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Stereochemistry: Chiral Molecules and Stereoisomers, Study notes of Stereochemistry

An in-depth exploration of stereochemistry, focusing on constitutional isomers and stereoisomers, with a particular emphasis on chiral molecules and their properties. It covers topics such as enantiomers, stereogenic centers, and the labeling of stereogenic centers using the Cahn-Ingold-Prelog system.

What you will learn

  • How are enantiomers labeled using the Cahn-Ingold-Prelog system?
  • How do you determine if a molecule is chiral or achiral?
  • What are enantiomers and how are they different from other stereoisomers?
  • What is the role of stereogenic centers in stereochemistry?
  • What is the difference between constitutional isomers and stereoisomers?

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Stereochemistry: Chiral Molecules
Chapter 5
Constitutional Isomers = same molecular formula, different
connectivity
Stereoisomers = same molecular formula, same connectivity
of atoms but different arrangement of atoms in space
Isomerism: Constitutional Isomers and Stereoisomers
Examples of Constitutional Isomers
formula constitutional isomers
C3H8O CH3CH2CH2OH CH3CHCH3
C4H10 CH3CH2CH2CH3 CH3CHCH3
OH
CH3
Constitutional Isomers - Review
Same molecular formula – different bond connectivities
Always different properties
Very different properties if different functional groups
Stereochemistry
Although everything has a mirror image, mirror images
may or may not be superimposable.
Some molecules are like hands. Left and right hands are
mirror images, but they are not identical, or
superimposable.
Chiral and Achiral Molecules
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Stereochemistry: Chiral Molecules

Chapter 5

Constitutional Isomers = same molecular formula, different

connectivity Stereoisomers = same molecular formula, same connectivity

of atoms but different arrangement of atoms in space

Isomerism: Constitutional Isomers and Stereoisomers

Examples of Constitutional Isomers

formula

constitutional isomers

C

H 3

O 8

CH

CH 3

CH 2

OH 2

CH

CHCH 3

3

C

H 4

10

CH

CH 3

CH 2

CH 2

3

CH

CHCH 3

3

OH CH

3

Constitutional Isomers - Review

Same molecular formula – different bond connectivitiesAlways different propertiesVery different properties if different functional groups

Stereochemistry

Although everything has a mirror image, mirror imagesmay or may not be superimposable.

Some molecules are like hands. Left and right hands aremirror images, but they are not identical, orsuperimposable.

Chiral and Achiral Molecules

Stereochemistry

•^

Other molecules are likesocks. Two socks from a pairare mirror images that aresuperimposable. A sock andits mirror image are identical.

-^

A molecule or object that issuperimposable on its mirrorimage is said to be achiral.

Chiral and Achiral Molecules

Stereochemistry

We can now consider several molecules to determinewhether or not they are chiral.

Chiral and Achiral Molecules

Mirror image = converts right hand into left

Stereochemistry

The molecule labeled A and its mirror image labeled Bare not superimposable. No matter how you rotate A andB, all the atoms never align. Thus, CHBrClF is a chiralmolecule, and A and B are different compounds.

A and B are stereoisomers—specifically, they areenantiomers. - A carbon atom with four different groups is a tetrahedralstereogenic center.

Chiral and Achiral Molecules

Stereochemistry

Larger organic molecules can have two, three or evenhundreds of stereogenic centers.

Stereogenic Centers

Stereochemistry

Stereogenic centers may also occur at carbon atomsthat are part of a ring.

To find stereogenic centers on ring carbons, alwaysdraw the rings as flat polygons, and look for tetrahedralcarbons that are bonded to four different groups.

Stereogenic Centers

Stereochemistry

In 3-methylcyclohexene, the CH

3

and H substituents that

are above and below the plane of the ring are drawn withwedges and dashes as usual.

Stereogenic Centers

Stereochemistry

Stereogenic Centers •^

Manybiologicallyactivemoleculescontainstereogeniccenters onring carbons.

Enantiomers: stereoisomers whose molecules arenonsuperposable mirror images

Diastereomers: stereoisomers whose molecules are notmirror images of each other

Î

Example: cis and trans double bond isomers Î

Example: cis and trans cycloalkane isomers

Two types of stereoisomers

Chiral molecule - has the property of handedness^ z

Not superimposable on its mirror image z

Can exist as a pair of enantiomers

Pair of enantiomers^ z

A chiral molecule and its mirror image

Achiral molecule^ z

Superimposable on its mirror image

Enantiomers and Chiral Molecules

A molecule with a single tetrahedral carbon bonded to fourdifferent groups will always be chiral

Switching two groups at the tetrahedral center leads to theenantiomeric molecule

A molecule with more than one tetrahedral carbon bonded tofour different groups is not always chiral]- LATERStereogenic Center (also called a “stereocenter”)^ Î

In general it is “an atom bearing groups of such nature that aninterchange of any two groups will produce a stereoisomer” Î

sp

3 carbon is the most common example of a tetrahedral stereogenic center. They are usually designated with an asterisk (*)

z

Example: 2-butanol

Chiral molecules and stereogenic centers

Mirror images not superimposable = enantiomers

Stereochemistry

Since enantiomers are two different compounds, theyneed to be distinguished by name. This is done byadding the prefix

R

or

S

to the IUPAC name of the

enantiomer.

Naming enantiomers with the prefixes

R

or

S

is called

the Cahn-Ingold-Prelog system.

To designate enantiomers as

R

or

S

, priorities must be

assigned to each group bonded to the stereogeniccenter, in order of decreasing atomic number. The atomof highest atomic number gets the highest priority (1).

Labeling Stereogenic Centers with

R

or

S

Stereochemistry

If two atoms on a stereogenic center are the same,assign priority based on the atomic number of the atomsbonded to these atoms. One atom of higher prioritydetermines the higher priority.

Labeling Stereogenic Centers with

R

or

S

Stereochemistry

•^

To assign a priority to an atom that is part of a multiple bond,treat a multiply bonded atom as an equivalent number ofsingly bonded atoms. For example, the C of a C=O isconsidered to be bonded to two O atoms. Labeling Stereogenic Centers with

R

or

S
•^

Other common multiple bonds are drawn below:

Stereochemistry

Labeling Stereogenic Centers with

R

or

S

Stereochemistry

Labeling Stereogenic Centers with

R

or

S

Stereochemistry

Labeling Stereogenic Centers with

R

or

S

Stereochemistry

Labeling Stereogenic Centers with

R

or

S

Stereochemistry

Labeling Stereogenic Centers with

R

or

S

Plane polarized light oscillates in a single plane

Like a rope through a picket

fence

The plane-polarized light cannot get throughTwo filters that are 90

˚^ to one another.

Schematic of a Polarimeter

Stereochemistry

With achiral compounds, the light that exits the sampletube remains unchanged. A compound that does notchange the plane of polarized light is said to be opticallyinactive.

Physical Properties of Stereoisomers

Stereochemistry

With chiral compounds, the plane of the polarized light isrotated through an angle

α

. The angle

α

is measured in

degrees (

0 ), and is called the observed rotation. A

compound that rotates polarized light is said to be opticallyactive.

Physical Properties of Stereoisomers

Stereochemistry

The rotation of polarized light can be clockwise oranticlockwise.

If the rotation is clockwise (to the right of the noonposition), the compound is called dextrorotatory. Therotation is labeled

d

or (+).

If the rotation is counterclockwise, (to the left of noon),the compound is called levorotatory. The rotation islabeled

l

or (-).

Two enantiomers rotate plane-polarized light to an equalextent but in opposite directions. Thus, if enantiomer Arotates polarized light +

0 , the same concentration of

enantiomer B rotates it –

0

No relationship exists between

R

and

S

prefixes and the

(+) and (-) designations that indicate optical rotation.

Physical Properties of Stereoisomers

Stereochemistry

An equal amount of two enantiomers is called a racemicmixture or a racemate. A racemic mixture is opticallyinactive. Because two enantiomers rotate plane-polarized light to an equal extent but in oppositedirections, the rotations cancel, and no rotation isobserved.

Physical Properties of Stereoisomers

No net optical rotation 

Often designated as (

Racemic mixture = racemate

Racemic Mixture = A 1:1 mixture of enantiomers

Equal amountsof each

Stereochemistry

Specific rotation is a standardized physical constant forthe amount that a chiral compound rotates plane-polarized light. Specific rotation is denoted by thesymbol [

α

] and defined using a specific sample tube

length (

l , in dm), concentration (

c

in g/mL), temperature

(^0) C) and wavelength (589 nm).

Physical Properties of Stereoisomers

Chiral Drugs and Pharmaceutical Companies

Typically only one enantiomer of a drug is biologically active

Ibuprofen (active)

(inactive)

(S)

(R)

HO

CH

3

H O

HO

H

CH

(^3) O

Stereochemistry

Chemical Properties of Enantiomers

Molecules with More than One Stereogenic Center

Each new stereogenic center may generate a potential pair ofstereoisomers, so the theoretical number of possible stereoisomersis 2

n

How many stereoisomers?

Relationship of 1 and 2 = enantiomersRelationship of 3 and 4 = enantiomers

(Enantiomers = same properties, cannot be separated)

Relationship of (1 and 3), (2 and 3), or (1 and 4) = diastereomers

z

Diastereomers: stereoisomers that are not mirror images ofeach other.They have

different physical properties

and can be separated

Four stereoisomers of 2,3-dibromopentane

Four stereoisomers of 2,3-dibromopentane

Let’s figure out the configurations of all 4 stereoisomers

CH

3 C

H

Br

C CH

CH 2

3

H

Br

CH

3 C

H

Br

C CH

CH 2

H^3

Br

CH

3 C

Br

H

C CH

CH 2

3

H

Br

CH

3 C

H

Br

C CH

CH 2

3

Br

H

S R Use the same rules, and assign eachstereogenic center separately

Stereochemistry

When a compound has more than one stereogeniccenter, the

R

and

S

configuration must be assigned to

each of them.

R

and

S

Assignments in Compounds with Two or

More Stereogenic Centers.

One stereoisomer of 2,3-dibromopentane

The complete name is (

S ,

R

)-2,3-dibromopentane

Sometimes molecules with 2 or more stereogenic centerswill have fewer than 2

n^

stereoisomers

Meso compounds

Because superposable on its mirror image 

Despite the presence of stereogenic centers 

Not optically active 

Has a plane of symmetry

Meso compound are achiral

Definition: a meso compound is a compound that is

achiral despite having stereogenic centers

Stereochemistry

•^

To draw the other two stereoisomers if they exist, draw mirrorimages of each compound and determine whether thecompound and its mirror image are superimposable.

Disubstituted Cycloalkanes^ •

The

cis

isomer is superimposable on its mirror image, making

the images identical. Thus, A is an achiral meso compound.

Stereochemistry

•^

The trans isomer is not superimposable on its mirror image,labeled C, making B and C different compounds. B and C areenantiomers.

Disubstituted Cycloalkanes^ •

Because one stereoisomer of 1,3-dibromocyclopentane issuperimposable on its mirror image, there are only threestereoisomers, not four.

z

1,4-dimethylcyclohexane

Î

Neither the cis not trans isomers is optically active Î

Stereoisomerism of Cyclic Compounds Each has a plane of symmetry

1,3-dimethylcyclohexane z

The trans and cis compounds each have twostereogenic centers z

The cis compound has a plane of symmetry and is

meso

z

The trans compound exists as a pair of enantiomers Ring flip of (

a)

produces another

(a),

not the mirror image (

b)

No plane of symmetry

Me Me H

H

plane

of sym

metry

Racemic Form (identical properties)

R S

reaction

R

+

Diastereomers (different properties)

R

R S

R

separate

R

R S

R

- -

R R

pure forms

R S

Separation of enantiomers = resolution

Cannot be separated directly Why not?Can be separated by a chiral reagent which creates diastereomeric relationship

is a resolving agent. It is

a single enantiomer

of a chiral compound

that can react with

both enantiomers of the racemic mixture toform a pair of diastereomers.

R

quinine

(primary alkaloid from variousspecies of

Cinchona

)

N

HO H

N

H

CH

O 3

General Approach to Resolution

Often used are organic acids or bases which are found optically pure innatureThey form acid-base salts which, as diastereomers, have differentsolubilities in water and can be separated by selective crystallizationOne can then easily regenerate starting acid or base


(+,-)-2-phenylpropanoic acid

(racemic form)

C

H 6

CCOOH 5 CH

3 H

+

(-)-alkaloid

(+)(-)-Salt(-)(-)-Salt diastereomers

(basic)

separate byfractionalcrystallization

(+)(-)-Salt

(-)(-)-Salt

organic phase

water phase


(+)-

(-)-alkaloid asammonium salt

organic phase

water phase


(-)-

(-)-alkaloid asammonium salt

H

O 3

+

C

H 6

CHCCOOH 5

3 H

H

O 3

+

C

H 6

CCOOH 5 CH

3 H

Resolution of a Carboxylic Acid