S
R
Stereochemistry:
biological significance of isomerism
Craig Wheelock
October 17th, 2008
[email protected]
http://www.metabolomics.se/
(copies of slides can be downloaded from my homepage)
Learning Objectives
• Understand concepts of
stereochemistry and isomerism
• Be able to assign isomer
configuration
• Rationalize energy-dependence of
cyclohexane conformations
• Know biological significance of
isomerism and optical activity
W
Stereochemistry
Types of Isomers
C
X
• Structural (constitutional)
Z
Y
– same molecular formula, different attachment order
• Geometric (cis and trans, E and Z )
– molecular rigidity (alkenes and cyclic systems)
• Conformational (cyclohexane)
– molecular shape
• Optical (chirality)
– arrangement (“right- or left-handedness”)
Importance of stereochemistry
• trans fat – elevated risk in coronary heart disease
cis
trans
• Thalidomide (Neurosedyn)
S
teratogenic
and causes
birth defects
R
effective against
morning sickness
Geometric Isomers
occurs in only 2 classes of compounds:
1. Alkenes
2. Cyclic systems
ALKENES
cis and trans
E and Z
ALKENE GEOMETRY
A REVIEW
π bond
sp2 π bond
R
R
C
R
sp2
C
R
R
R
R
R
R
R
σ bond
σ bond
SIDE VIEW
planar
END VIEW
R
R
ROTATION BREAKS THE
π BOND
Unlike σ bonds, π bonds do not rotate.
NO!
R
R
R
R
• requires 50-60 kcal/mole to break the π bond
• this does not happen at reasonable temperatures
CIS / TRANS ISOMERS
Because there is no rotation about a
carbon-carbon bond, isomers are possible
R
R
C
C
H
H
R
C
H
cis
substituents on
the same side of
main chain
C
R
H
trans
substituents on
opposite sides of
main chain
COMPARE cis / trans ISOMERS IN RING COMPOUNDS
R
R
C
H
C
C
H
C
R
H
cis
R
H
R
trans
R
R
R
In alkenes cis / trans isomers used to be called
geometric isomers, a term generally not generally
used for cyclic systems (rings)
TWO IDENTICAL SUBSTITUENTS
If an alkene has 2 identical substituents on one
of the double bond carbons, cis / trans (or E / Z )
isomers are not possible
H
H
CH3
CH2CH3
H3C
CH2CH3
H
H
H
H
CH2CH3
CH3
all of these compounds are identical
no cis / trans isomers
OTHER COMPOUNDS WITH NO CIS / TRANS
H
CH3
CH3CH2
CH3
H
CH3
CH3
H3C
no cis / trans isomers
CH3
NAMING
cis / trans ISOMERS OF ALKENES
main chain stays
on same side of
double bond = cis
CH3CH2
H
CH2CH3
main chain crosses
to other side of
double bond = trans
CH3CH2
H
cis-3-hexene
notice that these
prefixes are in
italics
H
H
CH2CH3
trans-3-hexene
E / Z SYSTEM OF NOMENCLATURE
To avoid the confusion between what the main
chain is doing and the relationship of two similar
groups ….. the IUPAC invented the E / Z system
Cl
I
F
H
cis ?
trans ?
This system also allows alkenes like the
one above to be classified …..
an impossibility with cis / trans
E / Z NOMENCLATURE
In this system the two groups attached to each carbon
are assigned a priority ( 1 or 2 )
If priority 1 groups are both on same side of double bond:
Z isomer = zusammen = together (in German)
same
side 1
1
2
2
Z
1
2
2
opposite
sides
1
E
If priority 1 groups on opposite sides of double bond:
E isomer = entgegen = opposite (in German)
ASSIGNING PRIORITIES
Cahn-Ingold-Prelog System
1. Look at the atoms attached to each carbon of
the double bond
2. Atom of higher atomic number has higher (1) priority
example
1
atomic number 9 > 1
1
F
F>H
2
bigger is better
H
I
Br
I > Br
2
53 > 35
Since the 1’s are on the same side, this compound is Z
(Z )-1-bromo-2-fluoro-1-iodoethene
notice use of parentheses
3. If you can’t decide using the first atoms attached,
go to the next atoms attached. If there are
non-equivalent paths, always follow the path with
atoms of higher atomic number.
Once you find a difference, you can stop.
1
C>H
6>1
1
CH3
H
2
H
C
CH2F
F
H
CH2CH3
H
2
path goes to
F not to H
comparison
stops here
C C
H
path goes to
C not to H
This molecule has Z configuration
F>C
9>6
4. The atoms in double bonds are “replicated” at either
end of the double bond.
C
CH CH2
C
2
CH CH2
O C
C O
C O
H
H
O>C
8>6
1
Then, when comparing groups, follow the path
of highest priority as before.
EXAMPLE USING REPLICATION
1
CH CH2
CH CH3
CH3
2
C
C
C C H
H H
H
H
C
C H
CH3 H
C>H
cis / trans with rings
H
H
CH3 H
CH3 CH3
cis-1,2-dimethylcyclohexane
H
CH3
trans-1,2-dimethylcyclohexane
CH3
H
H
H
H
CH3
CH3
cis-1,3-dimethylcyclohexane
CH3
trans-1,3-dimethylcyclohexane
H
H
H
CH3
CH3
CH3
CH3
H
cis-1,4-dimethylcyclohexane
trans-1,4-dimethylcyclohexane
DOUBLE BONDS IN RINGS
RINGS
trans double bonds are not possible until the ring
has at least eight carbon atoms
if C<8 then the
chain is too short
to join together
CH2
cis
C=5
CH2
cis
CH2
trans
CH2
C=8
cis
smallest ring that
can have a trans
double bond
C=6
trans
Note that both cis and trans exist for C8
cis and Z are not always the same for a given ring
O>C
8>6
2
1
CH2OH
H
1
2
C>H
6>1
bonds in the ring
are cis
but this compound
is E
Applying Cahn-Ingold-Prelog
Is this molecule cis or trans, E or Z ???
Cl
I
atomic number
cis ? Z ?
F
trans ? E ?
H
2
Cl
1 9 17 35 53
H F Cl Br I
1 I
Increasing priority
2
Cl
1 I
F
1
H 2
H
E
2
F 1
Z
atomic number for N=7
Lets’ Practice . . ..
• List the following atoms/groups in order of
increasing priority
O
1) -NH2, -H, -CH3, -Cl
C O H
-H, -CH3, -NH2, -Cl
O C
2) -CO2H, -CO2CH3, -CH2OH, -OH, -H
-H, -CH2OH, -CO2H, -CO2CH3, - OH
H
3)
CH2CCH2CH3
H
butyl
<
O
H
C
O C H
O C
H
H
CH2CCH3
C
CH3
isobutyl
H
H
O H
Why do we care about cis
and trans ?????
Trans-fat = Geometric isomers
contains trans vs. cis bond
saturated
cis double bond
Oleic acid – C18, cis
Melting point = 13°C
trans double bond
Elaidic acid – C18, trans
Melting point = 45°C
CYCLOHEXANE
Conformational isomers
PLANAR CYCLOHEXANE
(doesn’t exist)
120º
If cyclohexane were planar all of the hydrogens
would be eclipsed, resulting in torsional strain.
There would also be angle strain - a hexagon has
120o internal angles.
cyclohexane is not planar ...
CYCLOHEXANE CONFORMATIONS
CHAIR
BOAT
CHAIR
BOAT
CHAIR CONFORMATION
SELECTED DIMENSIONS
FOR THE CHAIR
Van der Waal’s
radius of H = 1.20 Å
distances greater
than 2.40 Å have no
steric interaction
2.40 Å
H
2.49 Å
H
2.50 Å
H
H
H
normal
C-H and
C-C bond
1.54 Å lengths
1.09 Å
H
H
H
1.20 Å
2.49 Å
All of the hydrogens are
more than 2.40 Å apart.
COMPLETE STAGGERING ABOUT ALL BONDS
axial
equatorial
AXIAL AND EQUATORIAL HYDROGENS
Chair conformations
H
H H
H
H
H
H H
H
H
H
axial
equatorial
H
BOAT CONFORMATION
SELECTED DIMENSIONS
FOR THE BOAT
Van der Waal’s
radius of H = 1.20 Å
distances greater
than 2.40 Å have no
steric interaction
2.40 Å
H
H
1.84 Å
H
H
2.27 Å
H
1.20 Å
H
Bond lengths
are normal.
H
2.27 Å
H
A number of pairs of
hydrogens are closer
than 2.40 Å.
THE CHAIR CONFORMATION HAS
LOWER ENERGY THAN THE BOAT
E
N
E
R
G
Y
29 kJ/mol
boat
0 kJ/mol
chair
INTERCONVERSIONS
RING INVERSION
RING INVERSION
starting ring
axial red
equatorial blue
axial blue
equatorial red
axial and equatorial hydrogens
are interchanged when the ring
is inverted
inverted ring
CONVERSION OF CHAIR TO BOAT
46 kJ/mol
29 kJ/mol
0 kJ/mol
(reference)
chair
conformation
envelope
transition state
boat
conformation
CYCLOHEXANE RING INVERSION
chair 1
envelope 1
boat
chair 2
envelope 2
TWIST BOAT
THE BOAT IS A FLEXIBLE CONFORMATION
IT WILL TWIST OR FLEX
twisting relieves the eclipsing
at the bottom of the ring ...
H
H
… and the top axial
hydrogens move apart
TWIST BOAT
SKEW BOAT
THE TWIST BOAT HAS LOWER ENERGY
THAN THE BOAT
E
N
E
R
G
Y
6 kJ/mol
boat
0 kJ/mol
twist
boat
THE COMPLETE PICTURE
cyclohexane conformation affects the energy state
OTHER MOLECULES THAT
HAVE CHAIR AND BOAT
CONFORMATIONS
NITROGEN AND OXYGEN HETEROATOMS
CAN REPLACE CARBON
H
O
O
N
O
O
O
N H
O
All of these atoms have sp3 hybridization
LARGER RINGS HAVE MANY CONFORMATIONS
…… AND THEY ARE MORE FLEXIBLE
C7
etc
C8
etc
The bigger the ring, the more flexible.
We study cyclobutane, cyclopentane and cyclohexane
specifically because the rings are common and they
have conformations that are easily defined.
LARGE MOLECULES HAVE MANY
POSSIBLE CONFORMATIONS
Drawn as a regular figure
One of its many possible
conformations involving
twisting and rotation
Conformations are not easy to define.
LARGE RINGS CAN FORM A “CROWN”
One of the more interesting conformations of
large rings is the crown.
If the peak carbons are replaced by oxygens
you get a “crown ether”. Crown ethers are
good at complexing (dissolving) metal cations.
..
.. ..
O
..
:O :O O : O :
.. ..
:O O :
O
KCl
+
K
O
O
O
O
Cl-
18-crown-6 coordinating ether
Nobel Prize in Chemistry 1987
To recapitulate . . .
• geometric isomers
– alkenes and cyclic systems
• cis / trans and E / Z
• use Cahn-Ingold-Prelog priority rules
• cyclohexane has multiple conformations
– affects substituent interaction & energy states
• stereoisomers can have significant
biological effects
What’s next ???
• After the break, we will discuss
optical isomers
• Homework assignment for the break
What is
symmetry??
WHICH OBJECTS ARE SYMMETRIC?
(mirror image is identical)
sym
asym (due to pattern)
asym
asym
sym
asym