Cyclization
Aldoses and ketoses can form cyclic hemiacetals and cyclic hemiketals by the reaction of a hydroxy group with the carbonyl. This is catalyzed in acid or base. The most common form is a 6-membered ring, although 5-membered rings are not uncommon. These assume the standard chair and envelope conformations of carbocyclic compounds. Six-membered rings are called pyranoses; five-membered rings are called furanoses.
The hemiacetal or hemiketal carbon is a stereocenter. When the ring closes, this stereocenter can assume either of two configurations; thus two diastereomers are possible. Diastereomers with this relationship are called anomers; one is called the a anomer, the other the b . The two anomers interconvert in aqueous solution, by way of the open-chain compound. For glucose, and for aldohexoses in general, the a anomer is less stable, by a factor of about 2. The anomers can be distinguished by their ability to rotate the plane of plane-polarized light. Thus, a solution of pure a -glucose has a different optical activity than one of b -glucose. If pure a -glucose is dissolved in water, it will slowly equilibrate with the b -glucose, changing the rotation of the light. This is called mutarotation.
Glycoside formation
Glycosides are acetals or ketals of monosaccharides. As in the formation of other acetals and ketals, this requires acid catalysis. For instance, a mixture of glucose and methanol in acid will form the two methyl glucosides, a and b . For reasons that are not completely understood, the a -methyl glucoside is more stable than the b anomer by a small amount. These glycosides are stable except in dilute solutions in aqueous acid. Hydrolysis can also be catalyzed by enzymes called glycosidases (glucosidases for glucosides). These enzymes are specific for the configuration of the anomeric carbon. Thus there are a -glucosidases and b -glucosidases.
If the alcohol involved in glycoside formation is another sugar, the glycoside formed is a disaccharide, and the extension of this chain forms a polysaccharide. Other bases besides alcohols can participate in this type of bond, and the functional group is still called a glycoside. For instance, adenine, guanine, cytosine and uracil can substitute at the anomeric carbon for a molecule of water and form glycosidic bonds, as in the nucleosides found in RNA.
Ether formation
In basic solution, the -OH groups can all accept alkyl groups from good alkyl donors, such as dimethylsulfate or methyl iodide. These are all ethers except for the acetal/ketal at the anomeric carbon. This linkage is labile in acid, unlike the ethers, so this alkyl group can be easily removed, leaving ethers at the other -OH's.
Cyclic acetal formation
The vicinal hydroxyls of monosaccharides are properly positioned to form cyclic acetals with ketones (like acetone), of the kind we formed before to protect carbonyls. One cyclic acetal between glucose and acetone is shown below.
Formation of the cyclic acetals can tell us which OH groups are involved in other bonding interactions, and can protect OH groups from reactions like oxidation, discussed below.
Ester formation
Just as the OH groups can be used as alkyl acceptors in ether formation, they can be used as acceptors of acyl groups in ester formation. The acyl donor usually used is acetic anhydride, a much less expensive source of acetyl groups than acetyl chloride. All OH groups are acetylated, including the anomeric group. The acetylated sugar shows the anomeric effect, with the a anomer being more stable, predominating at equilibrium by a factor of 7.
Reduction
As with any carbonyl, monosaccharides can be reduced with NaBH4 to an alcohol. This results in all functional groups being alcohols. Raney Ni with H2 can also be used for the reduction.
Oxidation
There are many ways to oxidize a compound with so many hydroxyl groups. In fact, the aldehyde group can be oxidized without affecting the OH groups at all. This produces an acid, an aldonic acid, at one end of the molecule. This oxidation can be carried out with Br2, a mild oxidant. Qualitative tests rely on the ability of the sugars to reduce Cu+2 or Ag+, producing a visible precipitate. Aldonic acids are usually found in the cyclic lactone form.
Sugars that can reduce copper or silver are called reducing sugars; non-reducing sugars are usually glycosides.
A stronger oxidant, HNO3, will oxidize both the aldehyde group and the primary alcohol at the other end of the chain. This produces the dicarboxylic acid, or glycaric acid. This diacid will form a dilactone:
An even stronger oxidant, HIO4, oxidizes adjacent OH groups, cleaving the C-C bond and forming aldehydes or ketones. Oxidation of an adjacent aldehyde and OH group cleaves the C-C bond producing another aldehyde/ketone and a molecule of formic acid. HIO4 oxidation of a glycoside gives complex results, depending on derivatization of the various OH groups. Oxidation of open chain forms yields one equivalent of formaldehyde, with the rest of the C's being oxidized completely to formic acid.
Reaction with H2N-NH-f , phenylhydrazine
Hydrazines react with carbonyls to form derivatives called hydrazones. These are imines, compounds with C-N double bonds. The reaction is carried out in acetic acid (HOAc). One equivalent of phenylhydrazine adds to the aldehyde carbon, leading to the elimination of water and formation of the hydrazone. Continued reaction with two more equivalents oxidizes the adjacent carbon and forms the hydrazone at that position as well. This derivative is called an osazone. Aniline and ammonia are the reduction products from the phenylhydrazone. These derivatives are useful for two reasons. They are much more readily crystallized than the sugars themselves, which makes it easier to purify them. And they have one less stereocenter, and so can be used to examine relationships between aldohexose isomers (and others). No further reaction with phenylhydrazine occurs.
Chain extension
The Kiliani (or Kiliani-Fischer) synthesis results in the formation of the two epimeric aldoses one carbon longer than the starting aldose. Reaction with cyanide in dilute base results in the nucleophilic addition of the cyanide to the carbonyl carbon, forming a cyanohydrin. This reaction is easily reversible, but hydrolysis of the nitrile group to the carboxylic acid makes reversal impossible. These aldonic acids are, again, usually found as lactones. The acid can be reduced with sodium amalgam (Na(Hg)) in HOAc to the aldose.
Chain shortening
The calcium salt of the aldonic acid can be oxidized by hydrogen peroxide and ferrous ion to CO2 and an aldose shorter by one carbon. This is a rather low yield reaction and is not a good preparative method.