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 – 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 = observed rotation
c = concentration in g/mLl = 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 [] # * 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 CenterCarbon has four different groups attached
Enantiomers nonsuperimposible mirror images
OH
CH3HO2CH
OH
CO2HCH3
H
mirrorplane
(S)(+) lactic acid (R)(-) lactic acid
from muscle tissue from milk[] = +13.5 [] = -13.5
oo
Enantiomeric Excess(Optical Purity)
actually 94.3% (+)
11.4% racemic88.6% (+)
= 88.6% e.e.
x 100 123.0109.0
e.e. =
oobserved rotation = +109
from oranges
o
[] = +123.0
H
from lemons
o[=
(S)-(-) Limonene (R)(+) Limonene
H
x 100 = enantiomeric excess (e.e.)rotation of pure enantiomerobserved rotation
Biological Activity
(R)(+) Thalidomide (S)(-) Thalidomide
N
NO
O
O
O
H
H
a sedative and hypnotic a teratogen
N
NO
O
O
O
H
H
SSRI Efficacy depends on Stereochemistry
ON(CH3)2
F
NC
*
(+/-) Celexa(-) Lexapro
Absolute Configuration
1
23
4
Use Cahn, Ingold, Prelog priorities
Place the lowest priority group back (focus down C - 4 bond)
(R)
clockwise
draw arrow from 1-2-31
2 34
(S)
counterclockwise
Assign Priority to each Group on Asymmetric Center
focus down C-4 bond
4
3
2
1I
ClHF
rotateI
FH
Cl
Lactic Acid
(S) (R)
4
3 2
1
4
32
1OH
CH3 CO2HH
OH
CH3HO2CH
C.I.P. Priorities
CH2CH2CH3 CH(CH3)2
CH2CH2OH CH2CH
O
CH2CH2CH3 CH=CH2
CO2H CH 2Cl
Low High
CH2CH2Br CH(CH3)2
Fischer Projections
Vertical bonds move away (dashed bonds)
Horizontal bonds approach you (wedge bonds)
OH
CO2H
CH3
HOH
CH3HO2CH
OH
CO2H
CH3
H
Assigning Absolute Configuration to Fischer
Projections
OH
CO2H
CH3
H
OH
CO2H
CH3
H
OH
CH3HO2CH
(S) (S) (S)rotate
Rotation of the Projection 90o
Reverses Absolute Configuration
90o
90oo
90
(S) (R) (S) (R)
CH3
H
OH
HO2C
CO2H
CH3
H
HO
H
OH
CO2H
CH3
OH
CO2H
CH3
H
DiastereomersStereoisomers That Are Not Mirror Images
3 322
opposite stereochemistry at C3
same stereochemistry at C2 (S)
CO2H
OHH
Br H
CO2H
OHH
BrH(2S,3S) (2S,3R)
Fischer Projections with 2 Chiral Centers
CO2H
CH3
H OH
Br H H Br
H OH
CO2H
CH3
(2S,3S) (2S,3R)
2
3
2
3
2 Chiral Centers4 Stereoisomers
Identical, Enantiomers or Diastereomers?
H
H
CH3
CH3
&
CH3
CH3
H
H CC
a)
CH2CH3
CH3
H
H
Br
Br
CH2CH3
CH3&
b)
OH
HO
NH2
NH2
Tartaric Acids
CO2H
CO2H
H OH
HO H H OH
HO H
CO2H
CO2H
CO2H
CO2H
H OH
H OH HO H
HO H
CO2H
CO2H
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
[] (degrees) - 12 + 12 0
(R,R) Tartaric acid (S,S) Tartaric Acid (+/-) Tartaric acid
Racemic Mixture (Racemate): 50/50 mixture of enantiomers
CO2H
CO2H
H OH
HO H H OH
HO H
CO2H
CO2H
R,R S,S
Meso CompoundInternal Plane of Symmetry
Optically Inactive
orotate 180
superimposible
CO2H
CO2H
H OH
H OH HO H
HO H
CO2H
CO2H
R,S S,R
mirror plane
2,3,4-trichlorohexaneHow many stereoisomers?
Cl
Cl
Cl3 asymmetric centers
8 stereoisomers
* **
2n, n= # asymmetric centers (3)
n = 3; 2n = 8
CH3
CH2CH3
H Cl
Cl H
H Cl Cl H
H Cl
Cl H
CH3
CH2CH3
CH3
CH2CH3
Cl H
H Cl
H Cl Cl H
Cl H
H Cl
CH3
CH2CH3
H Cl
H Cl
H Cl
CH3
CH2CH3
Cl H
Cl H
Cl H
CH3
CH2CH3
Cl H
H Cl
H Cl
CH3
CH2CH3
H Cl
Cl H
Cl H
CH3
CH2CH3
S
S
R
R
R
S
A CarbohydrateCHO
CH2OH
H OH
HO H
H OH
H OH
(+) D-Glucose
R
S
R
R
Internal Planes of Symmetry
CH3CH3
CH3CH3
CH3CH3
CH3 CH3
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
BrBr
Meso
Allenes can be Chiral
C C C
H
CH3
C CClHC
CH3
H
ClH
Mycomycin, an antibiotic
C C C
H
CH=CHCH=CHCH2CO2HCCCCHH
Nocardia acidophilus []D = -130o
Reactions that Generate Chirality Centers
Hydrogenation, syn
CH3CH3
CH2CH3CH2CH3
H2, Pt/C
CH2CH3 CH2CH3
CH3CH3
HH
CH2CH3
CH2CH3
H CH3
H CH3
product is meso
BrominationTrans is formed exclusively
No Meso is formed (cis)
racemic mixture
S SR RBr BrBr Br
Br2
Bromonium Ion is Opened Equally from Both Sides
Br2
Br Br Br BrR R S S
racemic mixture
Br
Br
Br
Br
Br Br + -
trans alkene + anti addition = MESO
CH2CH3
CH2CH3 H
H
Br2
CH2CH3
CH2CH3
HH
Br
Br
Br Br
CH2CH3CH2CH3HH
meso
cis Alkene + anti addition = racemic mixture
H
CH2CH3 CH2CH3
H
Br2
Br Br
CH2CH3CH2CH3 H
HR R
CH2CH3
CH2CH3
H
H
Br
Br
CH2CH3CH2CH3 H
H
Br BrS S
Br
H HCH2CH3CH2CH3
Br
Br
BrH
H
CH2CH3
CH2CH3
a b
a b
Brominations Often Generate Asymmetric Centers
Br2
R RS S
racemic mixture
CH3CH3
H H
CH3CH3
Br BrH H
CH3CH3
Br BrH H
CH3
CH3 H
H CH3
CH3 H
H
Br
Br
CH3CH3
Br BrH H
S Rmeso
Br2
Asymmetric Center is Generated Racemic Mixture Formed
H-Br
HH
Br
Br
a)
b)
Br
H
a) Br
H
b)(R) (S)
Asymmetric Induction
PPh2
PPh2
RuCl2
CH3
OHH2
Ru(BINAP)Cl2
CH3H
OH
96% e.e.
Noyori and Knowles shared Nobel Prize in Chemistry, 2001
Preparation of (L)-Dopafor Treatment of Parkinson’s
HO
HO
CH2C
CO2H
NH2
H
l-(-) Dopa
HO
HO
CH2CH2NH2
Dopaminecannot cross blood-brain
barrier
C=CNH2
CO2HH
HO
HO
H2Rh(DIOP)Cl2
enz.
Relevance of Stereochemistry
(S,S)(R,S)useful decongenstants
d-pseudoephedrine and l-ephedrine
4 stereoisomers
**
2 asymmetric centers
EPHEDRA from Ma Huong
NHCH3
CH3
OH
One-step synthesis
Pseudophed
*
d-(S)- "Meth"l-(R) - Vicks
(methamphetamine)"desoxyephedrine"NHCH3
CH3
-(p-isobutylphenyl)propionic acid
CH3 CO2HH
(S)(+) ibuprofen (R)(-) ibuprofen
CH3HO2C
H
anti-inflammatory 80-90% metabolized to (S)(+)
Model of Thalidomide
How Sweet it is!
Sucrose
O
HOOH
O
CH2OH
OCH2OH
CH2OH
HO
HO
OH
Sucralose or Splenda
O
Cl
HOOH
O
CH2OH
OCH2Cl
CH2Cl
HO
HO
Sucralose is 600 times sweeter and does not get metabolized.
Sildenafil (Viagra) and Caffeine
NN
N
N
CH3
H
O
CH3CH2O
S
N
N
CH3
O
O
N
N
N
N
CH3
O
O
CH3
CH3
Radiosensitizer of Choice Until 2004
Okadaic acid17 asymmetric centers
O
OH
HOOC
OH
OH
O
OH
HO
OH
HOH
O
O
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