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 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 215-216 HH W12 Notes – Dr. Masato Koreeda - Page 2 of 11. Date: March 28, 2012 (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 HO OH O O HO O CH H stereochem. HO 3 HO O CH 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 215-216 HH W12 Notes – Dr. Masato Koreeda - Page 3 of 11. Date: March 28, 2012 (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 215-216 HH W12 Notes – Dr. Masato Koreeda - Page 4 of 11. Date: March 28, 2012 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 215-216 HH W12 Notes – Dr. Masato Koreeda - Page 5 of 11. Date: March 28, 2012 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 215-216 HH W12 Notes – Dr. Masato Koreeda - Page 6 of 11. Date: March 28, 2012 Reactions of Carbohydrates (1) Isomerization of sugars: usually in the presence of acid or base epimer open chain form "ene-diol" ketose 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 215-216 HH W12 Notes – Dr. Masato Koreeda - Page 7 of 11. Date: March 28, 2012 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 Also, with Cu2+ (CuSO ) [deep blue color]/NaOH [Benedict's reagent] Cu O (Cu+1) [red ppts] 4 reducing sugar 2 Chem 215-216 HH W12 Notes – Dr.