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


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


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


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%)


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


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


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


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


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


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


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


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


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


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


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


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 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


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?


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

aldoses ald ose ketoses ket - personal.utdallas.edubiewerm/20h-carbohydrates.pdfcarbohydrates! the...

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