5.1. Background and Terminology: Carbohydrates/Saccharides
Carbohydrates are a broad class of molecules containing an aldehyde or ketone that also have one or more alcohol functional groups. The term “carbohydrate” comes from the original discoverer knowing the empirical formulae but not knowing the connectivity for these compounds (Figure 5.1).
Figure 5.1 – Glucose’s Molecular Formula as a “Hydrate of Carbon”.
For historical reasons many (bio)chemists use “saccharide” as a synonym for carbohydrate. This term comes from the Greek word for sugar. This text will preferentially use the term saccharide as it allows simpler descriptions of the differences between types of carbohydrate polymers. The word “sugar” itself is also widely when discussing small/simple carbohydrates.
Rarely, the term “glycosides” may be used as a synonym for specific types of carbohydrates. This term is more technical (it refers to a specific type of connectivity) and its use in this context is rare. However, familiarity with this term will help with recognition of other biomolecules that contain or derive from carbohydrates; glycoproteins are biomolecules made of carbohydrate(s) and peptide(s), glycolipids are biomolecules made of carbohydrate(s) and fatty acid(s), nucleosides are biomolecules made of nucleic acid(s) and carbohydrate(s), etc.
Although not discussed in this text, it is important to recognize that carbohydrates are a complex class of compounds that can contain more elements than simply carbon, hydrogen, and oxygen. A classic example is glucosamine (Figure 5.2) one of the most abundant carbohydrates in nature. It has widespread biological use for an array of functions (in shells/bones/cartilage, to make glycoproteins, etc.).
Carbohydrates with elements other than C, H, and O are typically explored in advanced bioorganic/biochemistry courses rather than in introductory material.
Individual carbohydrates often have multiple structures/forms (isomers) which may or may not look similar despite being the same compound. Saccharides and their different forms are classed several different ways, each with its own terminology. Accurately identifying and naming saccharides (see Sections 5.3 and 5.6.1) is an involved process that requires multiple considerations.
5.1.1. Classification: Mono-, Di-, and Poly-Saccharides
Recall that polymers made of biomolecules (biopolymers) are very common in nature (see Section 4.4.1). One way of classifying saccharides is by the number of monomers (simple sugars) in the molecule. The description of chains is similar to standard polymer naming but often uses “saccharide” (the type of monomer) instead of the term “mer” itself: a “monosaccharide” has one sugar unit, a “disaccharide” is a two-sugar carbohydrate polymer, etc. (Figure 5.3). There are multiple ways of forming polymers using monosaccharide subunits. For simplicity only one type of monomer and one type of linkage are shown.
Figure 5.3 – Examples of Carbohydrate Biopolymers as Monosaccharides, Disaccharides, and Polysaccharides.
In nature mono- and di-saccharides are very common while other short chains (tri-, tetra-, etc.) are rare. A third type of carbohydrate polymer is also very common. A “polysaccharide” is an n-sugar carbohydrate polymer where n can vary substantially (10 to 10,000 typically). Polysaccharides are classed this way because often the exact number of monomers in the chain does not matter and varies over time. For example, cellulose is a polysaccharide where the number of monomers can vary from a few hundred to a few thousand. Whether the chain has 200 subunits or 2000 subunits it would still be called cellulose.
5.1.2. Classification: Aldoses vs. Ketoses
Individual monosaccharides are classed based on which carbonyl-containing functional group they have in their open chain (non-cyclic) form (Figure 5.4). Aldoses have an aldehyde functional group. Ketoses have a ketone functional group. The suffix “ose” is often used to identify a molecule as a saccharide.
Figure 5.4 – Examples of Aldoses and Ketoses.
5.1.3. Stereochemistry: D/L Notation
With one exception, all monosaccharides have at least one stereocentre. It is possible to describe the stereochemistry using the Cahn-Ingold-Prelog (CIP) system of R/S absolute configurations. However, for historical reasons the overwhelming majority of chemists and biochemists instead use a different notation system.
Carbohydrates were characterized before the CIP system was implemented. Instead of assigning absolute configuration(s), a relative description of the stereocentres is used. This relates the stereochemistry to an arbitrarily chosen standard (2,3-dihydroxypropanal [glyceraldehyde]) when drawn using a classical style of depicting molecules.
Recall that Fischer projections are a style of drawing for chemical structures developed before the widespread adoption of line-angle (skeletal) structures with hashed/wedged bonds. In a Fischer projection the molecule is drawn similar to a Lewis structure, flat and typically with 90° angles (Figure 4.4). However, the perspective is chosen to indicate stereochemistry by ‘projecting’ the three-dimensional structure down onto a two-dimensional image.
Figure 4.4 – Generalized Concept of a Fischer Projection.
Recall that the Fischer projections of the enantiomers of glyceraldehyde (2,3-dihydroxypropanal) were arbitrarily chosen as the reference standard for the system (Figure 5.5). One has the alcohol of the stereocentre pointing “to the right” and is called D-glyceraldehyde (from the Latin “Dexter”, meaning “right”). The other has the alcohol of the stereocentre pointing “to the left” and is called L-glyceraldehyde (from the Latin “Laevus”, meaning “left”). The exact same D/L labels can be applied in the exact same way to other molecules, particularly saccharides (and amino acids, see Section 4.1.5.2). Saccharides often have multiple stereocentres. In these cases it is ONLY the relative position of the last alcohol in the chain (at the “bottom”; highest numbered carbon) that determines the D/L assignment.
Figure 5.5 – Origin of the D/L Notation for Relative Configuration to Glyceraldehyde (2,3-Dihydroxypropanal).
Again, for those familiar with d/l notation from organic chemistry (optical rotation), it is important remember that these two systems are not related in any way.
The common monosaccharides are all D-carbohydrates. Although various naturally occurring L-carbohydrates have been characterized, the overwhelming majority of saccharides in nature are D-carbohydrates.
Recall that the D/L notation is a relative descriptor that describes enantiomers by perspective. The D/L system does not directly translate to or from absolute configuration. Any apparent relationship is coincidental; for the common monosaccharides (see Section 5.1.4) the last stereocentre having R absolute configuration leads to a D assignment but this is coincidental. Having an R absolute configuration at the last stereocentre will not always correspond to a D-carbohydrate for other monosaccharides.
5.1.3.1. How to Convert a Line-Angle Structure to a Fischer Projection for Monosaccharides
Recall that Fischer projections are a classical style of drawing. While it is possible to generate Fischer projections for other types of molecules their use is only recommended for simple biomolecules, specifically amino acids and carbohydrates.
The process for converting a line-angle structure to a Fischer projection is straightforward but can be challenging when many stereocentres are present such as in longer monosaccharides. Use of a molecular model is not required but may be helpful in some instances. As with amino acids, there are two general approaches.
In the traditional approach:
Orient the line-angle structure. Identify and number the main carbon chain following the rules of the IUPAC naming process. Place all of the main-chain carbons in a row such that all other substituents face towards the “viewer’s perspective” for the Fischer projection. This includes hydrogens. You may change the conformation if needed. The resulting conformation may appear unusual but is required for the Fischer structure. Drawing in implied hydrogens is optional but is particularly helpful for introductory students.
Draw the Fischer projection backbone without adding any groups. Each numbered carbon is added as a point in the chain. You may choose to represent double bonds (non-tetrahedral geometry) now or add them in the next step. It is often helpful to number the carbons to keep track of what groups will go where. Orient the drawing so that position 1 is at the “top”.
Add substituents for each carbon. Depictions of non-tetrahedral geometries can be modified or used as-is. It may be helpful to visualize the hashed/wedged structure and/or imagine the hypothetical flattening of the molecule. It may be helpful to work systematically (e.g. add all groups for carbon 1, then carbon 2, etc.).
In the alternate approach:
Identify and number the main carbon chain following the rules of the IUPAC naming process. Assign R/S absolute configurations to all stereocentres.
Draw the Fischer projection backbone without adding any groups. Each numbered carbon is added as a point in the chain. You may choose to represent double bonds (non-tetrahedral geometry) now or add them in the next step. It is often helpful to number the carbons to keep track of what groups will go where. Orient the drawing so that position 1 is at the “top”.
Add substituents for each carbon. Depictions of non-tetrahedral geometries can be modified or used as-is. Add substituents to stereocentres arbitrarily and then check if the absolute configuration is correct. Re-draw if needed.
The alternative approach may or may not be faster depending on the number of stereocentres and the speed with which they can be assigned absolute configurations.
There is sometimes confusion when the monosaccharide is a ketose rather than an aldose. In either method it is still oriented so that position 1 is at the “top”, but this will not be the ketone itself. Placing the ketone on the left or right is arbitrary; both options are correct.
Some sources abbreviate Fischer projection drawings. Typically this is done such that non-stereogenic centres are not fully represented. Drawing Fischer projections in this way is not required. However, they may be encountered in other sources.
5.1.3.2. How to Assign D/L Notation to Monosaccharides
Assignment of D/L to a monosaccharide is generally straightforward provided the Fischer projection is correct and in the proper orientation. Simply look for which side, left or right, the alcohol of the last stereocentre (highest numbered carbon with a stereocentre) in the molecule is.
Convert the line-angle structure to a Fischer projection (see Section 4.1.5.1). If a Fischer projection is provided ensure it is in the correct orientation (the numbered chain proceeds down). Rotating the Fischer projection clockwise or counterclockwise is acceptable. Flipping a Fischer projection is not acceptable and will produce the incorrect assignment.
Determine the left/right directionality of the highest priority group (the alcohol) at the last stereocentre in the chain. If the group points to the left, it is the L-enantiomer of that compound. If the group points to the right, it is the D-enantiomer of that compound.
As before, there are two potential issues.
If a Fischer projection is provided it may be manipulated by rotating clockwise or counterclockwise but not flipped. Flipping the image will generate the enantiomer and lead to an incorrect assignment.
The D/L system only classes which enantiomer is being described. When there are multiple stereogenic centres present (almost all saccharides) this can be problematic.
5.1.4. The Twenty-Three Common Monosaccharides
Twenty-three monosaccharides are very common in organisms and merit special attention. These vary by the type of functional group (aldoses vs. ketoses), the number of carbons in the chain, and the relative configurations of the stereocentres. Each has its own trivial name. When shown together they are often represented using their Fischer projections which make the relationships between them more obvious.
There are fifteen common aldoses (Figure 5.6). For convenience these have been organized to highlight stereochemical relationships as the molecules become longer.
Figure 5.6 – Trivial Names and Structures for The Common Aldoses.
There are eight common ketoses (Figure 5.7). For convenience these have been organized to highlight stereochemical relationships as the molecules become longer. This also emphasizes the relationship between names of tetroses and pentoses between aldose and ketose saccharides.
Figure 5.7 – Trivial Names and Structures for The Common Ketoses.
The D/L assignment describes the enantiomer. The name describes whether there is an aldehyde or ketone, how many carbons are in the molecule, and the diastereomer.
The following is provided only to help rationalize the naming scheme. At an introductory level it is not necessary to memorize the relative configurations. However, understanding how the trivial names describe diastereomers may avoid confusion when drawing/naming saccharides.
Technically, the name describes the diastereomer by relative configuration in the Fischer projection (Figure 5.8). For example, “mannose” is the diastereomer of aldohexose where, in the Fischer projection, the side each alcohol is on relative to the previous alcohol is: the same side, the opposite side, the same side. This fully describes the relative configurations of the stereocentres in the diastereomer, regardless of which enantiomer is shown.
Figure 5.8 – Example of a Monosaccharide Trivial Name Describing the Functional Group, Chain Length, and Relative Configuration (Diastereomer).
When comparing and discussing saccharides a special type of relationship between diastereomers occurs frequently. Epimers are a pair of diastereomers that have opposite absolute configurations at exactly one stereocentre. For example, the relationship between D-allose and each of D-altrose, D-mannose, and D-glucose is diastereomers (Figure 5.9). Because they only differ at one stereocentre, the relationships between D-allose and D-altrose and D-glucose may also be described as epimers. Conversely, because they differ at multiple stereocentres the relationship between D-allose and D-mannose is also diastereomers but they are not also epimers.
Figure 5.9 – Examples of Diastereomer Relationships Between Aldohexoses with a Highlighted Epimer Relationship.
It is important to think critically when using absolute configurations. Consider the relationship between D-altrose (S,R,R,R) and D-glucose (R,S,R,R). Without considering the structures this may appear to be only one change. However, two stereocentres (position 2 and position 3) have opposite configurations. The relationship between these two is diastereomers but they are not epimers.
Epimers are a special type of diastereomer pair. D/L assignments are not important for determining if a pair of diastereomers are epimers. For example, the relationship between D-glucose and L-idose is diastereomers (Figure 5.10). Again, because they only differ at one stereocentre they may also be considered epimers. That one is the D-enantiomer and one is the L-enantiomer is irrelevant for classing them as epimers.
Figure 5.10 – Example of Epimer Relationship Between Aldohexoses Being Irrespective of D/L Assignment.
The concept of epimers is interesting but has only minor applications with open-form monosaccharides. However, the relationship between epimers is very important for saccharides in a different form.
