Stereochemistry Dr. Sapna Gupta
Introduction Stereo left and right handedness Any carbon that has four different groups will show chirality. hirality: the mirror image of the compound will not superimpose on the original molecule. Dr. Sapna Gupta/Stereochemistry 2
hirality When two mirror images are non imposable on each other. When the tetrahedral carbon has four different groups it is called a chiral center. The mirror image pair of the compounds are called enantiomers. The only thing different about the two molecules is how they rotate the plane polarized light. The rotation would be in equal and opposite direction. Drawing chiral molecules: draw dash (behind the plane) and wedges (coming out of paper) and plane line (in the plane) for bonds. ere are four representations of one compound. 3 O O O O 2 3 3 2 3 (1) (2) (3) (4) ere are two representations for the enantiomer of (4). O O O (4) representations for th e enantiomer of (4) Dr. Sapna Gupta/Stereochemistry 3
Some Enantiomers 2-hlorobutane l 3 2 3 l l 3-hlorocyclohexene l l Dr. Sapna Gupta/Stereochemistry 4
Another Example ow many chiral centers in the following compound? Dr. Sapna Gupta/Stereochemistry 5
Pasteur s Discovery of Enantiomers Louis Pasteur discovered that sodium ammonium salts of tartaric acid crystallize into right handed and left handed forms The optical rotations of equal concentrations of these forms have opposite optical rotations The solutions contain mirror image isomers, called enantiomers and they crystallized in mirror image shapes such an event is rare Dr. Sapna Gupta/Stereochemistry 6
Naming Enantiomers- The R,S System Also called the ahn-ingold-prelog system The four groups attached to the stereogenic/chiral carbon are assigned priorities from highest (a) to lowest (d) Priorities are assigned as follows Atoms directly attached to the chiral center are compared Atoms with higher atomic mass are given higher priority If priority cannot be assigned based on directly attached atoms, the next layer of atoms is examined Example Dr. Sapna Gupta/Stereochemistry 7
Naming Enantiomers- The R,S System, contd.. The molecule is rotated to put the lowest priority group back If the groups descend in priority (a,b then c) in clockwise direction the enantiomer is R If the groups descend in priority in counterclockwise direction the enantiomer is S Dr. Sapna Gupta/Stereochemistry 8
Assigning Priority 1. Look at the atom (not the group) directly attached to the carbon and arrange according to atomic weight (1) (6) (7) (8) 2. If priority cannot be assigned per the atoms bonded to the chiral center, look to the next set of atoms; priority is assigned at the first point of difference 3. Groups with double or -= triple 2 bonds are assigned -- priorities 2 as if their atoms were duplicated or triplicated -= 2 (16) Increasing priority (17) (35) (53) - - 3 -N 2 - O - S - l - Br - I (1) - 2 - (6) - -= 2 O - (7) - 2-3 - 2 -N 2 Increasing priority is treated as O is treated as is treated as is treated as is treated as is treated as (8) - 2 -O O O -- 2 O O O - is treated as is treated as is treated as Dr. Sapna Gupta/Stereochemistry 9 -- 2 O O
Examples (S)-2-hlorobutane l S 1 4 2 3 (R)-3-hlorocyclohexene 3 1 l 2 3 R 1 2 4 (R)-Mevalonic acid 1 4 O R 3 O 2 O O 3 2 3 1 Dr. Sapna Gupta/Stereochemistry 10
Identical or Not? Are A and B identical or enantiomers? Manipulate B to see if it will become superimposable with A Exchange 2 groups to try to convert B into A Dr. Sapna Gupta/Stereochemistry 11
Optical Activity Light restricted to pass through a plane is plane-polarized. Phenomenon discovered by Jean-Baptiste Biot in the early 19 th century Plane-polarized light that passes through solutions of achiral compounds retains its original plane of polarization Solutions of chiral compounds rotate plane-polarized light and the molecules are said to be optically active The instrument is called a polarimeter Rotation is measured in degrees, is [ ] lockwise rotation is called dextrorotatory (d) Anti-clockwise is levorotatory (l) Dr. Sapna Gupta/Stereochemistry 12
The Polarimeter The source passes through a polarizer and then is detected at a second polarizer The angle between the entrance and exit planes is the optical rotation. Dr. Sapna Gupta/Stereochemistry 13
Specific Rotation To have a basis for comparison, define specific rotation, [ ] D for an optically active compound Specific rotation is that observed for 1 g/ml in solution in cell with a 10 cm path using light from sodium metal vapor (589 nm) OO OO 3 D O (S)-(+)-Lactic acid [ ] 21 = +2.6 O D 3 (R)-(-)-Lactic acid [ ] 21 = -2.6 Dr. Sapna Gupta/Stereochemistry 14
Specific Rotation and Molecules A compound must be chiral for it to be optically active. The specific rotation of the enantiomer pair is equal in magnitude but opposite in sign There is no correlation between the R,S designation of an enantiomer and the direction [(+) or (-)] in which it rotates plane polarized light ([+ = d] and [ = l]) Racemic mixture A 1:1 mixture of enantiomers No net optical rotation Often designated as (+) Dr. Sapna Gupta/Stereochemistry 15
Two hiral enters - Diastereomers Molecules that have two or more chiral centers. Each of the two chiral centers will have a pair of enantiomers. The other stereoisomers are called diastereomers. Enantiomers rotate plane polarized in opposite direction. Diastereomers have no optical relationship. The number of isomers are given by 2 n, where n is the number of chiral centers. It is important to understand the concept of symmetry. If a molecule has internal symmetry then it will not be optically active it will be achiral. Dr. Sapna Gupta/Stereochemistry 16
Two hiral enters There are two pairs of enantiomers (1, 2) and (3,4) Enantiomers are not easily separable so 1 and 2 cannot be separated from each other Diastereomers: stereoisomers that are not mirror images of each other For instance 1 and 3 or 1 and 4 ave different physical properties and can be separated Dr. Sapna Gupta/Stereochemistry 17
Meso ompounds ompounds with two or more chiral centers but not the maximum number of stereoisomers (2n) This is because two enantiomers may be superimposable i.e. achiral (not optically active) This superimposability comes from the molecule having a plane of symmetry. as a plane of symmetry Dr. Sapna Gupta/Stereochemistry 18
Naming more than one hiral enter The molecule is manipulated to allow assignment of each stereogenic center separately This compound is (2R, 3R)-2,3-dibromobutane Dr. Sapna Gupta/Stereochemistry 19
More Examples 2-Methylcyclopentanol 1,2-yclopentanediol 3 O O 3 O O O O cis-2-methylcyclopentanol (a pair of enantiomers) diastereomers cis- 1,2-yclopentanediol (one meso compound) dia 3 3 O O O O trans- 2-Methylcyclopentanol (a pair of enantiomers) O O trans- 1,2-yclopentanediol (a pair of enantiomers) Dr. Sapna Gupta/Stereochemistry 20
Six Membered Rings 1,4-dimethylcyclohexane (shown on the right) Neither the cis not trans isomers is optically active Each has a plane of symmetry 1,3-dimethylcyclohexane The trans and cis compounds each have two stereogenic centers The cis compound has a plane of symmetry and is meso The trans compound exists as a pair of enantiomers Dr. Sapna Gupta/Stereochemistry 21
Fisher Projections A 2-dimensional representation of chiral molecules Vertical lines represent bonds that project behind the plane of the paper orizontal lines represent bonds that project out of the plane of the paper Dr. Sapna Gupta/Stereochemistry 22
Stereoisomers With no hiral enters If the conformer is sterically hindered, it may exist as enantiomers. Examples given below and allenes. Dr. Sapna Gupta/Stereochemistry 23
Properties of Stereoisomers Enantiomers have identical physical and chemical properties in achiral environments. Diastereomers are different compounds and have different physical and chemical properties. meso tartaric acid, for example, has different physical and chemical properties from the R,R and S,S enantiomers Some properties of the stereoisomers of tartaric acid. OO OO OO O O O O O O specific rotation m elting point ( ) density at 20 (g/cm 3 ) solubility in water at 20 (g/100 ml) pk 1 (25 ) pk 2 (25 ) OO OO (R,R)-Tartaric acid (S,S)-Tartaric acid +12.7 171-174 1.7598 139 2.98 4.34-12.7 171-174 1.7598 139 2.98 4.34 OO Meso tartaric acid 0 146-148 1.660 125 3.23 4.82 Dr. Sapna Gupta/Stereochemistry 24
Resolution 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. Resolution: The separation of a racemic mixture into its enantiomers. One means of resolution is to convert the pair of enantiomers into two diastereomers. Diastereomers are different compounds and have different physical properties. A common reaction for chemical resolution is salt formation. ROO + : B ROO - B + (R + S)-arboxylic acid (R)-Base (R,R)-Salt + ( S,R)-Salt) After separation of the diastereomers, the enantiomerically pure acids are recovered by addition of an achiral acid. Racemic acids can be resolved using commercially available chiral bases such as 1- phenylethanamine. N 2 N 2 (S)-1-Ph enylethan amin e Racemic bases can be resolved using chiral acids such as (R)-1-Phenylethan amin e O O O 3 3 OO O O O O O O O O OO (2S,3S)-(+)-Tartaric acid (S)-(-)-Malic acid Dr. Sapna (1S,3R)-(+)-amphoric Gupta/Stereochemistry acid 25 3
Review of all Isomers ere is a flowchart of all isomers we have done so far. stereocenters but no chiral centers is,trans (E,Z) Isomers (can be called diastereomers) ompounds with the same molecular formula same connectivity Stereoisomers Meso ompounds with chiral centers different connectivity m ore than one chiral center achiral onstitutional Isomers chiral not mirror images rotation about single bonds one chiral center mirror images onformations rotation restricted onformational Isomers Atropisomers Enantiomers Diastereomers Enantiomers Dr. Sapna Gupta/Stereochemistry 26
Determining Stereochemistry Dr. Sapna Gupta/Stereochemistry 27
hemical Properties of Enantiomers Enantiomers have exactly the same chemical properties except for their reaction with chiral nonracemic reagents. Many drugs are chiral and often must react with a chiral receptor or chiral enzyme to be effective. One enantiomer of a drug may effectively treat a disease whereas its enatiomer may be ineffective or toxic. Dr. Sapna Gupta/Stereochemistry 28
Amino Acids and Proteins The 20 most common amino acids have a central carbon, called an -carbon, bonded to an N 2 group and a OO group. In 19 of the 20, the -carbon is a chiral center. 18 of the 19 -carbons have the R configuration, one has the S configuration. At neutral p, an amino acid exists as an internal salt. The symbol R = a side chain. Proteins: Long chains of amino acids connected by amide bonds (here shown in red) formed between the carboxyl group of one amino acid and the amino group of another amino acid Amide bond side chain 3 N O O - R Ionized or zw itterion form of an amino acid 3 N R O N R O N R O N n R O O - for most proteins, n= 150-750 Dr. Sapna Gupta/Stereochemistry 29
hirality in the Biological World Except for inorganic salts and a few low-molecular-weight organic substances, the majority of 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. onsider chymotrypsin, a protein-digesting enzyme in the digestive system of animals. chymotrypsin contains 251 chiral centers. the maximum number of stereoisomers possible is 2 251 there are only 2 38 stars in our galaxy! Enzymes are like hands in a handshake. The substrate fits into a binding site on the enzyme surface. A left-handed molecule, like hands in gloves, will only fit into a lefthanded binding site and a right-handed molecule will only fit into a right-handed binding site. Because of the differences in their interactions with other chiral molecules in living systems, enantiomers have different physiological properties. Dr. Sapna Gupta/Stereochemistry 30
hirality in the Biological World.. A schematic diagram of an enzyme surface capable of binding with (R)- glyceraldehyde but not with (S)-glyceraldehyde. Dr. Sapna Gupta/Stereochemistry 31
Key Words/oncepts Stereoisomers hiral enter hirality Enantiomer Plane polarized light Dextrorotatory (d) Laevorotatory (l) Diastereomers Meso compounds ahn Ingold and Prelog nomenclature onfigurations (R and S) Racemic mixtures Fisher projections Enantiomeric excess Absolute configuration Resolution