Carbohydrates | Organic Chemistry 3

Carbohydrates are studied in this chapter: properties of carbohydrates, Fischer projection, naming and classification of carbohydrates, configuration of aldoses and ketoses, cyclic structures of sugars, Haworth projection, ester, ether, and N-glycoside formation, epimerization, oxidation and reduction of sugars, chain lengthening and shortening, polysaccharides.

Properties of Carbohydrates

Carbohydrates:

Carbohydrates, commonly referred to as sugars and starches, are polyhydroxy aldehydes and ketones (or compounds that can be hydrolyzed to them). The name "carbohydrate" comes from their molecular formulas, which could be written as Cn(H2O)m, making them hydrates of carbon. 

 

Carbohydrates are abundant in nature and are used for chemical energy storage and structural rigidity. For example, they are synthesized in green plants by photosynthesis, a process that uses the energy from the sun to convert CO2 and H2O into glucose and oxygen. This energy is released when glucose is metabolized. Carbohydrates make up a significant portion of the food we eat and provide us with the energy needed to drive most of the biochemical processes in our bodies.
 

 


Physical properties of monosaccharides:

  • Polarity: polar compounds with high melting points.
  • Water solubility: presence of many polar functional groups capable of hydrogen bonding, making them water soluble. They can be transported quickly and easily through the bloodstream to the tissues.
  • Solubility in organic solvents: the high polarity of monosaccharides makes them insoluble in organic solvents.

Fischer Projection

Fischer projection:

A way to represent three-dimensional structures of stereoisomers in organic chemistry. In a Fischer projection, the horizontal lines are considered to be going out of the page toward the viewer, while the vertical lines are considered to be going into the page away from the viewer. This projection is often used to depict the configuration of chiral molecules with multiple chirality centers, particularly for sugars and amino acids.
 

 

How to convert a skeletal structure to a Fischer projection:

 

Conversion of (1S,2R,3R)-2-amino-1-bromobutane-1,3-diol to a Fischer projection:

Naming and Classification of Carbohydrates

Monosaccharides:

Simple sugars containing three to seven carbon atoms in a chain, with a carbonyl group on either the terminal carbon or the adjacent carbon. In most carbohydrates, each of the remaining carbon atoms has a hydroxy group. Monosaccharides are drawn vertically, with the carbonyl group at the top. 

Monosaccharides generally contain multiple chirality centers. 2 diastereomers that differ in configuration only around one stereocenter are called epimers.

 

Aldoses vs. ketoses:

  • Aldoses contain an aldehyde moiety ("ald-"), while ketoses contain a ketone moiety ("ket-"). The suffix -ose is used to denote a carbohydrate.
  • Aldoses and ketoses can be further classified based on the number of carbon atoms they contain ⇒ tri-, tetra-, pent-, hex-, or hept- is added immediately before the -ose suffix depending on the number of carbon atoms.

 

Classification of carbohydrates:

  1. aldo or keto indicates whether the compound is an aldehyde or a ketone.
  2. tri-, tert-, pent-, hex-, or hept- indicates the number of carbon atoms.
  3. -ose indicates a carbohydrate.

 


 

D and L configuration:

  • Sugars are classified as D-sugars when the chirality center farthest from the carbonyl group has an R configuration. The OH group on this chirality center is on the right in a Fischer projection. All naturally occurring sugars are D-sugars.
  • Sugars are classified as L-sugars when the chirality center farthest from the carbonyl group has an S configuration. The OH group on this chirality center is on the left in a Fischer projection. L-sugar is the enantiomer of the corresponding D-sugar.

 

Configuration of Aldoses and Ketoses

Configuration of aldoses:

  • Aldotetroses:

Aldotetroses have 2 chirality centers and therefore 22 = 4 possible stereisomers. 2 of the possible aldotetroses are D-sugars, while the other 2 are L-sugars, enantiomers of the D-aldotetroses. The D-aldotetroses are called D-Erythrose and D-Threose:
 

 

  • Aldopentoses:

Aldopentoses have 3 chirality centers and therefore 23 = 8 possible stereisomers. 4 of the possible aldopentoses are D-sugars, while the other 4 are L-sugars, enantiomers of the D-aldopentoses. The D-aldopentoses are called D-Ribose, D-Arabinose, D-Xylose, and D-Lyxose:
 

 

  • Aldohexoses:

Aldohexoses have 4 chirality centers and therefore 24 = 16 possible stereisomers. 8 of the possible aldohexoses are D-sugars, while the other 8 are L-sugars, enantiomers of the D-aldohexoses. The D-aldohexoses are called D-Allose, D-Altrose, D-Glucose, D-Mannose, D-Gulose, D-Idose, D-Galactose, and D-Talose:
 


Of the D-aldohexoses, only D-glucose and D-galactose are found in nature. D-glucose is by far the most abundant of all D-aldoses.

 

Configuration of ketoses:

Because the carbonyl group is at C2 instead of C1, ketoses have one less chirality center than aldoses of the same molecular formula. As a result, there are only 2 D-ketopentoses (D-Ribulose and D-Xylulose) and 4 D-ketohexoses (D-Psicose, D-Fructose, D-Sorbose, and D-Tagatose):
 

D-ketopentose:
 

D-ketohexoses:
 


D-fructose is the most common naturally occurring ketose.

Cyclic Structures of Sugars

Cyclic structures of monosaccharides:

Pentoses and hexoses can undergo intramolecular cyclization and form 5- or 6-membered cyclic hemiacetals.
 

 

Mechanism: hemiacetal formation
 

 

A 5-membered ring is called furanose ring, while a 6-membered ring is called pyranose ring. These rings are relatively strain free ⇒ the equilibrium favors the formation of the cyclic hemiacetal.

 

α- and β-anomers:

During the cyclization process, the carbonyl carbon turns into a new chirality center called the anomeric carbon. The 2 anomers are called α- and β-anomers. In the α-anomer, the hydroxyl group is trans to the CH2OH group, while in the β-anomer, the hydroxyl group is cis to the CH2OH group. α- and β-anomers are in equilibrium and can equilibrate via an open-chain form, a process called mutarotation.
 

Haworth Projections

Haworth projections:

A Haworth projection is a way of representing the three-dimensional structure of cyclic organic molecules. It is commonly used to depict the cyclic structure of monosaccharides.

In a Haworth projection, the carbon chain of a sugar is depicted in a flat, two-dimensional plane, and the carbon atoms are usually represented as corners of a polygon. The substituents, such as hydroxyl groups (-OH) and other functional groups, are then shown either above or below the plane to indicate their spatial orientation.

 

 

How to convert a Fischer projection to a Haworth projection:

  1. Place the O atom in the upper right corner of a polygon, and add the CH2OH group on the 1st carbon counterclockwise from the O atom.
    For D-sugars, the CH2OH group is drawn up. For L-sugars, the CH2OH group is drawn down.
  2. Place the anomeric carbon on the 1st carbon clockwise from the O atom.
    For an α-anomer, the OH is drawn down (in a D-sugar). For a β-anomer, the OH is drawn up (in a D-sugar).
  3. Add the substituents to the remaining chirality centers clockwise around the ring.
    The substituents on the right side of the Fischer projection are drawn down. Those on the left are drawn up.

 

Reactions of Monosaccharides

Ester formation:
 


Conversion of a monosaccharide into its ester derivative.

Mechanism: addition-elimination.

 

Ether formation:
 


Conversion of a monosaccharide into its ether derivative by Williamson ether synthesis.

Mechanism:

  1. Deprotonation of alcohols with mild base Ag2O to form alkoxide ions.
  2. SN2 reaction between alkoxides and CH3I to form ether derivative.

 

Glycoside formation:
 


Conversion of a monosaccharide into an acetal called glycoside.

Mechanism (directly analogous to the acetal formation):

  1. Protonation of the anomeric hydroxyl group converting it into an excellent leaving group.
  2. Loss of water to form a resonance-stabilized carbocation.


     
  3. Nucleophilic attack of the alcohol on the anomeric position.
  4. Loss of a proton to form a glycoside.


     


During glycoside formation, only the anomeric hydroxyl group is replaced. A mixture of α and β anomers is obtained because the alcohol can attack the carbocation from both face of the planar carbocation.

Glycosides are named by placing the alkyl group as a prefix and the term -oside as a suffix.

 

Epimerization:
 

Mechanism:

  1. Base-catalyzed tautomerization of a D-sugar to form an enediol.
  2. Second base-catalyzed tautomerization of the intermediate to revert back to aldose leading to a mixture of two epimers.


     

The products of this reaction is a mixture of 2 epimers, stereoisomers that differ from each other in the configuration of only one chirality center.

Reduction and Oxidation of Monosaccharides

Reduction of monosaccharides:
 


Reduction of an aldose or ketose into an alditol (a 1o alcohol) using NaBH4.

The starting monosaccharide exists as an equilibrium of its hemiacetal form, which does not react with NaBH4, and a small amount of its open-chain form. According to Le Chatelier's principle, this equilibrium is shifted when the open-chain form begins to undergo reduction.

 

Oxidation of monosaccharides:

  • Oxidation to an aldonic acid:


Oxidation of an aldose into an aldonic acid using an aqueous solution of bromine at pH = 6. 
Under these conditions, ketoses are not reduced.
 

  • Oxidation to an aldaric acid:


Oxidation of an aldose into an aldaric acid (a dicarboxylic acid) using HNO3.

Chain Lengthening and Shortening

Chain lengthening - The Kiliani-Fischer synthesis:
 

Mechanism:

  1. Nucleophilic acyl addition of HCN to the carbonyl group to form a pair of stereoisomeric cyanohydrins.
  2. Hydrogenation of the nitrile with a poisoned Pd catalyst to form an imine.
  3. Hydrolysis of the imine to form an aldose.


     

This process only works with aldoses and results in a mixture of 2 epimers:
 


 

Chain shortening - The Wohl degradation:
 

Mechanism:

Reverse mechanism of the Kiliani-Fischer synthesis.

  1. Nucleophilic addition of hydroxylamine (NH2OH) to the carbonyl group to form an oxime.
  2. Dehydration of the oxime to form a cyanohydrin.
  3. Loss of HCN under basic conditions to form an aldose.

Polysaccharides

Polysaccharides are polymers of monosaccharides. Nature is remarkably conservative in the construction of such macromolecules: the 3 most abundant natural polysaccharides (cellulose, starch and glycogen) are derived from the glucose
 

Cellulose is a polysaccharide:
 

 

Many sugars exist in nature in modified form or as simple appendage to other structures. Modified sugars may contain nitrogen:
 

Check your knowledge about this Chapter

  • Carbohydrates are a class of biomolecules that consist of carbon, hydrogen, and oxygen, often in the proportions that reflect the general formula Cn(H2O)m.
  • Carbohydrates can be classified as monosaccharides (simple sugars), disaccharides (two monosaccharides linked), and polysaccharides (long chains of monosaccharides).
  • Carbohydrates play a vital role as a source of energy for living organisms, serve as structural components, and can be involved in cell recognition processes.
  • The solubility of carbohydrates in water varies: monosaccharides and disaccharides are generally soluble, while polysaccharides may not be.
  • Additionally, many carbohydrates exhibit isomerism, meaning they can have the same molecular formula but different structures and properties.

The Fischer projection is a two-dimensional representation that displays the configuration of a monosaccharide's chiral centers. In a Fischer projection, the longest carbon chain of the sugar molecule is oriented vertically with the most oxidized carbon at the top. Horizontal lines represent bonds coming out of the plane (towards the observer), while vertical lines represent bonds going into the plane (away from the observer). This allows for a clear depiction of the stereochemistry at each chiral center, showing which groups are on the right or left in the molecule's three-dimensional structure.

Carbohydrates are named and classified based on the number of carbon atoms, the functional groups present, and their stereochemistry. Simple carbohydrates, or monosaccharides, are categorized as trioses (3 carbons), tetroses (4 carbons), pentoses (5 carbons), hexoses (6 carbons), etc., based on the number of carbon atoms. They are further divided into aldoses and ketoses, where aldoses have an aldehyde group at the end of the carbon chain and ketoses have a ketone group usually at the second carbon.

An aldose contains an aldehyde group at the end of the carbon chain, while a ketose has a ketone group usually at the second carbon atom. A simple chemical test to distinguish between them is the Seliwanoff's test, where ketoses react more rapidly than aldoses, yielding a deep red color.

  • Sugars are classified as D-sugars when the chirality center farthest from the carbonyl group has an R configuration. The OH group on this chirality center is on the right in a Fischer projection. All naturally occurring sugars are D-sugars.
  • Sugars are classified as L-sugars when the chirality center farthest from the carbonyl group has an S configuration. The OH group on this chirality center is on the left in a Fischer projection. L-sugar is the enantiomer of the corresponding D-sugar.

Monosaccharides form cyclic structures through an intramolecular reaction where the carbonyl group (aldehyde or ketone) reacts with a hydroxyl group on the same molecule, leading to the formation of a hemiacetal (in aldoses) or a hemiketal (in ketoses). This reaction is often driven by the stabilization that comes from forming a five- or six-membered ring, which is less strained and more energetically favorable than other possible ring sizes.

The formation of cyclic structures is significant because it gives rise to different stereoisomers, known as anomers, at the carbonyl carbon, now called the anomeric carbon. These isomers have unique chemical behaviors and physical properties, and are crucial in biochemistry for the construction of complex carbohydrates and for the specific recognition and binding events between enzymes and substrates.

Haworth projections are simplified three-dimensional representations used to visualize the cyclic forms of sugars, which are more prevalent in nature than their linear forms. In this depiction, the rings are shown as planar with substituent groups either above or below the plane of the ring to indicate stereochemistry.

  1. Place the O atom in the upper right corner of a polygon, and add the CH2OH group on the 1st carbon counterclockwise from the O atom.
    For D-sugars, the CH2OH group is drawn up. For L-sugars, the CH2OH group is drawn down.
  2. Place the anomeric carbon on the 1st carbon clockwise from the O atom.
    For an α-anomer, the OH is drawn down (in a D-sugar). For a β-anomer, the OH is drawn up (in a D-sugar).
  3. Add the substituents to the remaining chirality centers clockwise around the ring.
    The substituents on the right side of the Fischer projection are drawn down. Those on the left are drawn up.

Monosaccharides are versatile molecules that can undergo a variety of chemical reactions. These include oxidation-reduction reactions, where aldehyde or ketone groups can be oxidized to carboxylic acids (oxidation) or reduced to alcohols (reduction). They also participate in glycoside formation when their hydroxyl groups react with other alcohols or with amines to form glycosides. Monosaccharides can undergo isomerization, forming epimers or anomers, and they can engage in ring-opening and ring-closing reactions to convert between linear and cyclic forms. Additionally, they can be phosphorylated, which is crucial in energy metabolism, or act as substrates in biochemical reactions such as transamination or glycosylation.

Monosaccharides typically undergo oxidation reactions to form saccharic acids. The aldehyde group of an aldose can be oxidized to a carboxylic acid group using an aqueous solution of bromine at pH = 6, yielding an aldonic acid. Ketoses are not reduced under these conditions. Similarly, the primary alcohol group of a monosaccharide can be oxidized to a carboxylic acid, converting an aldose into an aldaric acid using HNO3.

The chain lengthening of carbohydrates, specifically monosaccharides, typically involves the Kiliani-Fischer synthesis. This process adds one carbon to the sugar chain by converting the aldehyde group to a cyanohydrin followed by hydrolysis and subsequent reduction steps. The newly formed aldose contains one additional carbon atom than the starting material. This method can be used to progressively create a series of sugars, each with an additional carbon atom, helping to explore the structure and reactivity of larger carbohydrates.

 

Carbohydrate chain shortening, particularly in the context of Wohl degradation, involves several mechanistic steps. First, hydroxylamine (NH2OH) undergoes nucleophilic addition to the carbonyl group of the carbohydrate, resulting in the formation of an oxime. The oxime is then dehydrated to form a cyanohydrin. Finally, under basic conditions, the cyanohydrin loses hydrogen cyanide (HCN), resulting in the cleavage of the carbon chain and the formation of an aldose. This process essentially reverses the mechanism observed in the Kiliani-Fischer synthesis.

Polysaccharides are long chains of monosaccharides linked by glycosidic bonds. Unlike monosaccharides, which are simple sugars with fundamental structures such as glucose and fructose, polysaccharides are complex carbohydrates that can serve structural roles, as seen in cellulose in plants, or energy storage roles, such as in starch in plants and glycogen in animals.