aldoses ald ose ketoses ket - personal.utdallas.edubiewerm/20H-carbohydrates.pdfCarbohydrates! The...
Transcript of aldoses ald ose ketoses ket - personal.utdallas.edubiewerm/20H-carbohydrates.pdfCarbohydrates! The...
Carbohydrates
Carbohydrates are compounds that have the general formula CnH2nOn
Because CnH2nOn can also be written Cn(H2O)n, they appear to be “hydrates of carbon”
Carbohydrates are also called “sugars” or “saccharides”
Carbohydrates can be either aldoses (ald is for aldehyde and ose means a carbohydrate) or ketoses (ket is for ketone)
OHC CH2OHOH
OH
OH
OHHOH2C
CH2OHO
OH
OH
OH
An Aldose (D-Glucose)
A Ketose (D-Fructose)
Carbohydrates
Due to the multiple chiral centers along a linear carbon chain for carbohydrates, Emil Fischer developed the “Fischer Projection” in order to represent these compounds
Remember how to draw a Fischer projection:
1) View the linear carbon chain along the vertical axis (always place the more oxidized carbon [aldehyde in an aldose] towards the top)
2) The horizontal lines are coming out of the page toward the viewer
OHC CH2OHOH
OH
OH
OH
CHOOHHHHOOHHOHH
CH2OH
3) Will need to change the viewpoint for each carbon so the horizontal substituents are always pointing towards the viewer
Emil Fischer (1852-1919)
=
Carbohydrates
The aldoses are thus all related by having an aldehyde group at one end, a primary alcohol group at the other end, and the two ends connected by a series of H-C-OH groups
CHOOHH
CH2OH
Aldotriose D-glyceraldehyde
The D-aldoses are named according to glyceraldehyde, the D refers to the configurational carbon (H-C-OH group next to primary alcohol),
if OH is to the right in Fischer it is called D (after dextrorotatory – “to the right” in Latin), if OH is to the left in Fischer it is called L (after levorotatory – “to the left” in Latin)
CHOOHHOHH
CH2OH
Aldotetrose D-erythose
CHOOHHOHHOHH
CH2OH
Aldopentose D-ribose
CHOOHHOHHOHHOHH
CH2OH
Aldohexose D-allose
Aldohexose L-allose
Naturally occurring sugar molecules have the D configuration
CHOHHOHHOHHOHHO
CH2OH
Carbohydrates react similar to other aldehydes and carbonyl groups observed earlier
Due to the presence of the other alcohol groups in a carbohydrate, aldoses readily form acetal and hemiacetal linkages when the aldehyde reacts
HCOHHHHOOHHOHH
CH2OH
O
The hemiacetal formation thus forms ring structures, either 5-membered (furanoses) or 6-membered (pyranoses) rings are favored
When the aldehyde reacts, a new chiral center is formed, these isomers are called “anomers” and designated as the α- or β-anomer
O
O
Reactions of Carbohydrates
α-D-glucofuranose β-D-glucofuranose
α-D-glucopyranose β-D-glucopyranose
tetrahydrofuran
tetrahydropyran
OH
H
HH OH
HO HO
HHOHO
OH
HO
HHO
H
OHOHH H
OH
H
OH
HH OH
HO HO
HHOHO
OH
HO
HHO
H
HOHH OH
OH
Reactions of Carbohydrates
The majority of the sugar molecules in solution are in the cyclic hemiacetal form, although in equilibrium with the aldehyde open form
CHOOHHHHOOHHOHH
CH2OH
Aldohexose Pyranose form Furanose form
Allose 92 8
altrose 70 30
glucose ~100 <1
mannose ~100 <1
gulose 97 3
idose 75 25
galactose 93 7
talose 69 31
The ratio of the pyranose and furanose forms depends upon the aldohexose
being considered
OH
HO
HHO
H
HOHH OH
OH
H
OH
HH OH
HO HO
HHOHO
Reactions of Carbohydrates The 1H NMR of glucose also indicates the presence
of the two anomers of the predominant pyranose form
α-D-glucopyranose β-D-glucopyranose
Aldohexose α-‐Pyranose β-‐Pyranose α-‐Furanose β-‐Furanose
Allose 16 76 3 5
Altrose 27 43 17 13
Glucose 36 64 <1 <1
Mannose 66 34 <1 <1
Gulose 16 81 <1 3
Idose 39 36 11 14
Galactose 29 64 3 4
Talose 37 32 17 14
α
β
OH
HO
HHO
H
OHOHH H
OHO
H
HO
HHO
H
HOHH OH
OH
Haworth Form
Another representation of carbohydrates in the hemiacetal form is to draw a “Haworth form”
In the Haworth form, the ring is drawn in a planar perspective and the substituents are drawn either above or below the plane of the ring
The Haworth form does not indicate the axial and equatorial relationship as the chair conformation does, but it is a convenient representation for the pyranose and furanose rings
CHOOHHHHOOHHOHH
CH2OH
OH
HO
HHO
H
HOHH OH
OHO
OHOHOH
CH2OHOH
Fischer projection D-glucose
Chair conformation β-D-glucopyranose
Haworth form β-D-glucopyranose
Haworth form α-D-glucopyranose
O
OHOH
OHOH
CH2OH
Reactions of Carbohydrates
Carbohydrates can undergo a variety of reactions similar to any other carbonyl compound
The Kiliani-Fischer synthesis allows the conversion of a carbohydrate into another carbohydrate with one additional carbon, a so-called chain lengthening procedure
COHHHHOOHH
CH2OH
HO
NaCN
COHHHHOOHH
CH2OH
COHH
N
COHHHHOOHH
CH2OH
CHHO
N
H2/Pd
"poisoned"
COHHHHOOHH
CH2OH
COHH
HN H
COHHHHOOHH
CH2OH
CHHO
HN H
H+, H2O
COHHHHOOHH
CH2OH
COHH
O H
COHHHHOOHH
CH2OH
CHHO
O H
D-Xylose
D-Gulose D-Idose
Reaction of aldehyde with cyanide creates a cyanohydrin
But two stereoisomers are created with new chiral center
Reduction of nitrile with poisoned catalyst creates imine
Which upon hydrolysis creates two new sugar compounds with one additional carbon
(aldopentose becomes an aldohexose)
epimers
Reactions of Carbohydrates
Carbohydrates can also have a chain shortening procedure through a “Ruff degradation”
CHOOHHHHOOHHOHH
CH2OH
1) Br2, H2O2) Ca(OH)2
COHHHHOOHHOHH
CH2OH
O OCa
CHOHHOOHHOHH
CH2OH
D-Glucose D-Arabinose
First the carbohydrate is oxidized to a carboxylic acid (Br2 is a selective oxidant) and the calcium salt is obtained by reaction with calcium hydroxide
The calcium salt is then decarboxylated with ferric ion (need to use weak hydrogen peroxide to stop at aldehyde stage)
Thus overall a aldohexose is converted into an aldopentose, maintaining the chirality at all remaining chiral centers
1) Fe2(SO4)3, H2O2) H2O2 (30%)
Reactions of Carbohydrates
Aldohexose α-‐Pyranose β-‐Pyranose α-‐Furanose β-‐Furanose
Mannose 66 34 <1 <1
CHOHHOHHOOHHOHH
CH2OH
In solution, carbohydrates are in the cyclic hemiacetal form the majority of the time
The cyclic form equilibrates, however, with the open chain aldehyde form
When the open form recloses to the hemiacetal, it could create two anomers (α and β)
In solution, therefore, a carbohydrate equilibrates between the α and β forms (called mutarotation)
Each carbohydrate has its own ratio of these forms at equilibrium
OH
HO
HHO
HO
OHHH H
OHO
H
HO
HHO
HO
HHH OH
OH
α-D-mannopyranose β-D-mannopyranose
Reactions of Carbohydrates
While in neutral solution carbohydrates equilibrate between the two anomers, when treated with base a carbohydrate equilibrates into both an epimer (by inversion of the
stereocenter adjacent to the aldehyde) and by conversion of the aldose to a ketose
OH
HO
OHH
H
OHH
OH
OH
Ca(OH)2 OH
HO
OHH
HO
HH
OH
OH
Ca(OH)2
CH2OHOOHHOHHOHH
CH2OHD-Allose D-Altrose
D-Psicose
Squiggly line means both anomers
Epimerization occurs through enolate formation at α-position
CHOOHHOHHOHHOHH
CH2OH
Ca(OH)2OHOHHOHHOHH
CH2OH
O H CH2OHOOHHOHHOHH
CH2OH
When enolate is protonated at α position, two epimers are obtained
When enolate equilibrates with enol, a ketose is
obtained
Chirality has changed
Reactions of Carbohydrates
Any carbohydrate that contains a hemiacetal can equilibrate to the aldose form
In the presence of sodium borohydride, the aldehyde can be reduced to a primary alcohol (this is why the aldohexoses are called “reducing sugars”, the aldehyde is reduced to alcohol)
OH
HO
OHH
H
OHH
OH
OH
CHOOHHOHHOHHOHH
CH2OH
CHOOHHOHHOHHOHH
CH2OH
NaBH4
CH2OHOHHOHHOHHOHH
CH2OH
Notice that the carbohydrate after reduction has two terminal primary alcohol groups, depending upon the chirality of the initial carbohydrate a meso compound can be obtained
Reactions of Carbohydrates
Carbohydrate can also be oxidized, but due to the presence of an aldehyde in aldoses and a multitude of alcohol groups (primary and secondary),
different oxidizing conditions can selectively oxidize different parts of the carbohydrate
Bromine in water selectively oxidizes only the aldehyde group into a carboxylic acid (the other alcohols in the molecule are unaffected)
Br2H2O
D-Allose D-Allonic acid
CHOOHHOHHOHHOHH
CH2OH
CO2HOHHOHHOHHOHH
CH2OH
The two ends of the allonic acid are different, thus allonic acid is a chiral molecule
Reactions of Carbohydrates
If stronger oxidizing conditions are used, both the aldehyde and the primary alcohol can be oxidized to carboxylic acids (typically reagent is nitric acid) [called aldaric acids]
CHOOHHOHHOHHOHH
CH2OH
HNO3
CO2HOHHOHHOHHOHH
CO2H
Similar to the reduction of carbohydrates with NaBH4, this reaction also creates two identical end groups (both carboxylic acids) which can result in meso compounds
CHOOHHHHOOHHOHH
CH2OH
HNO3
CO2HOHHHHOOHHOHH
CO2H
CHOOHHHHOHHOOHH
CH2OH
HNO3
CO2HOHHHHOHHOOHH
CO2HD-Glucose Glucaric acid
chiral D-Galactose Galactaric acid
achiral
Reactions of Carbohydrates
Another oxidation observed earlier is when periodate reacts with vicinal diols
HO OH
IO
OOO
OI
OOO
O
CH2O
CH2O
O I O
O
Vicinal primary alcohols are thus oxidized to formaldehyde
O
H
OH H2O OHHO
HO H
IO
OOO
HO
O
H CH2O
OHHOOH I
OOO
O
OOHCH2
O IO
OOO
HO
O
H CH2O
Aldehydes hydrate to a geminal diol which can be oxidized to formic acid
Secondary alcohols of a carbohydrate will be also be oxidized twice to formic acid
Reactions of Carbohydrates
Due to the variety of carbonyl or alcohol groups on adjacent carbons of carbohydrates, periodate oxidation of sugars was historically convenient to determine structure
CHOOHHHHOOHHOHH
CH2OH
CH2OHOHHHHOOHHOHH
CH2OH
CH2OHOHHOOHHOHH
CH2OH
IO
OOO
IO
OOO
IO
OOOHCO2H
HCO2HHCO2HHCO2HHCO2HH2C O
H2C O
H2C O
HCO2HHCO2HHCO2HHCO2H
H2C O
H2C O
C OOHCO2HHCO2HHCO2H
D-Glucose
Sorbitol
D-Fructose
Oxidation of glucose, or any aldohexose, produces 5 equiv. of formic acid and one equiv. of formaldehyde
Oxidation of sorbitol produces instead 4 equiv. of formic acid and 2 equiv. of formaldehyde
Oxidation of fructose, or any ketohexose, produces 3 equiv. of formic acid, 2 equiv. of formaldehyde and 1
equiv. of carbon dioxide The ratio of products thus determines if structure was
an aldohexose, reduced sugar, or ketohexose
Reactions of Carbohydrates
The hemiacetal form of carbohydrates equilibrate with the open form and thus reactions of these carbohydrates can be written as occurring through the open form
While hemiacetals equilibrate with the open form, acetals are more stable and do not equilibrate
OH
HO
HHO
H
OHOHH H
OHO
H
HO
HHO
H
OH2OHH H
OHO
H
HO
HHO
H
OHH
OHCH3OH O
H
HO
HHO
H
OCH3OHH H
OHHCl
Under catalytic acid conditions, only the anomeric carbon will react due to the resonance stabilized cation after loss of water to allow formation of glycoside (a stable acetal)
OH
HO
HHO
H
OHOHH H
OHHCl
CH3OHO
H
HO
HHO
H
OCH3OHH H
OH
H3O+, !
As seen with acetals, this reaction is reversible under acidic aqueous conditions
Will obtain both α and β anomers
Reactions of Carbohydrates
The stable acetal forms allowed chemists to use the periodate oxidation procedure to also determine the ring size of the closed form (furanose versus pyranose)
OH
HO
HHO
H
OCH3OHH H
OH IO
OOO
OOHC
OCH3
HOHC
OH
HCO2H
H3O+, ! OHC
OHOH
OHC CHO
CH3OHD-Glucopyranoside
When the pyranoside ring structure is oxidized and then the acetal hydrolyzed, the products obtained are formic acid, glyceraldehyde, glyoxal and methanol
IO
OOO
D-Glucofuranoside
OCH3
H
HH OH
HO HO
HHOHO
O OCH3
CHO
OHC
CHO
H2C OH3O+, !
OHC OH
CHOCHOCHO
CH3OH
When the furanoside ring structure is oxidized, however, different products are obtained
Reactions of Carbohydrates
The aldehyde functionality present in the open form of a carbohydrate can undergo a variety of carbonyl reactions
If the carbohydrate is reacted with phenyl hydrazine, a phenyl hydrazone is obtained
OH
HO
HHO
H
OHOHH H
OHCHO
OHHHHOOHHOHH
CH2OH
PhNHNH2
With excess phenyl hydrazine, however, the phenyl hydrazone reacts again to form an osazone
PhNHNH2
OHHHHOOHHOHH
CH2OH
H NHN Ph
OHHHHOOHHOHH
CH2OH
H NHN Ph
NHHOOHHOHH
CH2OH
H N
NHPh
HN Ph
Reactions of Carbohydrates
The reaction involves the enamine in equilibrium with the imine also equilibrating with the ketone at the C2 carbon position, which then reacts with the phenyl hydrazine
OHHHHOOHHOHH
CH2OH
H NHN Ph
OHHHOOHHOHH
CH2OH
H NHHN Ph
OHHOOHHOHH
CH2OH
NHHN Ph
HH
PhNHNH2-NH3-PhNH2
NHHOOHHOHH
CH2OH
H N
NHPh
HN Ph
Since both the C1 and C2 carbons react in an osazone, the chirality at the C2 position is lost
CHOOHHHHOOHHOHH
CH2OH
NHHOOHHOHH
CH2OH
H N
NHPh
HN Ph
CHOHHOHHOOHHOHH
CH2OH
PhNHNH2 PhNHNH2
D-Glucose D-Mannose Osazone
Reactions of Carbohydrates
While the hemiacetal form of a carbohydrate can be alkylated at the anomeric carbon under catalytic conditions, the carbohydrate can be fully alkylated with excess alkyl halide
OH
HO
HHO
H
OHOHH H
OHHCl
CH3OH
catalyticO
H
HO
HHO
H
OCH3OHH H
OHCH3IAg2O
OH
H3CO
HH3CO
H
OCH3OCH3H H
OCH3
HClcatalytic
H2O
OH
H3CO
HH3CO
H
OHOCH3H H
OCH3
A similar reaction can occur with acid chlorides or acid anhydrides to form the fully acetylated version of carbohydrates
Due to the higher reactivity of the anomeric carbon, this position can be selectively dealkylated under catalytic acid hydrolysis
Through a series of related reactions, various hydroxyl groups of the carbohydrate can be protected selectively
Fischer Proof of Carbohydrate Chirality
CHOOHHOHHOHHOHH
CH2OH
CHOOHOHOHOH
CH2OH
In 1891 Fischer was able to prove the structure of each aldohexose sugar molecule
This was a stunning accomplishment as the concept of tetrahedral chirality of carbon was only first proposed in 1876 by van’t Hoff and was still debated at that time
Using the tetrahedral chirality, Fischer could rationalize that there were 16 chiral versions of an aldohexose
Fischer also realized that these 16 stereoisomers were related as two sets of enantiomers (8 L-sugars and 8 D-sugars)
CHO
OHOHOH
CH2OH
HOCHO
OH
OHOH
CH2OH
HO
CHO
OHOH
CH2OH
HOHO
CHOOHOH
OHCH2OH
HO
CHO
OH
OHCH2OH
HO
HO
CHOOH
OHCH2OH
HOHO
CHO
OHCH2OH
HOHOHO
While Fischer could rationalize that these are the 8 possible D-sugars, which structure corresponds to glucose (or any of the other sugars) is unknown
Fischer Proof of Carbohydrate Chirality
Fischer was able to correctly predict the absolute structure of each aldohexose by rationalizing the chirality and symmetry upon reactions of the sugars
Experimental evidence used by Fischer to prove structure of glucose:
Glucose Glucaric acid “Gulose”
Arabinose Gluconic and Mannonic acids
Fructose
Arabinose
Xylose
Glucitol and Mannitol
Glucose and Mannose
Gulose and Idose
Glucaric acid is chiral
Mannitol and Mannonic acid are chiral
Arabinose gives active Arabitol and Arabaric diacid Xylose gives inactive Xylitol and Xylaric diacid
HNO31) 1) !
2) reduce
2) Glucose and Mannose give same osazone
reduce
3) Kiliani-Fischer
Kiliani-Fischer
1) Kiliani-Fischer
2) oxidize CHO
Fischer Proof of Carbohydrate Chirality
CHOOHOHOHOH
CH2OH
CHO
OHOHOH
CH2OH
HOCHO
OH
OHOH
CH2OH
HO
CHO
OHOH
CH2OH
HOHO
CHOOHOH
OHCH2OH
HO
CHO
OH
OHCH2OH
HO
HO
CHOOH
OHCH2OH
HOHO
CHO
OHCH2OH
HOHOHO
CHOOH
CH2OHCHO
OHOH
CH2OH
CHO
OHCH2OH
HO
CHOOHOHOH
CH2OH
CHO
OHOH
CH2OH
HOCHO
OH
OHCH2OH
HO
CHO
OHCH2OH
HOHO
These will be all the D-sugars up to the aldohexoses
D-Glyceraldehyde
Kiliani-Fischer generates two new aldotetroses
An aldotriose is the shortest possible sugar
Which stereoisomer is naturally occurring glucose?
Fischer Proof of Carbohydrate Chirality
CHOOHOHOHOH
CH2OH
CHO
OHOHOH
CH2OH
HOCHO
OH
OHOH
CH2OH
HO
CHO
OHOH
CH2OH
HOHO
CHOOHOH
OHCH2OH
HO
CHO
OH
OHCH2OH
HO
HO
CHOOH
OHCH2OH
HOHO
CHO
OHCH2OH
HOHOHO
CHO
OHOH
CH2OH
HOCHO
OH
OHCH2OH
HO
Fischer used the results of known reactions to deduce which steroisomer is glucose
Glucose Gulose Mannose Idose
Arabinose Xylose
Ultimately the stereochemistry of the aldohexoses was determined through symmetry: 1) Diacid oxidized form of glucose is chiral, Gulose differs by converting CHO and 1˚ OH
2) Mannose differs only at C2, plus diacid form of Mannose is chiral 3) Arabinose yields Glucose and Mannose, oxidized form of Arabinose is chiral
Naming of Sugar Compounds
CHOOHOHOHOH
CH2OH
CHO
OHOHOH
CH2OH
HOCHO
OH
OHOH
CH2OH
HO
CHO
OHOH
CH2OH
HOHO
CHOOHOH
OHCH2OH
HO
CHO
OH
OHCH2OH
HO
HO
CHOOH
OHCH2OH
HOHO
CHO
OHCH2OH
HOHOHO
CHOOHOH
CH2OH
CHO
OHCH2OH
HO
CHOOHOHOH
CH2OH
CHO
OHOH
CH2OH
HOCHO
OH
OHCH2OH
HO
CHO
OHCH2OH
HOHO
A few of the sugars are natural and have common names
Erythrose Greek for “red”
Arabinose “Gum arabic”
Xylose Greek for “wood”
Glucose “sweet wine”
Galactose “milk sugar”
Mannose “manna”
Remaining names from Fischer Threose
Reverse “erth”
Ribose Transpose arabinose
Lyxose Reverse “xyl”
Gulose GLU - GUL
Talose LAT-TAL
Idose “Ibid–ID.”
Altrose “alter”
Allose
Disaccharides
Disaccharides are a result of two monosaccharides (sugars) connected through an acetal bond
Lactose (found in milk)
H+H2O
CHOOH
OHCH2OH
HOHO
CHOOH
OHOH
CH2OH
HO
D-Galactose D-Glucose
Sucrose (refined from cane sugar)
H+H2O
CHOOH
OHOH
CH2OH
HO
CH2OHO
OHOH
CH2OH
HO
D-Glucose D-Fructose
Sucrose is called a “nonreducing sugar” because there is no free aldehyde group to reduce (both anomeric carbons form the acetal – thus no equilibrium to free aldehyde or ketone)
Anomeric carbons
OHOHO
OOH
OH
OCH2OH
OH
OH
CH2OH
OOHO
OHOH
OHO
OH
HO OH
OH
Polysaccharides Polysaccharides are thus merely sugar polymers that have multiple carbohydrates connected
Plants store carbohydrates as polysaccharides in two common forms: Cellulose is a polysaccharide that has glucose molecules connected with a 1,4-β linkage
Starch also is a polysaccharide with glucose molecules connected 1,4, but with an α linkage
OOHO
OOH
OH
OHO
OOH
OH
OHO
OOH
OH
OHO
OOH
OH
n
OOHO OH
O
OH
OH
HO OHO
OH
OHO OH
O
OH
OHO OH
O
OH
n
β-linkage causes cellulose to have a linear shape that packs very well source of fiber
α-linkage causes starch to have a curved structure that
does not pack well
Humans have an enzyme that can break the α-linkage
in starch, but not the β-linkage in cellulose, thus
starch is a source of dietary sugar but cellulose is not
Glycosides
As observed earlier, when an alcohol reacts with a carbohydrate a stable acetal is formed (called a glycoside)
OH
HO
HHO
H
OHOHH H
OHHCl
CH3OHO
H
HO
HHO
H
OCH3OHH H
OH
H3O+, !
Will obtain both α and β anomers
If sugars are used as the nucleophile, then disaccharides and polysaccharides can thus be formed
In addition to alcohols, however, other nucleophiles can react at the anomeric carbon of carbohydrates to form glycosides including components of RNA and DNA
CHOOHOHOH
CH2OHN
NN
NH
NH2
N
NN
N
NH2
OHO
OHOHRibose Adenine
Adenosine
Glycoproteins
If the nucleophile is a protein, then the sugar molecules can be attached to protein chains (called glycoproteins – often the carbohydrate attached is called a “glycan”)
Glycoproteins are critical components of many cell membranes and play a critical component in cell-cell interactions at the membrane surface
The attachment of the carbohydrate to the protein is called a “glycosylation”
An extraordinary example is the total synthesis of erythropoietin (EPO), a glycoprotein that increases oxygen by increasing red blood cell production
Rebecca M. Wilson, Suwei Dong, Ping Wang, Samuel J. Danishefsky, Angew. Chem. Int. Ed., 2013, 52, 7646-7665
Glycoproteins
The type of glycoproteins present is the difference between human blood types
Humans can have four different blood types (called A, B, AB or O), the differences between the blood types is simply due to the type of carbohydrates
attached to the protein in the cell wall of red blood cells
Type O Trisaccharide
OOHO NH
O
OH
O
OOH
HO O
OH
OOH
OHHO
Protein
OOHO NH
O
OH
O
OOH
O O
OH
OOH
OHHO
Protein
OOH
HO
OH
NHO
OOHO NH
O
OH
O
OOH
O O
OH
OOH
OHHO
Protein
OOH
HO
OH
OH
Type A Tetrasaccharide
(same as O with an N-acetyl-D-galactosamine)
Type B Tetrasaccharide
(same as O with D-galactose)
Why type O is the “universal donor”, all blood types have same trisaccharide core but
types A, B or AB (which has some A and B) have different appendages