Carbohydrates

Overview and Biological Roles of Carbohydrates

Carbohydrates are a large class of natural products that are formally polyhydroxy aldehydes or ketones, or compounds that yield these on hydrolysis. In practice, they contain many C–OH groups and at least one C=O group (as an aldehyde or ketone) or are derived from such structures (e.g. in polysaccharides).

Biologically, carbohydrates play several central roles:

• Energy storage and fuel
• Short-term: glucose in blood, glycogen in animals, starch in plants.
• Major energy source in many diets.
• Structural materials
• Cellulose in plant cell walls.
• Chitin in arthropod exoskeletons (a modified carbohydrate).
• Recognition and communication
• Oligosaccharides on cell surfaces (glycoproteins, glycolipids) serve as “molecular barcodes” in immune recognition, blood group antigens, etc.
• Components of nucleic acids
• Ribose in RNA and deoxyribose in DNA are carbohydrates.

In this chapter, the focus is on the specific structural features and typical reactions of carbohydrates as organic molecules, not on general metabolism (covered elsewhere).

Classification of Carbohydrates

Carbohydrates can be classified according to:

Number of Basic Sugar Units

• Monosaccharides: the simplest sugars; cannot be hydrolyzed into smaller carbohydrates.
• Examples: glucose, fructose, ribose.
• Disaccharides: consist of two monosaccharide units linked via a glycosidic bond.
• Examples: sucrose (glucose–fructose), lactose (glucose–galactose), maltose (glucose–glucose).
• Oligosaccharides: 3–10 monosaccharide units; often attached to proteins and lipids.
• Polysaccharides: long chains (often hundreds to thousands) of monosaccharides.
• Examples: starch, glycogen, cellulose.

Nature of the Carbonyl Group

Monosaccharides are subdivided by the type of carbonyl group:

• Aldoses: polyhydroxy aldehydes; e.g. D-glucose is an aldohexose.
• Ketoses: polyhydroxy ketones; e.g. D-fructose is a ketohexose.

Number of Carbon Atoms

A common naming pattern combines the carbonyl type with the carbon count:

• 3 carbons: triose (glyceraldehyde, dihydroxyacetone).
• 4 carbons: tetrose.
• 5 carbons: pentose (ribose, deoxyribose).
• 6 carbons: hexose (glucose, fructose, galactose).

Thus, “aldohexose” = aldehyde sugar with 6 carbons.

Monosaccharides: Structure and Stereochemistry

Fischer Projections and D/L-System (Overview)

Monosaccharides are chiral molecules (except for some small ones). For sugars, Fischer projections are traditionally used to depict configuration.

In a Fischer projection:

• The longest carbon chain is drawn vertically.
• The most oxidized carbon (aldehyde or ketone carbon) is at the top.
• Horizontal lines point toward the viewer; vertical lines point away.

The D/L notation for sugars is defined by the configuration of the chiral center furthest from the carbonyl group:

• If the OH group on this reference carbon is on the right in the Fischer projection: D-sugar.
• If it is on the left: L-sugar.

D and L here refer to a stereochemical family (related to D- or L-glyceraldehyde), not to optical rotation (+/−), which must be determined experimentally.

Most naturally occurring monosaccharides in metabolism are D-sugars.

Number of Stereoisomers

An aldose with $n$ chiral centers has up to $2^n$ stereoisomers. For example:

• An aldohexose has 4 chiral centers $\Rightarrow 2^4 = 16$ stereoisomers (8 D and 8 L).
• Each pair of D/L forms an enantiomeric pair; different D-sugars are diastereomers of each other.

Understanding this combinatorics explains the large variety of possible monosaccharides.

Ring Formation: Hemiacetals and Hemiketals

In aqueous solution, most monosaccharides do not exist predominantly in the open-chain form; rather, they form intramolecular hemiacetals (aldoses) or hemiketals (ketoses), yielding cyclic structures.

Cyclization of Aldoses

For an aldohexose like D-glucose:

• The aldehyde group at C1 reacts with an OH group on a lower carbon, usually at C4 or C5.
• Reaction with the OH at C5 gives a 6-membered ring (5 C + 1 O), called a pyranose (by analogy to pyran).
• The result is a cyclic hemiacetal.

Schematically (simplified):

$$\text{Aldehyde group} + \text{Alcohol group} \rightleftharpoons \text{Hemiacetal (ring)}$$

This creates a new chiral center at the former carbonyl carbon (C1) – the anomeric center.

Cyclization of Ketoses

For a ketohexose like D-fructose:

• The ketone at C2 typically reacts with the OH at C5 (forming a 5-membered ring, furanose) or with the OH at C6 (6-membered ring).
• Furanoses (4 C + 1 O ring) are common for many ketoses and some aldoses.

The principle is the same: intramolecular addition of an OH to the carbonyl generates a cyclic hemiketal.

Anomers: α and β Forms

Cyclization produces two distinct stereoisomers at the anomeric carbon:

• If, in the conventional Haworth projection for a D-sugar:
• The anomeric OH is down (trans to the CH$_2$OH group at the highest-numbered chiral center) → α-anomer.
• The anomeric OH is up (cis to CH$_2$OH) → β-anomer.

For example, D-glucose in its pyranose form exists mainly as α-D-glucopyranose and β-D-glucopyranose.

These two forms are called anomers (a special type of diastereomer).

Mutarotation

In aqueous solution, α and β anomers interconvert via the open-chain form:

1. Ring opens to the linear aldehyde (or ketone).
2. Ring closes again, potentially as the other anomer.

This interconversion is called mutarotation and leads to a characteristic change in optical rotation until equilibrium between α and β is reached.

For D-glucose:

• Pure α-D-glucose in water gradually changes specific rotation as β-D-glucose forms.
• The same happens starting from the β-form, but approaching the same equilibrium mixture.

Conformational Aspects of Cyclic Sugars

Pyranose Rings: Chair Conformations

Six-membered rings such as glucopyranose are not flat; they adopt chair conformations similar to cyclohexane.

• Substituents can be axial (roughly perpendicular to the ring plane) or equatorial (roughly in the plane).
• For most D-aldohexoses, the most stable conformer is the one with bulky OH and CH$_2$OH groups in equatorial positions.

Example: In β-D-glucopyranose, all OH groups and the CH$_2$OH group can be equatorial in the lowest-energy chair, which helps explain:

• The high stability of β-D-glucose.
• The widespread biological use of glucose as a metabolic “standard” sugar.

Furanose Rings

Five-membered rings (furanoses) are somewhat more flexible:

• They can adopt envelope and twist conformations.
• For many biochemical purposes, furanoses (like ribofuranose in nucleotides) are drawn in simple planar “furanose” form, but their real shape is puckered.

Chemical Reactivity of Monosaccharides

Monosaccharides contain multiple OH groups and a (masked) carbonyl group, which govern their characteristic reactions. Here we focus on reactions that are particularly important for their behavior as natural products.

Reducing and Non-Reducing Sugars

Reducing Sugars

A reducing sugar is one that can act as a reducing agent because it has a free or potentially free anomeric carbon (i.e. can form an open-chain aldehyde or certain ketones under the conditions).

• All aldoses are reducing sugars in aqueous solution.
• Many ketoses are also reducing because they can isomerize (e.g. via enediol intermediates) to aldoses.

Reducing activity can be demonstrated with specific test reagents (e.g. Tollens’, Fehling’s, Benedict’s), in which the sugar reduces a metal ion and itself is oxidized to an acid or acid derivative.

Non-Reducing Sugars

A non-reducing sugar lacks a free anomeric hydroxyl group:

• Both anomeric carbons are involved in a glycosidic bond.
• The sugar cannot easily revert to an open-chain form under the test conditions, so it does not reduce the usual reagents.

Example: Sucrose (glucose–fructose with both anomeric carbons linked) is non-reducing, in contrast to maltose and lactose, which are reducing disaccharides.

Oxidation Reactions of Monosaccharides

Monosaccharides can undergo several types of oxidation, which have structural and analytical relevance.

• Mild oxidation at the aldehyde group (of an aldose) yields an aldonic acid:
• D-glucose $\rightarrow$ D-gluconic acid.
• Stronger oxidation can convert both the aldehyde group and the primary alcohol at the other end to a dicarboxylic sugar acid (aldaric acid).
• Selective oxidation at the terminal CH$_2$OH can produce uronic acids (common in polysaccharides like pectins and glycosaminoglycans).

Such transformations alter charge and solubility and are essential in many natural polysaccharides and metabolic pathways.

Reduction to Sugar Alcohols

Reduction of the carbonyl group (aldehyde or ketone) of a monosaccharide yields a sugar alcohol (alditol):

• D-glucose $\xrightarrow[\text{reduction}]{}$ D-sorbitol (glucitol).
• D-mannose $\xrightarrow[\text{reduction}]{}$ D-mannitol.

Sugar alcohols are generally sweet-tasting, often poorly absorbed, and used as low-calorie sweeteners (e.g. sorbitol, xylitol).

Isomerization and Epimerization (Brief Structural Note)

Monosaccharides can isomerize under certain conditions:

• Aldose–ketose isomerization via enediol intermediates.
• Epimerization at one chiral center (e.g. between D-glucose and D-mannose) in alkaline solutions.

These reactions underpin some interconversions in metabolism and also complicate analytical handling of sugars under strongly basic conditions.

Glycosides and Glycosidic Bonds

Formation of O-Glycosides

The anomeric OH group of a cyclic sugar is relatively reactive. Reaction of the anomeric OH with an alcohol ($\ce{ROH}$) under acidic conditions forms an O-glycoside:

$$
\text{Hemiacetal (sugar)} + \text{ROH} \xrightarrow[\text{acid}]{} \text{Acetal (glycoside)} + \ce{H2O}
$$

Key features:

• The anomeric carbon becomes part of an acetal (or ketal) linkage.
• The newly formed glycosidic bond can be α or β, leading to α-glycosides and β-glycosides.
• In contrast to the free hemiacetal, the anomeric center in a glycoside cannot freely mutarotate; configuration (α or β) is “locked” unless the glycosidic bond is broken.

Glycosides themselves are typically non-reducing at that anomeric center.

N-Glycosides and Biological Relevance

The same principle applies when the sugar reacts with an NH group (e.g. from an amine):

• N-glycosides are formed with nitrogen instead of oxygen.
• In nucleosides (components of DNA and RNA), the sugar (ribose or deoxyribose) is linked to a nucleobase through an N-glycosidic bond (at the anomeric carbon of the sugar).

Glycosidic Bonds in Oligo- and Polysaccharides

When the anomeric OH of one sugar reacts with a hydroxyl group of another sugar, a glycosidic bond between two monosaccharides is formed, yielding di-, oligo-, or polysaccharides.

Notation:

• Identify the carbon atoms participating and the configuration at the anomeric carbon: e.g. α(1→4), β(1→4), α(1→6), etc.
• For example, in maltose:
• Two D-glucose units are linked by an α(1→4) glycosidic bond.
• In cellobiose (the repeating unit of cellulose):
• Two D-glucose units are linked by a β(1→4) bond.

The type (α or β) and position of the glycosidic linkage have profound effects on the 3D structure and biological properties of the resulting polysaccharide (see below).

Disaccharides: Representative Structures

Although detailed biological roles may be covered elsewhere, it is important here to see the structural variety.

Sucrose

• Composition: α-D-glucopyranosyl-(1→2)-β-D-fructofuranoside.
• Both anomeric carbons participate in the glycosidic bond:
• C1 of glucose (α) linked to C2 of fructose (β).
• Consequence: sucrose is non-reducing.

Maltose

• Composition: two D-glucose units.
• Linkage: α-D-glucopyranosyl-(1→4)-D-glucose.
• The second glucose has a free anomeric center:
• Maltose is a reducing sugar.

Lactose

• Composition: galactose and glucose.
• Linkage: β-D-galactopyranosyl-(1→4)-D-glucose.
• The glucose unit has a free anomeric center:
• Lactose is a reducing sugar.

These examples illustrate how differences in stereochemistry and linkage position (α vs β; 1→2 vs 1→4, etc.) produce distinct molecules with different physical and biological properties, even from the same monosaccharide building blocks.

Polysaccharides: Structure–Property Relationships

Polysaccharides (also called glycans) are polymers of monosaccharides. Their properties depend mainly on:

• The nature of the monosaccharide units.
• The type and positions of glycosidic bonds.
• The presence of branching or linear structure.

Starch

Starch is the main storage polysaccharide in plants and consists of two components:

1. Amylose
• Mostly linear chain of α-D-glucose units.
• Linked via α(1→4) glycosidic bonds.
• Tends to form helical structures in solution.
2. Amylopectin
• Branched polymer of α-D-glucose.
• Main chain: α(1→4) linkages.
• Branch points: α(1→6) linkages every 20–30 glucose units (approximate).
• More compact and branched than amylose.

Both components use α-linkages, which can be readily hydrolyzed by many enzymes in animals and humans.

Glycogen

Glycogen is the main storage polysaccharide in animals and fungi.

• Structure similar to amylopectin, but more highly branched:
• α(1→4) glycosidic main chains.
• α(1→6) branch points approximately every 8–12 glucose units.
• Highly branched structure allows rapid release of glucose units (many chain ends accessible to enzymes).

Cellulose

Cellulose is the major structural polysaccharide in plants.

• Linear polymer of β-D-glucose units.
• Linked exclusively via β(1→4) glycosidic bonds.
• Each glucose unit is rotated relative to its neighbors, resulting in extended straight chains.
• Extensive inter- and intramolecular hydrogen bonds between OH groups lead to:
• Formation of strong fibrils and fibers.
• High tensile strength, low solubility in water.

The crucial point is the difference in linkage type:

• Starch/glycogen: α(1→4) (and α(1→6)), giving flexible, helical, and branched structures that enzymes in animals can digest.
• Cellulose: β(1→4), giving straight, rigid chains that most animals cannot hydrolyze due to the absence of appropriate enzymes (cellulases); some microorganisms can, enabling herbivores (via symbiosis) to digest cellulose.

Other Structurally Important Polysaccharides (Overview)

Without going into metabolic detail, several other classes of polysaccharides are structurally important:

• Hemicelluloses: mixed polysaccharides (various sugars, often branched) that associate with cellulose in plant cell walls.
• Pectins: polysaccharides rich in galacturonic acid; contribute to plant cell wall structure and gelling.
• Glycosaminoglycans (GAGs): long, often sulfated polysaccharides containing amino sugars and uronic acids; part of connective tissues and extracellular matrix.

Conceptually, they all illustrate how modifications of the monosaccharide units (e.g. amination, oxidation to acids, sulfation) and diverse linkages generate a wide variety of natural carbohydrate materials.

Carbohydrates in Biological Recognition and Nucleic Acids

Oligosaccharides on Cell Surfaces

Many sugars occur not as free molecules, but as short chains (oligosaccharides) covalently attached to proteins and lipids:

• Glycoproteins: proteins with attached oligosaccharides.
• Glycolipids: lipids with carbohydrate head groups.

These carbohydrate portions:

• Are often branched and structurally complex.
• Are recognized by specific proteins (lectins, antibodies, receptors).
• Determine, for example, blood group antigens (A, B, O) and participate in cell–cell communication and pathogen recognition.

Here, the key organic-chemical ideas are:

• Multiple types of monosaccharides (e.g. glucose, galactose, N-acetylglucosamine, sialic acids) can be combined.
• Different glycosidic linkages and branching patterns give a vast variety of structures.
• Small changes in stereochemistry or linkage pattern can drastically change biological recognition.

Ribose and Deoxyribose in Nucleic Acids

The sugars in nucleic acids are:

• D-ribose in RNA (as β-D-ribofuranose).
• 2-deoxy-D-ribose in DNA (lacking the OH at C2).

Structural features:

• Each sugar unit is linked by phosphodiester bonds (through its 3′- and 5′-OH groups) to form the sugar–phosphate backbone.
• Each sugar is attached via an N-glycosidic bond at its anomeric carbon to a nitrogenous base (adenine, guanine, cytosine, thymine, uracil).

These features show how carbohydrate chemistry (furanose rings, glycosidic bonds) underlies the architecture of genetic material.

Summary: Key Structural Themes in Carbohydrate Chemistry

• Carbohydrates are polyhydroxy aldehydes/ketones and their derivatives, occurring mainly as cyclic hemiacetals/hemiketals (pyranoses and furanoses).
• Stereochemistry is central: multiple chiral centers yield many isomers; D/L notation and anomeric α/β forms are fundamental descriptors.
• Intramolecular cyclization creates anomeric centers and leads to mutarotation in solution.
• The anomeric OH is especially reactive, forming glycosidic bonds (O- and N-glycosides) that connect sugars to each other and to other biomolecules.
• Reducing sugars possess a free or potentially free anomeric carbon; non-reducing sugars have this site locked in glycosidic bonds.
• Polysaccharides are built from monosaccharide units via specific glycosidic linkages:
• α-linkages (e.g. in starch and glycogen) give digestible, storage polysaccharides.
• β-linkages (e.g. in cellulose) give rigid, structural materials.
• Carbohydrates extend beyond simple energy storage to structural roles, molecular recognition on cell surfaces, and as integral components of nucleic acids.

These organic-structural principles provide the basis for understanding more detailed biochemical processes involving carbohydrates in metabolism and biological systems.