CHIRALITY, SYMMETRY PLANES
AND ENANTIOMERS
Craig Wheelock
October 17th, 2008
craig.wheelock@ki.se
http://www.metabolomics.se/
(copies of slides can be downloaded from my homepage)
WHICH OBJECTS ARE SYMMETRIC ?
(mirror image is identical)
sym (outside)
asym
asym
sym
asym
asym
sym
sym
PLANES OF SYMMETRY
A SYMMETRIC OBJECT HAS A PLANE OF SYMMETRY
- ALSO CALLED A MIRROR PLANE
plane of
symmetry
mirror
plane
IF AN OBJECT HAS A PLANE OF SYMMETRY,
ITS MIRROR IMAGE WILL BE IDENTICAL
IDENTICAL MIRROR IMAGES WILL SUPERIMPOSE
(MATCH EXACTLY WHEN PLACED ON TOP OF EACH OTHER)
CHIRALITY
An object without symmetry is CHIRAL
no symmetry
The mirror image
of a chiral object is
different and will not
superimpose on the
original object.
OBJECTS WHICH ARE CHIRAL
HAVE A SENSE OF “HANDEDNESS”
AND EXIST IN TWO FORMS
An object with symmetry is ACHIRAL (not chiral)
The mirror image of an achiral
object is identical and will
superimpose on the original object.
plane of
symmetry
ENANTIOMERS
Cl
H
non-superimposable
mirror images
F
Br
this molecule
is chiral
F
Br
Cl
rotate
H
Cl
H
Br
F
note that the fluorine
and bromine have been
interchanged in the
enantiomer
non-superimposable
OPTICAL ACTIVITY
PLANE-POLARIZED LIGHT
PLANE-POLARIZED LIGHT BEAM
single
ray or
photon
wavelength
λ
All sine waves (rays) in the
beam aligned in same plane.
.
SIDE
VIEW
A beam is a collection
of these rays.
polarized beam
NOT PLANE-POLARIZED
frequency ( ν )
ν =
Sine waves
are not aligned
in the same
plane.
c
λ
c = speed of light
END
VIEW
unpolarized
beam
Optically Active
• Refers to molecules that interact
with plane-polarized light
Jean Baptiste Biot
French Physicist - 1815
He discovered that some natural substances
(glucose, nicotine, sucrose) rotate the plane
of plane-polarized light and that others did not.
Optical Activity
angle of
rotation, α
α
incident
polarized
light
transmitted
light (rotated)
sample cell
(usually quartz)
a solution of the substance to be
examined is placed inside the cell
TYPES OF OPTICAL ACTIVITY
Dextrorotatory
new
older
(+)-
d-
Rotates the plane of plane-polarized light
to the right.
Levorotatory
new
older
(-)-
l-
Rotates the plane of plane-polarized light
to the left.
Specific Rotation [α]D
t
[α]D =
α
α
cl
= observed rotation
c = concentration ( g/mL )
This equation corrects
for differences in cell
length and concentration.
Specific rotation calculated
in this way is a physical
property of an optically
active substance.
You always get the same
value of
l = length of cell ( dm )
D = yellow light from sodium lamp
t = temperature ( Celsius )
t
[α]D
SPECIFIC ROTATIONS OF BIOACTIVE COMPOUNDS
COMPOUND
cholesterol
cocaine
morphine
codeine
heroin
epinephrine
progesterone
testosterone
sucrose
β-D-glucose
α-D-glucose
oxacillin
[α]D
-31.5
-16
-132
-136
-107
-5.0
+172
+109
+66.5
+18.7
+112
+201
PASTEUR’S DISCOVERY
Louis Pasteur 1848
Sorbonne, Paris
HOOC CH CH COOH
OH OH
tartaric acid
( found in wine must )
2-
+
Na OOC CH CH COO NH4+
OH OH
sodium ammonium tartrate
Pasteur crystallized this
substance on a cold day
Crystals of Sodium Ammonium Tartrate
hemihedral faces
Pasteur found two
different crystals.
mirror
images
Biot’s results :
(+)
(- )
Louis Pasteur separated these and gave them to Biot to measure.
Enantiomers
non-superimposable mirror images
(also called optical isomers)
X
W
W
C
C
Z
Y
Y
Z
X
Pasteur decided that the molecules that made the crystals,
just as the crystals themselves, must be mirror images.
Each crystal must contain a single type of enantiomer.
Pasteur’s hypothesis eventually led to the discovery
that tetravalent carbon atoms are tetrahedral.
Van’t Hoff and
LeBel (1874)
tetrahedral
carbon
C
Only tetrahedral geometry can lead to mirror image
molecules:
C
C
Square planar, square pyrimidal or trigonal pyramid
will not work:
C
C
C
ENANTIOMERS HAVE
EQUAL AND OPPOSITE
ROTATIONS
W
C
X
Z
W
Enantiomers
Y
(+)-nno
dextrorotatory
C
Y
Z
X
(-)-nno
levorotatory
ALL OTHER PHYSICAL PROPERTIES ARE THE SAME
TARTARIC ACID
from fermentation of wine
Enantiomers
OH OH
HOOC
H
OH OH
H
COOH
(+)-tartaric acid
OH OH
HOOC
H
H
H
HOOC
H
COOH
(-)-tartaric acid
meso
COOH
meso -tartaric acid
ALSO FOUND
(as a minor component)
[α ]D = 0
more about this
compound later
TARTARIC ACID
(-) - tartaric acid
(+) - tartaric acid
[α]D = -12.0o
[α]D = +12.0o
mp 168 - 170o
solubility of 1 g
0.75 mL H2O
1.7 mL methanol
250 mL ether
insoluble CHCl3
d = 1.758 g/mL
mp 168 - 170o
solubility of 1 g
0.75 mL H2O
1.7 mL methanol
250 mL ether
insoluble CHCl3
d = 1.758 g/mL
[α]D = 0o
meso - tartaric acid
mp 140o
d = 1.666 g/mL
solubility of 1 g
0.94 mL H2O
insoluble CHCl3
RACEMIC MIXTURE
an equimolar (50/50) mixture of enantiomers
[α ]D = 0 o
the effect of each molecule is
cancelled out by its enantiomer
STEREOISOMERS
ENANTIOMERS are a type of STEREOISOMER
Stereoisomers are the same constitutional
isomer, but differ in the way they are arranged
in 3-D space at one or more of their atoms.
STEREOCENTERS
One of the ways a molecule can be chiral is to have a
stereocenter
A stereocenter is an atom, or a group of atoms,
that can potentially cause a molecule to be chiral
stereocenters - can
give rise to chirality
STEREOGENIC CARBONS
( called “chiral carbons” in older literature )
Cl
This is one type of ….
stereocenter
…. others are possible
H
F
Br
A stereogenic carbon is tetrahedral
and has four different groups attached.
H
F
Cl
Br
ACHIRAL
F
Cl
Br
The plane of the paper
is a plane of symmetry
F
Br
F
Cl
Cl
Cl
Cl
TWO IDENTICAL GROUPS RENDERS A
TETRAHEDRAL CARBON ACHIRAL
Br
ONE PAIR OF ATOMS ATTACHED TO A TETRAHEDRAL
CARBON IS IN A PLANE PERPENDICULAR TO THE
OTHER PAIR
plane 1
plane 2
F
Cl
Br
Look at your
model set !!!!
TWO VIEWS OF THE PLANE OF SYMMETRY
plane of
symmetry
F
Br
F
Cl
Br
Cl
Cl
side
view
F
Cl
Cl
Br
edge
view
CONFIGURATION
ABSOLUTE CONFIGURATION ( R / S )
CONFIGURATION
The three dimensional arrangement of the
groups attached to an atom
Stereoisomers differ in the configuration at one or
more of their atoms.
CONFIGURATION - relates to the three dimensional
sense of attachment for groups attached to a chiral
atom or group of atoms (i.e., attached to a stereocenter).
clockwise
1
2
2
C
C
4
view with
substituent
of lowest
priority in
back
1
4
3
R
3
(rectus)
S
(sinister)
counter
clockwise
SPECIFICATION OF CONFIGURATION
Enantiomers are assigned a CONFIGURATION
using the same priority rules we developed for
E / Z stereoisomers.
1. Higher atomic number has higher priority.
2. If priority cannot be decided based on the first
atom attached move to the next atom, following
the path having the highest prioity atom.
3. Expand multiple bonds by replicating the atoms
attached to each end of the bond.
CAHN-INGOLD-PRELOG
SEQUENCE RULES
1
R
4
2
3
(R)-2-Butanol
Bromochlorofluoroiodomethane
1 9 17 35 53
H F Cl Br I
atomic
number
1
1
I
4
I
4
C
F
Cl
Br
2
F
3
R
C
Cl
Br
3
2
Enantiomers
S
NUMBER OF
STEREOISOMERS POSSIBLE
How Many Stereoisomers
Are Possible?
maximum number of stereoisomers
sometimes fewer
= 2n,
than this number
will exist
where n = number of stereocenters
(sterogenic carbons)
CH2OH
CH3
OH
*
C CH2 CH CH CH3
*
CH3
CH3
RR
RS
SR
SS
22 = 4 stereoisomers
CH3
*
*
CH3
*
CH
OH
CH3
RRR
RRS
RSR
SRR
RSS
SRS
SSR
SSS
23 = 8 stereoisomers
FINDING STEREOCENTERS
(STEREOGENIC CARBONS)
O
O
O
CH3
*
*
CH3
CH3
plane
( indicates no stereoisomers )
stereoisomers (max) :
20 = 1
21 = 2
21 = 2
FINDING STEREOCENTERS
(STEREOGENIC CARBONS)
O
O
O
CH3
*
*
CH3
*
*
CH3
stereoisomers (max) :
22 = 4
22 = 4
CH3
CH3
*
*
CH3
plane
( but only if cis )
22 = 4
FINDING STEREOCENTERS (CHIRAL CARBONS)
CH3
*
CH3
*
CH3
*
HO
*
*
*
*
CH3
*
H
CH3
n=8
28 = 256
MOLECULES WITH
TWO STEREOCENTERS
DIASTEREOMERS / MESO
2-Bromo-3-chlorobutane
*
*
CH3CHCHCH3
4
3
2
Cl Br
1
22 = 4 stereoisomers
possible
SR
RS
SS
RR
When comparing butanes, the comparisons
are done best using the eclipsed conformation.
The relationships and planes of symmetry
are not easily seen in other conformations.
PRIORITIES AND DETERMINING R and S
1
1
Cl
Cl Br
2
3
CH3
H
H
4
CH3
CH3
CH3
H
H
Br
1
H
CH3
S
1
CH3
4
2
Br
rotate
3
H
4
2
Cl Br
2
rotate
3
4
H
CH3
3
CH3
H
Cl
R
2-Bromo-3-chlorobutane
mirror
Cl Br
S
CH3
H
R
H
S
CH3
CH3
H
R
H
CH3
enantiomers 1
diastereomers
CH3
Br Cl
Cl Br
Br Cl
S
S
H
H
CH3
R
H
CH3
enantiomers 2
R
H
CH3
Models of the Isomers of 2-Bromo-3-chlorobutane
(methyl groups are reduced to a single red atom)
Br
Cl
CH3
enantiomers-1
H
diastereomers
enantiomers-2
MESO ISOMER
mirror
plane of symmetry
Cl Cl
CH3
*
H
*
CH3
H
S
CH3
H
Cl
Cl
R
CH3
H
Meso isomer - has a plane of symmetry and the
mirror image is identical to the
original molecule.
- must have ≥ 2 stereocenters
Models of the Isomers of 2,3-Dichlorobutane
(methyl groups are reduced to a single red atom)
Cl
CH3
H
meso
diastereomers
enantiomers
CIS / TRANS RINGS
DIASTEREOMERS
1-Bromo-2-chlorocyclopropane
note that the cis / trans isomers are also diastereomers
Br R
S
Cl
Cl R
S
Br
cis
enantiomers
diastereomers
Br R
R
S
S
Br
trans
Cl
Cl
enantiomers
1,2-Dibromocyclopropane
mirror image identical
Br
Br
Br
Br
cis
meso
diastereomers
Br
R
R
S
Br
Br
enantiomers
S
Br
trans
DISUBSTITUTED CYCLOHEXANES
USING PLANAR RINGS FOR STEREOCHEMICAL ANALYSIS
1-Bromo-2-chlorocyclohexane
cyclohexanes may be analyzed using planar rings
Br
S
Cl
Cl
S
R
Br
cis
R
enantiomers
diastereomers
Br
S
Br
S
R
Cl
Cl
enantiomers
R
trans
1,2-dichlorocyclohexane
mirror image identical
Cl
Cl
Cl
Cl
cis
Cl
trans
meso
diastereomers
Cl
S
S
R
Cl
Cl
enantiomers
R
CONCLUSION
2n = the maximum
number
When a molecule has
1. multiple stereocenters and
2. there is a possibility of an arrangement
with a plane of symmetry
you will not always find all of the 2n stereoisomers
that are possible.
Some of the stereoisomers may be meso isomers,
and their mirror images will be superimposable
(identical) - this will eliminate at least one of the
possible stereoisomers, and sometimes more.
PHYSICAL PROPERTIES OF
ENANTIOMERS, DIASTEREOMERS
AND MESO COMPOUNDS
ENANTIOMERS HAVE
EQUAL AND OPPOSITE
ROTATIONS
REMEMBER :
W
C
X
Z
W
Enantiomers
Y
(+)-nno
dextrorotatory
C
Y
Z
X
(-)-nno
levorotatory
ALL OTHER PHYSICAL PROPERTIES ARE THE SAME
IN CONTRAST :
DIASTEREOMERS
MAY HAVE
DIFFERENT ROTATIONS
AND ALSO DIFFERENT PHYSICAL PROPERTIES
RELATIONSHIPS
AMONG STEREOISOMERS
COMPARING TWO STEREOISOMERS
Two
Stereoisomers
nonsuperimposable
mirror images
Enantiomers
not
mirror images
Diastereomers
DETERMINING CHIRALITY / OPTICAL ACTIVITY
no plane of
symmetry
molecule has one or
more stereocenters
mirror image
superimposes
no
plane of
symmetry
yes
has an enantiomer
is meso
is chiral
is achiral
optically
active
optically
inactive
ISOMERS
Different compounds
with the same
molecular formula
each isomer could
have stereoisomers
STEREOISOMERS
Isomers with the same order
of attachment, but a different
configuration (3D arrangement)
of groups on one or more of
the atoms
double bond
or ring
cis/trans
ISOMERS
(geometric)
with a ring
both can apply
CONSTITUTIONAL
ISOMERS
Isomers with a different
order of attachment of
the atoms in their
molecules
ENANTIOMERS
Stereoisomers whose
molecules are nonsuperimposible mirror
images of each other
DIASTEREOMERS
Stereoisomers whose
molecules are not mirror
images of each other
TYPES OF ISOMERISM
Biological role of stereochemistry
(S)-amino acid
(R)-amino acid
Only one of the 2
amino acid
enantiomers can
achieve 3-point
binding with the
enzyme binding site
Importance of stereochemistry
• Thalidomide (Neurosedyn)
S
teratogenic
and causes
birth defects
R
effective
against
morning
sickness
• Ibuprofen (Ipren)
S
active
form
R
inactive
To recapitulate . . .
• chirality and optical activity
– plane of symmetry
• enantiomers and diastereomers
– R and S
• use Cahn-Ingold-Prelog priority rules
• meso compounds
– contain stereocenters, but are achiral
• stereoisomers can have significant
biological effects
Web resources
• ISIS Draw Structure Drawing Software
– http://www.mdli.com/
• Chime Molecular Display
– http://www.mdli.com/
• RasMol Molecular Display Software
– http://rasmol.org/
• Jmol Java viewer for 3D chemical structures
– http://jmol.sourceforge.net/
• General resource for organic chemistry
– http://www.organicworldwide.net/
• Spartan computational chemistry
– http://www.wavefun.com/
PROBLEM: ARE THESE IDENTICAL
OR ARE THEY ENANTIOMERS?
Br
1
Br
CH3
H
C
C
F
CH3
Br
C
C
F
H
CH3
CH3
H
F
2
H
ENANTIOMER
YOU CAN USE
INTERCHANGES
Br
F
H
H
C
C
CH3
SAME
F
Br
3
CH3
Br
F
ENANTIOMER
What is the best term to describe the relationship between A and each of the
other molecules?
Constitutional isomers?
Conformations?
Enantiomers?
Diastereomers?
Identical?
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Are any of these molecules
optically active?
Br
Br
Br
Br
Br
Br
ANSWERS
A-C and E are all the same constitutional isomer, 1,3,5-trichloro- ,
but F is 1,2,4-trichloro• F is a constitutional isomer to A and to any of the others.
• A (e,e,a) and B (a,a,e) are conformations
• A (e,e,a) and C (e,e,e) are diastereomers
• A and D are diastereomers (D is a conformation of C)
• A and E are diastereomers (E is identical to D, turned left-to-right)
• A and G are identical (G is the same as A turned left-to-right)
Only F is optically active, all the rest are meso molecules!
[α]D = 0
[α]D = 0