Carbohydrates

The name carbohydrates applies to certain naturally occurring compounds which are basically polyhydroxy aldehydes or ketones. Of course, not all polyhydroxy aldehydes or ketones are naturally occurring and thus would not be considered to be carbohydrates. Familiar examples of carbohydrates (which are also called sugars and saccharides) are sucrose, glucose, ribose, starch, and cellulose.

Before we discuss the structures and chemical reactions of carbohydrates, let’s consider some simple, prototype molecules which are structurally related to carbohydrates.

Glyceraldehyde.

Glyceraldehyde is a common name for the substance the IUPAC name of which is 2,3-dihydroxypropanal (see below). It has only two hydroxyl groups, so it is merely a prototype of the true carbohydrates. We note that C2 of glyceraldehydes has four different substituents, an H, an OH, a CH₂OH, and a CHO substituent. That carbon is therefore a stereocenter. Since there is only one stereocenter, this means that the molecule is chiral; there are two enantiomers. We could classify them according to the R,S nomenclature that we previously learned, but in sugar chemistry the designations are D and L and the method used to derive the appropriate designation is unrelated to that used to derive the classification of R or S.

q Please recall the conventions associated with Fischer structures, especially that vertical groups project directly away from the observer (behind the plane of the paper) and horizontal groups project outward toward the observer.

q According to the conventions originated by Nobel Laureate Emil Fischer, in writing carbohydrate structures, the aldehyde function is represented as the upward vertical group and the terminal hydroxymethylene group as the downward vertical group. When this convention is followed the hydroxy and hydrogen atoms of the various stereocenters (only one in this case) will be horizontally projecting groups. One of the enantiomers will have the OH projecting to the right and the other enantiomer to the left. The one which has the OH group projecting to the right is called the D enantiomer.

q Fischer structures are especially useful, as we shall see for displaying the stereochemistry at multiple stereocenters simultaneously and in a manner which facilitates discovering any planes of symmetry which may identify meso compounds.

Erythrose and Threose.

It should be noted that the characteristic suffix of carbohydrates is –ose. We want now to look at the next higher members of the series which begins with glyceraldehydes, namely erythrose and threose.

q Both erythrose and threose are 2,3,4-trihydroxybutanals.

q Both C2 and C3 are stereocenters, and they are non-equivalent, so there are 2ⁿ = 4 stereoisomrs; i.e., 2 diastereoisomeric pairs of enantiomers.

q In the conventional orientation, erythose is the diastereoisomer which has both OH’s oriented in the same direction (both to the right or both to the left). Threose is the diastereoisomer which has the OH groups oriented in opposite directions (one to the right and one to the left).

q IMPORTANT: The enantiomer is designated as D which has the OH at C3 oriented to the right. In general, the farthest stereocenter from the carbonyl function serves as the basis for the D or L designation, and the molecule which has the OH oriented to the right at this remote stereocenter is designated as the D enantiomer.

Subclassifications of Carbohydrates.

q Carbohydrates which have an aldehyde function, as illustrated above, are called aldoses, while those which have keto functions are called ketoses.

q Carbohydrates are further classified according to the number of carbon atoms in the main chain, e.g., erythrose is an aldotetrose. A carbohydrate which has 5 carbon atoms in the chain is called a pentose and glucose and others which have 6 carbon atoms in the chain are called hexoses. More specifically, glucose is an aldohexose.

q We shall see that all naturally occurring carbohydrates are of the D family. The L enantiomers are not found in nature, but can be prepared in the laboratory.

Aldopentoses

Aldopentoses are of the family 2,3,4,5-tetrahydroxypentanal. Since there are 3 stereocenters, there are a total of eight stereoisomers; four diastereoisomeric pairs of enantiomers. Below are given the structures of D-ribose and D-arabinose, two especially important carbohydrates.

q Note that D-ribose has all three hydroxyl groups to the right. Ribose is important because of its presence in RNA. Deoxyribose, which has lost its C2 OH (it is replaced by an H), is correspondingly important in DNA.

q Arabinose is of note in the present connection mainly because its structure is so closely related to that of D-glucose, as we shall see.

D-Glucose and Other Aldohexoses and Ketohexoses.

Glucose belongs to the family 2,3,4,5,6-pentahydroxyhexanal. The specific stereoisomer which we call D-glucose is shown below. The structure of D-mannose is also shown for reasons which will become apparent. Note that D-mannose differs from D-glucose only by the configuration at C2.

q Note that glucose has 4 stereocenters, so that there are 16 stereoisomers, consisting of 8 different diastereoisomeric pairs. Of course only the D family of diastereoisomers is naturally occurring.

q Just for practice, L-glucose is shown below as the mirror image of D-glucose. Note that the right/left configuration of every H/OH pair is inverted.

Glucose and Arabinose

Glucose is an aldohexose, while arabinose is an aldopentose. However, the structures are somewhat related in that the stereochemical configurations of the bottom 3 (3 of the 4) stereocenters of D-glucose is exactly that of the three stereocenters of D-arabinose. Thus if one knows the Fischer structure for glucose (which one should know!!), one would also be able to write the structure of arabinose.

Glucose and Mannose

In a similar way, the bottom three stereocenters of D-glucose and D-mannose are identical, so that knowing the structure of D-glucose one can easily derive the structure of D-mannose.

Glucose and Fructose

D-Fructose (fruit sugar) is found in a chemically bound form in table sugar (sucrose). It is a ketohexose which again has the same configuration as D-glucose at the bottom (and only) three stereocenters.

Cyclic Structures

We are award that aldehydes react with alcohols to give hemiacetals, and that this is especially favorable when the aldehyde function and the hydroxyl function are both present in the same molecule. In this situation, cyclic hemiacetals are formed. D-Glucose, and other sugars, fulfill these requirements and typically exist predominantly in the cyclic hemiacetal form.

q It is the OH at C5 which preferentially adds to the aldehyde function, because this results in a relatively strain-free six-membered ring. However, cyclization can sometimes occur using the OH group at C4, which provides a 5-membered ring.

q The six-membered ring hemiacetal is called a –pyranose in general. In the case of D-Glucose we have D-glucopyranose. The corresponding 5-membered ring hemiacetal is called D-glucofuranose. Naturally occurring D-glucose exists only in the pyranose form, but in solution in the laboratory, much of the furanose form is also present.

q It is not important to note that the acetal carbon has four different substituents, and thus is a new stereocenter. The molecule now has 5 stereocenters, affording 32 possible stereoisomers, Again, however, only the D enaniomers are present.

q This means that there are now twice as many diastereostereoisomers (16) as there were before in the acylic form (8).

q The two diastereoisomers of D-glucose are shown below. It is very important to note that the b-diastereoisomer has every substituent equatorial on the chair cyclohexane ring. The a-stereoisomer has one axial OH, so it is somewhat less stable than the b diastereoisomer.

q Diastereoisomers which differ only in their configurations at C1 (the hemiacetal carbon) are sometimes called anomers. They are readily interconverted by equilibrating with the open chain, free aldehyde form.

q We would like to note here that knowing the conformational structure of glucopyranose, we could immediately write the structure of D-mannopyranose, since it differs only by the configuration at C2. Note that even the b diastereoisomer of D-mannopyranose has one OH group equatorial and thus it is less thermodynamically stable than b-D-glucopyranose.

q So glucopyranose is the most stable of all of the pyranose structures.

Interconvertibility of Glucose and Mannose

q Note that, in their free aldehyde form, glucose and mannose differ only in their configurations at C2, which is an alpha type carbon (alpha to a carbonyl group), which therefore possesses acidic alpha type protons, which are easily removed to form the enol (in acidic solutions) or enolate (in alkaline solutions). Once the enol or enolate is formed, the alpha carbon is planar (sp²), and when it is protonated, it can be protonated from either face of the double bond.

Interconvertibility of The Glucose Anomers

q The alpha and beta anomers of glucose (or any of the other stereoisomers of glucose) are especially readily interconverted in the presence of even traces of acid or base, producing an equilibrium mixture of the two anomers.

q This is accomplished via the free aldehyde form, which we know is in equilibrium with the cyclic acetal form whenever even small amounts of acid or base are present (See the scheme below).

q If we start with the pure beta anomer, it will rapidly rearrange to the equilibrium mixture of 64:36. Likewise, if we start with the pure alpha anomer, it will gradually rearrange to the same equilibrium mixture.

q Since the alpha and beta anomers are diastereoisomers, they have different optical rotations, as shown above. The alpha anomer is more strongly dextrorotatory than the beta anomer.

q As the isomerization takes place, the optical rotation gradually changes from that of the pure anomer to that of the equilibrium mixture, which is intermediate between the two. This phenomenon, often observed in sugars, is called mutarotation.

q Note that mutarotation in basic or neutral solution can only occur when we have the hemiacetal function (or a hemiketal function), since the OH group of the acetal function is necessary to equilibrating it with the aldehyde form. In particular, if we have an acetal function, it is stable in basic solution and will not permit mutarotation.

Glycoside Formation.

Glycosides are acetals which correspond to the replacement of the hemiacetal hydroxyl group of a sugar being replaced by an –OR group, which R is any organic group.

q A glycoside of the sugar glucose is called a glucoside. A glycoside of mannose, would be called a mannoside.

q We are well aware that hemiacetals can be converted to acetals in the presence of an alcohol, but only in acidic solution.

q The equation below illustrates the conversioni of b-D-glucopyranose to methyl b-D-glucopyranoside in the presence of methanol. The R group in this case is CH₃.

q Note that the typical suffix for a glycoside is “-oside”.

q The mechanism for acetal formation has been studied previously this semester and is not repeated here [protonate the OH; lose water as the leaving group; the carbocation then reacts with methanol to give the acetal; note: both alpha and beta anomers will be formed, because the intermediate carbocation can react with methanol from either face.

Disaccharides and Polysaccharides

q We note that sugars have alcohol functional groups of their own. There is therefore no need to supply an alcohol function from a solvent such as methanol.

q The –OH group of one sugar molecule can serve as the alcohol function to replace the C1 –OH group of another molecule.

q The most common case is that the alcohol function is supplied by C4.

q In the illustration below, we see, first of all the formation of an acetal (or glycoside) linkage by bonding the C4 –OH group of one b-D-glucopyranose molecule to the C1 (hemiacetal) carbon of a second molecule of b-D-glucopyranose.

q The resulting molecule is called cellobiose. It is designated as a disaccharide, because it can be hydrolyzed to two molecules of simpler sugars.

q In a similar way, the alpha anomer of glucopyranose can bond to another molecule of glucopyranose at its C4 hydroxy group. The resulting disaccharide is called maltose.

q Note that, since both cellobiose and maltose have an acetal linkage, they can be hydrolyzed in aqueous acidic solution to their component simple sugars (monosaccharides). Both give two molecules of D-Glucopyranose (mixture of alpha and beta anomers: remember, they equilibrate in aqueous solution.

q Since maltose has one axial oxygen function, it is less thermodynamically stable than cellobiose, which has all substituents equatorial.

q The special importance of the cellobiose/maltose examples is that they provide a pattern, respectively, for the polysaccharides cellulose and starch.

q Finally, note that both cellobiose and maltose have both a hemiacetal and an acetal function. You should be able to find both.This is illustrated below for cellobiose.

Reducing Sugars. Aldehydes, via their specific aldehydic hydrogen (the one directly attached to the carbonyl carbon) are uniquely easily oxidizable amount carbon compounds. Even mild oxidants such as silver oxide and copper oxide will oxidize an aldehyde to a carboxyl group (remember: +2 to +3 oxidation state). The metal oxide is then reduced to the metal, which is revealed by its plating out on the reaction vessel.

q Sugars which behave in this way are called “reducing sugars”.

q Reducing sugars are those which are able to equilibrate with their free aldehyde form, because it is only the aldehyde which reactions with the oxidant.

q In alkaline solution, recall that only hemiacetals, not acetals (or, the same thing, glycosides), are able to equilibrate with the free aldehyde.

q Consequently, only sugars which have a hemiacetal carbon are “reducing sugars”. This includes all of the monosaccharides and disaccharides mentioned so far.

q By the way, since mutarotation also requires the free aldehyde form, those same sugars which are reducing sugars also exhibit mutarotation.

Sucrose.

The structure of sucrose, a common disaccharide (table sugar) is shown below.

q Sucrose corresponds to linking a D-glucopyranose molecule as the alpha anomer and from its C1 hemiacetal hydroxyl group, with a molecule of D-fructofuranose at its C2 (carbonyl) carbon. Note that the alcohol function in this case comes from the hemiacetal OH of D-glucopyranose, not the C4 normal alcohol function.

q Note that this disaccharide has no hemiacetal functions because C1 (the hemiacetal carbon)of the D-glucopyranose molecule has been converted to a glycoside linkage. This alcohol function has reacted with the acetal function of fructose.

q Since this sugar has no hemiacetal linkages, it cannot equilibrate with the free aldehyde form in neutral or alkaline solution, so it is not a reducing sugar.

q Similarly, it does not display mutarotation in alkaline or neutral solution.

Polysaccharides.

Cellulose, the important structural material of plants, and starch, an important energy source for plants and animals, are both examples of polysaccharides. They are high molecular weight molecules which consist exlusively of D-glucose molecules bound together via their C1 and C4 carbon atoms.

q Cellulose has a structure which is essentially that of cellobiose, which was discussed before, but with tens of thousands of glucose molecules instead of just two.

q This means that they are C1-C4 linked and at the C1 carbon, all of the linkages are of the beta type.

q Repeat structures of both starch and cellulose polymers are shown below.