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
HO 2C
OH
CH3
(S)(+) lactic acid
from muscle tissue
o
[a] = +13.5
CH3
H
CO2H
(R)(-) lactic acid
from milko
[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
(S)-(-) Limonene
(R)(+) Limonene
o
o
[a= 
from lemons
[a] = +123.0
from oranges
88.6% (+)
11.4% racemic
actually 94.3% (+)
Biological Activity
(R)(+) Thalidomide
O
O
H
(S)(-) Thalidomide
O
H
N
N
O
a sedative and hypnotic
O
O
H
N
O
a teratogen
H
N
O
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
4
2
2
3
3
(R)
(S)
Assign Priority to each Group
on Asymmetric Center
I
Cl
H
I
rotate
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
High
CH2CH2CH3
CH(CH 3)2
O
CH2CH2OH
CH2CH
CH2CH2CH3
CH=CH2
CO2H
CH 2Cl
CH2CH2Br
CH(CH3)2
Fischer Projections
H
HO2C
H
CH3
OH
OH
OH
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
OH
H
90
CO2H
CH3
(S)
o
H
CH3
90
OH
CO2H
(R)
CH3
o
HO2C
H
OH
(S)
o
CO2H
90
HO
CH3
H
(R)
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
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
CO 2H
H
HO
OH
H
S,S
CO2H
HO
H
H
OH
CO 2H
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 Mixture (Racemate): 50/50 mixture of enantiomers
o
m.p. C
[a] (degrees)
(g/mL)
(R,R) Tartaric acid
168-170
- 12
1.7598
(S,S) Tartaric Acid (+/-) Tartaric 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
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;
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-Glucose
Internal Planes of Symmetry
Both are Meso
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-dibromocyclohexane
nonsuperimposible but A flips into B
Meso
Allenes can be Chiral
H
Cl
H
C
C
H
C
C
CH3
CH3
C
C
H
Cl
Mycomycin, an antibiotic
H
H
H C C C C
C
C
Nocardia acidophilus
C
CH=CHCH=CHCH2CO2H
o
[a]D =
-130
Reactions that Generate
Chirality Centers
Hydrogenation, syn
CH3
CH2CH3
CH3
H
H2, Pt/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
Br 2
+
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
Br 2
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
Br 2
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
Br 2
CH3
H
Br
H
CH3 CH3
CH3
H
Br
H
Br
H
Br
R R
S S
racemic mixture
CH3
H
H
CH3
Br 2
CH3
H
Br
Br
H
CH3
CH3
H
Br
CH3
H
Br
S R
meso
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)Cl 2
OH
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
HO
l-(-) Dopa
H
NH2
enz.
HO
CH2CH2NH2
HO
Dopamine
cannot cross blood-brain
barrier
Relevance of Stereochemistry
EPHEDRA from Ma Huong
OH
* *
NHCH3
CH3
2 asymmetric centers
4 stereoisomers
d-pseudoephedrine and l-ephedrine
(R,S)
(S,S)
useful decongenstants
One-step synthesis
Pseudophed
*
NHCH3
CH3
"desoxyephedrine"
(methamphetamine)
l-(R) - Vicks
d-(S)- "Meth"
a-(p-isobutylphenyl)propionic acid
CH3
H
CO2H
(S)(+) ibuprofen
anti-inflammatory
H
HO2C
CH3
(R)(-) ibuprofen
80-90% metabolized to (S)(+)
Model of Thalidomide
How Sweet it is!
OH
Cl
CH2OH
O
CH2OH
O
HO
OH
O
HO
Sucrose
HO
CH2OH
O
CH2Cl
O
HO
OH
O
HO
CH2OH
HO
Sucralose or Splenda
Sucralose is 600 times sweeter
and does not get metabolized.
CH2Cl
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
Okadaic acid
17 asymmetric centers
O
OH