Stereochemistry

Internal Plane of Symmetry

• Cis-1,2-dichlorocyclopentane contains two asymmetric carbons but is
achiral.
• contains an internal mirror plane of symmetry
σ

H H

Cl Cl

• Any molecule that has an internal mirror plane of symmetry is achiral

even if it contains asymmetric carbon atoms.
Internal Plane of Symmetry
• Cis-1,2-dichlorocyclopentane is a meso compound:
• an achiral compound that contains chiral centers
• often contains an internal mirror plane of symmetry
 Labeling Stereogenic Centers with R or S
• Since enantiomers are two different compounds, they need to be
distinguished by name. This is done by adding 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 stereogenic center, in order of decreasing
atomic number. The atom of highest atomic number gets the highest
priority (1).
 Reactions involving stereoisomers:
(a) the conversion of an achiral molecule into a chiral
molecule, with the generation of a chiral center.
n-butane + Cl2, hv  sec-butyl chloride + etc.
achiral chiral
*
CH3CH2CHClCH3
CH3 CH3
H Cl Cl H
C2H5 C2H5

(S)-(+)-sec-butyl chloride (R)-(-)-sec-butyl chloride

product is optically inactive  racemic modification

The synthesis of chiral compounds from achiral reactants always yields the racemic modification.
(b) reaction of a chiral molecule where bonds to the chiral
center are not broken.

* *
CH3CH2CHClCH3 + Cl2, hv  CH3CH2CHClCH2Cl
+ etc.
A reaction that does not involve the breaking of a bond to a
chiral center proceeds with retention of configuration about
the chiral center.
Can be used to “relate” configurations. If a compound can be
synthesized by such a reaction from a compound of known
configuration, then the configuration is known in the product.
 * *
CH3CH2CHCH2OH + HCl CH3CH2CHCH2Cl + H2O
CH3 CH3

It is known from X-ray crystallography that (-)-2-methyl-1-butanol is the (S)-isomer.

When pure (-)-2-methyl-1-butanol is reacted with HCl, the product is dextrorotatory.
Since no bonds to the chiral center were broken in the reaction, the (+)-1-chloro-2-methyl
butane is now known to be the (S)-isomer.

CH3 CH3
H CH2OH + HCl H CH2-Cl
C2H5 C2H5
(C) reactions of chiral compounds with optically active
reagents.
Enantiomers have the same physical properties and cannot
be separated by normal separation techniques like
distillation, etc.
Enantiomers differ in reaction with optically active reagents.
Enantiomeric acids or bases can be reacted with an optically
active base or acid to form salts that are diastereomers.
Since diastereomers have different physical properties
they can be separated by physical methods. The salts
can then be converted back into the free acids or bases.
Resolution – the separation of enantiomers.
 (d) a reaction of a chiral compound in which a bond to a chiral
center is broken…
In a reaction of a chiral compound in which a bond to a chiral
center is broken, the stereochemistry depends on the
mechanism of the reaction.

CH3 CH3
CH3CH2CHCH2-Cl + Cl2, hv CH3CH2CCH2-Cl + isomers
* *Cl

(S)-(+)-1-chloro-2-methylbutane racemic-1,2-dichloro-2-methylbutane
optically inactive mixture
Cl-Cl 2 Cl.

CH3 CH3
C2H5 CH2-Cl + Cl. . + HCl
C2H5 CH2-Cl
H

Cl-Cl

CH3
sp2 hybridized flat free radical
C2H5 CH2-Cl

CH3 Cl
C2H5 CH2-Cl + C2H5 CH2-Cl
Cl CH3
 CH2Cl
H3C H Cl2, hv
C5H10Cl2 + HCl
CH2
CH3

(S)-(-)-1-chloro-2-methylbutane six fractions:

four optically active
two optically inactive
 CH2Cl CHCl2
H3C H Cl2, hv H3C H
CH2 CH2
CH3 CH3
A
No bonds to the chiral center
are broken, configuration is
retained. Product is optically
active
 CH2Cl CH2Cl CH2Cl
H3C H Cl2, hv H3C Cl Cl CH3
+
CH2 CH2 CH2
CH3 CH3 CH3
B
A bond is broken to the chiral center.
Stereochemistry depends on the
mechanism. Here, the intermediate
free radical is flat and a racemic
modification is formed. This fraction
is optically inactive.
 CH2Cl CH2Cl
H3C H Cl2, hv ClH2C C H
CH2 CH2
CH3 CH3
C
The product no longer has
a chiral center. It is achiral
and optically inactive.
 CH2Cl CH2Cl CH2Cl
H3C H Cl2, hv H3C H H3C H
+
CH2 H Cl Cl H
CH3 CH3 CH3

D E

No bond is broken to the chiral center

and a new chiral center is formed. The
products are diastereomers and each
fraction is optically active.
 CH2Cl CH2Cl
H3C H Cl2, hv H3C H
CH2 CH2
CH3 CH2Cl
F
No bonds to the chiral center
are broken, configuration is
retained. Product is optically
active
Determining the maximum number of Stereoisomers
 Multiple Stereocenters

1 stereocenter: 2 stereoisomers
Me H H Me

(S)-3-methylhexane (R)-3-methylhexane

Cl

2 stereocenter: 4 stereoisomers
Me

Cl H Cl H Cl H Cl H

Me H Me H Me H Me H

3(S), 4(S)-3-chloro-4-methylhexane 3(R), 4(S)-3-chloro-4-methylhexane 3(S), 4(R)-3-chloro-4-methylhexane 3(R), 4(R)-3-chloro-4-methylhexane

 Multiple Stereocenters
enantiomers

Cl H Cl H

3(S), 4(S)-3-chloro-4-methylhexane 3(R), 4(R)-3-chloro-4-methylhexane

Me H Me H

What about these relationships?

Cl H Cl H

3(R), 4(S)-3-chloro-4-methylhexane 3(S), 4(R)-3-chloro-4-methylhexane

Me H Me H

enantiomers

Stereoisomers that are not enantiomers (non-superimposable mirror images) are called diastereomers
 Multiple Stereocenters

(R), (R), (R) (S), (S), (S)

Br
∗ (S), (R), (R) (R), (S), (S)
∗ ∗

(R), (S), (R) (S), (R), (S)

CH3 Cl
(R), (R), (S) (S), (S), (R)
3 stereocenters
8 stereoisomers

For any compound, the maximum number of stereoisomers is 2n where n is the number of stereocenters.
 Multiple Stereocenters

Me

How many stereoisomers for 3,4-dimethylhexane?

Me

H Me Me H Me H H Me

Me H H Me Me H H Me
??-3,4-dimethylhexane ??-3,4-dimethylhexane (3S,4S)-3,4-dimethylhexane (3R,4R)-3,4-dimethylhexane

Me Me H H Me H H Me
H H Me Me H Me Me H

The same compound! enantiomers

(superimposable)
 Meso Compounds
Me

3,4-dimethylhexane has 3 stereoisomers!

Me

H Me Me H Me H H Me

Me H H Me Me H H Me
meso-3,4-dimethylhexane meso-3,4-dimethylhexane (3S,4S)-3,4-dimethylhexane (3R,4R)-3,4-dimethylhexane

Me Me H H Me H H Me
H H Me Me H Me Me H

A Meso Compound (achiral) Enantiomers (chiral)

 Meso Compounds
The best way to identify a meso compound is to prove that it is
superimposable with its mirror image. However, a quick test is to see if it
contains a plane of symmetry:

plane of symmetry

Me Me Me H H Me
H H H Me Me H

meso-3,4-dimethylhexane (3S,4S)-3,4-dimethylhexane (3R,4R)-3,4-dimethylhexane

Compounds containing a plane No plane of symmetry

of symmetry are achiral!
 Racemic Mixtures
H H
H
HBr H3C
H3C
CH3 CH3 But do we get (R) or (S)?
addition reaction Br
H H

(E)-2-butene 2-bromobutane
achiral chiral

We get both!

CH3 CH3
H3C H3C
H Br Br H

50% (S)-2-bromobutane 50% (R)-2-bromobutane

A 50:50 mixture of 2 enantiomers is called a racemic mixture or a racemate.

 Resolution of Enantiomers
this nitrogen lone
pair is basic
Me
(R)-α-methylbenzylamine

this hydrogen H2N O Me

O is acidic
Me
(S)-2-chloroproprionic acid Me O H3N
OH
Cl
Cl
The R,S-diastereomer of the salt
this nitrogen lone
pair is basic
Me
(R)-α-methylbenzylamine
this hydrogen O Me
is acidic H2N
O Me
O H3N
(R)-2-chloroproprionic acid Me
OH Cl

Cl
The R,R-diastereomer of the salt
separate

O O Me
O Me
acidify
Me Me
Me
OH O H3N
O H3N
Cl Cl
Cl
(R)-2-chloroproprionic acid
O
acidify
Me
OH

Cl (S)-2-chloroproprionic acid
 Fischer Projections - representation of a three-dimensional
molecule as a flat structure. A tetrahedral carbon is represented
by two crossed lines:

horizontal line is coming vertical line is going back

out of the plane of the behind the plane of the
page (toward you) paper (away from you)
carbon
substituent

CO2H CO2H CO2H

H OH H OH
(R)-lactic acid H3C
OH
CH3
H CH3

CO2H CO2H CO2H

(S)-lactic acid H HO H HO H
H3C
OH CH3 CH3
Manipulation of Fischer Projections
1. Fischer projections can be rotated by 180° only!

CO2H CH3 CO2H CH3

180 ° H OH HO H 180 ° HO H H OH
CH3 CO2H CH3 CO2H

(R) (R) (S) (S)

a 90° rotation inverts the stereochemistry and is illegal!
90 ° CO2H OH
H OH ° HO2C CH3
CH3 H

(R) (S)

2. If one group of a Fischer projection is held steady, the other

three groups can be rotated clockwise or counterclockwise.
hold CO2H H
CO2H CO2H
steady HO H HO2C OH
H OH HO CH3 hold CH3 CH3
CH3 H steady
(S) (S)
(R) (R)
Assigning R and S Configuration to Fischer Projections
1. Assign priorities to the four substitutents according to the
Cahn-Ingold-Prelog rules
2. Perform the two allowed manipulations of the Fischer
projection to place the lowest priority group at the top
(or bottom).
3. If the priority of the groups 1→2→3 are clockwise then assign
the center as R, if 1→2→3 are counterclockwise then assign
the center as S.
2
place at
CO2H the top 4
H
1 H2N H 4 2 HO2C NH2 1
hold steady CH3 CH3
rotate other 3 3
three groups
counterclockwise
1-2-3 counterclockwise = S

2
4 2
CO2H
H CO2H
4 H 1 2
NH2 1 H2N
H2N CO2H CH3
CH3 1 3
CH3 H
3 4
3

1-2-3 clockwise = R