Stereochemistry (Part-3) 2024 PDF

Prof. Dr. Mostafa El-Miligy Pharmaceutical Organic Chemistry I Stereochemistry (Part-3) Prof. Dr. Mostafa El-Miligy Professor of Pharm...

Prof. Dr. Mostafa El-Miligy Pharmaceutical Organic Chemistry I Stereochemistry (Part-3) Prof. Dr. Mostafa El-Miligy Professor of Pharmaceutical Chemistry Faculty of Pharmacy Alexandria University 1 Naming Compounds with More Than One Stereocenter Fischer Projection formulas 2 Stereochemistry (Part-3) 1 Prof. Dr. Mostafa El-Miligy Pharmaceutical Organic Chemistry I The carbon chain is drawn along the vertical line with the most highly oxidized end carbon atom at the top. 1) Vertical lines: bonds going into the page. 2) Horizontal lines: bonds out of the page Bonds out of page COOH COOH Bonds into page COOH H C OH H OH H C = = HO CH 3 CH3 CH3 (R)-Lactic acid Fischer projection 3 Allowed motions for Fischer projection: 1. 180° rotation (not 90° or 270°): COOH CH 3 H OH HO H CH 3 Same as COOH 4 Stereochemistry (Part-3) 2 Prof. Dr. Mostafa El-Miligy Pharmaceutical Organic Chemistry I 2. Rotation of a Fischer projection by 90° inverts its meaning. COOH H H OH H3C COOH CH3 Not same as OH 5 6 Stereochemistry (Part-3) 3 Prof. Dr. Mostafa El-Miligy Pharmaceutical Organic Chemistry I 3. One group hold steady and the other three can rotate: 7 4.Differentiate different Fischer projections: CH 2CH 3 OH H Hold CH3 Hold CH2CH3 HO H H CH 2CH 3 H 3C CH 2CH 3 Rotate other Rotate other CH 3 three groups CH 3 three groups OH B clockwise clockwise A OH CH2CH3 H Rotate Hold CH3 H CH 3 H3C H H3C OH 180o Rotate other CH 2CH 3 OH three groups CH 2CH3 C counterclockwise Not A 8 Stereochemistry (Part-3) 4 Prof. Dr. Mostafa El-Miligy Pharmaceutical Organic Chemistry I Assigning R,S Configurations to Fischer Projections COOH H2N H CH 3 Alanine 9 COOH Rotate counterclockwise 4H 2 2 1 1 H2N H = HOOC NH2 4 3CH3 3 CH3 Hold −CH3 steady 4H 2 4H 1 2 1 HOOC NH2 HOOC NH2 = 3 CH3 3 CH3 S stereochemistry 10 Stereochemistry (Part-3) 5 Prof. Dr. Mostafa El-Miligy Pharmaceutical Organic Chemistry I 3-Stereoisomerism in compounds with two stereocentres: Diastereomers and meso structure: The total number of stereoisomers will not exceed 2n where n is the number of chiral carbons. 11 Example: 2,3,4-trihydroxybutanal A and C are diastereomers B and D are diastereomers 12 Stereochemistry (Part-3) 6 Prof. Dr. Mostafa El-Miligy Pharmaceutical Organic Chemistry I 13 Example: Tartaric acid meso-tartaric acid (optically inactive) 14 Stereochemistry (Part-3) 7 Prof. Dr. Mostafa El-Miligy Pharmaceutical Organic Chemistry I Do Diastereomers have the same physical and chemical properties? 15 Stereoisomerism of Cyclic Compounds 16 Stereochemistry (Part-3) 8 Prof. Dr. Mostafa El-Miligy Pharmaceutical Organic Chemistry I Cyclopentane Derivatives Example: 1,2-Dimethylcyclopentane Trans-1,2-Dimethylcyclopentane Cis-1,2-Dimethylcyclopentane 17 Cyclohexane Derivatives A-Conformational isomerism in cyclohexane: 18 Stereochemistry (Part-3) 9 Prof. Dr. Mostafa El-Miligy Pharmaceutical Organic Chemistry I 19 Axial 5 6 1 ring 4 5 6 Equatorial 4 3 flip 2 1 2 3 Equatorial Axial 20 Stereochemistry (Part-3) 10 Prof. Dr. Mostafa El-Miligy Pharmaceutical Organic Chemistry I The most stable conformation of substituted chclohexanes: e.g. methylcyclohexane H CH (axial) H H H H 3 H H H H H H H H H CH 3 (equitorial) H H H H H H H H (1) (2) (less stable) (more stable by 7.5 kJ mol−) (a) H CH H H 5H H 3 H H 1 H H H H H H H CH 3 3 H H H H H H (b) H H 21 B-Configurational isomerism in cyclohexane: 1,4-Dimethylcyclohexane 22 Stereochemistry (Part-3) 11 Prof. Dr. Mostafa El-Miligy Pharmaceutical Organic Chemistry I 1,3-Dimethylcyclohexanes cis-1,3-Dimethylcyclohexane has a plane of symmetry and is therefore achiral. 23 24 Stereochemistry (Part-3) 12 Prof. Dr. Mostafa El-Miligy Pharmaceutical Organic Chemistry I trans-1,3-Dimethylcyclohexane does not have a plane of symmetry and exists as a pair of enantiomers. 25 26 Stereochemistry (Part-3) 13 Prof. Dr. Mostafa El-Miligy Pharmaceutical Organic Chemistry I 4-Geometrical isomers Found in alkenes and cyclic compounds. In alkenes, there is restricted rotation about the double bond. Substituents attached to the double bond can bond in different ways, resulting in: trans (opposite side) and cis (same side) geometrical isomers. 27 28 Stereochemistry (Part-3) 14 Prof. Dr. Mostafa El-Miligy Pharmaceutical Organic Chemistry I Geometric isomers have different chemical and physical properties. Each isomer can be converted to another when enough energy is supplied because the π bond breaks when energy is absorbed, and the two halves of the molecule can then rotate to form more stable π bond. 29 The E/Z system is used for naming geometrical isomers. Z stands for German Zusammen, which means the same side (Cis) E for German Entgegen, meaning on the opposite side (Trans). 30 Stereochemistry (Part-3) 15 Prof. Dr. Mostafa El-Miligy Pharmaceutical Organic Chemistry I Example: 1-bromo-1,2-dichloroethene 31 Chiral Molecules that Do Not Posses a Tetrahedral Atom with four Different Groups (Atropisomerism) Atropisomers are optically active compounds although they do not contain chiral centers. They do not have a plane of symmetry (Chiral molecule). Atropisomers include: I-Biphenyls. II-Allenes. 32 Stereochemistry (Part-3) 16 Prof. Dr. Mostafa El-Miligy Pharmaceutical Organic Chemistry I I- Biphenyls 3' 2' 2 3 1' 1 4' 4 5' 6' 6 5 the same plane perpendicular planes COOH NO2 COOH NO2 COOH COOH NO2 enantiomers NO2 6,6'-dinitrobiphenyl-2,2'-dicarboxylic acid no plane of sym. optically active 33 NO2 CH3 CH3 COOH COOH COOH Br COOH COOH Br COOH NO2 NO2 NO2 2',6'-dinitrobiphenyl-2,6- 3-Bromo-2'-methyl-6'-nitro- 4-Bromo-2'-methyl-6'-nitro- dicarboxylic acid biphenyl-2,6-dicarboxylic acid biphenyl-2,6-dicarboxylic acid optically inactive optically active optically inactive 34 Stereochemistry (Part-3) 17 Prof. Dr. Mostafa El-Miligy Pharmaceutical Organic Chemistry I II- Allenes 1-Allene (Propadiene): C C C 35 e.g. 1,3-dichloropropadiene H H H H C C C C C C Cl Cl Cl Cl Mirror These two molecules are nonsuperposable mirror images of each other and are therefore chiral. 36 Stereochemistry (Part-3) 18 Prof. Dr. Mostafa El-Miligy Pharmaceutical Organic Chemistry I Synthesis of Chiral Molecules Racemic Forms e.g. Nickel-catalyzed hydrogenation of 2-butanone Ni CH3CH2CCH 3 + H H (+)- CH3CH2*CHCH3 O OH 2-Butanone Hydrogen (±)-2-Butanol (achiral molecule) [50:50 mixture of (R) and (S)] 37 38 Stereochemistry (Part-3) 19 Prof. Dr. Mostafa El-Miligy Pharmaceutical Organic Chemistry I Enantioselective Syntheses In an enantioselective reaction, a chiral reagent, catalyst, or solvent must assert an influence on the course of the reaction. Enzymes: Enzymes possess an active site where the reactant molecules are bound. This active site is chiral, and only one enantiomer of a chiral reactant fits it properly and is able to undergo reaction. 39 40 Stereochemistry (Part-3) 20 Prof. Dr. Mostafa El-Miligy Pharmaceutical Organic Chemistry I Enzyme-catalyzed organic reactions: Lipase catalyzes hydrolysis of esters: O OEt H F O Ethyl (R)-(+)-2-fluorohexanoate lipase (>99% enantiomeric excess) OEt + + H O Et H OH O F Ethyl (+)-2-fluorohexanoate OH [an ester that is a racemate of (R) and (S) forms] F H (S)-(−)-2-Fluorohexanoic acid (>69% enantiomeric excess) 41 42 Stereochemistry (Part-3) 21 Prof. Dr. Mostafa El-Miligy Pharmaceutical Organic Chemistry I 43 44 Stereochemistry (Part-3) 22 Prof. Dr. Mostafa El-Miligy Pharmaceutical Organic Chemistry I Thank you Happy Studies Good luck 45 Stereochemistry (Part-3) 23