Stereochemistry

Stereochemistry refers to the 3-dimensional

properties and reactions of molecules. It has its
own language and terms that need to be learned in
order to fully communicate and understand the
concepts.
 Founding Fathers of Stereochemistry
Biot
• Biot: The solutions of many
naturally occurring compounds
rotate the plane of polarization of
polarized light (1815-1817) Pasteur

• Pasteur recognized in 1850 that

this optical activity was caused by
an asymmetric arrangement of
atoms in a molecule
• van’t Hoff and Le Bel described
in 1874 how the atoms of a Van’t Hoff
molecule are actually arranged in
space
 Definitions
• Stereoisomers – compounds with the same
connectivity, different arrangement in space
• Enantiomers – stereoisomers that are non-
superimposible mirror images; only properties
that differ are direction (+ or -) of optical
rotation
• Diastereomers – stereoisomers that are not
mirror images; different compounds with
different physical properties
 More Definitions
• Asymmetric center – sp3 carbon with 4
different groups attached
• Optical activity – the ability to rotate the plane of
plane –polarized light
• Chiral compound – a compound that is
optically active (achiral compound will not
rotate light)
• Polarimeter – device that measures the optical
rotation of the chiral compound
Plane-Polarized Light
Plane-Polarized Light through
an Achiral Compound
Plane-Polarized Light through
a Chiral Compound
Polarimeter Measures
Optical Rotation
 Specific Rotation, [α]

[α] = α / cl
a = observed rotation
c = concentration in g/mL
l = length of tube in dm

Dextrorotary designated as d or (+), clockwise

rotation
Levorotary designated as l or (-), counter-
clockwise rotation
 Specific Rotations of some
Common Organic Compounds
Compound [a] # * centers
Penicillin V +233.0 3
Sucrose +66.5 10
Camphor +44.3 2
MSG +25.5 1
Cholesterol -31.3 8
Morphine -132.0 5
 Chirality Center
Carbon has four different groups attached
A molecule with a single stereogenic center
must be chiral.

But, a molecule with two or more

stereogenic centers may be chiral
or it may not
 Molecular Asymmetry

• Chiral axis
• Chiral plane
• Chiral centre
 Symmetry tests for achiral structures

Any molecule with a plane of symmetry

or a center of symmetry must be achiral.
Rotational Axis
 Chiral Axisa b
a b
C
C
n(H2C) (CH2)n
C C

C C
a b a b

Allene Alkylidenecycloalkane
Reflection Plane
 Plane of symmetry

A plane of symmetry bisects a molecule into two

mirror image halves. Chlorodifluoromethane
has a plane of symmetry.
 Plane of symmetry

A plane of symmetry bisects a molecule into two

mirror image halves. Chlorodifluoromethane
has a plane of symmetry.
Center of symmetry

A point in the center of the

molecule is a center of
symmetry if a line drawn
from it to some element,
when extended an equal
distance in the opposite
direction, encounters an
identical element.
 Chiral Centre
CH3

CH3

Br Br CN
CN
H

H
 Enantiomers
nonsuperimposible mirror images
mirror
plane
OH OH

H CH3 CH3 H
HO2C CO2H

(S)(+) lactic acid (R)(-) lactic acid

from muscle tissue
o
from milko
[a] = +13.5 [a] = -13.5
 Enantiomeric Excess
(Optical Purity)
observed rotation
rotation of pure enantiomer x 100 = enantiomeric excess (e.e.)
o
observed rotation = +109
109.0
e.e. = 123.0 x 100

= 88.6% e.e.
H H
88.6% (+)
(S)-(-) Limonene (R)(+) Limonene 11.4% racemic
o o
[a=  [a] = +123.0 actually 94.3% (+)
from lemons from oranges
 Biological Activity

(R)(+) Thalidomide (S)(-) Thalidomide

O O H O O H
H N N
H
N O N O

O O
a sedative and hypnotic a teratogen
SSRI Efficacy depends on
Stereochemistry
NC
O
* N(CH3)2

(+/-) Celexa
(-) Lexapro

F
 Absolute Configuration
Use Cahn, Ingold, Prelog priorities
Place the lowest priority group back
(focus down C - 4 bond)
draw arrow from 1-2-3
1 1
clockwise counterclockwise
4 2 2 4
3 3
(R) (S)
Assign Priority to each Group
on Asymmetric Center

I I 1
rotate
Cl F 4 H Cl 2
H F3
focus down C-4 bond
 Lactic Acid
1 1
OH OH
4 4
H CH3 CH3 H
HO2C CO2H
3 3 2
2
(S) (R)
C.I.P. Priorities

Low High
CH2CH2CH3 CH(CH3)2
O
CH2CH2OH CH2CH

CH2CH2CH3 CH=CH2

CO2H CH2Cl

CH2CH2Br CH(CH3)2
 Fischer Projections

OH OH OH
H CO2H H CO2H
H CH3
HO2C CH3 CH3

Horizontal bonds approach you (wedge bonds)

Vertical bonds move away (dashed bonds)
 Assigning Absolute
Configuration to Fischer
Projections

OH OH OH
H CO2H H CO2H
H CH3
HO2C CH3 CH3
rotate
(S) (S) (S)
 Rotation of the Projection 90o
Reverses Absolute Configuration

OH o H CH3 o
90 o
90 CO2H
90
H CO2H CH3 OH HO2C H HO CH3
CH3 CO2H OH H
(S) (R) (S) (R)
 Diastereomers
Stereoisomers That Are Not Mirror Images

H OH H OH
3 3
2 2
CO2H CO2H
H Br Br H
(2S,3S) (2S,3R)
same stereochemistry at C 2 (S)
opposite stereochemistry at C 3
Fischer Projections with 2
Chiral Centers
CO2H CO2H
2 2
H OH H OH

3 3
Br H H Br

CH3 CH3
(2S,3S) (2S,3R)
2 Chiral Centers
4 Stereoisomers
Identical, Enantiomers or
Diastereomers?
H CH2CH3
a) Br CH3 & H CH3

CH2CH3 Br

CH3
HO H
b) CH3 H NH2
H C C &
CH3 NH2 H OH

CH3
 Tartaric Acids
R,R S,S
CO2H CO2H

H OH HO H

HO H H OH

CO2H CO2H
R,S S,R
CO2H CO2H

H OH HO H

H OH HO H

CO2H CO2H
 Racemic Mixture
R,R S,S
CO2H CO2H

H OH HO H

HO H H OH

CO2H CO2H
Racemic Mixture (Racemate): 50/50 mixture of enantiomers

(R,R) Tartaric acid (S,S) Tartaric Acid (+/-) Tartaric acid

o
m.p. C 168-170 168-170 210-212
[a] (degrees) - 12 + 12 0
(g/mL) 1.7598 1.7598 1.7723
 Meso Compound
Internal Plane of Symmetry
Optically Inactive
R,S S,R
CO2H CO2H

H OH HO H
mirror
plane
H OH HO H

CO2H CO2H
o
rotate 180
superimposible
 2,3,4-trichlorohexane
How many stereoisomers?
Cl

* * *
Cl Cl
3 asymmetric centers
2n, n= # asymmetric centers (3)
8 stereoisomers
 n = 3; 2 n =8
CH3 CH3 CH3 CH3
S H Cl Cl H R H Cl Cl H
S H Cl Cl H R H Cl Cl H
RH Cl Cl H S Cl H H Cl
CH2CH3 CH2CH3 CH2CH3 CH2CH3

CH3 CH3 CH3 CH3

H Cl Cl H Cl H H Cl
Cl H H Cl H Cl Cl H
H Cl Cl H H Cl Cl H
CH2CH3 CH2CH3 CH2CH3 CH2CH3
A Carbohydrate
CHO
H OH R

HO H S

H OH R
H OH R
CH2OH
(+) D-Glucose
Internal Planes of Symmetry
Both are Meso
CH3 CH3 CH3 CH3

CH3 CH3 CH3 CH3

Asymmetric Centers on Rings

Br Br
Br Br
Br Br

A B
1(R),2(S) cis 1,2-dibromocyclohexane
nonsuperimposible but A flips into B Meso
Different enantiomers of a drug
can have different effects.

H2N H H NH2
amphetamine

stimulant adverse
cardiovascular
effects
 Allenes can be Chiral

H H
H H
C C C C C C
Cl Cl
CH3 CH3
 Mycomycin, an antibiotic
H
H
C C C
H C C C C
CH=CHCH=CHCH2CO2H
o
Nocardia acidophilus [a]D = -130
 Reactions that Generate
Chirality Centers
Hydrogenation, syn
CH3 CH3 H H
H2, Pt/C
CH3 CH3
CH2CH3 CH2CH3 CH2CH3 CH2CH3

CH2CH3 product is meso

H CH3
H CH3
CH2CH3
 Bromination
Trans is formed exclusively
No Meso is formed (cis)

Br2

Br Br Br Br
R R S S
racemic mixture
Bromonium Ion is Opened
Equally from Both Sides
Br 2

-
+  Br Br Br Br
Br Br R R S S
racemic mixture

Br Br

Br Br
 trans alkene + anti addition = MESO

CH2CH3 H Br 2 CH2CH3 Br
H
H
H CH2CH3 Br CH2CH3

CH2CH3 CH2CH3
H H
meso
Br Br
 cis Alkene + anti addition =
racemic mixture
Br
CH2CH3 CH2CH3
H H
a Br b
CH2CH3 Br Br CH2CH3
CH2CH3 CH2CH3 H H
Br 2
CH2CH3 CH2CH3
H H Br H H Br
a b

CH2CH3 HCH CH H CH2CH3

H 2 3 CH CH
2 3 H
R R S S
Br Br Br Br
 Brominations Often Generate
Asymmetric Centers
CH3 CH3 Br 2 CH3 CH3 CH3 CH3
H H H H
H H Br Br Br Br
S S R R
racemic mixture

CH3 CH3 Br CH3 CH3

H Br 2 H
H H H
H CH3 Br CH3 Br Br
S R
meso
Asymmetric Center is Generated
Racemic Mixture Formed
Br
H-Br H
H

a) (R) Br b) (S)
a)
H Br
H

Br b)
 Asymmetric Induction

PPh2
RuCl2
PPh2

CH3 H CH3
H2
OH OH
Ru(BINAP)Cl 2
96% e.e.

Noyori and Knowles shared Nobel Prize in Chemistry, 2001

 Preparation of (L)-Dopa
for Treatment of Parkinson’s
HO

HO NH2
C=C
H CO2H
H2
Rh(DIOP)Cl 2

CO2H
HO CH2C enz. HO CH2CH2NH2
H
NH2
HO HO
l-(-) Dopa Dopamine
cannot cross blood-brain
barrier
Relevance of Stereochemistry

EPHEDRA from Ma Huong

OH
NHCH3 d-pseudoephedrine and l-ephedrine
* * (R,S) (S,S)
CH3 useful decongenstants

2 asymmetric centers
4 stereoisomers
 One-step synthesis
Pseudophed

* NHCH3 "desoxyephedrine"
(methamphetamine)
CH3 l-(R) - Vicks
d-(S)- "Meth"
a-(p-isobutylphenyl)propionic acid

H H CH3
CH3 CO 2H HO 2C
(S)(+) ibuprofen (R)(-) ibuprofen
anti-inflammatory 80-90% metabolized to (S)(+)
Model of Thalidomide
 How Sweet it is!

OH Cl
CH2OH CH2OH
O O
CH2OH HO CH2Cl
HO O
O OH
OH
O HO O HO
CH2OH CH2Cl
HO HO
Sucrose Sucralose or Splenda

Sucralose is 600 times sweeter

and does not get metabolized.
 Sildenafil (Viagra) and
Caffeine
CH3 CH3
O N N O N

H N CH3 N N

CH3CH2O N N
O CH3

O
S
O
N

N
CH3
 Radiosensitizer of Choice Until
2004

OH
H
HOOC O O
O O O
OH H
O O
OH H H
OH

Okadaic acid
17 asymmetric centers
Questions/Remarks ?