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Transcript
Stereochemistry at
Tetrahedral Centers
Different Types of Isomerism
Constitutional Isomers
• Different order of connections gives different carbon
backbone and/or different functional groups
Stereochemistry
• For pharmaceuticals, slight differences in 3D spatial
arrangement can make the difference between targeted
treatment and undesired side-effects.
• Isomers that have the same connectivity between atoms
but different 3D, spatial arrangement of their atoms are
called STEREOisomers
Stereochemistry of Organic Compounds
Stereoisomers:
• Same molecular formula
• Same sequence of bonded atoms (constitution),
• Different 3-D orientations of their atoms in space.
Enantiomers: Stereoisomers that are mirror images of each other.
Diastereomers: Stereoisomers that differ at chiral centers, but no every chiral
center.
enantiomers
Seager SL, Slabaugh MR, Chemistry for Today: General, Organic and Biochemistry, 7 th Edition, 2011; http://web.fccj.org/~ethall/stereo/stereo.htm
Stereochemistry of Organic Compounds
Chiral Carbon: Carbon in organic compound that has four different groups
attached to it.
Chirality: “Handedness”. Refers to compounds that cannot be superimposed on
mirror image.
-Defined relative to central, chiral atom (carbon)
Chiral carbon
H
CHO indicates
aldehyde
OHC
C
H
OH
HO
CH2OH
OHC
OH
C
CH2OH
enantiomers
Seager SL, Slabaugh MR, Chemistry for Today: General, Organic and Biochemistry, 7 th Edition, 2011
C
CHO
CH2OH
HO
CHO
C
CH2OH
Cis-trans Isomers
• C-C bonds that are constrained in a cyclic structure can not freely
rotate
• To maintain orbital overlap in the pi bond, C=C double bonds can
not freely rotate.
Cis-trans Isomers
• With rings and with C=C double bonds, cis-trans
notation is used to distinguish between stereoisomers
• Cis – identical groups are positioned on the SAME side
of a ring
• Trans – identical groups are positioned on OPPOSITE
sides of a ring
Copyright © 2015 John Wiley
& Sons, Inc. All rights reserved.
5-8
Klein, Organic Chemistry 2e
Isomers
• Identify the following pairs as either constitutional
isomers, stereoisomers, or identical.
1.
2.
3.
4.
5.
Stereoisomers
• Beyond cis-trans isomers, there are many other important
stereoisomers
• To identify such stereoisomers, we must be able to identify
chiral molecules
• A chiral object is NOT identical to its mirror image
• You are a chiral object. Look in a mirror and raise your right
hand. Your mirror image raises his or her left hand.
• You can test whether two objects are identical by seeing if
they are superimposable.
• Chirality is important in molecules.
– Because two chiral molecules are mirror images, they will have
many identical properties, but because they are not identical, their
pharmacology may be very different
Stereochemistry
• Some objects are not the
same as their mirror
images (technically, they
have no plane of
symmetry)
– A right-hand glove is
different froma lefthand glove. The
property is commonly
called “handedness”
• Organic molecules
(including many drugs)
have handedness that
results from substitution
patterns on sp3 hybridized
carbon
Stereoisomers
• Chirality most often results when a carbon atom is
bonded to 4 unique groups of atoms.
Stereoisomers
• Same connections, different spatial arrangement of atoms
– Enantiomers (nonsuperimposable mirror images)
– Diastereomers (all other stereoisomers)
• Includes cis, trans, configurational
Chirality Centers
• A point in a molecule where four different groups (or atoms)
are attached to carbon is called a chirality center
(stereocenter).
• There are two nonsuperimposable ways that 4 different
different groups (or atoms) can be attached to one carbon
atom
• A chiral molecule usually has at least one chirality center
Chirality Centers
Stereoisomers
• Identify all of the chirality centers (if any) in the
following molecules
Examples of Enantiomers
• Molecules that have one carbon with 4 different substituents
have a nonsuperimposable mirror image – enantiomer
• Build molecular models to see this
The Reason for Handedness: Chirality
• Molecules that are not superimposable with their
mirror images are chiral (have handedness)
• A plane of symmetry divides an entire molecule
into two pieces that are exact mirror images
• A molecule with a plane of symmetry is the same
as its mirror image and is said to be achiral.
Plane of Symmetry
• The plane has the same
thing on both sides for
the flask
• There is no mirror plane
for a hand
Chirality Centers in Chiral
Molecules
• Groups are considered “different” if there is any structural
variation (if the groups could not be superimposed if
detached, they are different)
• In cyclic molecules, we compare by following in each
direction in a ring
Designating Configurations
• Enantiomers are NOT identical, so they must not have
identical names
• Their names must be different, so we use the CahnIngold-Prelog system to designate each molecule as
either R or S.
Designating Configurations
• The Cahn, Ingold and Prelog system
1. Using atomic numbers, prioritize the 4 groups attached to
the chirality center
2. Arrange the molecule in space so the lowest priority group
faces away from you
3. Count the group priorities 1…2…3 to determine whether the
order progresses in a clockwise or counterclockwise direction
4. Clockwise = R and Counterclockwise = S
Designating Configurations
• The Cahn, Ingold and Prelog system
1. Using atomic numbers, prioritize the 4 groups attached to
the chirality center. The higher the atomic number, the
higher the priority
– Prioritize the groups on this molecule
Designating Configurations
• The Cahn, Ingold and Prelog system
2. Arrange the molecule in space so the lowest priority group
faces away from you
– This is the step where it is most helpful to have a handheld
model
Designating Configurations
• If a decision cannot be reached by ranking the first atoms in the
substituents, look at the second, third, or fourth atoms until
difference is found
Designating Configurations
• The Cahn, Ingold and Prelog system
3. Counting the other group priorities, 1…2…3, determine
whether the order progresses in a clockwise or
counterclockwise direction
4. Clockwise = R and Counterclockwise = S
Designating Configurations
• Designate each chirality center below as either R or S.
Designating Configurations
• When the groups attached to a chirality center are
similar, it can be tricky to prioritize them
• Analyze the atomic numbers one layer of atoms at a
1
time
4
First layer
Tie
Second layer
2
• Is this molecule R
or S?
3
Designating Configurations
• Analyze the atomic numbers one layer of atoms at a
4 1
time
• The priority is
• First layer
based on the first
Tie
• Second layer
2
3
point of difference,
NOT the sum of
the atomic
numbers
• Is this molecule R
or S?
Designating Configurations
• When prioritizing for the Cahn, Ingold and Prelog
system, double bonds count as two single bonds
• Determine R or S for the following molecule
Designating Configurations
• Handheld molecular models can be very helpful when
arranging the molecule in space so the lowest priority
group faces away from you
• Here are some other tricks that can use
– Switching two groups on a chirality center will produce its
opposite configuration
Designating Configurations
• Switching two groups on a chirality center will produce
its opposite configuration
• You can use this trick to adjust a molecule so that the
lowest priority group faces away from you
• With the 4th priority group facing away, you can
designate the configuration as R
• Work backwards to show how the original structure’s
configuration is also R
Designating Configurations
Designating Configurations
• The R or S configuration is used in the IUPAC name for
a molecule to distinguish it from its stereoisomer(s)
Copyright © 2015 John Wiley
& Sons, Inc. All rights reserved.
5-34
Klein, Organic Chemistry 2e
Optical Activity
• Light restricted to pass through a plane is plane-polarized
• Plane-polarized light that passes through solutions of achiral
compounds retains its original plane of polarization
• Solutions of chiral compounds rotate plane-polarized light
and the molecules are said to be optically active
• Phenomenon discovered by Jean-Baptiste Biot in the early
19th century
Optical Activity
• Light passes through a plane polarizer
• Plane polarized light is rotated in solutions of optically active
compounds
• Measured with polarimeter
• Rotation, in degrees, is []
• Clockwise rotation is called dextrorotatory
• Anti-clockwise is levorotatory
Measurement of Optical Rotation
• A polarimeter measures the rotation of plane-polarized light
that has passed through a solution
• The source passes through a polarizer and then is detected at
a second polarizer
• The angle between the entrance and exit planes is the optical
rotation.
Optical Activity
• Enantiomers will rotate the plane of the light to equal
degrees but in opposite directions
• The degree to which light is rotated depends on the
sample concentration and the pathlength of the light
• Standard optical rotation measurements are taken with
1 gram of compound dissolved in 1 mL of solution, and
with a pathlength of 1 dm for the light
• Temperature and the wavelength of light can also
affect rotation and must be reported with
measurements that are taken
Optical Activity
• Consider the enantiomers of 2-bromobutane
• R and S refer to the configuration of the chirality center
• (+) and (-) signs refer to the direction that the plane of
light is rotated
• The specific rotation of the enantiomer is equal in
magnitude but opposite in sign
Optical Activity
•
•
•
•
There is no relationship between the R/S configuration and the
direction of light rotation (+/-)
The magnitude and direction of optical rotation can not be
predicted from a chiral molecule’s structure or configuration. It
can ONLY be determined experimentally
As long as its bonds are not rearranged, its configuration
CANNOT change
Racemic Mixtures (samples with equal amounts of two
enantiomers) exhibit no optical activity
Optical Activity
• For unequal amounts of enantiomers, the
enantiomeric excess (% ee) can be determined from
the optical rotation
• For a mixture of 70% (R) and 30% (S), what is the % ee?
Copyright © 2015 John Wiley
& Sons, Inc. All rights reserved.
5-41
Klein, Organic Chemistry 2e
Optical Activity
• If the mixture has an optical rotation of +4.6, use the
formula to calculate the % ee and the ratio of R/S
Diastereomers
• Molecules with more than one chirality center usually have
mirror image stereoisomers that are enantiomers
• In addition they can have stereoisomeric forms that are not
mirror images, called diastereomers
Stereoisomeric Relationships
• The number of possible stereoisomers for a compound
depends on the number of chirality centers (n) in the
compound
• What is the maximum number of possible cholesterol
isomers?
Symmetry and Chirality
•
•
•
•
•
Any compound with only ONE chirality center will be chiral and have an
optical rotation
However, compounds with an even number (2,4,6, etc.) of chirality centers
may or may not be chiral
If a molecule has a plane of symmetry, it will be achiral
Half of the molecule reflects the other half
Its optical activity will be canceled out within the molecule, similar to how a
pair or mirror image enantiomers cancel out each others optical rotation
Symmetry and Chirality
• Molecules with an even number of chirality
centers that have a plane of symmetry are
called meso compounds
• Another way to test if a compound is a
meso compound is to see if it is identical to
its mirror image
• Draw the mirror image of the cis isomer and show that
it can be superimposed on its mirror image
• By definition, when a compound is identical to its
mirror image, it is NOT chiral. It is achiral
Copyright © 2015 John Wiley
& Sons, Inc. All rights reserved.
5-46
Klein, Organic Chemistry 2e
Symmetry and Chirality
• In another example, the plane of symmetry identifies it
as a meso compound
• meso compounds also have less than the predicted
number of stereoisomers based on the 2(n) formula
• Draw all four expected isomers and show how two of
them are identical. A handheld model might be helpful
Chirality at Nitrogen, Phosphorus, and Sulfur
• N, P, S commonly found in organic compounds, and can have
chirality centers
• Trivalent nitrogen is tetrahedral
• Does not form a chirality center since it rapidly flips
• Individual enantiomers cannot be isolated
Chirality at Nitrogen, Phosphorus, and Sulfur
• May also apply to phosphorus but it flips more slowly
Fischer Projections
• Fischer projections can also be used to represent
molecules with chirality centers
• Horizontal lines represent attachments coming out of
the page
• Vertical lines represent attachments going back into
the page
Fischer Projections
• Fischer projections can be used to quickly draw
molecules with multiple chirality centers
Fischer Projections
• Fischer projections can also be used to quickly assess
stereoisomeric relationships
Interconverting Enantiomers
• Molecules can rotate around single bonds.
• Recall the gauche rotational conformation
of butane
• Is the gauche conformation of butane
chiral?
• Draw its mirror image. Is it superimposable on its
mirror image?
• Why is butane’s optical rotation equal to zero?
• To be chiral, a compound cannot be a rotational
conformer of its mirror image
Interconverting Enantiomers
• Compare the (cis)-1,2-dimethylcyclohexane chair with
the Haworth projection
• The Haworth image can be used to quickly identify the
compound as an achiral meso compound.
• However, a plane of symmetry can NOT be found in the
chair conformation
Interconverting Enantiomers
• The freely interconverting mirror images cancel out
their optical rotation, so it is achiral
• This analysis is much easier to do with a handheld
models than in your mind
• If the Haworth image has a mirror plane, then the chair
will be able to interconvert with its enantiomer, and it
will be achiral.
Prochirality
• A molecule that is achiral but that can become chiral by a single
alteration is a prochiral molecule
Prochiral Distinctions: Faces
• Planar faces that can become tetrahedral are different from the top
or bottom
• A center at the planar face at a carbon atom is designated re if the
three groups in priority sequence are clockwise, and si if they are
counterclockwise
Prochiral Distinctions: Faces
• An sp3 carbon with two groups that are the same is a
prochirality center
• The two identical groups are distinguished by considering
either and seeing if it wereincreased in priority in comparison
with the other
• If the center becomes R the group is pro-R and pro-S if the
center becomes S
Prochiral Distinctions in Nature
• Biological reactions often involve making distinctions between
prochiral faces or groups
• Chiral entities (such as enzymes) can always make such a
distinction
• Example: addition of water to fumarate
Chirality in Nature and Chiral Environments
• Stereoisomers are readily distinguished by chiral
receptors in nature
• Properties of drugs depend on stereochemistry
• Think of biological recognition as equivalent to 3point interaction