Organic Chemistry M. R. Naimi-Jamal Faculty of Chemistry Iran University of Science & Technology
Chapter 6. Stereochemistry Based on McMurry s Organic Chemistry, 6 th edition
Stereochemistry Some objects are not the same as their mirror images (they have no plane of symmetry) A right-hand glove is different than a left-hand glove The property is commonly called handedness Many organic molecules (including most biochemical compounds) have handedness that results from substitution patterns on sp 3 hybridized carbon 3
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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 5
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Enantiomers and the Tetrahedral Carbon Enantiomers are molecules that are not the same as their mirror image They are the same if the positions of the atoms can coincide on a one-to-one basis (we test if they are superimposable, which is imaginary) This is illustrated by enantiomers of lactic acid 7
Examples of Enantiomers Molecules that have one carbon with 4 different substituents have a nonsuperimposable mirror image enantiomer 8
Mirror-image Forms of Lactic Acid When H and OH substituents match up, COOH and CH 3 don t when COOH and CH 3 coincide, H and OH don t 9
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The Reason for Handedness: Chirality Molecules that are not superimposable with their mirror images are chiral (have handedness) A plane of symmetry divides an entire molecule into two pieces that are exact mirror images A molecule with a plane of symmetry is the same as its mirror image and is said to be achiral 11
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Chirality 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 13
The flask has a mirror plane, or plane of symmetry There is no mirror plane for a hand 14
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 groups (or atoms) can be attached to one carbon atom A chiral molecule usually has at least one chirality center 15
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Chirality Centers in Chiral Molecules Groups are considered different if there is any structural variation (if the groups could not be superimposed if detached, they are different) In cyclic molecules, we compare by following in each direction in a ring 17
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Problem: Chirality Centers? 20
Problem: Same structure or Enantiomers? 21
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 planepolarized light and the molecules are said to be optically active Phenomenon discovered by Biot in the early 19 th century 22
Measurement of Optical Rotation A polarimeter measures the rotation of plane-polarized that has passed through a solution 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. 23
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 24
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A Simple Polarimeter Measures extent of rotation of plane polarized light Operator lines up polarizing analyzer and measures angle between incoming and outgoing light 26
Specific Rotation To have a basis for comparison, define specific rotation, [ ] D for an optically active compound [ ] D = observed rotation/(pathlength x concentration) = /(l x C) = degrees/(dm x g/ml) 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 nanometers) 27
Specific Rotation and Molecules Characteristic property of a compound that is optically active the compound must be chiral The specific rotation of the enantiomer is equal in magnitude but opposite in sign (or direction). 28
Pasteur s Discovery of Enantiomers (1849) 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 distinctly different shapes such an event is rare 29
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Relative 3-Dimensionl Structure The original method was a correlation system, classifying related molecules into families based on carbohydrates Correlate to D- and L- glyceraldehyde D-erythrose is the mirror image of L-erythrose This does not apply in general 31
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Sequence Rules for Specification of Configuration The configuration is specified by the relative positions of all the groups with respect to each other at the chirality center The groups are ranked in an established priority sequence (the same as the one used to determine E or Z) and compared. The relationship of the groups in priority order in space determines the label applied to the configuration, according to a rule 33
Sequence Rules (IUPAC) Assign each group priority according to the Cahn- Ingold-Prelog scheme With the lowest priority group pointing away, look at remaining 3 groups in a plane Clockwise is designated R (from Rectus Latin for right ) Counterclockwise is designated S (from Sinister Latin word for left ) 34
R-Configuration at Chirality Center Lowest priority group is pointed away and direction of higher 3 is clockwise, or right turn 35
Examples of Applying Sequence Rules If lowest priority is back, clockwise is R and counterclockwise is S 36
Practice Problem 37
Problem: Assign R or S 38
Problem: R or S? 39
Problem: Same structure or Enantiomers? 40
Diastereomers 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 41
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Problem: Assign configurations 44
Problem: R or S? 45
Problem: Assign R or S 46
Tartaric acid: Tartaric acid has two chirality centers and two diastereomeric forms One form is chiral and the other is achiral, but both have two chirality centers An achiral compound with chirality centers is called a meso compound it has a plane of symmetry 47
Enantiomers Meso forms 48
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Another example of a meso compound 50
Molecules with More Than Two Chirality Centers Molecules can have very many chirality centers Each center has two possible permanent arrangements (R or S), generating two possible stereoisomers The number of possible stereoisomers with n chirality centers is 2 n 51
Problem: How many Chirality centers? 52
Physical Properties of Stereoisomers Enantiomeric molecules differ in the direction in which they rotate plane polarized but their other common physical properties are the same Diastereomers have a complete set of different common physical properties 53
Racemic Mixtures and Their Resolution A 50:50 mixture of two chiral compounds that are mirror images does not rotate light called a racemic mixture (named for racemic acid that was the double salt of (+) and (-) tartaric acid The pure compounds need to be separated or resolved from the mixture (called a racemate) 54
Racemic Mixtures and Their Resolution To separate components of a racemate (reversibly) we make a derivative of each with a chiral substance that is free of its enantiomer (resolving agent) This gives diastereomers that are separated by their differing solubility The resolving agent is then removed 55
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A Brief Review of Isomerism 57
Constitutional Isomers Different order of connections gives different carbon backbone and/or different functional groups 58
Stereoisomers Same connections, different spatial arrangement of atoms Enantiomers (nonsuperimposable mirror images) Diastereomers (all other stereoisomers) Includes cis, trans and configurational 59
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Stereochemistry of Reactions: Addition of HBr to Alkenes Many reactions can produce new chirality centers from compounds without them What is the stereochemistry of the chiral product? What relative amounts of stereoisomers form? 62
Stereochemistry of Reactions: Addition of HBr to Alkenes Example addition of HBr to 1-butene 63
Achiral Intermediate Gives Racemic Product Addition via carbocation Top and bottom are equally accessible 64
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Mirror Image Transition States Transition states are mirror images and product is racemic Br 66
Stereochemistry pf Reactions: Addition of Br2 to Alkenes Stereospecific Forms racemic mixture Bromonium ion leads to anti (trans) addition 67
Addition of Bromine to cis-2-butene Racemic product 68
Addition of Bromine to Trans 2- Butene Gives meso product (both are the same because of symmetry) 69
Stereochemistry of Reactions: Addition of HBr to a Chiral Alkene Gives diastereomers in unequal amounts. Facial approaches are different in energy 70
Chirality at Atoms Other Than Carbon Trivalent nitrogen is tetrahedral Does not form a stable chirality center since it rapidly inverts 71
Prilosec (omeprazole): Chiral Sulfur Racemic (at sulfur); the S enantiomer is physiologically active 72
Nexium (esomeprazole): Pure (S) enantiomer 73
Chirality in Nature Stereoisomers are readily distinguished by chiral receptors in nature Properties of drugs depend on stereochemistry Think of biological recognition as equivalent to 3-point interaction 74
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Chapter 6, Questions 22, 23, 25, 26, 29, 33, 39, 47, 57, 60 76