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:

W

C

ZY

X

W

C

ZY

X* *

Enantiomers• Example:

• (+) and (-)-lactic acid are a pair of enantiomers

Identify the chirality centers

CH3 CH3

OBr

Molecule Stereocenter?Plane of

Symmetry?Chrial?

CH3 CH2 CH2 CH3

CH3 CH CH2 CH3

Br

Cl H

Molecule Stereocenter?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

1. Higher atomic number (of atom bonded to C*) = higher priority

-Br > -Cl > -OH > -NH2 > -CH3 > -H

2. If 2 of the same atom are bonded to C*, look at atomic number of the next set of atoms

C H

H

H

C CH3

H

H

C OH

H

H

highest

• Continue process until first point of difference

• Some more examples:

CH2

higher

CH2 CH2 CH2 CH3 CH2 CH2 CH2 CH2 NH2

Priority Rules

3. Atoms in double bonds count twice; atoms in triple bonds count three times

CH CH2C C H

C

O

OH C N

bonded to H, C, C bonded to C, C, C

bonded to O, O, O bonded to N, N, N

Which substituent has the higher priority?

a) -Br -Cl

b) -CH2CH3 -CH(CH3)2

c) -CH=CH2 -CH2CH3

d) -CHO -CO2H

e) -CH2OH -CH2CH2OH

To designate R or S:

1. Locate chirality center

2. Assign priority to the 4 groups (1 = highest; 4 = lowest)

3. Orient molecule so substituent 4 is point away from you

(with model or on paper)

4. Read the other groups 1→2→3 (draw arrow on paper)

5. Groups read clockwise = R; counterclockwise = S

Example: 2-bromobutane

C

CH3 CH2CH3

C

CH3CH3CH2

BrBrH H

* *

Example: 2-bromobutane

C

CH3 CH2CH3

C

CH3CH3CH2

BrBrH H

* *

1 1

23

4 4

2 3

(R)-2-bromobutane (S)-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

CH3 H H CH3

Classify these as chiral or achiral:

CH3

OH

CH3

OH

CH3

OH

How many chirality centers?

O

OHCH3

CH3

testosterone

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

C

CH3

H

BrCl

rotateC

CH3

Br

ClH

Classify these molecules as R or S:

CH3

C

H

BrCl CH2

C

CH2CH2OH

OHH3C

HCl

C

HO

O

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

a)

b)

CH3

C

Br

ClH

C ClH

Br

CH3

CH2CH3

C

H

BrCH3

CH3

C

CH2CH3

HBr

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

C ZX

W

Y

ZX

W

Y

is the same as

What is the relationship between these two molecules?

BrH

CH3

CH2CH3

BrCH3

CH2CH3

H

Molecules With Multiple Stereocenters• Maximum # stereoisomers = 2n where n = # stereocenters

# Stereocenters # Stereoisomers Stereoisomers

1 2RS

2 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

CH3 CH CH CH2CH3

OHOH

* *

CH3

HO H

CH2CH3

H OH

CH3

H OH

CH2CH3

HO H

CH3

HO H

CH2CH3

HO H

CH3

H OH

CH2CH3

H OH

C2

C3

A B C D

2R,3R 2S,3S 2R,3S 2S,3R

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

CH3

HO H

CH2CH3

H OH

CH3

H OH

CH2CH3

HO H

CH3

HO H

CH2CH3

HO H

CH3

H OH

CH2CH3

H OH

C2

C3

A B C D

2R,3R 2S,3S 2R,3S 2S,3R

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 diastereomersCH3

H H

CH3 CH3

H CH3

H

CH3

HO H

CH2CH3

H OH

CH3

HO H

CH2CH3

HO H

A C

2R, 3R 2R, 3S

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

CH3

HO H

CH3

H OH

CH3

H OH

CH3

HO H

CH3

HO H

CH3

HO H

CH3

H OH

CH3

H OH

A B C D

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

1. 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)

H H

prochiralcenter

pro-R

pro-S

Br2

h

Br H H Br

+

Applications of Stereochemistry

2. 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

O

OH

OO

Thalidomide

• How many chirality centers?• How many stereoisomers?• How was the drug administered?• What effect did this have on

patients who used thalidomide?

N

N

O

O O

O

H

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:

a)

b)

CN

CH2CH2OH

CH3

CO2H

CH2OH

HO

H

Name these alkenes:

a)

b)

CH3

BrCl

H

CH2CH3

CH3CH2

CH3

Cl

Isomerism Worksheet

Next…• Organic reactions