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Carbohydrates 387

Another important nucleophile that can react with gly-
cosides is X , to produce glycosyl halides, which are syn-
−
thetically valuable intermediates. In general, glycosides
are hydrolyzed by acids and are stable toward bases. Ex-
ceptions to this rule are glycosides having, as the aglycon,
a group derived from a phenol, an enol, or an alcohol hav-
ing an electronegative group in the β position, as these are
labile toward bases.
Aldofuranosides are hydrolyzed much faster (50–
200 times the rate) than the aldopyranosides, and, among
the furanosides, the less stable isomers (those having ad-
SCHEME 11 Formation of a phenylglucoside from a glycosyl jacent bulky groups in the cis orientation) are hydrolyzed
chloride. the fastest. Similarly, methyl β-D-glycopyranosides are
hydrolyzed faster than their (more stable) α-D anomers,
because of the anomeric effect. (The situation is reversed
fluorides are too inert, requiring drastic conditions when bulky aglycons are used, because of the considerable
for reaction. The glycosyl halides can be prepared by axial–axial interactions.) Ketofuranosides and ketopyra-
bubbling HCl or HBr into a solution of a peracetylated nosides are also hydrolyzed faster than the corresponding
or perbenzoylated monosaccharide. Alternatively, as aldosides. Finally, aldopyranoses and aldofuranoses hav-
will be seen later, they can be obtained in the same way ing a 2- or 3-deoxy or a 2,3-dideoxy functionality are
from glycosides. Although many halides are isolated in hydrolyzed considerably faster than their hydroxylated
crystalline form, they are often caused to react directly counterparts; this is due to a decrease in steric interac-
with a nucleophile after removal of the dissolved acid. tion during the conversion of the chair conformer of the
glycopyranoside to the half-chair conformer of the carbo-
b. Nucleophilic displacement of OR groups. Nu- nium ion and during the bimolecular displacement of the
cleophilic substitution reactions on the anomeric carbon alcohol by water in the glycofuranosides.
atom include displacement of the anomeric OH groups, The accepted mechanism for the acid hydrolysis of gly-
acetoxyl groups and halogens but may involve displace- cosides starts, as usual, with protonation. Although pro-
ment of the OR group of glycosides by a nucleophile. tonation of either the glycosidic oxygen atom (that of the
The nucleophiles discussed in this section are the OH and OR group attached to the anomeric carbon atom) or the
OR groups, as well as halides. Acid catalysts are always ring oxygen atom is possible, there is evidence that it is
needed in the anomeric displacement reactions in order to usually the former (the glycosidic oxygen atom) that is
produce the reactive species, a resonance-stabilized car- protonated. The next step in the reaction, namely, the for-
bonium ion. The latter is usually formed when the oxygen mation of a carbonium ion by shifting of the electrons
atom of the OR group attached to the anomeric carbon of the C O R bonds, can be achieved in two ways: ei-
atom becomes protonated and the aglycon is eliminated ther by breaking the C O bond and shifting the positive
as ROH. If the glycoside reacts with the same nucleophile charge to the anomeric carbon atom or by breaking the
found in its aglycon (e.g., if a methyl glycoside is treated O R bond and shifting the charge to the R group of the
with methanol in the presence of an acid catalyst), anomer- aglycon. The first route is favored, because the saccha-
ization will result, that is, the two anomers of the same ride carbonium ion is stabilized by resonance with the
glycoside will be produced, and the anomer having the form having the charge on the ring oxygen atom, and
OR group axially attached will predominate (the anomeric most hydrolyses follow this route. In rare cases, for ex-
effect). If, on the other hand, the glycoside reacts with a ample, during the acid hydrolysis of tert-butyl glycosides,
different nucleophile, for example, if a methyl glycoside is the bond between the oxygen atom and the R group is
treated with water (in a hydrolysis) or with another alcohol preferentially broken, because of the remarkable stability
(in a transglycosidation), the OR group will be replaced of the tert-butyl carbocation. The foregoing mechanisms
by an OH group in the first case and by an OR group in have been confirmed by conducting hydrolyses of glyco-

the second. In such reactions, if the OH group attached to sides in 18 O-labeled water and locating the labeled oxy-
C-4 of glycopyranosides and C-5 glycofuranosides is not gen atom in the products (the free sugar or the alcohol).
blocked, the foregoing displacement reactions will afford With most aglycons the label was found to be attached
mixtures of α- and β-furanoses (or furanosides) and α- to the free sugar liberated, whereas with tert-butyl glyco-
and β-pyranoses (or pyranosides), irrespective of whether sides the label was found to be on the alcohol formed (see
the starting glycoside is a furanoside or a pyranoside. Scheme 12).