Chapter 6 - Stereochemisty

Why You Care

Frances Oldham Kelsey
1914-2015

Thalidomide

Pioneering Work
Tartaric acid salts

Louis Pasteur
1822-1895
Concept of isomerism

Carvone - Different Smells

spearmint

Caraway seed

Carvone - Different Smells

Isomers
Compounds that have the
same molecular formula but
different structures.

Constitutional Isomers

Constitutional isomers differ in the way the atoms are connected.

CisTrans Isomers in Rings

Cistrans isomers result from restricted rotation.
Cyclic structures restrict rotation.

Cis: The substituents are on the same side of the ring.

Trans: The substituents are on opposite sides of the ring.

CisTrans Isomers in Alkenes

Double bonds restrict rotation.

Cis: The hydrogens are on the same side of the double bond.
Trans: The hydrogens are on opposite sides of the double bond.

Stereochemistry, Odd Terminology but

Easy Concepts
Chiral, chirality, chiral center, achiral
Plane of symmetry
Asymmetric center
Enantiomer, diastereomer, meso compound
Absolute configuration
Fischer projections
Optical activity, plane polarized light
Racemic

Stereoisomers: Chiral and Achiral Objects

Chiral objects

Achiral objects

Chiral Molecules
A chiral center is an atom that is attached to four different groups.

Finding a Chiral Center

4-octanol
Look for a carbon bound to 4 different groups

Enantiomers

Enantiomers are different compounds but can be difficult to separate.

Enantiomers have the same physical and chemical properties.

Enantiomers

Plane-Polarized Light

A Chiral Compound is Optically Active

A chiral compound rotates

the plane of polarization of plane-polarized light.
If it rotates the plane clockwise = (+)
If it rotates the place counterclockwise = ()

Chiral and Achiral Molecules

Chiral compounds have nonsuperimposable mirror images.

Achiral compounds have superimposable mirror images
(there is a plane of symmetry).

Chiral and Achiral Molecules

achiral

achiral

chiral

Tetrahedral carbon with 4 different groups is just a

shortcut to thinking about symmetry.
Chiral compounds lack a plane of symmetry
Achiral compounds possess a plane of
symmetry

How to Draw Enantiomers

Wedge and Dash

Fischer projections

Fischer projections are just another way of showing a tetrahedral center

Naming Enantiomers

Assign relative priorities to the four groups.

1 = highest priority; 4 = lowest priority

Naming Enantiomers

Prioritize Groups
1 = highest priority
4 = lowest priority

Identify chiral carbon, assign priorities 1 and 4 first. Evaluate connections for
assigning priorities 2 and 3.

Naming Enantiomers

clockwise = R
and
counterclockwise = S

Naming Enantiomers
draw an arrow from 1 to 2 to 3

if the lowest priority group is on a hatched wedge, then

clockwise = R
and
counterclockwise = S

Naming Enantiomers

(S)

(R)

Swapping two groups (but only two groups) will give the
opposite enatiomer.
Sometimes it is easier to draw the R enantiomer and
convert to S.

R and S Versus (+) and ()

Some R enantiomers are (+) and some are ().
Some S enantiomers are (+) and some are ().

Compounds with Two Asymmetric Centers

maximum # of stereoisomers = 2n
(n = # of asymmetric centers)

1 and 2 are enantiomers.

3 and 4 are enantiomers.

Diastereomers

1 and 2 are enantiomers.

3 and 4 are enantiomers.

Diastereomers are stereoisomers that are not enantiomers.

1 and 3 are diastereomers.

2 and 3 are diastereomers.

1 and 4 are diastereomers.

2 and 4 are diastereomers.

Diastereomers have different physical and chemical properties.

Chirality in Rings

Two Asymmetric Centers,

Four Stereoisomers

The cis stereoisomers are a pair of enantiomers.

The trans stereoisomers are a pair of enantiomers.

Identifying an Asymmetric Center

An asymmetric center is attached to four different groups.

two asymmetric centers, four stereoisomers

No Asymmetric Centers

There are only two stereoisomers: cis and trans.

Two Asymmetric Centers: Three Stereoisomers

(a meso compound and a pair of enantiomers for
symmetrically substituted compounds)

A Meso Compound Has a

Superimposable Mirror Image

Meso compounds are optically inactive even though they have asymmetric centers.

A Meso Compound Has a

Plane of Symmetry

A Meso Compound

A compound with two asymmetric centers that have the same four groups
bonded to each asymmetric center will have three stereoisomers:
a meso compound and a pair of enantiomers.

Naming Stereoisomers

Naming Stereoisomers

Physical Properties of Stereoisomers

Stereochemistry Presents Challenges to Synthetic Chemistry

In the 90s, over 30 teams worked to achieve a total synthesis

C
D

Paclitaxel was harvested from

the pacific yew, a species that
is near threatened

The pacific yew

Stereochemistry Presents Challenges to Synthetic Chemistry

In the 90s, over 30 teams worked to achieve a total synthesis

C
D

Annual sales reached US$1.6

billion in 2000; Paclitaxel is now
available in generic form.

K. C. Nicolaou

R. H. Holton

Contrave weight-loss formulation FDA approved 9/10/14

Bupropion Wellbutrin
Antidepressant/smoking cessation

Naltrexone an
opioid antagonist:
binds opioid receptor
with higher affinity
than the agonist
without activating the
receptor

Morphine an opioid
agonist: binds opioid
receptor with
activation

Controlling Stereochemistry is Critical in Drug Manufacture.

Top 5 Drugs in 2013