Comprehensive Study Guide: Structure and Chemistry of Carbohydrates

Introduction to Carbohydrates

Definition and Etymology: * The term "carbohydrate" literally means "hydrate of carbon." * It was suggested in 1844 for compounds following the empirical formula $(CH_2O)_n$ . * While many compounds now classified as carbohydrates do not follow this exact empirical formula, the name has been retained.
Structural Variety: * Structures range from simple molecules with only three carbon atoms to extremely large molecules consisting of thousands of rings.
Chemical Nature: * Carbohydrates are defined as polyhydroxy aldehydes or polyhydroxy ketones. * They can also be compounds that yield polyhydroxy aldehydes or ketones upon hydrolysis.
Biological Significance: * They provide a major source of metabolic energy. * They serve as essential components of DNA and RNA. * Glycoproteins are formed when proteins are attached to carbohydrates. * They are critical structural components in many cells. * Surface-bound carbohydrates act as antigenic determinants for cellular identity (e.g., the antigens of the ABO blood group).

Classification of Carbohydrates

Monosaccharides (Simple Sugars): * The simplest forms of carbohydrates. * Contain three to six carbon atoms. * Cannot be hydrolyzed into smaller molecules. * Examples include glucose and fructose.
Oligosaccharides: * Consist of a few monosaccharides, typically 2 to 10. * Can be hydrolyzed into monosaccharides. * Sub-classifications include disaccharides and trisaccharides. * Examples include lactose, maltose, sucrose, and maltodextrin.
Polysaccharides: * Consist of thousands of covalently linked monosaccharides. * Classified into homopolysaccharides and heteropolysaccharides. * Examples include starch, cellulose, glycogen, heparin, and hyaluronic acid.

Monosaccharide Structure and Nomenclature

Functional Groups: * Aldoses: Monosaccharides where the most highly oxidized functional group is an aldehyde. * Ketoses: Monosaccharides where the most highly oxidized functional group is a ketone.
Naming Conventions: * Suffix: The suffix "-ose" indicates a carbohydrate. * Prefixes: "Aldo-" or "keto-" indicates the type of carbonyl group. * Chain Length: Prefixes like "tri-", "tetr-", "pent-", and "hex-" indicate the number of carbon atoms. * Example: An aldotetrose is a four-carbon sugar with an aldehyde; a ketohexose is a six-carbon sugar with a ketone.
Numbering Rules: * Aldoses are numbered starting from the carbonyl carbon atom (C1). * Ketoses are numbered from the end of the carbon chain closest to the carbonyl carbon atom.
Example: D-Ribulose: * Classified as a ketopentose (5-carbon chain with a ketone). * It is an intermediate in the pentose phosphate pathway used to produce ribose for nucleic acid biosynthesis.

Fischer Projection Formulas

Standard Method for Representation: * The vertical line represents the carbon chain. * Vertical bonds (at the top and bottom) represent bonds going into the page. * Horizontal lines represent bonds coming out of the page. * The most oxidized carbon atom is placed near the "top." * Carbon atoms are implicit at the intersections. * Hydrogen atoms and hydroxyl groups point out to the right and left of the main chain.
Glyceraldehyde as the Parent Sugar: * D-glyceraldehyde is the simplest aldose and serves as the "parent" sugar for the D-series. * The central carbon (C-2) is a tetrahedral chiral carbon. * In the D configuration (or R), the hydroxyl group on C-2 is located on the right of the Fischer projection. * Naturally occurring D-glyceraldehyde is dextrorotatory, symbolized as D(+)-glyceraldehyde, meaning it rotates plane-polarized light clockwise. * Optical rotation (+ or -) is an experimental parameter and is distinct from the D/L (R/S) configuration.

Stereochemistry of Monosaccharides

Chirality: * A molecule is chiral if it contains at least one carbon atom attached to four different atoms or groups ( $sp^3$ hybridized stereogenic center). * The number of possible stereoisomers for a molecule with $n$ stereogenic centers is calculated as $2^n$ .
D and L Series Configuration: * In the Fischer system, the configuration of a monosaccharide is determined by the highest-numbered stereogenic center (the chiral center farthest from the carbonyl group). * If the configuration of this center matches D-glyceraldehyde (hydroxyl on the right), the sugar is a D-sugar. * The name "D-ribose" specifically defines the absolute configuration at every stereogenic center in the molecule.
Diastereomers vs. Enantiomers: * Stereoisomers in the D-series (e.g., D-glucose, D-mannose, D-galactose) are diastereomers of each other, not enantiomers, because they are not mirror images.
Precursor-based Synthesis: * Cells synthesize monosaccharides from the three-carbon precursor D-glyceraldehyde by extending the chain from C-1. * Consequently, nearly all naturally occurring sugars possess the same configuration at the highest-numbered chiral center as D-glyceraldehyde.

Specific Monosaccharide Relationships

Epimers: * Definition: Diastereomers that contain two or more stereogenic centers but differ in configuration at only one specific center. * Examples relative to D-glucose: * D-mannose is the C-2 epimer of D-glucose. * D-galactose is the C-4 epimer of D-glucose. * Epimerization is the chemical reaction that inverts the configuration at a single center.
Interconversion of Aldoses and Ketoses: * Isomerization occurs either in the presence of a weak base or via enzyme-catalyzed reactions near pH 7.

Cyclic Structures and Hemiacetals/Hemiketals

Nucleophilic Addition of Alcohols: * An aldehyde reacting with one mole of alcohol forms a hemiacetal. * A ketone reacting with one mole of alcohol forms a hemiketal. * Intramolecular nucleophilic addition occurs when the hydroxyl and carbonyl groups are on the same molecule, resulting in a cyclic structure.
Predominant Cyclic Forms: * Five- and six-membered rings are the most common and stable. * Furanoses: Five-membered rings (based on furan). * Pyranoses: Six-membered rings (based on pyran).
Glucose Cyclization: * In aqueous solution, glucose exists predominantly as a six-membered pyranose ring. * Formed by the addition of the C-5 hydroxyl group to the C-1 aldehyde. * This creates a new chiral center at C-1, known as the anomeric carbon.
Anomers: * Two diastereomers called anomers are formed: $\alpha$ and $\beta$ . * In D-glucose at equilibrium: $36\%$ is $\alpha$ -D-glucopyranose and $64\%$ is $\beta$ -D-glucopyranose.
Fructose Cyclization: * Exists as both a six-membered pyranose (C-6 OH to C-2 ketone) and a five-membered furanose (C-5 OH to C-2 ketone). * Equilibrium distribution of D-fructose in solution: * $\beta$ -D-fructopyranose: $66\%$ * $\alpha$ -D-fructopyranose: $2\%$ * $\beta$ -D-fructofuranose: $22\%$ * $\alpha$ -D-fructofuranose: $7\%$

Haworth Projection Formulas

Rules for Drawing: * The ring is viewed from the edge. * For D-sugars, the $-CH_2OH$ group is positioned "up." * Beta (\beta) Anomer: The anomeric hydroxyl group is "up" (cis to the terminal $-CH_2OH$ ). * Alpha (\alpha) Anomer: The anomeric hydroxyl group is "down" (trans to the terminal $-CH_2OH$ ).

Mutarotation

Definition: The gradual change in optical rotation of a solution to an equilibrium point.
Physical Properties of Anomers: * $\alpha$ -D-glucopyranose: Melting point $146^\circ \text{C}$ , $[\alpha]_D = +112.2^\circ$ . * $\beta$ -D-glucopyranose: Melting point $150^\circ \text{C}$ , $[\alpha]_D = +18.7^\circ$ .
The Process: * Mutarotation results from cyclic hemiacetals interconverting with the open-chain form (<0.01\% at equilibrium) in solution. * In both cases for glucose, the optical rotation settles at an equilibrium value of $+54^\circ$ . * In biological systems, the enzyme mutarotase catalyzes this interconversion.

Modified Carbohydrates

Amino Sugars: A hydroxyl group is replaced by an amino ( $-NH_2$ ) or amide group. Important in antibiotics and blood group antigens.
Glycoconjugates: Modified sugars expressed on cell surfaces for recognition and cellular identity.
Inositol: * Has nine possible stereoisomers. * The most natural form is myo-inositol (cis-1,2,3,5-trans-4,6-cyclohexanehexol). * It is a carbohydrate but not a classical sugar (it is a cyclic polyol). * Functions of Inositol and its Phosphates: Acting as secondary messengers, involved in insulin signal transduction, cytoskeleton assembly, nerve guidance (Epsin), Ca $^{2+}$ concentration control, membrane potential maintenance, fat breakdown (cholesterol reduction), and gene expression.

Chemical Properties and Reactions

Carbonyl Reactivity: Reactions occur via the small amount of open-chain form. As the open-chain form reacts, the equilibrium shifts to produce more until all the sugar is converted.
Reduction: * Aldoses or ketoses treated with sodium borohydride ( $NaBH_4$ ) are reduced to polyalcohols called alditols. * Example: D-glucose is reduced to D-glucitol, commonly known as sorbitol, a commercial sugar substitute.
Oxidation: * Mild Oxidation (Aldonic Acids): * Aldoses are oxidized at C-1 to form aldonic acids (e.g., D-gluconic acid). * Reagents: Tollens’s reagent ( $Ag$ mirror), Benedict’s solution ( $Cu_2O$ red precipitate), Fehling’s solution ( $Cu_2O$ red precipitate), or bromine water ( $Br_2/H_2O$ at pH 6). * These reagents do not oxidize hydroxyl groups. * Reducing Sugars: * Sugars that react with Tollens, Benedict’s, or Fehling’s solutions are "reducing sugars." * All aldoses and ketoses are reducing sugars. * Ketoses react because they tautomerize into aldoses in basic solution (pH > 7) via an enediol intermediate. * Strong Oxidation (Aldaric Acids): * Nitric acid ( $HNO_3$ ) oxidizes both the C-1 aldehyde and the primary alcohol ( $-CH_2OH$ ) to form aldaric acids (e.g., D-glucaric acid). * Enzymatic Oxidation (Uronic Acids): * Oxidation of only the terminal $-CH_2OH$ group without affecting the aldehyde. * Catalyzed by NADP$^+$-dependent dehydrogenase. * Resulting product is a uronic acid (e.g., D-glucuronic acid).

Glycoside Formation

Reaction: Hemiacetals/hemiketals react with alcohols in the presence of an acid catalyst ( $HCl$ ) to form acetals/ketals called glycosides.
Glycosidic Bond: The new carbon-oxygen bond at the anomeric center.
Key Characteristics: * Glycosides are NOT in equilibrium with the open-chain form in aqueous solution. * The group bonded to the anomeric carbon is called the aglycone. * In most aglycones, the bond is to an oxygen atom (alcohol/phenol), but nucleosides and nucleotides contain nitrogen-linked aglycones.
Naming: Name the aglycone first, then replace the "-ose" suffix with "-oside" (e.g., methyl $\alpha$ -D-glucopyranoside).

Esterification

General Esterification: All hydroxyl groups on a sugar can react to form esters, such as $\alpha$ -D-glucose pentaacetate.
Biological Phosphates: Sugars are often modified into phosphate esters for metabolic pathways. * Examples: Glucose-1-phosphate, glucose-6-phosphate, glucose-1,6-bisphosphate, and fructose-1,6-bisphosphate.

Chain Modification of Aldoses

Kiliani-Fischer Synthesis (Chain Extension): * Step 1: Aldose ( $C_n$ ) reacts with $HCN$ to form diastereomeric cyanohydrins ( $C_{n+1}$ , adding a new stereogenic center). * Step 2: Nitrile is partially reduced to an imine. * Step 3: Imine is hydrolyzed to form a new aldehyde.
Wohl Degradation (Chain Shortening): * Step 1: Aldose ( $C_n$ ) reacts to form an oxime. * Step 2: Acetic anhydride dehydrates the oxime to a nitrile while converting hydroxyls to acetates. * Step 3: Sodium methoxide removes acetate groups and the basic conditions cause the loss of $HCN$ , yielding a chain-shortened aldose ( $C_{n-1}$ ).

Microbial Fermentation

To Ethanol: Processed by yeast into alcoholic beverages ( $glucose \rightarrow pyruvate \rightarrow acetaldehyde \rightarrow ethanol + CO_2$ ).
To Lactic Acid: Processed by bacteria or in muscle cells ( $glucose \rightarrow pyruvate \rightarrow lactic acid$ ).