1. Chapter 25. Biomolecules: Carbohydrates
Based on McMurry’s Organic Chemistry, 6th edition
©2003 Ronald Kluger
Department of Chemistry
University of Toronto

2. Importance of Carbohydrates
Distributed widely in nature
Key intermediates of metabolism (sugars)
Structural components of plants (cellulose)
Central to materials of industrial products: paper, lumber, fibers
Key component of food sources: sugars, flour, vegetable fiber
Contain OH groups on most carbons in linear chains or in rings
Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003

3. Chemical Formula and Name
Carbohydrates have roughly as many O’s as C’s (highly oxidized)
Since H’s are about connected to each H and O the empirical formulas are roughly (C(H2O))n
Appears to be “carbon hydrate” from formula
Current terminology: natural materials that contain many hydroxyls and other oxygen-containing groups
Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003

4. Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003
Sources
Glucose is produced in plants through photosynthesis from CO2 and H2O
Glucose is converted in plants to other small sugars and polymers (cellulose, starch)
Dietary carbohydrates provide the major source of energy required by organisms
Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003

5. 25.1 Classification of Carbohydrates
Simple sugars (monosaccharides) can't be converted into smaller sugars by hydrolysis.
Carbohydrates are made of two or more simple sugars connected as acetals (aldehyde and alcohol), oligosaccharides and polysaccharides
Sucrose (table sugar): disaccharide from two monosaccharides (glucose linked to fructose),
Cellulose is a polysaccharide of several thousand glucose units connected by acetal linkages (aldehyde and alcohol)
A disaccharide derived from
cellulose
Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003

6. Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003
Aldoses and Ketoses
aldo- and keto- prefixes identify the nature of the carbonyl group
-ose suffix designates a carbohydrate
Number of C’s in the monosaccharide indicated by root (-tri-, tetr-, pent-, hex-)
Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003

7. 25.2 Depicting Carbohydrate Stereochemistry: Fischer Projections
Carbohydrates have multiple chirality centers and common sets of atoms
A chirality center C is projected into the plane of the paper and other groups are horizontal or vertical lines
Groups forward from paper are always in horizontal line. The oxidized end of the molecule is always higher on the page (“up”)
The “projection” can be seen with molecular models
Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003

8. Stereochemical Reference
The reference compounds are the two enantiomers of glyceraldehyde, C3H6O3
A compound is “D” if the hydroxyl group at the chirality center farthest from the oxidized end of the sugar is on the right or “L” if it is on the left.
D-glyceraldehyde is (R)-2,3-dihydroxypropanal
L-glyceraldehyde is (S)-2,3-dihydroxypropanal
Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003

9. Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003
The D-Sugar Family
Correlation is always with D-(+)-glyceraldehyde
(R) in C-I-P sense
Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003

10. Rosanoff Structural Families
The structures show how the “D” and “L” family members are identified by projection of the bottom chirality center
The rest of the structure is designated in the name of the compound
The convention is still widely used
Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003

11. Working With Fischer Projections
If groups are not in corresponding positions, they can be exchanged three at a time in rotation – work with molecular models to see how this is done
The entire structure may only be rotated by 180
While R, S designations can be deduced from Fischer projections (with practice), it is best to make molecular models from the projected structure and work with the model
Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003

12. Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003
25.3 D, L Sugars
Glyceraldehyde exists as two enantiomers, first identified by their opposite rotation of plane polarized light
Naturally occurring glyceraldehyde rotates plane-polarized light in a clockwise direction, denoted (+) and is designated “(+)-glyceraldehyde”
The enantiomer gives the opposite rotation and has a (-) or “l” (levorotatory) prefix
The direction of rotation of light does not correlate to any structural feature
Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003

13. Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003
IUPAC Definitions1996
Fischer-Rosanoff Convention - according to which (+)-glyceraldehyde, now known to be (R)-2,3-dihydroxypropanal, was named D-glyceraldehyde (with the enantiomer L-glyceraldehyde and its racemate DL-glyceraldehyde) and taken to have the absolute configuration represented by the Fischer projection formula shown below. The atom numbered 1 according to normal nomenclature rules is conventionally placed at the top of the main chain, which is drawn vertically and other groups are drawn on either side of that main chain. The convention is still in use for -amino acids and for sugars
IUPAC, Commission on Nomenclature of Organic Chemistry, Section E: Stereochemistry (Recommendations 1974), Pure Appl. Chem. 45, (1976)
D-glyceraldehyde
L-glyceraldehyde
Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003

14. 25.4 Configurations of the Aldoses
Stereoisomeric aldoses are distinguished by trivial names, rather than by systematic designations
Enantiomers have the same names but different D,L prefixes
R,S designations are difficult to work with when there are multiple similar chirality centers
Systematic methods for drawing and recalling structures are based on the use of Fischer projections
Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003

15. Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003
Four Carbon Aldoses
Aldotetroses have two chirality centers
There are 4 stereoisomeric aldotetroses, two pairs of enantiomers: erythrose and threose
D-erythrose is a a diastereomer of D-threose and L-threose
Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003

16. Minimal Fischer Projections
In order to work with structures of aldoses more easily, only essential elements are shown
OH at a chirality center is “” and the carbonyl is an arrow 
The terminal OH in the CH2OH group is not shown
Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003

17. Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003
Aldopentoses
Three chirality centers and 23 = 8 stereoisomers, four pairs of enantiomers: ribose, arabinose, xylose, and lyxose
Only D enantiomers will be shown
Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003

18. Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003
Systematic Drawing
A chirality center is added with each CHOH adding twice the number of diastereomers and enantiomers
Each diastereomer has a distinct name
Start with the fact that they are D
Go up to next center in 2 sets of 2
Finish with alternating pairs
Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003

19. Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003
Apply to Aldhexoses
There are eight sets of enantiomers (from four chirality centers)
Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003

20. 25.4 Configurations of the Aldohexoses
8 pairs of enantiomers: allose, altrose, glucose, mannose, gulose, idose, galactose, talose
Name the 8 isomers using the mnemonic "All altruists gladly make gum in gallon tanks"
Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003

21. 25.5 Cyclic Structures of Monosaccharides: Hemiacetal Formation
Alcohols add reversibly to aldehydes and ketones, forming hemiacetals
Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003

22. Internal Hemiacetals of Sugars
Intramolecular nucleophilic addition creates cyclic hemiacetals in sugars
Five- and six-membered cyclic hemiacetals are particularly stable
Five-membered rings are furanoses. Six-membered are pyanoses
Formation of the the cyclic hemiacetal creates an additional chirality center giving two diasteromeric forms, desigmated  and b
These diastereomers are called anomers
The designation  indicates that the OH at the anomeric center is on the same side of the Fischer projection structure as hydroxyl that designates whether the structure us D or L
Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003

23. Fischer Projection Structures of Anomers: Allopyranose from Allose
Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003

24. Converting to Proper Structures
The Fischer projection structures must be redrawn to consider real bond lengths
Note that all bonds on the same side of the Fischer projection will be cis in the actual ring structure
Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003

25. Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003
Conformations of Pyranoses
Pyranose rings have a chair-like geometry with axial and equatorial substituents
Rings are usually drawn placing the hemiacetal oxygen atom at the right rear
Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003

26. 25.6 Monosaccharide Anomers: Mutarotation
The two anomers of D-glucopyranose can be crystallized and purified
-D-glucopyranose melts at 146° and its specific rotation, []D = 112.2°;
b-D-glucopyranose melts at 148–155°C a specific rotation of []D = 18.7°
Rotation of solutions of either pure anomer slowly change due to slow conversion of the pure anomers into a 37:63 equilibrium mixture ot :b called mutarotation
Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003

27. Mechanism of Mutarotation Glucose
Occurs by reversible ring-opening of each anomer to the open-chain aldehyde, followed by reclosure
Catalyzed by both acid and base
Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003

28. 25.7 Reactions of Monosaccharides
OH groups can be converted into esters and ethers, which are often easier to work with than the free sugars and are soluble in organic solvents.
Esterification by treating with an acid chloride or acid anhydride in the presence of a base
All OH groups react
Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003

29. Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003
Ethers
Treatment with an alkyl halide in the presence of base—the Williamson ether synthesis
Use silver oxide as a catalyst with base-sensitive compounds
Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003

30. Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003
Glycoside Formation
Treatment of a monosaccharide hemiacetal with an alcohol and an acid catalyst yields an acetal in which the anomeric OH has been replaced by an OR group
b-D-glucopyranose with methanol and acid gives a mixture of  and b methyl D-glucopyranosides
Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003

31. Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003
Glycosides
Carbohydrate acetals are named by first citing the alkyl group and then replacing the -ose ending of the sugar with –oside
Stable in water, requiring acid for hydrolysis
Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003

32. Selective Formation of C1-Acetal
Synthesis requires distinguishing the numerous OH groups
Treatment of glucose pentaacetate with HBr converts anomeric OH to Br
Addition of alcohol (with Ag2O) gives a b glycoside (Koenigs–Knorr reaction)
Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003

33. Koenigs-Knorr Reaction Mechanism
 and b anomers of tetraacetyl-D-glucopyranosyl bromide give b -glycoside
Suggests either bromide leaves and cation is stabilized by neighboring acetyl nucleophile from  side
Incoming alcohol displaces acetyl oxygen to give b glycoside
Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003

34. Reduction of Monosaccharides
Treatment of an aldose or ketose with NaBH4 reduces it to a polyalcohol (alditol)
Reaction via the open-chain form in the aldehyde/ketone hemiacetal equilibrium
Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003

35. Oxidation of Monosaccharides
Aldoses are easily oxidized to carboxylic acids by: Tollens' reagent (Ag+, NH3), Fehling's reagent (Cu2+, sodium tartrate), Benedict`s reagent (Cu2+ sodium citrate)
Oxidations generate metal mirrors; serve as tests for “reducing” sugars (produce metallic mirrors)
Ketoses are reducing sugars if they can isomerize to aldoses
Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003

36. Oxidation of Monosaccharides with Bromine
Br2 in water is an effective oxidizing reagent for converting aldoses to carboxylic acid, called aldonic acids (the metal reagents are for analysis only)
Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003

37. Formation of Dicarboxylic Acids
Warm dilute HNO3 oxidizes aldoses to dicarboxylic acids, called aldaric acids
The CHO group and the terminal CH2OH group are oxidized to COOH
Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003

38. Chain Lengthening: The Kiliani–Fischer Synthesis
Lengthening aldose chain by one CH(OH), an aldopentose is converted into an aldohexose
Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003

39. Kiliani-Fischer Synthesis Method
Aldoses form cyanohydrins with HCN
Follow by hydrolysis, ester formation, reduction
Modern improvement: reduce nitrile over a palladium catalyst, yielding an imine intermediate that is hydrolyzed to an aldehyde
Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003

40. Stereoisomers from Kiliani-Fischer Synthesis
Cyanohydrin is formed as a mixture of stereoisomers at the new chirality center, resulting in two aldoses
Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003

41. Chain Shortening: The Wohl Degradation
Shortens aldose chain by one CH2OH
Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003

42. 25.8 Stereochemistry of Glucose: The Fischer Proof (1891)
Chemical analysis revealed that (+)-glucose has the formula C6H12O6, and is linear with OH on each carbon except carbonyl of aldehyde
Such a structure has four chirality centers and can be any one of 16 possible stereoisomers
Since D and L could not be set, there were 8 possibilities to distinguish
Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003

43. Possible Structures of D-Glucose
Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003

44. Fischer’s Proof – Elongation of Arabinose
Arabinose, an aldopentose, is converted by Kiliani–Fischer chain extension into a mixture of glucose and mannose
Glucose and mannose must differ only at C2
Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003

45. Fischer’s Proof – Oxidation with HNO3
Arabinose is oxidized by warm HNO3 to an optically active aldaric acid
Only B and D give optically active product
Arabinose must be either B or D
Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003

46. Fischer’s Proof: Oxidation of Hexoses with HNO3
These could all come from arabinose
Glucose and mannose oxidize to optically active dicarboxylic acids
Only structures 3 and 4 are possible
Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003

47. Fischer’s Proof: Interchanging Ends Reveals the Answer
Oxidation with nitric acid followed by reduction gives two products from glucose and only one from mannose
This is equivalent to putting aldehyde at C-6
Structure 4 must be mannose since it would give itself and 3 must be glucose
Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003

48. Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003
25.9 Disaccharides
A disaccharide combines a hydroxyl of one monosaccharide in an acetal linkage with another
A glycosidic bond between C1 of the first sugar ( or ) and the OH at C4 of the second sugar is particularly common (a 1,4 link)
Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003

49. Maltose and Cellobiose
Maltose: two D-glucopyranose units with a 1,4--glycoside bond (from starch hydrolysis)
Cellobiose: two D-glucopyranose units with a 1,4--glycoside bond (from cellulose hydrolysis)
Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003

50. Hemiacetals in Disaccharides
Maltose and cellobiose are both reducing sugars
The  and  anomers equilibrate, causing mutarotation
Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003

51. You Can’t Eat Cellobiose
The 1-4’--D-glucopyranosyl linkage in cellobiose is not attacked by any digestive enzyme
The 1-4’--D-glucopyrnaosyl linkage in maltose is a substrate for digestive enzymes and cleaves to give glucose
Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003

52. Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003
Lactose
A disaccharide that occurs naturally in milk
Lactose is a reducing sugar. It exhibits mutarotation
It is 1,4’--D-galactopyranosyl-D-glucopyranoside
The structure is cleaved in digestion to glucose and galactose
Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003

53. Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003
Sucrose
“Table Sugar” is pure sucrose, a disaccharide that hydrolyzes to glucose and fructose
Not a reducing sugar and does not undergo mutarotation (not a hemiacetal)
Connected as acetal from both anomeric carbons (aldehyde to ketone)
Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003

54. 25.10 Polysaccharides and Their Synthesis
Complex carbohydrates in which very many simple sugars are linked
Cellulose and starch are the two most widely occurring polysaccharides
Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003

55. Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003
Cellulose
Consists of thousands of D-glucopyranosyl 1,4--glucopyranosides as in cellobiose
Cellulose molecules form a large aggregate structures held together by hydrogen bonds
Cellulose is the main component of wood and plant fiber
Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003

56. Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003
Starch and Glycogen
Starch is a 1,4--glupyranosyl-glucopyranoside polymer
It is digested into glucose
There are two components
amylose, insoluble in water – 20% of starch
1,4’--glycoside polymer
amylopectin, soluble in water – 80% of starch
Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003

57. Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003
Amylopectin
More complex in structure than amylose
Has 1,6--glycoside branches approximately every 25 glucose units in addition to 1,4--links
Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003

58. Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003
Glycogen
A polysaccharide that serves the same energy storage function in animals that starch serves in plants
Highly branched and larger than amylopectin—up to 100,000 glucose units
Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003

59. Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003
Glycals
Tetracetyl glucosyl bromide (see Glycosides) reacts with zinc and acetic acid to form a vinyl ether, a glycal (the one from glucose is glucal)
Glycals undergo acid catalyzed addition reactions with other sugar hydroxyls, forming anhydro disaccharide derivatives
Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003

60. Synthesis of Polysaccharides – via Glycals
Difficult to do efficiently, due to many OH groups
Glycal assembly is one approach to being selective
Protect C6 OH as silyl ether, C3OH and C4OH as cyclic carbonate
Glycal C=C is converted to epoxide
Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003

61. Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003
Glycal Coupling
React glycal epoxide with a second glycal having a free OH (with ZnCl2 catayst) yields a disaccharide
The disaccharide is a glycal, so it can be epoxidized and coupled again to yield a trisaccharide, and then extended
Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003

62. 25.11 Other Important Carbohydrates
Deoxy sugars have an OH group is replaced by an H.
Derivatives of 2-deoxyribose are the fundamental units of DNA (deoxyribonucleic acid)
Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003

63. Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003
Amino Sugars
OH group is replaced by an NH2
Amino sugars are found in antibiotics such as streptomycin and gentamicin
Occur in cartilage
Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003

64. 25.12 Cell-Surface Carbohydrates and Carbohydrate Vaccines
Polysaccharides are centrally involved in cell–cell recognition - how one type of cell distinguishes itself from another
Small polysaccharide chains, covalently bound by glycosidic links to hydroxyl groups on proteins (glycoproteins), act as biochemical markers on cell surfaces, determining such things as blood type
Based on McMurry, Organic Chemistry, Chapter 25, 6th edition, (c) 2003