The Acid-Catalyzed Hydrolysis of Glycopyranosides

The removal of the hydroxyl group from either the C2 or the C6 carlxMi accelerates the acid-catalyzed hydrolysis. Whereas the rate acceleration of acid-catalyzed hydrolysis is enormous for the C2 deoxy glycopyranosides (ca. 2 to 5 X 10 times), the rate acceleration for the C6 deoxy glycopyranosides is much smaller (only ca. 8 times). 

The acid-catalyzed hydrolysis of pentopyranosides is generally faster than that of hexopyranosides (4.5-9.0 times) but slower than the acid-catalyzed hydrolysis of 6-deoxy-hexopyranosides. 

The introduction of an electron-withdrawing group at the C6 carbon reduces the rate of acid-catalyzed hydrolysis (die acid-catalyzed hydrolysis of methyl glycoside of D-glucuronic acid is ca. 2 times slower than methyl glycoside of o-glucose). 

In Table 3.2 the rate coefficients and kinetic parameters for the hydrolysis of select glycosides in 2.0N HCl extrapolated to 60 °C are given. The concentratiOTi of HCl for the hydrolysis of methyl 2-deoxy-a and p-D-glucopyranoside was O.IN. 

Methyl D-glycopyranoside Relative rates a p ratio Orientation of 1-OMe group 

---

Obviously, few of the results presented thus far can be taken as unequivocal evidence for the cyclic mechanism (see equation 1). However, there is little, if any, evidence for the acyclic mechanism (equation 2) (see, however. Ref. 1), and it is generally agreed that the acid-catalyzed hydrolysis of glycopyranosides proceeds through a cyclic, carbonium-ion intermediate. The following discussions will, therefore, be based on the first mechanism. 

All kinetic studies have thus far strongly supported the hypothesis that the acid-catalyzed hydrolysis of glycopyranosides proceeds via formation of a positively charged oxocarbenium ion and that the cleavage of the Cl-Ol bond is the rate-determining step. The initial reversible protonation of one of the two acetal oxygens and the nucleophilic attack of the water molecule to the oxocarbenium ion transition state intermediate are very fast processes. 

Feather MS, Harris JF (1965) The acid-catalyzed hydrolysis of glycopyranosides. J Org Chem 30 153-157... 

Unlike numerous kinetic and mechanistic studies of acid-catalyzed hydrolysis of glycopyranosides [5, 7, 9, 12, 16, 24-30] that led to the conclusion that glycopyranosides are hydrolyzed via an A-1 mechanism (the molecularity of the reaction and the entropy of activation (positive AS ), dissociation of methanol, and the formation of oxocarbenium ion transition state intermediate) (42 in Fig. 3.9), the acid-catalyzed hydrolysis of glycofuranosides has been studied much less [4, 9, 31-34]. 

Bols and coworkers reported linear free energy relationships for the hydrolysis of glycopyranosides.48 Axial and equatorial substituent effects, determined from amine basicity of similarly configured compounds, were employed.49 The two reactions studied were the spontaneous hydrolysis of 2,4-DNP glycosides, and the specific acid-catalyzed hydrolysis of methyl glycosides (Scheme 21). 

By examining these TS geometries, Nerinckx et al. [59] have recently suggested an explanation as to why there is such a small difference in energy between these transition states and also as to why the rates of acid-catalyzed hydrolysis of a- and P-D-glycopyranosides are so close. 

The cleavage of a glycosidic bond by acetolysis is an alternative method to hydrolysis. Although both methods are acid-catalyzed, and presumably in the case of glycopyranosides involve the formation of a cyclic oxocarbenium transition state, they also have their differences. Thus, for example, the most important difference is that the hydrolysis is always performed either in aqueous solutions or in a solvent containing water, whereas the acetolysis is performed in nonaqueous... 

---