Transcript Chapter 25. Biomolecules: Carbohydrates

Chapter 25. Biomolecules:
Carbohydrates
Based on McMurry’s Organic Chemistry, 6th
edition
©2003 Ronald Kluger
Department of Chemistry
University of Toronto
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
2
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
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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
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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
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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
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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
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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
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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
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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
10
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
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25.3 D, L Sugars
 Glyceraldehyde exists as two enantiomers, first
identified by their opposite rotation of plane polarized
light
 Naturally occurring glyceraldehyde rotates planepolarized 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
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IUPAC Definitions1996
 Fischer-Rosanoff Convention - according to which (+)-
glyceraldehyde, now known to be (R)-2,3-dihydroxypropanal,
was named D-glyceraldehyde (with the enantiomer Lglyceraldehyde 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, 11-30
(1976)
D-glyceraldehyde
L-glyceraldehyde
Based on McMurry, Organic Chemistry, Chapter
25, 6th edition, (c) 2003
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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
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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 Lthreose
Based on McMurry, Organic Chemistry, Chapter
25, 6th edition, (c) 2003
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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
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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
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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
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Apply to Aldhexoses
 There are eight sets of enantiomers (from
four chirality centers)
Based on McMurry, Organic Chemistry, Chapter
25, 6th edition, (c) 2003
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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
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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
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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
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Fischer Projection Structures of Anomers:
Allopyranose from Allose
Based on McMurry, Organic Chemistry, Chapter
25, 6th edition, (c) 2003
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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Chain Shortening: The Wohl
Degradation
 Shortens aldose chain by one CH2OH
Based on McMurry, Organic Chemistry, Chapter
25, 6th edition, (c) 2003
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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
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Possible Structures of D-Glucose
Based on McMurry, Organic Chemistry, Chapter
25, 6th edition, (c) 2003
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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
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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
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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
46
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
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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
b) 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
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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-b-glycoside bond (from cellulose hydrolysis)
Based on McMurry, Organic Chemistry, Chapter
25, 6th edition, (c) 2003
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Hemiacetals in Disaccharides
 Maltose and cellobiose are both reducing sugars
 The  and b anomers equilibrate, causing
mutarotation
Based on McMurry, Organic Chemistry, Chapter
25, 6th edition, (c) 2003
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You Can’t Eat Cellobiose
 The 1-4’-b-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
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Lactose
 A disaccharide that occurs naturally in milk
 Lactose is a reducing sugar. It exhibits mutarotation
 It is 1,4’-b-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
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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
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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
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Cellulose
 Consists of thousands of D-glucopyranosyl 1,4-b-
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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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