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.
Definitions
• Stereoisomers – compounds with the same
connectivity, different arrangement in space
• Enantiomers – stereoisomers that are nonsuperimposible 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 (-), counterclockwise rotation
Specific Rotations of some
Common Organic Compounds
Compound
Penicillin V
Sucrose
Camphor
MSG
Cholesterol
Morphine
[a]
+233.0
+66.5
+44.3
+25.5
-31.3
-132.0
#
*
centers
3
10
2
1
8
5
Chirality Center
Carbon has four different groups attached
Enantiomers
nonsuperimposible mirror images
mirror
plane
OH
H
HO2C
CH3
(S)(+) lact ic acid
OH
CH3
H
CO2H
(R)(-) lactic acid
from m u scl e ti
ssu e
fromo m i lk
o
[a] = +13.5
a]
[ = -13.5
Enantiomeric Excess
(Optical Purity)
observed rot at ion
x 100 =e n an ti om e ri c e xce(e.e.)
ss
rot at ion of pure enant iomer
o
observed rot at ion = +10
109.0
e.e. = 123.0 x 100
H
H
(S)-(-) Limonene
o
[a= 
from lemons
= 88.6% e .e .
88.6% (+)
(R)(+) Limonene 11.4% racemic
o
[a] = +123.0
act ually 94.3% (+)
from oranges
Biological Activity
(R)(+) Thalidomide
O O
H
N
(S)(-) Thalidomide
O O
H
N
O
O
a sedative and hypnotic
H
H
N
O
N
O
a teratogen
SSRI Efficacy depends on
Stereochemistry
NC
O
*
F
Lexapro® and
N(CH3)2 Celexa® are both
prescription
medications classified
as selective serotonin
(+/-) C e l e xa
reuptake inhibitors,
(-) Le xapro
licensed to treat
depression.
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
4
2
2
3
3
(R)
(S)
Assign Priority to each Group
on Asymmetric Center
I
Cl
H
I
rot at e
F
4
H
F3
1
Cl
2
focus down C-4 bond
Lactic Acid
1
OH
1
OH
4
H
HO2C
2
4
CH3
3
(S)
CH3
3
H
CO2H
2
(R)
C.I.P. Priorities
Low
CH2CH2CH3
High
CH(CH3)2
O
CH2CH2OH
CH
2CH
CH2CH2CH3
CH=CH2
CO2H
CH2CH2Br
CH
2Cl
CH(CH3)2
Fischer Projections
H
HO2C
OH
OH
OH
H
CH3
CO2H
CH3
H
CO2H
CH3
Horizontal bonds approach you (wedge bonds)
Vertical bonds move away (dashed bonds)
Assigning Absolute
Configuration to Fischer
Projections
H
H
HO2C
CH3
(S)
OH
OH
OH
CO2H
CH3
rotate
(S)
H
CO2H
CH3
(S)
Rotation of the Projection 90o
Reverses Absolute Configuration
o
OH
H
H
90
CO2H
CH3
(S)
CH3
CH3
o
90
OH
CO2H
(R)
HO2C
o
CO2H
90
H
HO
OH
CH3
H
(S)
(R
Exercise:
(1) Assign R/S configurations to the ff molecules:
Br
(A)
H
(B)
COOH
HO
H
(C)
COOH
NC
H
NH2
(D)
H
(2) Draw a tetrahedral representation of (S)-2hydroxypentane.
OCH3
Lexapro and Celexa are formulations of an anti-depressant drug.
Celexa was available first and is a mixture of R and S
enantiomers of citalopram. Lexapro is just the S enantiomer of
citalopram. Draw the molecular structure of each enantiomer.
Celexa was available first and is a mixture of R and S
enantiomers of citalopram. Lexapro is just the S enantiomer of
citalopram. Which one is Lexapro? Which one is Celexa?
NC
NC
(R)
F
O
(S)
N
F
O
N
Diastereomers
Stereoisomers That Are Not Mirror Images
H OH
3
2
CO2H
H OH
3
2
CO2H
Br H
H Br
(2S,3S)
(2S,3R)
same stereochemistry at C 2 (S)
opposite stereochemistry at C 3
Fischer Projections with 2
Chiral Centers
CO2H
H
Br
2
3
OH
H
CH3
(2S,3S)
CO2H
H
H
2
3
OH
Br
CH3
(2S,3R)
2 Chiral Centers
4 Stereoisomers
OH
Cl
OH
Cl
OH
Cl
OH
Cl
Identical, Enantiomers or
Diastereomers?
CH2CH3
H
a) Br
CH3
&
H
CH2CH3
b)
Br
HO
H C
CH3
CH3
C
H
CH3
NH2
CH3
&
H
NH2
H
OH
CH3
Tartaric Acids
R,R
CO2H
H
HO
OH
H
S ,S
CO2H
HO
H
H
OH
CO2H
CO2H
R,S
CO2H
S ,R
CO2H
H
OH
HO
H
H
OH
HO
H
CO2H
CO2H
Racemic Mixture
R,R
S ,S
CO2H
CO2H
H
OH
HO
H
CO2H
HO
H
H
OH
CO2H
Racemic Mixt ure (Racemat e): 50/50 mixt ure of enantiomers
o
m.p. C
(R,R) T artaric acid
168-170
[a] (degrees)
 (g/mL)
- 12
1.7598
(S,S) T artaric Acid (+/-) T art aric acid
168-170
210-212
+ 12
1.7598
0
1.7723
Meso Compound
Internal Plane of Symmetry
Optically Inactive
R,S
CO2H
mirror
plane
S ,R
CO2H
H
OH
HO
H
H
OH
HO
H
CO2H
CO2H
o
rot ate 180
superimposible
2,3,4-trichlorohexane
How many stereoisomers?
Cl
* *
*
Cl
Cl
3 asymmetric centers
2n, n= # asymmetric centers (3)
8 stereoisomers
n = 3;
CH3
n
2
=8
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
H
H
Cl
H
Cl
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH3
CH3
CH3
CH3
Cl
Cl
H
H
Cl
CH2CH3
Cl
H
Cl
H
H
H
Cl
H
Cl
Cl
H
H
H
Cl
Cl
H
Cl
CH2CH3
CH2CH3
Cl
CH2CH3
A Carbohydrate
CHO
OH
R
H
S
H
OH
R
H
OH
R
H
HO
CH2OH
(+) D-Glu cose
Internal Planes of Symmetry
Both are Me so
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
Asymmetric Centers on Rings
Br
Br
Br
Br
A
Br
Br
B
1(R),2(S )cis 1,2-dibrom ocycl oh e xan e
nonsuperimposible butA flips intoB
Me so
Which are meso compounds?
OH
Br
OH
OH
H
OH
Br
H
Reactions that Generate
Chirality Centers
Hydrogenation, syn
CH3
CH2CH3
CH3
H
H2, P t/C
CH3
CH2CH3
CH2CH3
H
CH3
CH2CH3
CH2CH3 product is meso
H
CH3
H
CH3
CH2CH3
Bromination
Trans is formed exclusively
No Meso is formed (cis)
Br2
Br
Br
R R
Br
Br
S S
racemic mixture
Bromonium Ion is Opened
Equally from Both Sides
Br2
+
Br

Br
Br
Br
R R
Br
Br
S S
racemic mixture
Br
Br
Br
Br
trans alkene + anti addition = MESO
CH2CH3
H
H
CH2CH3
Br2
CH2CH3
H
Br
CH2CH3
H
meso
Br
Br
H
CH2CH3
CH2CH3
H
Br
cis Alkene + anti addition =
racemic mixture
Br
CH2CH3
H
a
CH2CH3
H
CH2CH3
H
CH2CH3
H
Br2
Br
CH2CH3 CH2CH3
H
H
a
Br
CH2CH3
H
Br
b
H
HCH CH
2
3 CH CH
2
3
CH2CH3
H
CH2CH3
H
S S
R R
Br
CH2CH3
H
b
Br
Br
Br
Br
Br
Brominations Often Generate
Asymmetric Centers
CH3
H
CH3
Br2
CH3 CH3
CH3
H
Br
H
Br
H
S S
CH3
H
Br
H
Br
R R
race m i c m ixtu re
CH3
H
H
CH3
Br2
CH3
H
Br
Br
H
CH3
CH3
H
Br
CH3
H
Br
S R
m e so
Asymmetric Center is Generated
Racemic Mixture Formed
Br
H-Br
H
a) (R)
H
Br
a)
H
Br
b)
H
Br b) (S)
Asymmetric Induction
PPh2
RuCl2
PPh2
CH3
H
CH3
H2
OH
Ru(BINAP )Cl2
OH
96% e.e.
Noyori an d Kn owl e s sh are d Nobe l Pri z e in C h e m istry, 2001
Preparation of (L)-Dopa
for Treatment of Parkinson’s
HO
HO
NH2
C=C
H
CO2H
H2
Rh(DIOP)Cl2
CO2H
HO
CH2C
HO
l-(-) Dopa
H
NH2
enz.
HO
CH2CH2NH2
HO
Dopam i n e
cannot cross blood-brain
barrier
Relevance of Stereochemistry
EPHEDRA from Ma Huong
OH
* *
NHCH3
CH3
2 asymmet ric cent ers
4 stereoisomers
d-pseudoephedrine and l-ephedrine
(R,S)
(S,S)
useful decongenstants
One-step synthesis
Pse u doph e d
*
NHCH3
CH3
"desoxyephedrine"
(met hamphet amine)
l-(R) - Vicks
d-(S)- "Met h"
a-(p-isobutylphenyl)propionic acid
CH3
H
CO 2H
(S )(+) i bu profe n
ant i-inflammat ory
H
HO 2C
CH3
(R)(-) i bu profe n
80-90% met abolized t o (S)(+)
Model of Thalidomide
How Sweet it is!
OH
Cl
CH2OH
O
CH2OH
O
HO
OH
O
HO
S u crose
HO
CH2OH
O
CH2Cl
O
HO
OH
O
HO
CH2OH
CH2Cl
HO
S u cralose or S pl e n da
Sucralose is 600 times sweeter
and does not get metabolized.
Sildenafil (Viagra) and
Caffeine
CH3
CH3
O
N
O
N
CH3
H N
N
O
O
N
N
CH3
S
O
N
N
N
CH3CH2O
N
CH3
Radiosensitizer of Choice Until
2004
HOOC
O
O
OH
O
OH
H
H
OH
O
O
H
O
H
O
OH
Okadaic acid
17 asym me tric ce nte rs