Transcript Organic Chemistry Introduction

Organic Chemistry I
Stereochemistry
Unit 9
Dr. Ralph C. Gatrone
Department of Chemistry and Physics
Virginia State University
Fall, 2009
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Chapter Objectives
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Enantiomers
Chirality
Optical Activity
Specifying Configuration
Diastereomers
Resolution
Prochirality
Chirality in Nature
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Stereochemistry
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Consider your hands
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Consider molecules shown on left
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Right Hand mirror image of Left Hand
Non-superimposable
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First and Second sets are superimposable
Third set is non-superimposable with mirror image
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Plane of Symmetry
• The plane has the
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same thing on both
sides for the flask
There is no mirror
plane for a hand
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Stereochemistry
• Some objects are not the same as their mirror
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images
no plane of symmetry
– A right-hand glove is different than a left-hand
glove
– The property is commonly called “handedness”
• Organic molecules (including many drugs) have
handedness that results from substitution
patterns on sp3 hybridized carbon
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Enantiomers – Mirror Images
• Molecules exist as three-dimensional objects
– Some molecules are the same as their mirror image
– Some molecules are different than their mirror image
• Stereoisomers that are non-superimposable
with their mirror images are
– Enantiomers
– Arises when we have 4 different groups on an sp3
Carbon atom
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Chirality and Enantiomers
• Chirality arises
– sp3 C atom has 4 different substituents
• The C is referred to as
– A chiral center
– A stereogenic center
– An asymmetric center
• Chirality is a molecular property
– Due to presence of a chiral center
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Enantiomers and the Tetrahedral
Carbon
• Enantiomers are molecules that are not
superimposable with their mirror image
• Illustrated by enantiomers of lactic acid
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Examples of Enantiomers
• Molecules that have one carbon with 4 different
substituents have a nonsuperimposable mirror
image – enantiomer
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Chirality Centers
• A point in a molecule where four different groups (or atoms) are attached
to carbon is called a chirality center
• There are two nonsuperimposable ways that 4 different different groups (or
atoms) can be attached to one carbon atom
– If two groups are the same, then there is only one way
• A chiral molecule usually has at least one chirality center
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Chirality Centers in Chiral Molecules
• Groups are considered “different” if there is any
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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
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Light
• As light travels it oscillates at right angles
to the forward direction
• If it passes through a thin slit, all light
except one plane (the slit) is topped
• That single plane of light is known as
“Plane Polarized Light”
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Optical Activity
• Biot in early 19th Century discovered
– Plane-polarized light that passes through solutions of
achiral compounds remains in that plane
– Solutions of chiral compounds rotate plane-polarized
light and the molecules are said to be optically active
• Some molecules caused plane polarized light to
rotate to the right (dextrorotatory), others to the
left (levorotatory)
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Optical Activity
• Light passes through a plane polarizer
• Plane polarized light is rotated in solutions of
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optically active compounds
Measured with polarimeter
Rotation, in degrees, is []
Clockwise rotation is called dextrorotatory
Counterclockwise is levorotatory
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Measurement of Optical
Rotation
• A polarimeter measures the rotation of plane•
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polarized 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.
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A Simple Polarimeter
• Measures extent of
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rotation of plane
polarized light
Operator lines up
polarizing analyzer and
measures angle
between incoming and
outgoing light
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Specific Rotation
• Amount of rotation is dependent upon number
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of molecules encountered
Therefore define specific rotation, []D for an
optically active compound
• []D = observed rotation/(pathlength x concentration)
= /(l x C) = degrees/(dm x g/mL)
• Specific rotation is that observed for 1 g/mL in
solution in cell with a 10 cm path using light
from sodium metal vapor (589 nanometers)
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Discovery of Enantiomers
• Louis Pasteur (1849) discovered that sodium
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ammonium salts of tartaric acid crystallize into
right handed and left handed forms
The optical rotations of equal concentrations of
these forms have opposite optical rotations
The solutions contain mirror image isomers,
called enantiomers and they crystallized in
distinctly different shapes – such an event is rare
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Enantiomers
• (+)-tartaric acid and (-) tartaric acid
– Identical in every respect
• Chemical properties are identical
• Spectroscopic properties are identical
• Physical properties are identical
– Except
• Direction plane polarized light rotates
• Biological properties
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Enantiomers - Description
• How do we describe enantiomers?
• Need a method to specify the
arrangement of the groups on a chiral
center.
• Comparative Method
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Relative 3-Dimensionl Structure
• a correlation system
classifying related
molecules into “families”
focused on carbohydrates
– Correlate to D- and Lglyceraldehyde
– D-erythrose is the mirror
image of L-erythrose
• Does not apply in general
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Sequence Rules for Specification of
Configuration
• A general method applies to the configuration at each
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chirality center (instead of to the the whole molecule)
The configuration is specified by the relative positions of
all the groups with respect to each other at the chiral
center
The groups are ranked in an established priority
sequence and compared
The relationship of the groups in priority order in space
determines the label applied to the configuration,
according to a rule
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Sequence Rules
H
H3C
OH
CO2 H
Assign priorities to each group on chiral carbon using CahnIngold-Prelog Rules
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Sequence Rules
H 4
3 H3C
OH 1
CO2 H
2
Priorities are based on atomic number
O: AN = 8 priority = 1
H: AN = 1, priority = 4
C = C = 6, tie, use next atom, CO2H is O while CH3 is H
CO2H priority = 2 and CH3 priority is 3
Rewrite structure just using numbers – no atoms
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Sequence Rules
4
1
3
2
Must have the priority 4 group on upper dashed line
Ignore the group
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Sequence Rules
1
3
2
If rotation is clockwise the configuration of the C is R
If the rotation is counterclockwise the configuration is S
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Sequence Rules
• What if 4 isn’t in upper dashed position?
1
4
3
2
Switch the 4 with the number that is in the upper dashed position.
If you do this switch, you MUST switch the other positions also.
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Sequence Rules
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1
4
3
becomes
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23
23
2
ignore
2
1
3
counterclockwise
assigned S
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What if the structure is written
differently?
Right Hand
Left Hand
H3 C
fingers
OH
CO2 H
arm
thumb
H
fingers
HO
H
CH3
HO2 C
arm
thumb
rotate
H
HO2 C
H
OH
CH3
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HO
CO2H
CH3
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Fischer Projections
• Developed by Emil Fischer for carbohydrates
• Demonstrating projections on flat surface
H
H
H3C
OH
CO2 H
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= H3C
OH
CO2 H
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Fischer Projections
• Useful for molecules with more
than one chiral center
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important point (structure is eclipsed)
=
bond is down, eclipsing front bond that is also down
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Two Chiral Centers
• Molecules with more
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than one chirality
center have mirror
image stereoisomers
that are enantiomers
In addition they can
have stereoisomeric
forms that are not
mirror images, called
diastereomers
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2R,3R
2R,3S
2S,3S
2S,3R
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Diastereomers
• Cis and trans alkenes are diastereomers
• Molecules have different chemical and physical properties
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Tartaric Acid
• Tartaric acid has two chiral centers and two diastereomeric forms
• One form is chiral and the other is achiral, but both have two chiral
centers
• An achiral compound with chirality centers is called a meso
compound – it has a plane of symmetry
• The two structures on the right in the figure are identical so the
compound (2R, 3S) is achiral
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Physical Properties of
Stereoisomers
• Enantiomeric molecules differ in the direction in
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which they rotate plane polarized but their other
common physical properties are the same
Diastereomers have a complete set of different
common physical properties
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Molecules with More Than Two
Chirality Centers
• Molecules can have very many chirality centers
• Each point has two possible permanent arrangements
(R or S), generating two possible stereoisomers
• So the number of possible stereoisomers with n chirality
centers is 2n
CH3
CH3
H
H
H
H
HO
Cholesterol has eight chiral centers and 28 possible
isomers
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Racemic Mixtures
• A 50:50 mixture of a pair of enantiomers does
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not rotate light
called a racemic mixture
Separation of a racemic mixture into individual
enantiomers is resolution
Important
– Albuterol – enantiomeric pair
• One causes bronchial passages to expand
• Other causes bronchial passages to contract
– Ibuprofen
• R analgesic
• S no biological activity
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A Brief Review of Isomerism
• The flowchart summarizes the types of isomers
we have seen
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Constitutional Isomers
• Different order of connections gives different
carbon backbone and/or different functional
groups
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Stereoisomers
• Same connections, different spatial arrangement of atoms
– Enantiomers (nonsuperimposable mirror images)
– Diastereomers (all other stereoisomers)
• Includes cis, trans and configurational
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Stereochemistry and Reactions
• Most reactions generate a chiral center
1. Hg(OAc)2
H
OH
2. NaBH4
chiral carbon
• Alcohol is prepared as a racemic mixture
• Why?
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Racemic Mixture Forms
• Addition of Hg(II)
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gives rise to two
cations
Addition of water
gives rise to both
enantiomers
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H O
+
H
Hg H
H
H
O
H
H
H
+
Hg H
H
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Biological Chemistry
• Enzymes yield a single enantiomer
• Enzymes are chiral and induce chirality
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Reactions with Chiral Substrates
H
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CH3
H
CH3
H
OH
Reaction goes through chiral carbocation
Provides some stereochemical preference
Do not observe a 50:50 mixture
Products are diastereomeric
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General Rule
• Reactions of chiral substrates with:
• An achiral reactant gives unequal amounts
of diastereomers
• A chiral reactant gives a chiral product
• Reactions of achiral substrates with
• An achiral reactant gives an achiral
product
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Prochirality
• a molecule is prochiral if it can become
chiral in a single chemical step
• sp2 carbons are designated
• Re (similar to R) or Si (similar to S)
• Consider the following:
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sp3 hybridized carbon atoms
• Prochiral center
• Becomes chiral by changing one attached
group
• Consider the following:
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Designation
• pro-R: replaced atom leads to R
configuration
• pro-S: replaced atom leads to S
configuration
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Biological Chemistry
• Many biological reactions involve prochiral
centers
• Chiral centers are extremely important in
biological processes and drug
development
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Chiral Drugs
H
O
N
O
O
enantiomer: treatment for morning sickness
enantiomer: teratogenic
N
O
thalidomide
OH
OH
H
N
D-enantiomer: restricts airway
L-enantiomer: opens airway
HO
alburerol
COOH
HO
enantiomer: treatment for allergies
enatiomer: fatal heart arrhythmias
N
OH
allgegra
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