sign in sign up
<<
Home , Fischer projection, Haworth projection

Chem 215 F11 Notes – Dr. Masato Koreeda - Page 1 of 18. Date: November 9, 2011

Chapters 14.8; 23-1, 2, 5, and 7: – Part I

Carbohydrate nomenclature: http://www.chem.qmul.ac.uk/iupac/2carb/

Carbohydrates: e.g., • Polyhydroxylated and and their equivalents H O • Important constituents of both plants and animals (CHOH)n • D-: The primary source of energy in the human body CH OH 2 • : Sugars possessing six atoms. • Pentoses: Sugars possessing five carbon atoms. • : Sugars containing an group. • : Sugars containing a group. • : Carbohydrates that do not undergo cleavage on hydrolysis (treatment with water) to smaller molecules.

I.

OH OH H H H OH 6 H 6 H 6 H 4 anomeric carbon 4 4 anomeric carbon HO O HO OH HO O 5 2 5 2 5 2 HO OH HO O HO H 3 1 3 1 H H 3 H 1 axial HO HO H H equatorial H H H HO OH one hemiacetal form of D-glucose open-chain form of D-glucose another hemiacetal form of D-glucose

These are anomers and (C-1) epimers.

Glucose reacts like an aldehyde since small amounts of the open-chain form are present at equilibrium.

Glucose has 4 stereocenters → 24 = 16 stereoisomers possible → 8 pairs of enantiomers

(1) formulas (a) (+)-: configurational reference compound for all monosaccharides

This stereochemistry is defined as "D" if the OH is projected to the right. O H O H O H vertical bonds go in R H OH H C OH C and horizontal bonds H HO CH2OH come out CH2OH CH2OH

D-(+)-glyceraldehyde R-(+)-glyceraldehyde sign of optical rotation at the sodium D-line (589 nm) small upper-case D configurational designation

• S-(-)-Glyceraldehyde has an L-configuration. • D-Stereochemistry and the sign of optical rotation have no direct correlation, although many D sugars are dextrorotatory (d or +). Chem 215 F11 Notes – Dr. Masato Koreeda - Page 2 of 18. Date: November 9, 2011

I. Stereochemistry (1) Fischer projection (cont’d) The configurational relatioship was established between D-glyceraldehyde and the naturally occurring positive-rotating grape sugar, (+)-glucose.

OH OH OH O OH O 5 5 H 5 OH 4 2 HO 6 4 2 HO 6 4 2 HO 3 1 H 3 1 3 1 D HO HO O D HO HO D HO

D-glucose D-fructose (found in many fruits) D-2- (found in DNA) [an aldohexose] [a ketohexose] [a deoxyaldopentose] (in its open-chain (in its open-chain (in its open-chain aldehyde form) aldehyde form) keto form) ------

The Fischer projection of (+)-glucose • The more oxidized end of the chain (i.e., the aldehyde in this case) on top of the Fischer chain. • The first chiral center from the bottom of the chain determines the configuration (i.e., D or L). "view" through the "view" O O H surface of the paper 1 1 OH H H OH H OH H H OH 2 2 5 3 H HO 6 4 2 H H D-configuration HO 1 3 HO 3 H H OH HO H OH O H OH O H 6 H 4 4 "view" "view" HOH2C OH H OH (+)-glucose 5 5 H OH

zig-zag conformation: 6 CH2OH CH2OH most favorable, all eclipsed! D-(+)-glucose natural conformation not a natural, D-(+)-glyceraldehyde in solution. stable conformation!

For the conversion from the curved, eclipsed chain structure to the Fischer projection:

90° rotation O 1 HO HO OH H OH H OH 6 H H CH OH H H H 2 H 2 6 6 5 4 3 2 HO H H 1 5 H HO 1 5 H HO HO 4 1 H 3 O O HO H OH O H 2 3 OH HO 4 3 H 6 H 4 OH 2 "rotate" along HOH C HO H "rotate" along H the C -C -bond 2 5 OH HO H OH 1 2 the C3-C4-bond Look from this direction through the surface of the paper for the Fischer projection.

Chem 215 F11 Notes – Dr. Masato Koreeda - Page 3 of 18. Date: November 9, 2011

Carbohydrate families: All aldoses are called “reducing sugars” because of the aldehyde group; they reduce certain metal ions and can be easily oxidized. Two well known reagents for reducing sugars are:

1) Ag(I) → Ag (0) in NaOH/H2O (Tollens test) 2) Cu(II)SO4 (blue) in NaOH/H2O → red Cu2O (Benedict’s reagent)

Note: In addition to aldoses, ketoses are also reducing sugars. α-Hydroxyketones in general react with these reagents and can readily be oxidized.

aldotriose: aldotetraoses: pentoses: O H O H O H O H O H

H OH H OH HO H H OH H OH H OH H OH H OH HO H L! CH OH 2 H OH HO H CH2OH CH2OH CH OH CH OH D-glyceraldehyde D- D- 2 2 D-: found in RNA L-arabinose

Hexoses: There are 16 stereoisomers and 8 of these are D-sugars.

Mnemonics for 8 D-aldohexoses:

1 1CHO 2 HO 2 H 3 HO 3 H H 4 HO 4 5 H 5 OH allose altrose glucose mannose gulose idose talose 6 CH2OH All altruists gladly make gum in gallon tanks.

Remember the structures of D-glucose and D-glyceraldehyde. You don’t need to memorize the structures of any other sugars.

1) Which of the eight D-hexoses shown above represent epimeric pairs? 2) Draw the Fischer projection structures of L-glucose, D-galactose (C-4 epimer of D- glucose; a milk sugar), and D-mannose (C-2 epimer of D-glucose). + - 3) Draw the Fischer projection structure of L-alanine, (H3C)-CH(NH3 )C(=O)O .

Chem 215 F11 Notes – Dr. Masato Koreeda - Page 4 of 18. Date: November 9, 2011

I. Stereochemistry: (1) Mutarotation OH OH H H H OH 6 H β-OH 6 H 6 H 4 H O 4 H O 4 HO 2 HO H 2 HO 5 2 5 2 5 2 HO OH HO O HO H 3 1 3 1 1 axial H H 3 H HO HO H H equatorial H H H HO OH α-OH open-chain form of D-glucose β−anomer α−anomer [α] +18.7° [α] +112° D virtually no concentration of this species D β−D-(+)-glucopyranose in the equilibrium mixture; only a transient α−D-(+)-glucopyranose intermediate. or β−D-glucose or α−D-glucose

• After the equilibrium is reached, the optical rotation of the mixture shows: [α]D +53°.

Therefore, the mixture consists of 63% of β-D- and 37% of α-D-glucopyranose.

Based on: X • 18.7 + (1 - X) • 112 = 53

Note: (1) Pyranose vs furanose

6-membered ring 5-membered ring O O (HO)n (HO)n OH OH O O pyranose furanose pyran furan

(2) β− vs α−stereochemistry: anomeric stereoisomers (see pages 5-6 for definitions)

Cyclic sugars such as furanoses and pyranoses: the stereochemistry at the anomeric carbon relative to that at the stereo-defining center whether the sugar is D or L. If a D-sugar and the non-ether part of the ring For D-sugars: drawn in front and the ether portion drawn β behind a group (usually OH, OR, or X) O O ponting up at the anomeric center OH H 1 (i.e., at C-1) is defined as β 1 H α and the one pointing down is OH defined as α. non-ether part of the ring For L-sugars: • The C-6 group such as CH2OH, C(=O)OH usually α adopts an equatorial orientation. O O • The or has nothing to do with the axial or OH H α β 1 equatorial orientation of the group attached at C-1. 1 H β • For L-sugars definition is reversed OH axial Examples equatorial equatorial OH HO 6 OH 6 β-OH equatorial 4 H 4 O HO α-OH O 5 OH HO 5 2 HO 2 6 5 O 1 H HO OH HO OH 1 OH 3 1 3 3 H equatorial β-OH OH H 4 2 HO H H HO β−D-glucose enantiomers!! β−L-glucose α−L-glucose

Chem 215 F11 Notes – Dr. Masato Koreeda - Page 5 of 18. Date: November 9, 2011

α- or β- at the anomeric carbon – Taken from: http://www.chem.qmul.ac.uk/iupac/2carb/06n07.html

The anomeric center: The new center of chirality generated by hemiacetal or hemiketal ring closure is called the anomeric center. The two stereoisomers are referred to as anomers, designated α or β according to the configurational relationship between the anomeric center and a specified anomeric reference atom. The anomeric reference atom and the anomeric configurational symbol (α or β): The anomeric reference atom is the configurational atom of the parent, unless multiple configurational prefixes are used. If multiple configurational prefixes are used, the anomeric reference atom is the highest-numbered atom of the group of chiral centers next to the anomeric center that is involved in the heterocyclic ring and specified by a single configurational prefix. In the α anomer, the exocyclic oxygen atom at the anomeric center is formally cis, in the Fischer projection (i.e., the same side with respect to the carbon main chain), to the oxygen attached to the anomeric reference atom; in the β anomer these oxygen atoms are formally trans. The anomeric symbol α or β, followed by a hyphen, is placed immediately before the configurational symbol D or L of the trivial name or of the configurational prefix.

D-Sugars α! at C-1 1 (anomeric center) configurational H OH CH OH atom (D) 2 H OH H O H 2 H HO 3 H same side of the ring OH H H 4 OH HO OH anomeric reference H O position 5 H OH CH2OH 6 α-D-glucopyranose configurational atom (D)

β! at C-1 configurational (anomeric center) atom (D) CH2OH HO 1 H H O OH H OH 2 H HO H OH H 3 HO and O on the HO H H 4 OH opposite sides of the ring anomeric reference H OH position H 5 O β-D-glucopyranose CH2OH 6 configurational atom (D)

L-Sugar α! at C-1 (anomeric center)

same side of the ring H HO 1 H HO O OH H OH configurational H 2 atom (L) OH H HO H 3 H H anomeric reference HO H position 4 H OH H 5 H configurational atom (L) α-L-arabinopyranose O

Chem 215 F11 Notes – Dr. Masato Koreeda - Page 6 of 18. Date: November 9, 2011

For simple aldoses up to aldohexoses, and ketoses up to hepto-2-uloses,* the anomeric reference atom and the configurational atom are the same.

β! at C-1 (anomeric center) 1 H3CO H 2 H OH O OCH3 H3CO and OH H OH on the opposite sides 3 4 H HO H configurational of the ring 4 atom (D) H O H H 5 OH 5 H OH anomeric reference H OH position CH2OH CH2OH configurational atom (D) methyl β-D-galactofuranoside

“If multiple configurational prefixes are used, the anomeric reference atom is the highest- numbered atom of the group of chiral centers next to the anomeric center that is involved in the heterocyclic ring and specified by a single configurational prefix. In the α anomer, the exocyclic oxygen atom at the anomeric center is formally cis, in the Fischer projection (i.e., the same side with respect to the carbon main chain), to the oxygen attached to the anomeric reference atom; in the β anomer these oxygen atoms are formally trans. The anomeric symbol α or β, followed by a hyphen, is placed immediately before the configurational symbol D or L of the trivial name or of the configurational prefix.”

α! at C-1 1 same side of the ring (anomeric center) H OCH3 HO H 2 HO 3 H H OH D-manno anomeric reference 4 position H 5 O 7 CH2OH 6 configurational HO 6 H H OH atom (L) L-glycero 5 7 CH2OH H O H H HO 4 OH HO OCH3 H H methyl L-glycero- α-D-manno-heptopyranoside

1 * CH2OH 2 O 3 HO H 4 HO H 5 D-manno- H OH hepto-2-ulose H 6 OH 7 CH2OH Chem 215 F11 Notes – Dr. Masato Koreeda - Page 7 of 18. Date: November 9, 2011

I. Stereochemistry: (3) formulas above the plane OH of the ring 6 6 H 6 CH2OH CH2OH push down H 4 5 O 5 O HO O H OH 5 2 H H HO H H H 4 OH H 1 4 OH H 1 3 H 1 push up above the plane HO OH H H OH HO 3 2 HO 3 2 of the ring H OH H OH α-D-glucopyranose in the chair form α-D-glucopyranose β-D-glucopyranose in a Haworth projection in a Haworth projection formula formula

(3)-1. Drawing the pyranose (6-membered ring) Haworth projection structure from the Fischer projection structure of D-glucose:

1. Turn the Fischer projection O H 1 on the plane of the paper by 90° clockwise H OH H H OH H 2 O HO H 3 HOH2C H 4 OH HO HO H OH H H 5 OH 2. Curve the Fischer 6 CH2OH HO 6 H H main carbon chain as 1 O The Fischer projection H OH H H CH2 6 O defined. H structure of D-glucose. HOH C H OH 2 5 4 3 2 1 5 H 2 HO HO H OH HO 4 3 OH HO H

3. Rotate along the C4-C5 bond by 120 ° counterclockwise to bring the C5 OH to the same hemiacetal; α-anomer hemiacetal; β-anomer plane as the C1 aldehyde 6 CH OH 6 CH OH 2 2 4. Make the 6-membered make a ring 5 O 5 O OH H H H H H ring by connecting C5-OH 6 1 O H H and C aldehyde C. HOH2C O 4 OH H 1 or 4 OH H 1 1 H 5 H OH 2 HO 3 2 OH HO 3 2 H H 4 3 H OH H OH OH HO α-D-glucopyranose β-D-glucopyranose H Or tie up Curve the chain Alternatively, directly! as defined. Rotate! This may be easier!! 6 H H OH H HOH C H OH H HOH2C H OH H O 2 O O HOH C HO HO 2 5 4 3 2 1 H H H H H H HO HO OH HO OH H HO H OH

Chem 215 F11 Notes – Dr. Masato Koreeda - Page 8 of 18. Date: November 9, 2011

I. Stereochemistry: (3) Haworth projection formulas (3)-2. Drawing the furanose (5-membered ring) Haworth projection structure from the Fischer projection structure of D-glucose:

O H 1. Turm the Fischer projection 1 on the plane of the paper H OH by 90° clockwise. H H OH H 2 O HOH C HO 3 H 2 HO HO H OH H H 4 OH H 5 OH 6 CH2OH 6 CH OH 2. Curve the Fischer HO 2 H main carbon chain as H H OH H H 5 The Fischer projection 6 O defined (C1 through C5). H HOH C OH H 1 structure of D-glucose. 2 5 4 3 2 1 4 H HO HO H OH HO 3 2 O H OH

3. Rotate along the C3-C4 bond by 120 ° counterclockwise to bring the C4-OH to the same plane as the C-1 aldehyde hemicaetal; α-anomer β-anomer

6 6 HOH C6 make a ring CH2OH CH2OH 2 4. Make the 5-membered H H HO H HO H H HO H OH ring by connecting C4-OH 5 OH H 5 OH H 5 O O O O and C1 aldehyde C. 4 1 or 4 1 HO 1 3 2 3 H 2 4 H OH H H H 2 H HO H HO 3 α-D-glucofuranose β-D-glucofuranose H HO Curve the chain Alternatively, Or connect and 6 as defined. make a ring! HOH C Rotate! HOH2C 2 HO H HO H H H OH H H 5 H O OH O OH HOH C O 2 HO HO H 4 3 2 1 HO O H OH H H OH H H H H H OH (3) Draw the pyranose and furanose structures, both in β-anomeric forms, of L-ketohexose shown below. They exist as hemiketals. answers: 1. Rotate the Fischer projection 1 on the plane of the paper CH2OH by 90° clockwise 6 O 2 O OH OH H 1 H OH 5 2 3 HOH2C CH2OH β-L-pyranose HO H 4 H H OH O 4 3 HO 5 H furanose 6 CH2OH pyranose 1 The Fischer projection O structure of an L- HO OH OH H 5 2 1 4 3 ketohexose. 2 6 6 5 4 3 CH2OH β-L-furanose O H H OH

Chem 215 F11 Notes – Dr. Masato Koreeda - Page 9 of 18. Date: November 9, 2011

Carbohydrate stereochemistry practice examples

I. Draw the α-pyranose forms and β-furanose forms of each of the following. For pyranose forms draw as a Haworth projection and as a conformational representation (i.e., chair form).

(a) (b) (c) (d) H O H H O O CH2OH C C C O HO H HO H HO H HO H HO H H OH H OH H OH H OH HO H H OH H OH HO H CH2OH CH2OH CH OH 2 CH2OH

II. Draw the open-chain form as a Fischer projection for each of the following.

(a) H (b) HO H (c) OH HO HO O OH CH2OH OH H H H H O H H H C O OH H H H 3 OH H H OH OH H OH H HO H

(e) (d) H O H H H HOH2C O CH2OH OH H H OH OH H OH H OH OH OH CH2OH

Chem 215 F11 Notes – Dr. Masato Koreeda - Page 10 of 18. Date: November 9, 2011

Chapters 14.8, 23-1,2, 5, and 7: Carbohydrates - Part II

II. – A general term used to describe organic molecules covalently bound to carbohydrate molecules (through anomeric bonds).

(1) Formation of glycosides

C1-epimers; anomers; diastereomers

HO 6 HO 4 O O HO 5 2 1 HO 1 OH HO HO 3 anomeric carbon HO HO anomeric carbon α-anomer OH β-anomer

CH3OH, 0.7 % HCl, 10 °C (short time) Kinetic conditions (for this reaction)!

6 CH2OH CH2OH HO H HO H 5 H OCH + OH 3 OHO H O H 1 1 anomeric carbon 4 anomeric carbon 3 2 H OCH3 H H H HO H HO α-anomer β-anomer

methyl α-D-glucofuranoside methy β-D-glucofuranoside

CH3OH, 4 % HCl, rt Thermodynamic conditions!

HO 6 HO 4 O O HO 1 HO 5 2 1 + OCH3 HO HO 3 anomeric carbon HO anomeric carbon HO ~33% OCH3 β-anomer MAJOR PRODUCT α-anomer ~66% MINOR PRODUCT methyl α-D-glucopyranoside methyl β-D-glucopyranoside

In general, (5-membered) furanosides are formed preferentially under the kinetic conditions, whereas (6-membered) pyranosides are formed under the thermodynamic conditions, i.e., more stable. Five membered systems have a number of eclipsing interactions, thus less stable.

Chem 215 F11 Notes – Dr. Masato Koreeda - Page 11 of 18. Date: November 9, 2011

(2) Mechanism for the formation of anomeric glycosides

HO 6 When protonation occurs HO H 4 O on the anometic OH. O HO 5 2 1 OH HO O HO HO 1 H 3 HO HO β-anomer anomeric carbon lone pair-assisted ionization.

When protonation occurs HO on the ether oxygen atom. O HO H HO 1 O CH3 H H HO or HO lone pair-assisted HO O ionization. O H HO HO O H O H O CH3 H HO HO 1 or HO HO O CH3 H H HO H O HO O CH3 H H HO 1 HO OH HO HO O O H O CH3 CH stereochem. HO HO O 3 mixture HO 1 HO 1 O H O H H HO HO H H H H O CH3

lone pair-assisted ionization. H H HO rotation along HO O O the C1-C2 bond H HO 2 O CH3 HO H H HO HO 1 O CH3 1 O CH3 HO HO O H CH3 H H HO HO O O HO OCH HO H HO 3 HO HO HO H HO HO OCH3 O O HO 1 OCH HO H HO 3 HO HO HO β-anomer H α-anomer OCH3

Comments:

• The α-anomeric hemiacetal undergoes similar processes to produce a mixture of anomeric glycosides.

• Protonation on the lone pairs of the oxygen atoms other than the anomeric (i.e., C1-O) and ether ring oxygen ones does not lead to the ready elimination of the protonated hydroxyl groups due to the lack of the lone pair-assisted ionization.

Chem 215 F11 Notes – Dr. Masato Koreeda - Page 12 of 18. Date: November 9, 2011

(3) Hydrolysis of the Glycosidic Linkages a. Lactose – milk sugar; disaccharide; reducing sugar (one hemiacetal group) anomeric anomeric HO 6' OH carbon OH OH 6 OH carbon HO 4 4' O 4 + O O 2' O H3O H 5' 5 2 + HO OH HO OH HO OH 3' 1' HO 1 HO 3 HO HO HO hemiacetal β-glycosidic D-galactose D-glucose β-D-lactose linkage (or bond) reducing sugar anomeric anomeric mixture mixture permethylation with NaOH (excess), (CH3)2SO4 (excess) or NaH (excess), CH3I (excess) All OHs except the anomeric OH methylated.

H CO 6' OCH OCH OCH 3 3 6 OCH3 H3CO 3 3 + 4 4' O 4 H3O O H O 5' 2' O 5 2 OCH + H3CO 3 H3CO OH H3CO OH 3' 1' H3CO 1 H CO 3 3 H3CO H3CO H3CO All glycosidic bonds 2,3,4,6-tetra-O- 2,3,6-tri-O- get hydrolyzed methyl D-galactose methyl D-glucose 4-OH is free. Thus, terminal sugar! the other sugar is Taken together, D-lactose must be: (D-galactose)-O-(D-glucose) attached at the attached to the C4-OH. C4-OH of D-glucose; O-β-D-galactopyranosyl-(1->4)-β-D-glucopyranose or β-D-Galp-(1->4)-β-D-Glcp. This reaction concept can be used for sequencing polysaccharides.

b. Sucrose (“Sugar”): disaccharide; non-reducing sugar (no anomeric hemiacetal nor hemiketals)

OH D-fructose 1 OH O CH OH 6 1 HO 2 HO HOH2C HO H O H O CH2OH HO 2 + HO H O 5 H3O OH 2 HO + 5 HO 3 4 OH CH OH HO 4 3 D-glucose 2 OH H6 OH H D-glucose α-glycosidic linkage (anomeric D-fructose to glucose β-glycosidic linkage to fructose mixture) (anomeric + mixture) OH H H Both of these are reducing sugars! D-glucose O HO HO α-glycosidic linkage HO to glucose Sucrose: 6 D D HOH2C HO O-β- -fructofuranosyl-(2<->1)-α- -gluco- H O β-glycosidic linkage pyranoside or β-D-Fruf-(2<->1)-α-D-Glcp 5 2 to fructose D-fructose 4 3 f: furanosyl; p: pyranosyl CH2OH OH H 1

Chem 215 F11 Notes – Dr. Masato Koreeda - Page 13 of 18. Date: November 9, 2011

III. The Anomeric Effect: The inherent preference of electronegative substituents (usually OR, SR or halogen atoms) for the axial position at the anomeric carbon; largest for halogen atoms.

See: Juaristi, E.; Cuevas, G. The Anomeric Effect; CRC Press: Boca Raton, FL; 1995.

Examples: (1) X O O X ______X = Cl ΔG° 1.8 kcal/mol Br 1.8

OCH3 0.9 OCH2CH3 0.8 SCH3 0.5 OH -0.3 ~ -0.1

NHCH3 -0.9

Note: OH

OH 11% 89%

ΔG°25°C = -1.24 kcal/mol

(2) HO 6 HO 4 O O HO 5 2 1 HO 1 OH HO HO 3 HO HO 36% OH 64%

ΔG°25°C = -0.34 kcal/mol

So, the inherent anomeric effect (AE) for an OH may be estimated to be:

AE (OH) = ΔG° (pyranose) - ΔG° (cyclohexane) = -0.34 – (-1.24) = 0.90 kcal/mol

Chem 215 F11 Notes – Dr. Masato Koreeda - Page 14 of 18. Date: November 9, 2011

Explanations for the Anomeric Effect

(1) Repulsive lone pair-lone pair interactions: axial Axial C -OCH equatorial Equatorial C1-OCH3 axial equatorial 1 3 (stabler) 5 O 2 5 O H 2 O 3 1 H 1 O CH H View through the equatorial 3 C1 - ring O bond H CH View through the 1,3-diaxial 3 interactions Stays away from the ring C1 - ring O bond portion, avoiding the steric repulsion.

repulsive lone pair-lone pair axial orbital interaction! axial C C2 H 1 Ring oxygen C2 O C1 equatorial C5 CH C5 3 O H repulsive Ring oxygen repulsive lone pair-lone pair equatorial lone pair-lone pair orbital interaction! orbital interaction! CH3

Only one bad interaction!! (2) The hyperconjugative orbital interaction concept axial Axial C1-OCH3 n σ∗ FMO interpretation (stabler) C1-OCH3 5 O H 2 1 ∗ anti-bonding orbitals σ C1-OCH3 axial O n CH3 hyperconjugative, stabilizing orbital interaction: the oxygen lone-pair electrons are delocalizing into the antibonding C1-O orbital (σ* orbital) of the axial C1-O bond.

This hyperconjugation should make the C1-O bond shorter and the C-X bond longer.

Cl Cl O O 1 O 1 hyperconjudation Cl 1

Bond length comparisons: Cl Cl 1.39Å 1.82Å 1.43Å 1.39Å 1.82Å O 1 1 O Cl O O Cl 1 1.72Å 1.43Å 1.78Å

Chem 215 F11 Notes – Dr. Masato Koreeda - Page 15 of 18. Date: November 9, 2011

Reactions of Carbohydrates (1) Isomerization of sugars: usually in the presence of acid or base

epimer

open chain form "ene-diol"

HO 6 4 H 1 O O 6 HO 5 2 1 2 HO OH HO OH HO H 4 O 3 HO 3 HO HO H 5 1 HO 2 OH H OH 3 H OH C2-epimer of D-glucose H 1 O H 1 OH CH2OH 2 H OH 2 OH D-mannose HO 3 H HO 3 H H OH H OH H H OH H OH H OH 1 CH2OH CH2OH 6 2 O HOH2C HO 1 D-glucose 3 H O CH2OH "ene-diol" HO H 2 5 H OH 4 3 OH H OH OH H CH2OH D-fructose

Under base-catalyzed conditions H 1 O 6 2 HO OH HO 6 HO H 4 4 O O 3 HO 5 1 HO 5 2 1 D-glucose + HO H HO 2 OH HO OH (~69%) H OH 3 3 HO H OH C2-epimer of D-glucose CH2OH D-mannose (~1%) H 1 O + NaOH (0.04%) 2 H H OH H OH 3 H O, 35 °C 1 HO H 2 6 50 h 2 O HOH2C HO 1 H OH 3 H CH2OH HO H O 2 H OH 5 H OH OH CH2OH 4 3 H OH OH H D-glucose CH2OH D-fructose (~20%)

Chem 215 F11 Notes – Dr. Masato Koreeda - Page 16 of 18. Date: November 9, 2011

Mechanism: a b H 1 O H 1 O O H 1 OH b O H H HO 2 2 b 2 H OH H H a a OH O 3 3 3 HO H HO H HO H H OH Protonation at C2 glucose from the bottom face "ene-diol"

a H H 1 O 2 O HO H H 3 H OH H HO H 1 H OH 2 O Protonation at C1 3 1 mannose HO H 2 O H OH 3 H OH HO H D-fructose CH2OH

------+ Mechanism under H3O conditions H H O H 1 O H H H 1 O 2 H O 2 H OH 2 H OH HO 3 H HO 3 H

glucose H2O H H H 1 O H 1 O H 1 O Loss of H+ Protonation at C O H 1 H 2 C=O H 2 2 OH HO H HO H (fructose) 3 3 HO H HO H HO 3 H Protonation at C2 from the bottom face mannose

(2) Reducing sugars: Sugars that contain a hemiacetal or hemiketal, and are therefore in equilibrium with open form, are called “reducing sugars.”

Tollens test H 1 O O 1 O HO 2 H OH Ag2O H OH O HO 3 H NaOH/H2O HO H 0 HO 1 + Ag (silver mirror) HO OH H OH H OH HO H OH H OH

CH2OH CH2OH

2+ +1 Also, with Cu (CuSO4) [deep blue color]/NaOH [Benedict's reagent] Cu2O (Cu ) [red ppts] reducing sugar

Chem 215 F11 Notes – Dr. Masato Koreeda - Page 17 of 18. Date: November 9, 2011

(3) Oxidation reactions involving C1-OH or C1- and C6-OHs (a) Br2 in H2O oxidizes only aldoses HO O HO 1 HO OH HO HO HO OH Br + 3 H O HO OH + O 2 2 HO H3O HO O HO HO HO O OH HO HO - + H + 2 Br + 2 H3O Under the acidic conditions, HO this hydroxy acid closes to HO O form the six-membered lactone. note: Br2 + H2O HBr + HOBr

(b) HNO3 oxidation: HNO3 is a stronger oxidizing agent than Br2–H2O, oxidizing both the aldehyde group and the terminal –CH2OH of an to the corresponding di-acid.

Both C and C ends get oxidized H 1 O 1 6 HO 1 O to COOH's. 2 H OH H 2 OH 3 HO H HNO3, Δ 3 HO H galactaric acid 4 4 HO H HO H (meso; optically H 5 OH H 5 OH inactive) 6 6 CH2OH O OH D-galactose (optically active)

(4) Both (hemiacetal) aldoses and (hemiketal) ketoses undergo reactions observed for aldehydes and ketones, respectively.

H 1 O C N C N * H OH HO H HO 2 * * H OH H OH H OH O 3 HCN HO 1 HO H + HO OH HO H HO H H OH H2O HO H OH H OH H OH H OH H OH CH2OH CH OH CH OH 2 2

1 CH OH 2 1 1 CH OH CH OH HO 6 2 O 2 2 1 2 2 HO CH OH 3 H OH HO H H O 2 HO H 2 NaBH4 3 3 5 H OH HO H + HO H 4 3 OH CH OH-H O H OH 3 2 H OH H OH OH H H OH H OH CH2OH α-/β-D-fructofuranose CH2OH CH2OH D-fructose

Chem 215 F11 Notes – Dr. Masato Koreeda - Page 18 of 18. Date: November 9, 2011

(4) Reactions of hydroxyl groups and their derivatives

Selective reactions of anomeric OHs and their derivatives under acidic conditions (by an SN1 process) and formation of the anomeric bromide (by an SN2 process). (a)

K H CO H3CO H3CO 3 HBr O-CH Ph O O O 2 (gas) H CO H CO H3CO 1 3 1 3 H3CO H3CO H3CO 1 CH2Cl2 H3CO H3CO H3CO OCH3 Br SN1 Br

The α-bromide formed due mainly to the anomeric effect of Br. SN2 !

H3CO O H3CO O H3CO 1 CH2Ph H3CO + KBr (b) H3C O O O HO O O H3C O CH3 O H C O HO 1 (excess) 3 O 1 HO O H3C HO OH * O O O CH3 N O CH3 O HBr (gas) SN1 acetic acid OH (0 °C) more acidic HO H3C OH O K KOH, Δ O O O H C O 3 O H3C O 1 O H3C O O OH O O Br O S 2 H C O N 3 O O CH3 O 1 H3C O O O * CH3 + KBr O O O O H C O H3C O CH3 3 H3C NaOH-H O O CH3 H 2 N N N O R HO OH O HO 1 O HO OH O salicin R H C O 3