chapters 14.8, 23-1,2, 5, and 7: carbohydrates - part ii ...chem215/215-216 hh w12...

Chem 215-216 HH W12 Notes – Dr. Masato Koreeda - Page 1 of 11. Date: March 28, 2012 Chapters 14.8, 23-1,2, 5, and 7: Carbohydrates - Part II

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

(1) Formation of glycosides

O

HOHO

HO OH

OCH3

H

HH HO

OH HO

HOO

HOHO

HO

OH

HO

12

4

3

5

6

1

anomeric carbonanomeric carbonβ-anomerα-anomer

C1-epimers; anomers; diastereomers

CH3OH, 0.7 % HCl, 10 °C (short time)

HO HCH2OH

H

OCH3

HH HO

OH HOHO H

CH2OH

23

4

5

6

1+

β-anomerα-anomer

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

anomeric carbonanomeric carbon

1

O

HOHO

HO OCH3

HO

O

HOHO

HO

OCH3

HO

12

4

3

5

6

anomeric carbonanomeric carbonβ-anomer

α-anomer

1

CH3OH, 4 % HCl, rt

methyl α-D-glucopyranoside methyl β-D-glucopyranoside

Kinetic conditions (for this reaction)!

Thermodynamic conditions!

MAJOR PRODUCT MINOR PRODUCT~66%~33%

+

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 215-216 HH W12 Notes – Dr. Masato Koreeda - Page 2 of 11. Date: March 28, 2012

(2) Mechanism for the formation of anomeric glycosides

O

HOHO

HO O

HO

O

HOHO

HO OH

HO

12

4

3

5

6

anomeric carbonβ-anomer

1

When protonation occurs on the anometic OH. O

HOHO

HO O

HO

1

H

H

O

HOHO

HO

HO

1

lone pair-assisted ionization.

HO CH3

or

When protonation occurs on the ether oxygen atom.

H

HO

HOHO

HO O

HO H

H

H

HO CH3

or


1

O

HOHO

HO

HOH

HOH

O CH3

H

stereochem. mixture

HO CH3

1

O

HOHO

HO

HOH

HO

O CH3

H H

O CH3H

1

O

HOHO

HO

HOH

HO

O CH3

H

H


1

O

HOHO

HO

HOH

H

O CH31

O

HOHO

HO

HOH

H

OCH3

O

HOHO

HO OCH3

HO

1O

HOHO

HO

OCH3

HO

O

HOHO

HO OCH3

HOO

HOHO

HO

OCH3

HOH H

H

H

H

H

HO CH3

HO CH3

β-anomer α-anomer

rotation along the C1-C2 bond

2

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.


(3) Hydrolysis of the Glycosidic Linkages a. Lactose – milk sugar; disaccharide; reducing sugar (one hemiacetal group)

O

HOHO

HO OH

1'

2'4'

3'

5'

6'anomeric

carbon

β-glycosidic linkage (or bond)

O

HO

HO OH

OH

1

6

54

3

2

anomeric carbon

hemiacetal

β-D-lactose reducing sugar

O

HOHO

HO OHO

HOHO OH

OH4

OH

anomeric mixture

+H3O+

D-galactoseanomeric mixture

D-glucose

H

NaOH (excess), (CH3)2SO4 (excess)

NaH (excess), CH3I (excess)or

permethylation with

O

H3COH3CO

H3CO OCH3

1'

2'4'

3'

5'

6'

O

H3CO

H3COOCH3

OCH3

1

6

54

3

2

H3O+ O

H3COH3CO

H3CO OCH3O

H3COH3CO OH

OCH34

OH +

All glycosidic bonds get hydrolyzed

2,3,4,6-tetra-O-methyl D-galactose

2,3,6-tri-O-methyl D-glucose

Taken together, D-lactose must be: (D-galactose)-O-(D-glucose) attached at the 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.

terminal sugar!4-OH is free. Thus,the other sugar is attached to the C4-OH.

All OHs except the anomeric OH methylated.

H

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

O

HOHO

OH

HO

D-glucose CH2OH

HCH2OH

OH H

HHO

O

1

2

3 4

5

6

O

HOHO

OH

HO

D-glucose(anomeric mixture)

OH

CH2OH

HOH2C

OH H

HHO

O

1

2

345

6

H3O+CH2OH

HOH2C

OH H

HHO

O1

2

345

6

OH

D-fructose(anomeric mixture)

+

β-glycosidic linkageto fructose

α-glycosidic linkageto glucose

Both of these are reducing sugars!O

HOHO

OH

HOD-glucose

β-glycosidic linkageto fructose

α-glycosidic linkageto glucose

D-fructose

D-fructose

Sucrose:O-β-D-fructofuranosyl-(21)-α-D-gluco-pyranoside or β-D-Fruf-(21)-α-D-Glcp

f: furanosyl; p: pyranosyl

H H+


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)

O

O

X

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

11% 89%

ΔG°25°C = -1.24 kcal/mol

Note:

OH

OH

(2)

O

HOHO

HO OH

HOO

HOHO

HO

OH

HO

124

3

5

6

1

64%36%

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


Explanations for the Anomeric Effect

(1) Repulsive lone pair-lone pair interactions:

OO

CH3H

equatorial

axial equatorial

OH

O

axialequatorial

CH3

1

25

1

25

Stays away from the ringportion, avoiding the steric repulsion.

3

HH

1,3-diaxialinteractions

View through theC1 - ring O bond

View through theC1 - ring O bond

Equatorial C1-OCH3 Axial C1-OCH3(stabler)

Ring oxygen

C5H

OC2C1

axial

CH3

equatorialrepulsivelone pair-lone pairorbital interaction!

repulsive lone pair-lone pairorbital interaction!

Ring oxygen

C5O

HC2C1

axial

equatorial

repulsivelone pair-lone pairorbital interaction!CH3

Only one bad interaction!! (2) The hyperconjugative orbital interaction concept

axialAxial C1-OCH3(stabler)

axial

OH

OCH3

12

5C1-OCH3

σ∗n

anti-bonding orbitals

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.

C1-OCH3σ∗

n

FMO interpretation

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

O

Cl

O

Cl1 1 hyperconjudation

1

O

Cl

1

Bond length comparisons:

OCl

1

OCl

1.43Å 1.82Å1.39Å

1.72Å 1.43Å 1.78Å

OO

Cl

11.82Å1.39Å

Cl


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

OHHHHOOHHOHH

CH2OH

OH

D-glucose

open chain form "ene-diol"

epimer

ketose

1

2

3OHHHOOHHOHH

CH2OH

OHH 1

23

HHOHHOOHHOHH

CH2OH

OH

D-mannose

1

2

3

OHHOOHHOHH

CH2OH

OHH

D-fructose

123"ene-diol"

H

OOH

HOHO

OH

HO

12

4

3

5

6

C2-epimer of D-glucose

O

HOHO

HOOH

HO

124

3

5

6

CH2OHHOH2C

OH H

HHO

O1

2

34

5

6

OH

OHHHHOOHHOHH

CH2OH

OH

D-glucose

1

2

3

HHOHHOOHHOHH

CH2OH

OH

D-mannose

1

2

3

OHHOOHHOHH

CH2OH

OHH

D-fructose

123

H

OOH

HOHO

OH

HO

12

4

3

5

6

C2-epimer of D-glucose

O

HOHO

HOOH

HO

12

4

3

5

6

CH2OHHOH2C

OH H

HHO

O1

2

34

5

6

OH

Under base-catalyzed conditions

D-glucose

NaOH (0.04%)

H2O, 35 °C50 h

(~69%)

(~1%)

(~20%)

+

+


OHHHHO

OH 12

3

HOOH

HHO

OH 1

3

2HO

H

HHOHHO

OH 12

3

Protonation at C2 from the bottom faceglucose

mannose

HO

Hb

a

aa

b

OHHO

OHH 1

3

2

H

"ene-diol"

OH

a

OHHO

OHH1

3

2

H

OH

OHHOOHHOHH

CH2OH

OHH1

23

H

D-fructose

Mechanism:

Protonation at C1

b

--------------------------------------------------------------------------

OHHHHO

OH 1

2

3OHHHHO

OH 12

3

H

H2O

OHHHO

OH 1

3

H

H2O

2

HO

H

H

HO

H

H

HHOHHO

OH 12

3

H

HHOHHO

OH 12

3

Protonation at C2 from the bottom face

Protonation at C1Loss of H+C=O

(fructose)

glucose

mannose

Mechanism under H3O+ conditions

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

O

HOHO

HOOH

HO

1

OHHHHOOHHOHH

CH2OH

OO 1

OHHHHOOHHOHH

CH2OH

OH 1

2

3Ag2O

NaOH/H2O Ag0 (silver mirror)+

Also, with Cu2+ (CuSO4) [deep blue color]/NaOH [Benedict's reagent] reducing sugarCu2O (Cu+1) [red ppts]

Tollens test

Chem 215-216 HH W12 Notes – Dr. Masato Koreeda - Page 8 of 11. Date: March 28, 2012 (3) Oxidation reactions involving C1-OH or C1- and C6-OHs (a) Br2 in H2O oxidizes only aldoses

O

HOHO

HOOH

HO

1

OH

HOHO

HO

HO

OH

OH

HOHO

HO

HO

OOH O

HOHO

HO

HO

O

Br2 + 3 H2O

+ 2 Br- + 2 H3O+

H3O+

note: Br2 + H2O HBr + HOBr

Under the acidic conditions, this hydroxy acid closes to form the six-membered lactone.

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

OHHHHOHHOOHH

CH2OH

OH

D-galactose(optically active)

1

2

3

4

5

6

OHHHHOHHOOHH

OHO

galactaric acid(meso; optically

inactive)

1

2

3

4

5

6

O OH

HNO3, Δ

Both C1 and C6 ends get oxidized to COOH's.

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

O

HOHO

HOOH

HO

1OHHHHOOHHOHH

CH2OH

OHHHHOOHHOHH

CH2OH

OH 1

2

3 HCN

H2O

H OHC N

OHHHHOOHHOHH

CH2OH

HO HC N

* * *

+

CH2OHOHHOOHHOHH

CH2OH

D-fructose

1

23CH2OH

OH H

HHO

O1

2

34

5

6

OH

HO

α-/β-D-fructofuranose

CH2OHOHHHOOHHOHH

CH2OH

1

2

3

CH2OHHHHOOHHOHH

CH2OH

1

2

3NaBH4CH3OH-H2O

H HO+

Chem 215-216 HH W12 Notes – Dr. Masato Koreeda - Page 9 of 11. Date: March 28, 2012 (4) Reactions of hydroxyl groups and their derivatives

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

(a)

O

H3COH3CO

H3CO

OCH3

H3CO

1O

H3COH3CO

H3CO

H3CO

1O

H3COH3CO

H3CO

Br

H3CO

1

HBr(gas)

CH2Cl2

BrSN1

KO-CH2Ph

O

H3COH3CO

H3CO

H3CO

1O

CH2Ph

+ KBr

SN2 !The α-bromide formed due mainly

to the anomeric effect of Br.

(b)

O

HOHO

HO

HO

1O

OO

O

O

O

1

CH3

OCH3

H3C

H3C

H3C

OO

OO

OH

H3C O CH3

O O

N

(excess)

O

OO

O

Br

O

1

CH3

H3C

H3C

H3C

OO

OO

OH

O

OH

HO

HBr (gas)acetic acid

(0 °C)

KOH, ΔK

O

OO

O

O

1

CH3

H3C

H3C

H3C

OO

OO

OH

OSN2

SN1

O

OHHO

HO

HO

1

OH

O

salicin

NaOH-H2O

more acidic

+ KBr

H3C O CH3

O O

N

H3C O CH3

O O

N

H3C O

N

*

*

O

H

H3C OR

O

R

Chem 215-216 HH W12 Notes – Dr. Masato Koreeda - Page 10 of 11. Date: March 28, 2012 Summary of Carbohydrate Reactions The reactions applied to carbohydrates are not new and have been covered in earlier chapters, but they often exhibit uniquely carbohydrate behaviors. 1. Base or acid-catalyzed isomerization between aldoses and ketoses via ene-diol intermediates, particularly the mechanism. 2. Reactions of aldoses/ketoses with those that react with an aldehyde or ketone C=O group such as NaBH4/CH3OH and a primary amine, NH2R. 3. Acid-catalyzed reactions at the anomeric center of a carbohydrate, particularly the mechanism that involves the lone pair-assisted ionization. 4. Ether formation from ROH: R’X/NaH or (CH3)2SO4/NaOH 5. Acylation of ROH:

6. Selective reactions of a primary alcohol with electrophiles For example,

For the deprotection of the trityl group [Ph3C-], mild acidic conditions such as aq CF3C(=O)OH are used.

7. Hydrolysis (with HO-) [see p 9 (b) of Carbo notes Part II] or methanolysis (NaOCH3/CH3OH) of esters such as acetates. For example,

Chem 215-216 HH W12 Notes – Dr. Masato Koreeda - Page 11 of 11. Date: March 28, 2012 8. SN2 reactions of mesylate, tosylate, and triflate [OTf; trifluoromethanesulfonate, OS(O)2CF3] derivatives of primary and secondary hydroxy groups. For example,

9. Acetal/ketal derivatives of diols and their hydrolysis. For the formation of acetal/ketal derivatives, RR’C(OCH3)2 [such as Ph-CH(OCH3)2] is usually used especially when a sugar has 1-OR group, instead of an aldehyde [e.g., Ph-C(=O)H] or ketone [e.g., (CH3)2C=O]. This is to avoid the hydrolysis of 1-OR by the water generated as a result of acetal/ketal formation from a diol when a RR’C=O is used. Preferred formation of acetals/ketals from 1,2-cis-diol

The acetal/ketal derivative of a trans-diol is considerably more strained compared with those formed from cis-diols.

When there is no cis-diol in the pyranose ring, the six-membered acetal/ketal involving 4- and 6-OH’s is formed.

chapters 14.8, 23-1,2, 5, and 7: carbohydrates - part ii ...chem215/215-216 hh w12...

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