Chapter 9: Stereochemistry

Two forms of Thalidomide

-One is a sedative used in 1960’s
-One caused birth defects

O O
H H
N N

O O
N N
O O O O

O
H
N

O
N
O O
Chapter 9: Stereochemistry
Stereoisomers of Limonene: Lemons vs Oranges

S-(-) Limonene R-(+) Limonene

(lemons) (oranges)
 Stereochemistry Vocabulary

Enantiomers = non-
superimposable mirror
images (stereoisomers)

Chiral molecules = molecules

th t are nott superimposable
that i bl
with mirror image
(handedness)

Achiral molecules = molecules

that are superimposable
with mirror image (have
some symmetry element)
a a

Chiral Centers = tetrahedral C * *

d d
sp3 bonded to four different c b b c
groups (stereocenter)

Configurational Isomers = How do we differentiate

stereoisomers that differ in
their configuration of a
chiral center
these two enantiomers?
- By name?
- Chemically? Enantiomers
have same physical properties
(mp, bp, etc)
Configurations of Chiral Centers
IUPAC sequence rules for R and S Configuration

1 Assign
1. A i priority
i it letters
l tt tot the
th four
f groups (A-D)
(A D) using
i
same rules we used for E & Z alkenes (based on atomic
number of atoms connected to chiral center, if same find
first point of difference; multiple bonds count multiple
times).
times)

2. View molecule so group D points away from you.

3. Trace from group A to B to C:

Clockwise = R
Counterclockwise = S
Cl Cl

(2R) – 2-chloropentane (2S) – 2-chloropentane

a

R * • easy when group D already

d points away from you
c b

a • note the wedge and dash are

S * always next to each other
d
b c
 Configurations of Chiral Centers
What do you do when group D does not point away from you?

1. View from a different perspective:

view
(behind board)
a view
i a

b c
d c b d
a a
R c b
R c b

2. Shortcut
h – if you switch
i h two groups (on
( paper)) you invert
i
stereocenter (go from R to S and vice versa)

a a

b d
d c b c
S
So original must be R!

(Note that a second switch would give you the R enantiomer again)
Configurations of Chiral Centers

CH3 CH3
(R)
Br H (original = S)
HO H HO Br

O O
CH3 OH (S)
OH CH3 (original = R)

O
H2N
OH
(R)-Phenylalanine
(-amino acid)
Optical Activity: Rotation of Plane
Polarized Light
How do you physically tell the two enantiomers apart?

• Clockwise
Cl k i = dextrorotatory
d t t t (+)
• Counterclockwise = levorotatory (-)
• Enantiomers rotate equally in opposite direction
 = observed rotation (o)
Specific Rotation []D =  c = concentration (g/mL)
cxl l = path length (dm)

Br Br

(2R) – 2-bromobutane (2S) – 2-bromobutane

23 1o
[]D = - 23.1 23 1o
[]D = + 23.1

Note: No correlation between R & S with (+) and (-)

Optical Activity and Enantiomeric
Excess (% ee)
Can we determine the amounts of each enantiomer present?

• 11:11 ((equal)
l) mixtures
i t off enantiomers
ti
- optically inactive (does not rotate plane polarized light)
- referred to as a racemic mixture (racemate)
(100% pure referred to as optically pure)

• Unequal mixtures: enantiomeric excess (% ee)

[] observed
% ee = x 100%
[] pure enantiomer

%R - %S
= x 100%
%R + %S

Ex: Mixture of R & S 2-bromobutane [] = - 11.55o

11 55
-11.55
% ee = x 100% = 50%
23.10

50% excess (-) R enantiomer Total 75% R

50% racemic 25% S
Compounds with Multiple Chiral Centers
Now how many stereoisomers are possible?

• For n chiral centers, 2n possible stereoisomers

Br
22 = 4 stereoisomers
* *
Cl (2R, 3R) (2S, 3S)
2-bromo-3-chlorobutane (2R, 3S) (2S, 3R)

Br Br Br

Cl Cl Cl

(2R, 3R) (2S, 3S) (2S, 3S)

• For enantiomers, configuration at every chiral center inverted

Br Br

Cl Cl

(2S 3R)
(2S, (2R 3S)
(2R,

• How are these last two related to the first two?

Diastereomers
A new type of stereoisomers

Definition = stereoisomers NOT related as an object and its

non-superimposable mirror image (not enantiomers)
1. cis / trans diastereomers
Cl Cl
Cl

Cl

2. configurational (R and S) diastereomers

Br Br Br Cl Br

Cl Cl Cl Br Cl

Br Br

Cl Cl

(2R, 3R) (2S, 3R)

• Do not have opposite configuration at every chiral center

• Unlike enantiomers, diastereomers have completely different
physical properties (i.e. mp, bp, [], etc)
 Resolution
If enantiomers have the same properties, can you separate them?

1. Convert enantiomers into diastereomers

2. Separate diastereomers
3. Convert diastereomers back into pure enantiomers

1. 2. Pure 1R, 2S Pure 1R

1R 1R, 2S
3.
1S 1S, 2S
Pure 1S, 2S Pure 1S
 Meso Compounds
Molecules with chiral centers, but are achiral due to symmetry

R R S
* *
* *
S R S

Plane of Symmetry Chiral

(Achiral) (no symmetry plane)

Br Br
R S S S
R S
Br Br
Br Br
Br
Enantiomers

Br
Br Br
S R
R S S R
Br Br
Br Br

Meso (identical!)
2 identical chiral centers with opposite configuration
Fischer Projections
Alternative way to draw chiral centers

a a a
d d c d c
b
c b b
view
i horizontal = coming out of page
vertical = going into page
To assign R/S configuration, place group “D” on top and trace
from A to B to C

- Only certain ‘rotations’ allowed (180o)

-- Easier to use method that switches groups

a d d
d c a c a b
b b c
(S) (R)
(so original R)
 Fischer Projections:
j Multiple Chiral
Centers

d
H c a H
R
H3C * OH H3 C OH
b bottom d
H3C * H b H3 C H
c b R
OH c d OH
a
a

What does the enantiomer look like?

H H
H 3C * OH HO *
CH3 Confirm that this is the
* CH
H 3C * H H 3 S, S stereoisomer
OH OH

Any other stereoisomers possible?

centers 22 = 4 possible (maximum)
Two chiral centers,

H MESO! Only other stereoisomer possible

H3 C OH
(total of three stereoisomers)
H3 C OH
H
(R S and
(R,S dS S,R
R are id
identical)
ti l)
Stereochemistry of Reactions
Part I: Reactions that make a chiral center

Achiral intermediates give achiral (racemic) products

- Carbocation intermediates
- Nuc can attack from ‘top’ or ‘bottom’

HBr 50% (R)

*
50% (S)
Br Racemic Mixture

• The two transition states are enantiomeric, thus have equal

energy so products form in equal amounts

• Achiral reagents lead to optically inactive products

Stereochemistry of Reactions
Part II: Chiral reactants that make new chiral centers

Chiral intermediates give chiral products

- form unequal mixtures of diastereomers
- transition states are now diastereotopic
(
(unequall energy so form
f in
i unequall amounts)
t)

• Optically active reactants leads to optically active products

Stereochemistry of Reactions
Examples

B 2
Br Br Br
+
Br Br

Equal amounts (racemate)

(optically inactive)

Br2 Br Br
+
Br Br

Unequal
q amounts (diastereomers)
( )
(optically active)

1. OsO4 OH OH
2. NaHSO3
+
OH OH

Meso – same product!

(optically inactive)
 Stereochemistry of Reactions
Stereoselectivity – predominant formation of one of several
possible stereoisomeric products

Ci and
Cis d ttrans 22-butene
b t produce
d different
diff t stereoisomeric
t i i products
d t
Chirality at Atoms Other than Carbon
Requires tetrahedral atom with four unique groups

Chirality without chiral centers:

a c c a
C C C C C C
b d d b
Prochirality
If an achiral molecule can be turned into a chiral molecule
in a single chemical step it is “Prochiral”

sp2 Prochiral Centers: Re and Si Faces

O H OH Produce a Racemic
Mixture
Prochiral Chiral

Note Re does not necessarily give (R) product!

sp3 Prochiral Centers: Pro-R and Pro-S