Stereochemistry
Structural or constitutional isomers...
 have the same molecular formula but different
connectivity (skeletal, positional, functional)
Stereoisomers...
 have the same connectivity but a different
arrangement of atoms in space
Recall:
2-butene
H
H
C
H3C
H
C
CH3
C
CH3
cis-2-butene
H3C
C
H
trans-2-butene
 Trans and Cis can also be used for disubstituted cycloalkanes (no
bond rotation):
1,2-dimethylcyclopropane
H3C
H3C
CH3
H
H
H
CH3
H
cis
trans
 What if there are less than 2 H atoms?
 What if more than one bonded to the alkene is the same?
H
CH2F
C
H3C
H
C
CH2Cl
C
CH2Cl
H3C
C
CH2F
The Cahn-Ingold-Prelog Rules for determining substituent
priority:
Substituents are evaluated by comparing atoms that are equidistant f rom the
point of interest.
1) The higher the atomic number, Z, the higher the priority (higher atomic weight).
2) For atoms with the same Z, the heavier (isotope) has higher priority (13C vs. 12C
2
H (D) vs. H).
3) If the atoms attached are the same, then move out to the next shell of atoms one bond
f urther always comparing atoms that are equidistant.
4) If a substituent contains -bonds, interpret them as multiple -bonds between the
same atoms (e.g. an aldehyde has a carbon which is bonded to 2 oxygen atoms and one
hydrogen atom).
CH2CH3
C
CH2OH
CH2F
C
CH2CH2Br
H
OCH3
C
C
H
C
OCH3
OCH3
H
CF3
C
CH2SH
H3C
CF3
C
H
C
CH2SH
Another level of complexity with multiple bonds:
N000
C
N
C
C000
N
C000
N000
O
O
C000
C
C
O
OH
H
O000
CH3
C
C
H
vs.
C
CH3
CH3
How do you know when molecules are the same?
Molecules are identical if, in equivalent conformations, they are
superimposable.
H
H
C
H3C
H3C
C
H
C
CH2CH3
H
H3H
C
CH2CH3
H
C
H3H
C
C
C
CH2CH3
 If the connectivity of two molecules differs, then they are constitutional isomers.
If the connectivity is the same but the molecules are not superimposable, then they
are stereoisomers.
How about these two?
Y axis
F
HO
X axis
F
Z axis
OH
Rotate about y-axis to
place most atoms in
the plane of the page.
Rotate ~160º
counterclockwise
about z-axis
F
OH
F
HO
Stereochemistry at tetrahedral centres:
H
C
Cl
H
CH3
CH2CH3
H3C
H3CH2C
C
Cl
Are these molecules the same?
H
Cl
C
H
CH3
CH2CH3
Rotate 180°
around CH bond
Cl
C
CH2CH3
CH3
Configuration: the actual arrangement in space of the substituents
around a given asymmetric atom that can be
designated R or S. Also applies to E/Z.
Chiral or stereogenic centre: Any tetrahedral atom, frequently carbon,
which has 4 different substituents. Also
called stereocentre
There are only 2 possible configuration for tetrahedral centres:
H
Cl
C
H
CH2CH3
CH3
C
Cl
CH3
CH2CH3
These two configurations cannot be interchanged without breaking bonds!
If you switch any two substituents, then the configuration changes:
H
Cl
C
H
CH2CH3
CH3
C
Cl
Cl
CH2CH3
CH3
Make 2 models, convince yourself this is true…
C
H
H
CH3
CH2CH3
C
H3C
Cl
CH2CH3
Solutions that rotate plane-polarized light are said to be "optically active".
H
C
HO
H
CH3
CH2CH3
(-)-2-Butanol
H3C
H3CH2C
C
OH
(+)-2-Butanol
Dextrotatory - rotates ppl in a clockwise direction.
Levorotatory - rotates ppl in counterclockwise direction
How do we distinguish between different absolute configurations? How do
we label them?
Historically…(bit still used today for certain classes of molecules)
The D/L Convention of Fischer
Absolute configuration: The actual three-dimensional arrangement of groups around an
asymmetric center.
H
HO
CH2OH
CHO
D-Glyceraldehyde
All sugars with the same absolute configuration next to the
CH2OH group are "D". Those with opposite absolute
configuration are "L"
Note that this designation now has nothing to do with
the direction the molecule rotates ppl.
How do we name compounds such that their absolute configuration is indicated?
1. We assign priorities, 1 to 4 (using the rules established by Cahn, Ingold and
Prelog), to the substituents of an asymmetric atom
2. Reorient the centre such that the lowest priority, 4, is positioned into the plane
of the board.
3. If the remaining substituents are arrayed 1-2-3 in clockwise order, then the
center has R configuration:
1
C
1
4
2
C
3
2
4
4. If the order is counterclockwise,
the centre is S:
3
3
2
4
C
1
2
4
3
1
Try to assign these (a model kit is exceedingly helpful!):
H3C
CO2H
CH2OH
C
C
Cl
H
H3C
C
H
HO
H
Br
H3C
Cl
CH3
O
Cl
H
H Br
C
CH3
O
Enantiomers: are molecules that are non-superimposable mirror-images
of one another.
H
C
Cl
R
H
CH3
CH2CH3
H3C
H3CH2C
C
Cl
S
 Enantiomers have identical physical properties in all respects (thus difficult
to separate from each other), except they rotate plane polarized light in
opposite directions (unrelated to absolute configuration). Such molecules are
said to be optically active.
 Thus, a 50/50 mixture of two enantiomers (a racemic mixture) will not
rotate plane polarized light.
 A mixture of enantiomers that is optically active (i.e. not a 50/50 mxture)
is said to be scalemic.
Why would only one enantiomer cause a certain problem/react
with a given substrate?
H
H
Cl
Br
F
Cl
Br
H
H
Br
Cl
B
C
F
F
A
Enzyme
Cl
Br
B
C
F
A-F
B - Br
C - Cl
A
Enzyme
 An object is chiral if it is nonsuperimposable on its mirror image.
 Achiral : an object (molecule) which is superimposable upon its mirror image.
If a molecule has a plane of symmetry it is not chiral.
Can a molecule without any chiral centres be chiral?
Br
Br
C
C
C
Br
H
Br
H
C
C
C
H
H
HO
OH
BINAP
OH
HO
Can a molecule with centres be achiral?
H3C
C
C
H3C
H
Br
H
Br
H
Br
H
Br
CH3
C
C
CH3
 Only if there is an even number of chiral centres.
Meso compounds have chiral centres, but are achiral (they have
an internal plane of symmetry)
H
OH
H
H
Invert
ring
H
OH
H
spin 180° HO
H
OH
OH
H
OH
H
OH
HO
If there exists any (accessible) conformation in which a molecule is achiral,
then it is achiral, period.
H
H
HO
H
OH
H
HO
HO
Atoms other than carbon?
Inversion of Configuration
H3CH2C
N
Ph
H3CH2C
CH3
N
Ph
Ph
H3CH2C
N
CH3
CH3CH2Br
H3CH2C
Ph
N
CH3
Br-
CH2CH3
H3CH2C
P
Ph
CH3
H3CH2C
S
Ph
O
CH3
Molecules with two chiral centers...
H
H3C
C
Br
Br
H
C
H
HO
CH3
C
CH3
2
Br
H
C
Br
H
C
H
HO
H
OH
H3C
1
H3C
C
CH3
C
CH3
C
H
OH
H3C
3
4
Diastereomers: non-superimposable, non-mirror images
 Diastereomers have different physical properties and can easily be separated
from one another.
 A molecule can have a maximum of 2n possible stereoisomers (n = number of
chiral centres).
Draw all possible stereoisomers and indicate which are enantiomers and which
are diastereomers:
H I
Br
Cl
Br
H
CH3
F
H3C Cl
Fischer Projections: a shorthand notation for showing absolute configurations. In no
way do these diagrams attempt to show the actual shape of molecules.
H
C
90°
CHO
CHO
OH
=
H
OH
H
HOH2C
CH2OH
CH2OH
CHO
OH
=
=
180°
CH2OH
HO
C
H
CHO
CH2OH
=
HO
H
HOH2C
H
CHO
OH
CHO
A 90° or 270° rotation of a Fischer projection generates…
A 180° rotation of a Fischer projection generates…
Use models to convince yourself this is true!
Fischer projections were developed to aid in drawing molecules (sugars) with many
chiral centers. It is easy to spot enantiomers and superimposable molecules when
drawn as these projections.
CHO
CHO
CH2OH
CH2OH
HO
H
H
OH
HO
H
H
HO
H
H
OH
HO
H
HO
CH2OH
CH2OH
CHO
OH
H
CHO
Amino acids are chiral and have the same absolute configuration.
Amino acids
H2NCH2CO2H
Glycine
CO2H
H2N
H2NCHCH3CO2H
Alanine
CHO
CO2H
H
H2N
CH3
L-Alanine
H
H
D-Glyceraldehyde
OH
CH2OH
CH3
CO2H
CO2H
H2N
CO2H
H
CH2SH
L-cysteine
H2N
H
CH2OH
L-Serine
H2N
H
H2C
L-tryptophan
NH
CO2H
H2N
H
H2C
NH
L-Histidine
N
These are called L-amino acids not because they all rotate
plane-polarized light in a levorotatory fashion (they don't)
but because of their structural relationship to Dglyceraldehyde.
H
C
CN
+
H
CH2
CN
CN
H2C
HC
H2C
O
O
O
C
O
C
CH2(CH2)16CH3
CH2(CH2)16CH3
O
C
H
Hydrolase
Enzyme
H2O
H2C
H
C
H2C
CH2(CH2)16CH3
O
Tristearyl glycerol, a triglyceride
HO
OH
O
O
C
CH2(CH2)16CH3
O
C
CH2(CH2)16CH3
O
C
CH2(CH2)16CH3
O
A diglyceride.
You cannot make one enantiomer of a product preferentially
starting only with achiral molecules. In other words, you must
use optically active material (catalyst, reactant, solvent etc.) in
order to prepare something that is optically active.
The chiral pool...
H OH
CO2H
HO
H
HO
HO
OH
CO2H
R-+-Pinene
OHO
H
O
R-+-Camphor
D-Tartaric acid
Asymmetric
Catalysis
Ph
Ph
P
Ph
H
H
D-Mannose
OH
CO2H
O
O
Ph
H
O
Ru
P
H
O
H2,cat.
H
CO2H
S-BINAP
Stereochemistree
So, you've got two molecules and you want to know their relationship...
Is the connectivity
the same?
No
Yes
Structural
Isomers (Positional or Functional)
Are they
superimposable?
Yes
No
Identical
molecules
Identical after rotation about single bonds
to equivaent conformations?
Yes
No
Conformers
They are stereoisomers.
Are they mirror images
of each other?
Yes
Enantiomers
No
Diastereomers