Hydrolysis specific/general acid catalysis

It was pointed out in the mechanistic discussion concerning acetal and ketal hydrolysis that general acid catalysis occurs only for acetals and ketal having special structural features. Usually, specific acid catalysis operates. The question of whether general acid catalysis could be observed in intramolecular reactions has been of interest because intramolecular general acid catalysis is postulated to play a part in the mechanism of action of the enzyme lysozyme, which hydrolyzes the acetal linkage present in certain polysacharides. One group of molecules that has been examined as a model system are acetals derived from o-hydroxybenzoic acid (sali-... 

Acid catalysis of ester hydrolysis is also very effective. Oxygen exchange from water is observed under most cases, supporting addition-elimination. Specific-acid catalysis is the most common mode of hydrolysis, although general-acid catalysis is observed with more electrophilic esters. 

Specific and general acid catalysis. Formulate the rate law for the acid-catalyzed hydrolysis reaction42... 

The term acid catalysis is often taken to mean proton catalysis ( specific acid catalysis ) in contrast to general acid catalysis. In this sense, acid-catalyzed hydrolysis begins with protonation of the carbonyl O-atom, which renders the carbonyl C-atom more susceptible to nucleophilic attack. The reaction continues as depicted in Fig. 7. l.a (Pathway a) with hydration of the car-bonium ion to form a tetrahedral intermediate. This is followed by acyl cleavage (heterolytic cleavage of the acyl-0 bond). Pathway b presents an mechanism that can be observed in the presence of concentrated inorganic acids, but which appears irrelevant to hydrolysis under physiological conditions. The same is true for another mechanism of alkyl cleavage not shown in Fig. 7.Fa. All mechanisms of proton-catalyzed ester hydrolysis are reversible. 

Fig. 7.1. a) Specific acid catalysis (proton catalysis) with acyl cleavage in ester hydrolysis. Pathway a is the common mechanism involving a tetrahedral intermediate. Pathway b is SN1 mechanism observed in the presence of concentrated inorganic acids. Not shown here is a mechanism of alkyl cleavage, which can also be observed in the presence of concentrated inorganic acids, b) Schematic mechanism of general acid catalysis in ester hydrolysis. 

It is primarily this difference in carbonium ion stability that makes 2-methoxytetrahydropyran 3x10 times more reactive than methyl a-D-glucopyranoside (Dyer et al., 1962). A phenohc leaving group and moderate carbonium ion stability must be present together for general acid catalysis to occur the hydrolysis of 2-ethoxytetrahydro-pyran is specific acid-catalysed (Fife and Jao, 1968). 

Explain why general acid catalysis is found in the hydrolysis of tropone diethyl-ketal (1), despite the fact that hydrolysis of dialkyl ketals ordinarily shows only specific hydronium ion catalysis. 

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. 

In the case of apparent general acid catalysis of acetylimidazole hydrolysis, the mechanism can be defined as a specific acid-general base process by comparison with the general base catalysis of N-methyl,N -acetylimidazolium ion. The rate of disappearance of N-methyl,N -acetylimidazolium ion in water at 25° is proportional to the concentration of the basic form of buffer components such as acetate, phosphate, N-methylimidazole, etc., (equation 30) (Wolfenden and Jencks, 1961). The buffer terms show a 1 1 correlation with the general acid-catalyzed rate of acetylimidazole disappearance (Jencks and Carriuolo, 1959) in water at 25°, when the rate expression for the latter reaction is written in terms of equation (32) rather than equation (31), that is, in terms of a general base-catalyzed hydration of protonated acetylimidazole (pX= 3-6). 

The interpretation of the observed rate increase of the reaction of epichlorohydrin with iodide ion in the presence of acetic acid was questioned by Long and Paul, who suggested that specific effects of the medium brought about by 4.0 M acetic acid may be responsible for the rate increase rather than general acid catalysis.72 However, the alternative mechanism for acid-catalyzed epoxide hydrolysis proposed by these workers, an A-l mechanism involving a carbocation intermediate, has been ruled... 

Figure 3.17 Molecular mechanisms giving rise to enhanced hydrolysis rates of glycosides with carboxylic acid groups. In the case of salicyl fi-glucoside, frontside nucleophilic attack is stereoelectronically prohibited and distinction between specific acid catalysis of the hydrolysis of the anion and intramolecular general acid catalysis was made on the basis of solvent isotope effects in related systems. ...

Amide participation appears to be about as effective in specific acid-catalysed hydrolysis (of the methyl glycosides) as in spontaneous hydrolysis (of the 2,4-dinitrophenyl glycosides). There is some evidence for simultaneous general acid catalysis and amide participation in the hydrolysis of p-D-GlcNAcp-OoCfiH4COOH. 

An obvious starting point was to look for general acid catalysis of the attack of nucleophiles on a methyoxymethyl acetal known to be subject to efficient carboxyl-catalyzed hydrolysis. Participation by nucleophiles other than water in the hydrolysis of the salicylic acid derivative 3.17 could not be convincingly distinguished from specific salt effects (the range of nucleophiles is limited by the requirement that the COOH group (pKa 3.77) be protonated) [49]. On the other hand there is clear involvement of nucleophiles, including carboxylate anions, in the reaction of the dimethylammonium system 3.18 [44] (Scheme 2.24). The difference is presumably simply quantitative. 

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