C 341 F 2011 Chapter 5 Stereochemistry

C341/Fall 2011 Chapter 5: Stereochemistry
Chapter 5: Stereochemistry & Chirality

1. Chiral & Achiral Compounds ‐ Identifying Stereocenters
2. Naming Stereocenters – employing R & S configurations
3. Diastereomers ‐ Molecules with two or more stereocenters
4. Properties of Stereoisomers & Optical Activity

Of course I would want you to do all the problems at the end of the chapter, but
your doing the following problems would be a bare minimum:
5.32‐5.23, 5.36‐5.42, 5.45‐5.51, 5.53‐5.57

Stereoisomers – WHERE DO THEY FIT INTO THE BIG PICTURE?

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Why does stereochemistry matter?

(R)-limonene (S)-limonene
Orange smell Lemon smell

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Thalidomide – an example of enantiomers having different properties

o Thalidomide was released in 1956 as a mild sedative used to treat
nausea in pregnant women. (Withdrawn from the market in 1961
once it was discovered thalidomide was a human teratogen.)

o As little as one dose could cause a significant birth defect
administered in the 1st trimester.

o Between 10,000‐20,000 infants were born with birth defects to
women who ingested thalidomide during pregnancy.

o In 1998, it was re‐released for leprosy
selling over $300M in sales.

o In Sept 2010, the FDA awarded the 1st
Kelsey award after the woman (Dr.
Frances Oldham Kelsey) who refused the
application for thalidomide into the US
due to need for more testing.

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®
Aspartame is a sweetening agent (Equal) that is more than a 180 times sweeter
than sucrose. Only the R‐enantiomer is desired as the S‐enantiomer does not have
the correct shape to fit the binding site of the 'sweetness' receptors on the tongue.
Neotame (NutraSweet) is between 7,000‐13,000 times sweeter than sucrose.
O NH2 H O
N
HO O
O

Aspartame Neotame

Ibuprofen
o R – enantiomer is relatively “inactive” in the body
o S – enantiomer is 160 times more active as a pain killer!

Naproxen Sodium

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1. Chiral & Achiral Compounds
Chirality is encountered in a host of everyday examples where
asymmetry exists:

Chiral =
A simplified rule applies to tetrahedrally‐bonded carbons, where all four
substituents are different, the carbon is a called stereocenter = chiral
center.
o If there are two equivalent groups on the same carbon, that carbon
CANNOT be a stereocenter.

Achiral =
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How do you identify a chiral compound?
OH

HO HO

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Q: Identify all the stereocenters in the following molecules.

TAXOL is a potent anticancer natural product (with activity against a number of
leukemias and solid tumors in the breast, ovary, brain, and lung in humans) was
isolated from the bark of the pacific yew in 1971.

Rifampin is a bactericidal antibiotic drug isolated from a sample of soil coming
from a pine wood on the French Riviera. It is used primarily for treatment for
treatment of tuberculosis and inactive meningitis.
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Let’s practice drawing mirror images and testing for superimposability

Cl

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2. Assigning R & S Stereocenters
A. Assign priority to the four atoms attached to the stereocenters.
a. Each atom is assigned a priority based on atomic number. Heavier isotopes
get higher priority.

b. If priority cannot be assigned based solely on atomic number, then look at
the next atom attached. Priority is assigned by the first point of difference.

c. Atoms participating in multiple bonds are considered to be bonded to the
equivalent number of similar atoms by a single bond.

B. Orient the molecule in space so that the lowest priority is directed away
from you.

C. “Read” the groups projected toward you in order
from highest to lowest.
 Groups in a clockwise fashion → R
(R stands for Latin, rectus = correct)
 Groups in a counterclockwise fashion → S
(S stands for Latin sinister = left)
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Practice assigning R or S configurations:

O O
OH OH
OH OH

Cl
O

H2N

OH O

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Practice assigning R or S configurations:
What if the 4th priority is IN the plane of the paper? Then what do you
do?

Naming compounds with stereochemistry:

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Work with your neighbor(s) to answer these old exam problems:

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3. Diastereomers ‐‐ Molecules with TWO or MORE stereocenters
“How many different configurations can one obtain with more than one
chiral center in a molecule?”

o The possible number of stereoisomers for any molecule is .

Chymotrypsin – digestive enzyme found in intestines and secreted by
the pancreas of mammals that catalyze the hydrolysis of proteins during
digestion.

o It has 251 stereocenters, with 2251 possible stereoisomers! But only
one is synthesized and utilized in mammals!

Draw all possible stereoisomers for the following OH
compound:
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Diastereomers

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Fischer Projections
Fischer projections are used usually when molecules have more than one
chiral center in the backbone. They impart three dimensional
information in a two dimensional method.

CHO CHO CHO CHO
H OH HO H H OH HO H
H OH HO H HO H H OH
CH2OH CH2OH CH2OH CH2OH
A B C D

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Assign an R or S configuration to each stereocenter and determine the
relationships between them.

How many stereoisomers do you expect for the following molecule?
How many enantiomers and how many diastereomers?

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What if a molecule has a plane of symmetry in one stereoisomer?

mirror
Meso Compounds = plane

HO OH

Assign an R or S configuration to each stereocenter and determine the
relationships between them.

For example:

CH 3 CH 3 CH 3 CH 3
H Br H Br Br H Br H
Br H H Br H Br Br H
CH 3 CH 3 CH 3 CH 3
1 2 3 4

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How many stereoisomers exist for the following molecules?

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Draw an enantiomers or diastereomer for the following compounds:

Cl

Br
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4. Properties of Stereoisomers & Optical Activity

o Enantiomers have identical physical properties, i.e. the same melting
point, boiling point, and solubility in standard solvents.
o “Optical activity” =

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Polarimeter:

o Optical activity is based on temperature. For example, the compound
below is levorotatory (‐) at 20°C, while at 100°C, it is dextrorotatory (+).

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When chemists run a reaction, do they always end up preparing a
mixture that is 50:50 mixture of each enantiomer?

Enantiomeric excess (ee) is a way to describe the product composition of
a mixture of enantiomers:

For a mixture of 70% (R) and 30% (S), what is the % ee?

If the mixture has an optical rotation of +4.6, use the formula to calculate
the % ee and the ratio of R/S.

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Separating enantiomers is difficult but can be done physically:

Chiral resolving agents:
• The differing physical properties of diastereomers allow them to be
more easily separated.

• Chiral chromatography is often used to separate compounds.

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C 341 F 2011 Chapter 5 Stereochemistry

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Chapter 5: Stereochemistry & Chirality

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