Stereochemistry

1. Stereochemistry

2. Definitions • Stereochemistry refers to the 3-dimensional properties and reactions of molecules. • It has its own language and terms that need to be learned in order to fully communicate and understand the concepts. • Stereoisomers are compounds with the same connectivity, different arrangement in space.

3. A Brief Review of Isomerism • The flowchart summarizes the types of isomers.

4. Constitutional Isomers(Structural) • Different order of connections gives different carbon backbone and/or different functional groups

5. Stereoisomers(Configurational) • Same connections, different spatial arrangement of atoms. • Enantiomers: (nonsuperimposable mirror images) • Diastereomers: (all other stereoisomers) • Includes cis, trans isomers.

8. Constitutional Isomers vs Stereoisomers

9. Enantiomers – Mirror Images • Molecules exist as three-dimensional objects. • Some molecules are the same as their mirror image. • Some molecules are different than their mirror image. • These are stereoisomers called enantiomers.

10. Enantiomers and the Tetrahedral Carbon • Enantiomers are molecules that are not the same as their mirror image. • This is illustrated by enantiomers of lactic acid.

11. Mirror-image Forms of Lactic Acid • When H and OH substituents match up, COOHand CH3don’t • when COOH and CH3coincide, Hand OH don’t .

12. Examples of Enantiomers • Molecules that have one carbon with 4 different substituents have a nonsuperimposable mirror image – enantiomer.

13. Diastereomers • Stereoisomers that are not mirror images. • Geometric isomers (cis-trans). • The cis isomer has two groups on the same side. • The trans isomer has two groups on opposite sides.

14. Stereoisomers • Enantiomers …. pair of stereoisomers that are related to each other as non-super-imposable mirror image isomers • Meso compounds … stereoisomers that have more than one chiral center and are super-imposable on their mirror images • Diastereomers …. pair of stereoisomers containing more than one chiral center and are not mirror images of each other

15. Chirality • Chiral: from the Greek, cheir, (hand). • If an object has a plane of symmetry it is necessarily the same as its mirror image • The lack of a plane of symmetry is called “handedness”, chirality. • Hands, gloves are prime examples of chiral object. • They have a “left” and a “right” version.

16. Chirality Centers • A point in a molecule where four different groups (or atoms) are attached to carbon is called a chirality center. • There are two nonsuperimposable ways that 4 different different groups (or atoms) can be attached to one carbon atom. • If two groups are the same, then there is only one way. • A chiral molecule usually has at least one chirality center.

18. Chirality Centers • For a molecule with 1 chiral center, 21 = 2 stereoisomers are possible. • For a molecule with 2 chiral centers, a maximum of 22 = 4 stereoisomers are possible. • For a molecule with n chiral centers, a maximum of 2nstereoisomers are possible. • Larger organic molecules can have two, three or even hundreds of stereogenic centers.

19. 2,3,4-trichlorohexaneHow many stereoisomers?

20. 2S,3S 2R,3R 2R,3S 2S,3R Two Chiral Centers • Molecules with more than one chirality center have mirror image stereoisomers that are enantiomers. • In addition they can have stereoisomeric forms that are not mirror images, called diastereomers.

21. Meso Compounds • A meso compound is an achiral compound that contains tetrahedral stereogenic centers. All meso compounds contain a plane of symmetry. • Compound C has two stereogenic centers but it contains a plane of symmetry, and is achiral; C is a meso compound.

22. Labeling Stereogenic Centers with R or S • Since enantiomers are two different compounds, they need to be distinguished by name. This is done by adding the prefix R or S to the IUPAC name of the enantiomer. • Naming enantiomers with the prefixes R or S is called the Cahn-Ingold-Prelog system. * To designate enantiomers as R or S, priorities must be assigned to each group bonded to the stereogenic center, in order of decreasing atomic number. The atom of highest atomic number gets the highest priority (1).

23. R-Configuration at Chirality Center • Lowest priority group is pointed away and direction of higher 3 is clockwise, or right turn.

24. Chiral vs Achiral • In general, a molecule with no stereogenic centers will not be chiral. There are exceptions to this. • With one stereogenic center, a molecule will always be chiral. • With two or more stereogenic centers, a molecule may or may not be chiral, e.g. Meso compound (contains a plane of symmetry or a mirror plane) • Achiral molecules contain a plane of symmetry but chiral molecules do not. • A plane of symmetry is a mirror plane that cuts the molecule in half, so that one half of the molecule is a reflection of the other half.

25. Optical Activity • Light restricted to pass through a plane is plane-polarized . • Plane-polarized light that passes through solutions of achiral compounds remains in that plane. • Solutions of chiral compounds rotate plane-polarized light and the molecules are said to be optically active.

26. Plane-Polarized Light through an Achiral Compound

27. Plane-Polarized Light through a Chiral Compound

28. Optical Activity • Light passes through a plane polarizer. • Plane polarized light is rotated in solutions of optically active compounds. • Measured with polarimeter. • Rotation, in degrees, is []. • Clockwise rotation is called dextrorotatory. • Anti-clockwise is levorotatory.

29. Optical Activity • The rotation of polarized light can be clockwise or anticlockwise. • If the rotation is clockwise, the compound is called dextrorotatory. The rotation is labeled d or (+). • If the rotation is counterclockwise, the compound is called levorotatory. The rotation is labeled l or (-). • Two enantiomers rotate plane-polarized light to an equal extent but in opposite directions. Thus, if enantiomer A rotates polarized light +50, the same concentration of enantiomer B rotates it –50. • No relationship exists between R and S prefixes and the (+) and (-) designations that indicate optical rotation.

30. Specific Rotations of some Common Organic Compounds Compound [a] # * centers Penicillin V +233.0 3 Sucrose +66.5 10  Camphor +44.3 2 MSG +25.5 1 Cholesterol -31.3 8 Morphine -132.0 5

31. Racemic Mixture • An equimolar mixture of two enantiomers • because a racemic mixture contains equal numbers of dextrorotatory and levorotatory molecules, its specific rotation is zero.

32. Polarimetry • Use monochromatic light, usually sodium D • Movable polarizing filter to measure angle • Clockwise = dextrorotatory = d or (+) • Counterclockwise = levorotatory = l or (-) • Not related to (R) and (S)

33. Chirality in the Biological World • Except for inorganic salts and a few low-molecular-weight organic substances, the molecules of living systems are chiral. • Although these molecules can exist as a number of stereoisomers, generally only one is produced and used in a given biological system. • Enzymes are Chiral and enhance Chirality: • chymotrypsin contains 251 chiral centers. • the maximum number of stereoisomers possible is 2251 .

34. A schematic diagram of an enzyme surface capable of binding with (R)-enantiomer but not with (S)-enantiomer.

35. * Chiral centers are extremely important in biological processes and drug development.* Properties of drugs depend on stereochemistry. Biological Activity

36. Stereochemistry of Reactions:Addition of HBr to Alkenes • Many reactions can produce new chirality centers from compounds without them.

37. إن الله وملائكتــه يصلــون على النبي يــأيــها الذيـن آمنوا صلــوا عليه وسلمـــوا تسليمـــا