Stereochemistry Dr. Sheppard CHEM 2411 Spring 2015 Klein (2nd ed.) sections 5.1-5.9, 8.4

Stereochemistry Branch of chemistry concerned with the spatial arrangement of atoms in molecules Stereoisomers: Same molecular formula Same connectivity Different 3D orientation (cannot be converted via bond rotation) Previously: Cis and trans Now: Stereochemistry at tetrahedral centers Enantiomers, diastereomers E and Z

Chirality “handedness” Has a mirror image that is nonsuperimposable Example: hand Example: sunglasses Chiral or not? Chiral or not?

Chirality A molecular example: Try this with your model kit

Achiral molecules Are superimposable on their mirror images Contain a plane of symmetry Cuts through the middle of the molecule so that one half reflects the other half achiral chiral

Enantiomers Chiral molecules form enantiomers Nonsuperimposable mirror images Result from tetrahedral C (sp3) with 4 different substituents This C is called a chirality center (or stereocenter, or asymmetric center) and are often marked with * Examples of stereocenters:

Enantiomers Example: (+) and (-)-lactic acid are a pair of enantiomers

Identify the chirality centers

Molecule Stereocenter? Plane of Symmetry? Chrial?

Not all molecules with stereocenters are chiral! Plane of Symmetry? Chrial? Not all molecules with stereocenters are chiral!

Enantiomer Similarities and Differences Same molecular formula, connectivity Different 3D arrangement Same physical properties (mp, bp, solubility) Same spectroscopic properties (IR, NMR, etc.) Same reactivity, in general Products will have different stereochemistry Only one will react with an enzyme (like a hand fitting in a glove) Different designations (R vs. S) Different optical activity

Optical Activity Rotation of plane- polarized light Seen in chiral molecules a = observed rotation; measured by the polarimeter One enantiomer rotates light to the left a degrees Levorotatory (-) The other rotates light to the right a degrees Dextrorotatory (+)

Optical Rotation Depends on polarimeter pathlength (l) and sample concentration (c) Specific rotation [a]D is observed under standard conditions l = 589.6 nm l = 1 dm (10 cm) c = 1 g/cm3 (-)-Lactic acid has a [a]D of -3.82 (+)-Lactic acid has a [a]D of +3.82 What is [a]D of a 50:50 mixture of (-) and (+)-lactic acid?

R and S designations Used to describe 3D configuration about a chirality center Not related to direction of optical rotation (+) and (-) To designate R and S need to assign priorities to each group bonded to the stereocenter Cahn-Ingold-Prelog system

Priority Rules Higher atomic number (of atom bonded to C*) = higher priority -Br > -Cl > -OH > -NH2 > -CH3 > -H If 2 of the same atom are bonded to C*, look at atomic number of the next set of atoms

Continue process until first point of difference Some more examples:

Priority Rules Atoms in double bonds count twice; atoms in triple bonds count three times

Which substituent has the higher priority? -Br -Cl -CH2CH3 -CH(CH3)2 -CH=CH2 -CH2CH3 -CHO -CO2H -CH2OH -CH2CH2OH

To designate R or S: Locate chirality center Assign priority to the 4 groups (1 = highest; 4 = lowest) Orient molecule so substituent 4 is point away from you (with model or on paper) Read the other groups 1→2→3 (draw arrow on paper) Groups read clockwise = R; counterclockwise = S

Example: 2-bromobutane

Example: 2-bromobutane

Rank the following groups in order of priority from highest (1) to lowest (4): -NHC(O)CH3 -OCH3 -OH -F

Draw R and S stereoisomers for 2-hydroxypropanal:

R and S stereoisomers for 3-methylhexane: Hints: Switch any two groups to draw the enantiomer When substituent 4 is forward, 1→2→3 clockwise is S

Classify these as chiral or achiral:

How many chirality centers?

Rotating a Tetrahedral Carbon To rotate a carbon and not accidentally change the R/S designation, keep one substituent in the same place, and rotate the other three. Make sure all three groups are rotating in the same direction Do not switch two groups; this changes the R/S designation

Classify these molecules as R or S:

Determine whether the two structures in each pair represent constitutional isomers, enantiomers, or identical compounds.

Fischer Projections Another way of drawing tetrahedral carbons Horizontal lines = out of page Vertical lines = into page Frequently used for chirality centers, especially if a molecule has more than one chiral center

What is the relationship between these two molecules?

Molecules With Multiple Stereocenters Maximum # stereoisomers = 2n where n = # stereocenters # Stereocenters # Stereoisomers Stereoisomers 1 2 R S 4 (R,R) (S,S) (R,S) (S,R)

Example: 2,3-Pentanediol Draw Fischer projections for the 4 stereoisomers Carbon chain vertical, C1 at top

Relationships A and B are enantiomers C and D are enantiomers A and C, A and D, B and C, B and D are diastereomers

Diastereomers Stereoisomers that are not mirror images of each other Different physical properties With tetrahedral carbons, require at least 2 stereocenters Cis-trans stereoisomers are also diastereomers

Meso Compounds Maximum # stereoisomers = 2n where n = # stereocenters The # stereoisomers will be less than 2n when there is a meso compound Meso compound An achiral compound which contains chirality centers Not optically active The chirality centers typically are identical (have the same 4 substituents) and reflect each other in a plane of symmetry Example:

Another Example: 2,3-Butanediol A = (2R,3R)-2,3-butanediol B = (2S,3S)-2,3-butanediol C = D = meso-2,3-butanediol C and D are superimposable mirror images (the same molecule) Relationship between enantiomers and meso? Diastereomers

Racemic Mixtures aka Racemate, + pair, or d,l pair 50% mixture of two enantiomers Not optically active Separation of enantiomers is difficult Separation methods: React with chiral compound to convert to a pair of diastereomeric salts, which can be separated by distillation, crystallization, etc. Separate on chiral column Separate with enzyme

Applications of Stereochemistry Stereochemistry of reactions If a product has a stereocenter, is the stereochemistry all R, all S, or a mixture? To understand details, need to look at mechanism (next)

Applications of Stereochemistry Reactions with enzymes Receptors/enzymes react with only one enantiomer (like a handshake) Limonene R = orange odor S = pine odor Ibuprofen R = inactive S = active D-Decalactone R = porcupine emits to alert predators S = coconut

Thalidomide How many chirality centers? How many stereoisomers? How was the drug administered? What effect did this have on patients who used thalidomide? Francisco Goya

Alkene Stereochemistry Previously, cis-trans stereoisomers Now, E,Z-designation of alkenes Use E,Z instead of cis-trans when More than two substituents on C=C Heteroatoms on C=C To assign E or Z: Rank the two groups on each carbon of the C=C according to the Cahn-Ingold-Prelog priority rules If the higher priority groups are on the same side of the C=C, the alkene has Z geometry If the higher priority groups are on opposite sides of the C=C, the alkene has E geometry

E and Z Configurations

Classify these alkenes as E or Z:

Name these alkenes:

Isomerism Worksheet

Next… Organic reactions