form 4,6-0-benzyhdene-D-glucopyranose [25152-90-3]. The 4,6-0-(l-carboxyethyhdine) group (related to pymvic acid) occurs naturally in some polysaccharides. 

---