Comprehensive Notes on Carbohydrate Chemistry: Structures, Reactions, and Biological Significance

Topic 4: Introduction to Carbohydrates and Fundamental Chemistry

• The study of carbohydrates in Chemistry 2223B (Winter 2025-26) focuses on their fundamental chemistry, properties, and a specific emphasis on monosaccharides.

• The course introduces the mechanistic chemistry of glucose catabolism into pyruvate, a process known as glycolysis.

• Prerequisites and background material necessary for understanding this topic include:     - Stereochemistry: Enantiomers, diastereomers, and Fischer projections.     - Reactions of alcohols, carbonyl compounds, and carboxylic acids.     - Key reaction types: Nucleophilic addition, nucleophilic substitution, and oxidation and reduction.

Biological Significance and Categories of Carbohydrates

• Carbohydrates are the most abundant class of naturally occurring biomolecules, constituting $50\%$ of the world’s biomass (by dry weight).

• Formation and Storage:     - They are primarily synthesized by plants through photosynthesis: $\text{Light energy} + CO_2 + H_2O \rightarrow \text{carbohydrates} + O_2$.     - They serve as a primary mechanism for energy storage in living organisms.

• Structural Roles:     - Carbohydrates provide structural integrity, notably in substances like cellulose and chitin.

• Medicinal Components:     - They are components of various drugs, such as:         - Salicin: Found in willow bark.         - Adriamycin: Derived from Streptomyces achromogenes.

Classification of Carbohydrate-Based Biopolymers

• Carbohydrates exist as components in small biomolecules and large, high-molecular-weight biopolymers, categorized by their structural links:     - Glycoproteins: Proteins bonded to short, branched carbohydrate chains attached to amino acid side chains. These are essential for cell receptors, recognition, and cell-to-cell interactions (e.g., blood-group antigens $A$ and $B$).     - Proteoglycans (Mucopolysaccharides): Proteins with long, linear carbohydrate chains bonded to amino acid side chains, typically found in cartilage and connective tissue.     - Peptidoglycans: Long, linear carbohydrates crosslinked by short oligopeptides, serving as a primary component of bacterial cell walls.     - Lipopolysaccharides: Fatty acids linked to carbohydrates, commonly found in the outer envelope of Gram-negative bacteria.

Chemical Definitions and Simple Sugar Classification

• Definition: Chemically, carbohydrates are organic compounds composed mainly of $C$, $H$, and $O$.

• Simple Sugars:     - Their empirical formula is that of a "hydrated carbon": $C(H_2O)$.     - Their molecular formula is $C_n(H_2O)<em>n$ or $C_nH</em>{2n}O_n$.     - They are defined as polyhydroxyaldehydes or polyhydroxyketones, or compounds that yield these upon hydrolysis.     - The sequence of transformation often involves aldose/ketose $\rightarrow$ hemiacetal $\rightarrow$ acetal.

• Monosaccharides:     - A monosaccharide ("one sugar") is a carbohydrate that cannot be hydrolyzed into a simpler carbohydrate using $H^+ / H_2O$ in a laboratory setting.     - Polysaccharides are chains containing many monosaccharides, typically exceeding $10$ units. These are usually isolated naturally rather than synthesized due to lab difficulty.     - Oligosaccharides refer to short chains of monosaccharides.

Nomenclature and Structural Classification of Monosaccharides

• Classification by Carbon Count: Uses a prefix for the number of carbons and the suffix -ose.     - $3$ carbons: Triose.     - $4$ carbons: Tetrose.     - $5$ carbons: Pentose.     - $6$ carbons: Hexose.     - $8$ carbons: Octose.

• Classification by Carbonyl Group:     - Aldoses: Contain an aldehyde group.     - Ketoses: Contain a ketone group (typically at position #2 unless specified).

• Combined Classification Examples:     - D-glucose is an aldohexose.     - D-ribulose is a ketopentose (also called a pentulose; the suffix -ulose implies a ketose).

Representations and Fischer Projections

• Simplest Sugars: Trioses ($C_3$ sugars).     - Glyceraldehyde: An aldotriose ($CHO-CHOH-CH_2OH$).     - Dihydroxyacetone: A ketotriose or triulose ($CH_2OH-C=O-CH_2OH$).

• Fischer Projections:     - Used to draw open-chain forms of monosaccharides.     - Convention: The most-oxidized carbon is placed at the top.     - Geometry: Horizontal bonds project toward the viewer (front of page); vertical bonds project away from the viewer (back of page).

The D/L System of Nomenclature

• Historical Context: In $1891$, Emil Fischer identified two enantiomeric forms of glyceraldehyde based on optical activity in a polarimeter.

• Optical Activity:     - One enantiomer rotated plane-polarized light (PPL) to the right ($[\alpha] = +$, dextrorotatory).     - The other rotated PPL to the left ($[\alpha] = -$, levorotatory).     - Enantiomers rotate PPL with the same magnitude but in opposite directions. Diastereomers have unpredictable optical rotations; meso compounds have zero rotation.

• Fischer’s Assumptions:     - Fischer assumed the structure with the $OH$ group on the right in his projection corresponded to the dextrorotatory ($D$) form.     - He assumed the structure with the $OH$ group on the left corresponded to the levorotatory ($L$) form.     - X-ray crystallography proved these assumptions correct half a century later.     - D-Glyceraldehyde has $[\alpha] = +13.5^{\circ}$.     - L-Glyceraldehyde has $[\alpha] = -13.5^{\circ}$.

• Extension to Other Sugars:     - For sugars with multiple stereocenters, the $D/L$ designation is determined by the stereocenter furthest from the carbonyl group (usually the penultimate carbon).     - $D$-monosaccharide: penultimate $OH$ is on the right.     - $L$-monosaccharide: penultimate $OH$ is on the left.     - Except for glyceraldehyde, there is no consistent correlation between the $D/L$ prefix and the actual direction ($+/-$) of PPL rotation.     - $D$ and $L$ versions of a sugar with the same common name (e.g., $D$-Xylose and $L$-Xylose) are exact enantiomers, meaning every chiral center has the opposite configuration.

Chart of D-Aldoses

• Triose:     - Glyceraldehyde.

• Tetroses:     - Erythrose, Threose.

• Pentoses:     - Ribose, Arabinose, Xylose, Lyxose.

• Hexoses:     - Allose, Altrose, Glucose, Mannose, Gulose, Idose, Galactose, Talose.

Chart of D-Ketoses

• Triulose:     - Dihydroxyacetone.

• Tetrulose:     - Erythrulose.

• Pentuloses:     - Ribulose, Xylulose.

• Hexuloses:     - Psicose, Fructose, Sorbose, Tagatose.

Modified Monosaccharides

• Naturally occurring modified sugars include:     - 2-deoxy-D-ribose: Missing the $OH$ at carbon $2$.     - Glucosamine (2-deoxy-2-amino-D-glucose).     - N-acetyl glucosamine (2-deoxy-2-N-acetylamino-D-glucose or GlcNac).     - D-glucuronic acid: Carbon $6$ is oxidized to a carboxylic acid.     - Mannosamine (2-deoxy-2-amino-D-mannose).     - Galactosamine (2-deoxy-2-amino-D-galactose) and GalNac.

Intramolecular Formation of Hemiacetals

• Process: The hydroxyl and carbonyl groups of a monosaccharide react intramolecularly to form cyclic hemiacetals.

• Favorability: Intramolecular reactions are much more favorable than intermolecular ones, resulting in monosaccharides existing almost entirely in cyclic forms.

• Ring Sizes:     - Furanose: A five-membered cyclic sugar (named after furan).     - Pyranose: A six-membered cyclic sugar (named after pyran).

• Hemiacetal formation typically involves the $OH$ on the penultimate carbon.

• Haworth Projections: Used to represent cyclic sugars from a side view, as Fischer projections are inconvenient for cyclic structures.

• Stereocenters: A new stereocenter is formed at the carbonyl carbon during cyclization.

Mechanisms of Hemiacetal Formation

• Acid-Catalyzed (Reversible):     - Protonation of the carbonyl oxygen.     - Nucleophilic attack by the alcohol ($R'-OH$).     - Deprotonation to yield the neutral hemiacetal.

• Base-Catalyzed (Reversible):     - Deprotonation of the alcohol to form an alkoxide ($R'O^-$).     - Nucleophilic attack on the carbonyl carbon.     - Protonation of the oxygen from the solvent ($H_2O$ or $ROH$) to yield the hemiacetal.

The Anomeric Carbon and Anomers

• Definition: The new stereocenter formed from the original carbonyl carbon is the anomeric carbon.

• Anomers: Two stereoisomers (diastereomers) that differ only in the configuration at the anomeric carbon. This occurs because the $sp^2$ carbonyl carbon is flat, allowing nucleophilic attack from either side.

• Designation Rules ($D$-sugars):     - $\alpha$ anomer: The $OH$ group on the anomeric carbon is trans to the terminal $CH_2OH$.     - $\beta$ anomer: The $OH$ group on the anomeric carbon is cis to the terminal $CH_2OH$.

• These designations hold true even in conformational chair representations.

Mutarotation

• Definition: The interconversion of anomers in aqueous solution until an equilibrium mixture is reached. This process is catalyzed by even trace amounts of acid found at neutral $pH$.

• Monitoring: The process is tracked using optical rotation change over time.

• Equilibrium Data for D-Glucose:     - Pure $\alpha$-D-glucose: $[\alpha] = +112.2$.     - Equilibrium Mixture: $[\alpha] = +52.7$.     - Distribution: $36\%$ $\alpha$, $64\%$ $\beta$ (The $\beta$ form is more stable due to reduced steric hindrance).

• Equilibrium Data for D-Galactose:     - Pure $\alpha$-D-galactose: $[\alpha] = +150.7$.     - Pure $\beta$-D-galactose: $[\alpha] = +52.8$.     - Equilibrium Mixture: $[\alpha] = +80.2$ ($28\%$ $\alpha$, $72\%$ $\beta$).

Formation of Glycosides (Sugar Acetals)

• O-Glycosides: Formed when a cyclic hemiacetal reacts with another alcohol ($ROH$) under acid catalysis to form an acetal.

• Nomenclature: Named by stating the attached group (e.g., methyl) followed by the carbohydrate name ending in -ide (e.g., Methyl $\alpha$-D-glucopyranoside).

• Mechanism: An acid-catalyzed $S_N1$ reaction involving a carbocation intermediate. This results in a mixture of $\alpha$ and $\beta$ glycosides regardless of the starting anomer.

• Stability: Glycosides (acetals) are stable in basic and neutral $pH$; they only revert to open-chain forms in the presence of acid or specific glycosidase enzymes.

• N-Glycosides: Formed when the anomeric carbon reacts with an amine. These are found in nucleosides (nucleic acid components).

• Example: Coniferin is the primary glycoside found in conifer tree sap.

Oxidation Reactions of Monosaccharides

• Oxidation to Aldonic Acids:     - Only the aldehyde group of an aldose is oxidized to a carboxylic acid.     - Weak Oxidizing Agents:         - Bromine water ($Br_2, H_2O$): Gentler technique where $Br_2$ is reduced to $2 Br^-$.         - Tollen’s Reagent ($[Ag(NH_3)_2]^+$): Reduced to $Ag(s)$, creating a silver mirror.         - Benedict’s or Fehling’s Reagents ($Cu^{2+}$ complexed with citrate or tartrate): Reduced to $Cu_2O(s)$, forming a red solid.     - Reducing Sugars: Sugars that can reduce these oxidants are called reducing sugars.

• Oxidation to Aldaric Acids:     - Stronger agent: Nitric acid ($HNO_3$).     - Oxidizes both the aldehyde and the primary alcohol to carboxylic acids.     - Too weak to oxidize secondary alcohols.     - Structural Info: The symmetry of the resulting aldaric acid can identify the sugar; meso compounds are optically inactive (e.g., Galactaric acid).

• Oxidation to Uronic Acids:     - Selective oxidation of only the primary alcohol ($CH_2OH$) to a carboxylic acid ($COOH$), leaving the aldehyde intact.     - Requires enzymes for this selectivity.     - Glucuronic Acid: Used by the liver to detoxify substances by forming glucuronides (increasing water solubility for excretion). Morphine, THC, and anabolic steroids are excreted as glucuronide metabolites.

Reduction and $\alpha$-Carbon Reactions

• Reduction to Alditols:     - Carbonyl groups are reduced to alcohols using $H_2/\text{metal}$, $NaBH_4$, or $LiAlH_4$.     - Examples: Sorbitol (D-Glucitol) in sugar-free candy, Xylitol in sugar-free gum.     - Reduction of ketoses can create a new stereocenter.

• Reactions of the $\alpha$-Carbon:     - Alpha-hydrocarbons have a $pKa \approx 20$. Enolate formation destroys stereochemistry at the $\alpha$-carbon.     - Epimerization: Placing D-glucose in base creates an equilibrium mixture involving D-glucose ($65\%$), D-mannose ($3\%$), and D-fructose ($32\%$). Epimers are diastereomers differing at only one stereocenter.     - Isomerization: Involves an ene-diol rearrangement (successive tautomerizations) to convert an aldose to a ketose.     - False Positive: Because Benedict's Reagent is basic, ketoses will isomerize to aldoses and give a positive test for reducing sugars.

Aldol Reactions and Acylation

• Aldol Reactions:     - Nucleophilic addition where an enolate attacks another carbonyl, forming a new carbon-carbon bond.     - Results in a $\beta$-hydroxy carbonyl compound.     - Biological Instance: The enzyme aldolase catalyzes the reversible formation of fructose-1,6-bisphosphate in glucose biosynthesis.     - Retro-aldol reaction: The reverse process occurring in glycolysis.

• Acylation of Hydroxyl Groups (Esterification):     - Alcohol groups can be converted into acetyl esters by reacting with more reactive acid derivatives like acetic anhydride.     - Nucleophilic acyl substitution reaction.     - Laboratory Application: Preparation of cellulose acetate by acetylating cellulose.