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Home , Aldose, Anomer, Epimer, Gulose, Hemiacetal, Idose

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 “” or “saccharides”

Carbohydrates can be either (ald is for and ose means a ) or (ket is for )

OH OH O OH

CH2OH CH2OH OHC HOH2C OH OH OH OH

An A (D-) (D-) Carbohydrates

Due to the multiple chiral centers along a linear carbon chain for carbohydrates, Emil Fischer developed the “” 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

3) Will need to change the viewpoint for each carbon so the horizontal substituents are always pointing towards the viewer

CHO OH OH H OH HO H CH2OH = OHC H OH OH OH H OH

CH2OH Emil Fischer (1852-1919) Carbohydrates

The aldoses are thus all related by having an aldehyde group at one end, a primary group at the other end, and the two ends connected by a series of H-C-OH groups

CHO CHO CHO CHO CHO H OH H OH H OH H OH HO H

CH2OH H OH H OH H OH HO H CH2OH H OH H OH HO H CH2OH H OH HO H CH2OH CH2OH Aldotriose Aldotetrose Aldopentose Aldohexose Aldohexose D- D-erythose D- D- L-allose

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)

Naturally occurring molecules have the D configuration Reactions of Carbohydrates

Carbohydrates react similar to other and carbonyl groups observed earlier Due to the presence of the other alcohol groups in a carbohydrate, aldoses readily form and linkages when the aldehyde reacts H H H OH HOHO O HO O O O HO H HO HO H HC H OH H H OH OH H OH H H tetrahydrofuran HO H α-D-glucofuranose β-D-glucofuranose H OH H OH HOH HOH CH OH H O H O O 2 HO HO HO H HO OH H OH H OH OH H H H tetrahydropyran α-D-glucopyranose β-D-glucopyranose

The hemiacetal formation thus forms ring structures, either 5-membered () or 6-membered () rings are favored When the aldehyde reacts, a new chiral center is formed, these are called “” and designated as the α- or β- 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 CHO H HOH OH H OH O H HOHO HO H O HO H HO H OH HO OH H H H OH H OH H OH H H

CH2OH

Aldohexose form form Allose 92 8 70 30 The ratio of the pyranose and furanose glucose ~100 <1 forms depends upon the aldohexose mannose ~100 <1 being considered gulose 97 3 idose 75 25 93 7 69 31 Reactions of Carbohydrates The 1H NMR of glucose also indicates the presence of the two anomers of the predominant pyranose form

β HOH HOH H O H O HO HO HO H HO OH H OH H OH α H OH H H

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 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

CHO OH H OH H CH2OH CH2OH H O OOH O HO H HO OH OH H OH HO OH H OH OH OH OH H OH H H OH OH

CH2OH

Fischer projection Chair conformation Haworth form Haworth form D-glucose β-D-glucopyranose β-D-glucopyranose α-D-glucopyranose 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 N N HN H HN H C C C C O H C H C OH HO C H H C OH HO C H H OH H OH H OH H OH H OH NaCN H2/Pd HO H HO H HO H HO H HO H H OH H OH H OH "poisoned" H OH H OH

CH2OH CH2OH CH2OH CH2OH CH2OH

D- H+, H2O

O H O H Reaction of aldehyde with cyanide creates a cyanohydrin C C But two stereoisomers are created with new chiral center H C OH HO C H H OH H OH Reduction of nitrile with poisoned catalyst creates imine HO H HO H Which upon hydrolysis creates two new sugar compounds H OH H OH with one additional carbon CH2OH CH2OH (aldopentose becomes an aldohexose) D-Gulose D-Idose Reactions of Carbohydrates

Carbohydrates can also have a chain shortening procedure through a “Ruff degradation”

Ca O O CHO C 1) Fe2(SO4)3, H OH 1) Br2, H2O H OH H2O CHO HO H 2) Ca(OH)2 HO H 2) H2O2 (30%) HO H H OH H OH H OH H OH H OH H OH

CH2OH CH2OH CH2OH

D-Glucose D-

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 Reactions of Carbohydrates

In solution, carbohydrates are in the cyclic hemiacetal form the majority of the time

CHO H OH HO H H OH HO O HO H HO O HO HO HO H H OH HO OH H H H H H OH H OH H H CH2OH α-D-mannopyranose β-D-mannopyranose

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 ) Each carbohydrate has its own ratio of these forms at equilibrium

Aldohexose α-Pyranose β-Pyranose α-Furanose β-Furanose Mannose 66 34 <1 <1 Reactions of Carbohydrates

While in neutral solution carbohydrates equilibrate between the two anomers, when treated with base a carbohydrate equilibrates into both an (by inversion of the stereocenter adjacent to the aldehyde) and by conversion of the aldose to a ketose

Squiggly line means Chirality has CH2OH HOH both anomers HOH changed O H OH H O Ca(OH)2 HO O Ca(OH)2 HO HO H OH H H H OH H H OH OH H OH OH OH CH2OH D-Allose D-Altrose D-

Epimerization occurs through enolate formation at α-position O H When enolate is CHO CH2OH H OH OH O protonated at α position, two epimers are obtained H OH Ca(OH)2 H OH H OH H OH H OH H OH When enolate equilibrates H OH H OH H OH with , a ketose is CH2OH CH2OH CH2OH obtained Reactions of Carbohydrates

Any carbohydrate that contains a hemiacetal can equilibrate to the aldose form

CHO HOH H OH H O H OH HO H H OH H OH OH OH H OH CH2OH 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)

CHO CH2OH H OH H OH

H OH NaBH4 H OH H OH H OH H OH H OH

CH2OH 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 in the molecule are unaffected)

CHO CO2H H OH H OH H OH Br2 H OH

H OH H2O H OH H OH H OH

CH2OH CH2OH

D-Allose D-Allonic acid

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]

CHO CO2H H OH H OH H OH HNO3 H OH H OH H OH H OH H OH

CH2OH 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

CHO CO2H CHO CO2H H OH H OH H OH H OH HO H HNO3 HO H HO H HNO3 HO H H OH H OH HO H HO H H OH H OH H OH H OH

CH2OH CO2H CH2OH CO2H D-Glucose Glucaric acid D-Galactose Galactaric acid chiral achiral Reactions of Carbohydrates Another oxidation observed earlier is when periodate reacts with vicinal diols

O O O I O I O O O O O O I O O HO OH O O CH2 CH2 Vicinal primary alcohols are thus oxidized to

O O I O O OH H2O HO OH O O O HO CH H H HO H 2 Aldehydes hydrate to a geminal diol which can be oxidized to formic acid

O O O I O O I O OH O O O O O O HO OH CH2 OH HO H CH2 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

O O CHO HCO2H CH2OH H2C O O O O O H OH I HCO2H O I O C O HO H O HCO2H HO H O HCO2H H OH HCO2H H OH HCO2H H OH HCO2H H OH HCO2H CH2OH H2C O CH2OH H2C O D-Glucose D-Fructose

Oxidation of glucose, or any aldohexose, produces 5 CH2OH O H2C O O O equiv. of formic acid and one equiv. of formaldehyde H OH I HCO2H Oxidation of sorbitol produces instead 4 equiv. of HO H O HCO2H formic acid and 2 equiv. of formaldehyde H OH HCO2H H OH HCO2H Oxidation of fructose, or any ketohexose, produces 3 equiv. of formic acid, 2 equiv. of formaldehyde and 1 CH2OH H2C O equiv. of carbon dioxide Sorbitol 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 equilibrate with the open form, are more stable and do not equilibrate

HOH HOH HOH HOH H H H H O HCl O O CH3OH O HO HO HO HO HO H HO H HO HO H H OH H OH H OH H OH H OH H OH2 H H OCH3

Under catalytic acid conditions, only the anomeric carbon will react due to the resonance stabilized cation after loss of water to allow formation of (a stable acetal)

HOH CH3OH HOH H O HCl H O Will obtain both α HO HO HO H HO H and β anomers H OH H3O+, ! H OH H OH H OCH3

As seen with acetals, this reaction is reversible under acidic aqueous conditions 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)

O HOH O I O OH OH H O O OHC O H3O+, ! OH HO OHC HO H OHC H H OH HCO2H OHC CHO H OCH3 OCH3 CH OH D-Glucopyranoside 3

When the pyranoside ring structure is oxidized and then the acetal hydrolyzed, the products obtained are formic acid, glyceraldehyde, glyoxal and O H O O H I H2C O CH3OH HO O HO O H3O+, ! HO H OHC O OCH OHC OH 3 CHO H OCH3 H OH CHO CHO CHO CHO D-Glucofuranoside

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 Ph HN H N CHO HOH H OH H OH H O HO HO H PhNHNH2 HO H HO H H OH H OH H OH H OH H OH H OH CH OH 2 CH2OH With excess phenyl hydrazine, however, the phenyl hydrazone reacts again to form an osazone Ph Ph HN HN H N H N

H OH N Ph PhNHNH N HO H 2 HO H H H OH H OH H OH H OH

CH2OH CH2OH 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 Ph Ph Ph Ph HN HN HN HN H N H NH H NH H N H H OH OH O N Ph N HO H HO H HO H PhNHNH2 HO H H

H OH H OH H OH -NH3 H OH H OH H OH H OH -PhNH2 H OH CH2OH CH2OH CH2OH CH2OH Since both the C1 and C2 carbons react in an osazone, the chirality at the C2 position is lost Ph HN H N CHO CHO H OH N Ph HO H N HO H PhNHNH2 HO H H PhNHNH2 HO H H OH H OH H OH H OH H OH H OH

CH2OH CH2OH CH2OH D-Glucose Osazone D-Mannose 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

HOCH3 HOH catalytic HOH H O CH3I H O HCl H O H3CO HO HO H3CO H Ag2O HO H CH3OH HO H H OCH3 H OH H OH H OCH3 H OH H OCH3

catalytic HCl A similar reaction can occur with acid chlorides or acid anhydrides H2O to form the fully acetylated version of carbohydrates

HOCH3 H O Due to the higher reactivity of the anomeric carbon, this position can H3CO be selectively dealkylated under catalytic acid hydrolysis H3CO H H OCH3 H OH Through a series of related reactions, various hydroxyl groups of the carbohydrate can be protected selectively Fischer Proof of Carbohydrate Chirality

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 (8 L-sugars and 8 D-sugars)

CHO CHO CHO CHO CHO CHO CHO CHO H OH HO OH HO OH HO OH HO H OH OH HO HO OH OH HO HO H OH OH OH OH HO HO HO HO H OH OH OH OH OH OH OH OH

CH2OH CH2OH CH2OH CH2OH CH2OH CH2OH CH2OH CH2OH

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: 1) 1) ! HNO3 2) reduce Glucose Glucaric acid “Gulose” Glucaric acid is chiral

2) Glucose and Mannose give same osazone 1) Kiliani-Fischer Arabinose Gluconic and Mannonic acids 2) oxidize CHO Fructose reduce Glucitol and Mannitol Mannitol and Mannonic acid are chiral

3) Kiliani-Fischer Arabinose Glucose and Mannose Xylose Kiliani-Fischer Gulose and Idose Arabinose gives active Arabitol and Arabaric diacid Xylose gives inactive Xylitol and Xylaric diacid Fischer Proof of Carbohydrate Chirality

CHO An aldotriose is the OH D-Glyceraldehyde shortest possible sugar CH2OH CHO CHO OH Kiliani-Fischer generates HO OH two new aldotetroses OH

CH2OH CH2OH CHO CHO CHO CHO OH HO OH HO OH OH HO HO OH OH OH OH

CH2OH CH2OH CH2OH CH2OH CHO CHO CHO CHO CHO CHO CHO CHO OH HO OH HO OH HO OH HO OH OH HO HO OH OH HO HO OH OH OH OH HO HO HO HO OH OH OH OH OH OH OH OH

CH2OH CH2OH CH2OH CH2OH CH2OH CH2OH CH2OH CH2OH These will be all the D-sugars up to the aldohexoses Which stereoisomer is naturally occurring glucose? Fischer Proof of Carbohydrate Chirality Fischer used the results of known reactions to deduce which steroisomer is glucose Ultimately the 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 CHO CHO HO OH OH HO OH OH

CH2OH CH2OH Arabinose Xylose CHO CHO CHO CHO CHO CHO CHO CHO OH HO OH HO OH HO OH HO OH OH HO HO OH OH HO HO OH OH OH OH HO HO HO HO OH OH OH OH OH OH OH OH

CH2OH CH2OH CH2OH CH2OH CH2OH CH2OH CH2OH CH2OH Glucose Mannose Gulose Idose Naming of Sugar Compounds CHO A few of the sugars are natural CHO OH and have common names HO OH OH Remaining names from Fischer CH2OH CH2OH Greek for “red” Reverse “erth” CHO CHO CHO CHO OH HO OH HO OH OH HO HO OH OH OH OH

CH2OH CH2OH CH2OH CH2OH Ribose Arabinose Xylose Transpose arabinose “Gum arabic” Greek for “wood” Reverse “xyl” CHO CHO CHO CHO CHO CHO CHO CHO OH HO OH HO OH HO OH HO OH OH HO HO OH OH HO HO OH OH OH OH HO HO HO HO OH OH OH OH OH OH OH OH

CH2OH CH2OH CH2OH CH2OH CH2OH CH2OH CH2OH CH2OH Allose Altrose Glucose Mannose Gulose Idose Galactose Talose “alter” “sweet wine” “manna” GLU - GUL “Ibid–ID.” “milk sugar” LAT-TAL Disaccharides are a result of two (sugars) connected through an acetal bond CHO CHO OH OH OH OH OH O O H+ HO HO O HO HO H O HO OH OH OH 2 OH OH OH CH2OH CH2OH (found in milk) D-Galactose D-Glucose

Anomeric CHO CH OH OH carbons 2 O OH O HO CH2OH HO OH H+ HO HO OH O OH OH O H2O CH2OH OH OH OH CH OH CH OH 2 2 (refined from cane sugar) 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) Polysaccharides are thus merely sugar polymers that have multiple carbohydrates connected Plants store carbohydrates as polysaccharides in two common forms: is a that has glucose molecules connected with a 1,4-β linkage

OH β-linkage causes HOH O OH cellulose to have a O OH O O HO O O linear shape that OH HO O OH HO O packs very well OH HO O n OH source of fiber also is a polysaccharide with glucose molecules connected 1,4, but with an α linkage OH α-linkage causes starch to O O OH have a curved structure that HO OH O does not pack well O OH HO Humans have an enzyme OH O O OH that can break the α-linkage HO OH O in starch, but not the β- O HO linkage in cellulose, thus OH starch is a source of dietary O n sugar but cellulose is not

As observed earlier, when an alcohol reacts with a carbohydrate a stable acetal is formed (called a glycoside)

HOH CH3OH HOH H O HCl H O Will obtain both α HO HO HO H HO H and β anomers H OH H3O+, ! H OH H OH H OCH3

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

NH2

CHO NH2 N N OH N HO N N N OH O Adenosine OH N N H CH2OH OH OH Ribose Adenine 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 OH OH OH O O Why type O is the “universal donor”, HO O O HO O all blood types have same core but NH Protein types A, B or AB (which has some A and B) O OH O have different appendages HO OH Type O OH OH Trisaccharide OH OH O O OH OH OH OH OH OH HO O HO O NH O OH O O O O O O O HO O O HO O NH Protein NH Protein O O OH O OH O HO HO OH OH Type A Type B Tetrasaccharide (same as O with an N-acetyl-D-galactosamine) (same as O with D-galactose)