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 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 sp
3
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, []

[] = / cl
o = 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 [o] #
*
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
Enantiomers
nonsuperimposible mirror images
OH
CH
3
HO
2
C
H
OH
CO
2
H
CH
3
H
mirror
plane
(S)(+) lactic acid (R)(-) lactic acid
from muscle tissue from milk
[o] = +13.5 [ o] = -13.5
o
o
Enantiomeric Excess
(Optical Purity)

actually 94.3% (+)
11.4% racemic
88.6% (+)
= 88.6% e.e.
x 100
123.0
109.0
e.e. =
o
observed rotation = +109
from oranges
o
[o] = +123.0
H
from lemons
o
[o| = 123.0
(S)-(-) Limonene (R)(+) Limonene
H
x 100 = enantiomeric excess(e.e.)
rotation of pure enantiomer
observed rotation
Biological Activity
(R)(+) Thalidomide (S)(-) Thalidomide
N
N
O
O
O
O
H
H
a sedative and hypnotic a teratogen
N
N
O
O
O
O
H
H
SSRI Efficacy depends on
Stereochemistry
O
N(CH
3
)
2
F
NC
*
(+/-) Celexa
(-) Lexapro
Absolute Configuration
1
2
3
4
Use Cahn, Ingold, Prelog priorities
Place the lowest priority group back
(focus down C - 4 bond)
(R)
clockwise
draw arrow from 1-2-3
1
2
3
4
(S)
counterclockwise
Assign Priority to each Group
on Asymmetric Center
focus down C-4 bond
4
3
2
1
I
Cl
H
F
rotate
I
F
H
Cl
Lactic Acid
(S) (R)
4
3
2
1
4
3
2
1
OH
CH
3
CO
2
H
H
OH
CH
3
HO
2
C
H
C.I.P. Priorities
CH
2
CH
2
CH
3
CH(CH
3
)
2
CH
2
CH
2
OH CH
2
CH
O
CH
2
CH
2
CH
3
CH=CH
2
CO
2
H CH
2
Cl
Low High
CH
2
CH
2
Br
CH(CH
3
)
2
Fischer Projections
Vertical bonds move away (dashed bonds)
Horizontal bonds approach you (wedge bonds)
OH
CO
2
H
CH
3
H
OH
CH
3
HO
2
C
H
OH
CO
2
H
CH
3
H
Assigning Absolute
Configuration to Fischer
Projections
OH
CO
2
H
CH
3
H
OH
CO
2
H
CH
3
H
OH
CH
3
HO
2
C
H
(S) (S) (S)
rotate
Rotation of the Projection 90
o
Reverses Absolute Configuration
90
o
90
o
o
90
(S) (R) (S) (R)
CH
3
H
OH
HO
2
C
CO
2
H
CH
3
H
HO
H
OH
CO
2
H
CH
3
OH
CO
2
H
CH
3
H
Diastereomers
Stereoisomers That Are Not Mirror Images
3
3
2
2
opposite stereochemistry at C
3
same stereochemistry at C
2
(S)
CO
2
H
OH H
Br H
CO
2
H
OH
H
Br
H
(2S,3S) (2S,3R)
Fischer Projections with 2
Chiral Centers
CO
2
H
CH
3
H OH
Br H H Br
H OH
CO
2
H
CH
3
(2S,3S) (2S,3R)
2
3
2
3
2 Chiral Centers
4 Stereoisomers
Identical, Enantiomers or
Diastereomers?
H
H
CH
3
CH
3
&
CH
3
CH
3
H
H
C C
a)
CH
2
CH
3
CH
3
H
H
Br
Br
CH
2
CH
3
CH
3
&
b)
OH
HO
NH
2
NH
2
Tartaric Acids
CO
2
H
CO
2
H
H OH
HO H
H OH
HO H
CO
2
H
CO
2
H
CO
2
H
CO
2
H
H OH
H OH
HO H
HO H
CO
2
H
CO
2
H
R,R S,S
R,S S,R
Racemic Mixture
o
(g/mL) 1.7598 1.7598 1.7723
m.p. C 168-170 168-170 210-212
[o] (degrees) - 12 + 12 0
(R,R) Tartaric acid (S,S) Tartaric Acid (+/-) Tartaric acid
Racemic Mixture (Racemate): 50/50 mixture of enantiomers
CO
2
H
CO
2
H
H OH
HO H
H OH
HO H
CO
2
H
CO
2
H
R,R S,S
Meso Compound
Internal Plane of Symmetry
Optically Inactive
o
rotate 180
superimposible
CO
2
H
CO
2
H
H OH
H OH
HO H
HO H
CO
2
H
CO
2
H
R,S S,R
mirror
plane
2,3,4-trichlorohexane
How many stereoisomers?
Cl
Cl
Cl
3 asymmetric centers
8 stereoisomers
*
*
*
2
n
, n= # asymmetric centers (3)
n = 3; 2
n
= 8
CH
3
CH
2
CH
3
H Cl
Cl H
H Cl
Cl H
H Cl
Cl H
CH
3
CH
2
CH
3
CH
3
CH
2
CH
3
Cl H
H Cl
H Cl Cl H
Cl H
H Cl
CH
3
CH
2
CH
3
H Cl
H Cl
H Cl
CH
3
CH
2
CH
3
Cl H
Cl H
Cl H
CH
3
CH
2
CH
3
Cl H
H Cl
H Cl
CH
3
CH
2
CH
3
H Cl
Cl H
Cl H
CH
3
CH
2
CH
3
S
S
R
R
R
S
A Carbohydrate
CHO
CH
2
OH
H OH
HO H
H OH
H OH
(+) D-Glucose
R
S
R
R
Internal Planes of Symmetry
CH
3
CH
3
CH
3
CH
3
CH
3
CH
3
CH
3
CH
3
Both are Meso
Asymmetric Centers on Rings
Br
Br
Br
Br
1(R),2(S) cis 1,2-dibromocyclohexane
nonsuperimposible but A flips into B
A B
Br Br
Meso
Allenes can be Chiral
C
C C
H
CH
3
C C
Cl
H
C
CH
3
H
Cl
H
Mycomycin, an antibiotic
C C C
H
CH=CHCH=CHCH
2
CO
2
H
C C C C H
H
Nocardia acidophilus
[o]
D
= -130
o
Reactions that Generate
Chirality Centers
Hydrogenation, syn
CH
3 CH
3
CH
2
CH
3
CH
2
CH
3
H
2
, Pt/C
CH
2
CH
3
CH
2
CH
3
CH
3
CH
3
H H
CH
2
CH
3
CH
2
CH
3
H CH
3
H CH
3
product is meso
Bromination
Trans is formed exclusively
No Meso is formed (cis)
racemic mixture
S S
R R
Br
Br
Br
Br
Br
2
Bromonium Ion is Opened
Equally from Both Sides
Br
2
Br
Br
Br
Br
R R
S S
racemic mixture
Br
Br
Br
Br
Br
Br
o o
+
-
trans alkene + anti addition = MESO
CH
2
CH
3
CH
2
CH
3
H
H
Br
2
CH
2
CH
3
CH
2
CH
3
H
H
Br
Br
Br Br
CH
2
CH
3
CH
2
CH
3
H
H
meso
cis Alkene + anti addition =
racemic mixture
H
CH
2
CH
3
CH
2
CH
3
H
Br
2
Br Br
CH
2
CH
3
CH
2
CH
3 H
H
R R
CH
2
CH
3
CH
2
CH
3
H
H
Br
Br
CH
2
CH
3
CH
2
CH
3
H
H
Br Br
S S
Br
H
H
CH
2
CH
3
CH
2
CH
3
Br
Br
Br
H
H
CH
2
CH
3
CH
2
CH
3
a b
a b
Brominations Often Generate
Asymmetric Centers
Br
2
R R
S S
racemic mixture
CH
3
CH
3
H H
CH
3
CH
3
Br
Br
H
H
CH
3
CH
3
Br
Br
H
H
CH
3
CH
3
H
H
CH
3
CH
3
H
H
Br
Br
CH
3
CH
3
Br
Br
H
H
S R
meso
Br
2
Asymmetric Center is Generated
Racemic Mixture Formed
H-Br
H
H
Br
Br
a)
b)
Br
H
a)
Br
H
b) (R)
(S)
Asymmetric Induction
PPh
2
PPh
2
RuCl
2
CH
3
OH
H
2
Ru(BINAP)Cl
2
CH
3 H
OH
96% e.e.
Noyori and Knowles shared Nobel Prize in Chemistry, 2001
Preparation of (L)-Dopa
for Treatment of Parkinsons
HO
HO
CH
2
C
CO
2
H
NH
2
H
l-(-) Dopa
HO
HO
CH
2
CH
2
NH
2
Dopamine
cannot cross blood-brain
barrier
C=C
NH
2
CO
2
H H
HO
HO
H
2
Rh(DIOP)Cl
2
enz.
Relevance of Stereochemistry
(S,S)
(R, S)
useful decongenstants
d-pseudoephedrine and l-ephedrine
4 stereoisomers
*
*
2 asymmetric centers
EPHEDRA from Ma Huong
NHCH
3
CH
3
OH
One-step synthesis
Pseudophed
*
d-(S)- "Meth"
l-(R) - Vicks
(methamphetamine)
"desoxyephedrine"
NHCH
3
CH
3
o-(p-isobutylphenyl)propionic acid
CH
3
CO
2
H
H
(S)(+) ibuprofen (R)(-) ibuprofen
CH
3
HO
2
C
H
anti-inflammatory 80-90% metabolized to (S)(+)
Model of Thalidomide
How Sweet it is!
Sucrose
O
HO
OH
O
CH
2
OH
O
CH
2
OH
CH
2
OH
HO
HO
OH
Sucralose or Splenda
O
Cl
HO
OH
O
CH
2
OH
O
CH
2
Cl
CH
2
Cl
HO
HO
Sucralose is 600 times sweeter
and does not get metabolized.
Sildenafil (Viagra) and
Caffeine
N
N
N
N
CH
3
H
O
CH
3
CH
2
O
S
N
N
CH
3
O
O
N
N
N
N
CH
3
O
O
CH
3
CH
3
Radiosensitizer of Choice Until
2004
Okadaic acid
17 asymmetric centers
O
OH
HOOC
OH
O
H
O
O
H
H
O
OH
H
OH
O
O