Hydrolysis of an acetal

The THP group can be removed by dilute aqueous acid. The chemistry involved in both the introduction and deprotection stages is the reversible acid-catalyzed formation and hydrolysis of an acetal (see Part A, Section 7.1). 

The conversion of 7 to 8 is a simple hydrolysis of an acetal. Acetals are functionally equivalent to alcohols + carbonyls and can be interconverted with them under acidic conditions. Several reasonable mechanisms can be drawn for this transformation, but all must proceed via S l substitutions. 

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-... 

This protective group is introduced by an acid-catalyzed addition of the alcohol to the vinyl ether moiety in dihydropyran. />-Toluenesulfonic acid or its pyridinium salt is used most frequently as the catalyst,3 although other catalysts are advantageous in special cases. The THP group can be removed by dilute aqueous acid. The chemistry involved in both the introduction and deprotection stages is the reversible acid-catalyzed formation and hydrolysis of an acetal (see Part A, Section 8.1). 

The uncatalyzed hydrolysis of an acetal involves a transition state that is close in structure to an oxocarbenium ion and an alkoxide ion (equation 2.9). 

The formation or the hydrolysis of an acetal function proceeds by the mechanism described in Fig. 16 in which oxonium ions and hemiacetals occur as intermediates. It has also been established (76) that the rate determining step in acetal hydrolysis is generally the cleavage of the C—bond of the protonated acetal 100 to form the oxonium ion 111, This ion is then rapidly hydrated to yield the protonated hemiacetal 112 which can give the aldehyde product after appropriate proton transfers. It is pertinent therefore to find out if stereoelectronic effects influence the rate determining step (110 111) of this hydrolysis reaction. 

The first step is acid hydrolysis of an acetal protecting group. Step 1 ... 

The difference between the hydrolysis of an orthoester and the hydrolysis of an acetal is that profanation and C-O bond cleavage occur together in the former. In the hydrolysis of an acetal, the protonated form of the acetal is produced as an intermediate in the reaction. While we will not go into details here, the hydrolysis of the orthoester constitutes a case of what is known as general acid catalysis, while that of an acetal is specific acid catalysis. 

Here we apply the general principles for proposing reaction mechanisms to the hydrolysis of an acetal. These principles were introduced in Chapters 7 and 11 and are summarized in Appendix 3A. Remember that you should draw all the bonds and substituents of each carbon atom involved in a mechanism. Show each step separately, using curved arrows to show the movement of electron pairs (from the nucleophile to the electrophile). 

Ethyl orthoformate resembles an acetal with an extra alkoxy group, so this mechanism should resemble the hydrolysis of an acetal (Section 18-17). There are three equivalent basic sites the three oxygen atoms. Protonation of one of these sites allows ethanol to leave, giving a resonance-stabilized cation. Attack by water gives an intermediate that resembles a hemiacetal with an extra alkoxy group. 

Successful SPS produces a final resin-bound target molecule that is released into solution by breaking a bond between the resin and a functional group in the final compound. Two examples are shown in Fig. 1.6. On the left, the basic hydrolysis of an ester bond releases a carboxylic acid into solution and simultaneously re-forms the original hydroxy PS resin. On the right, the acidic hydrolysis of an acetal function provides the starting aldehyde resin and a diol compound. 

Esters at C4 are formed as intermediates in acylations at C3 (69JHC13), although they can be isolated (see Section V,A,l,a). Special esters are the methanesulfonates (85JHC433) and the 4-toluenesulfonates (7111043 85S699). Hydrolysis of an acetate has also been described (85JMC1828). 

In the textbook (p. 227) we showed you a selective hydrolysis of an acetal. Why were the other acetals (one is a thioacetal) not affected by this treatment How would you hydrolyse them Chloroform (CHCb) is the solvent. 

Let us consider the reverse of acetal formation, i.e., acid hydrolysis of an acetal within the ambit of stereoelectronic effects and explore the underlying features. We begin by understanding the conformational profile and the associated conformational effects by representing the acetal in such a way that it appears to be part of a cyclohexane chair. In doing so, we understand the geometrical relationship of various bonds on this ring system much better. 

Show the mechanism for the acid-catalyzed hydrolysis of an acetal. 

Intermolecular general acid catalysis of the hydrolysis of acetals and ketals Fig. 8 shows, in general terms, the reaction profile for the specific acid-catalysed hydrolysis of an acetal or a ketal. 

Pentenyl acetals are often used in glycoside synthesis since they can be readily hydrolyzed under neutral conditions by halonium ions, e.g., Br as liberated in NBS/CH3CN/H2O mixtures (Mootoo et al, 1988). This hydrolysis of an acetal without the use of an acid is driven by a cascade of ionic intermediates starting with the bromonium adduct to the terminal double bond (Scheme 4.4.3). 

If you think back to Chapter 11, you wiU recall that the first step in the hydrolysis of an acetal is a similar reaction, with one alkoxy group replaced by water to give a hemiacetal. We considered the mechanism for this reaction in Chapter 11 but did not then concern ourselves with a label for the first step. It is in effect an Sjjl substitution reaction the decomposition of the protonated acetal to give an oxonium ion. If you compare this step with the reaction of the chloroether we have just described you will see that they are very similar in mechanism. 

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