6.6%20%20Acid-Catalyzed%20Hydration%20of%20Alkenes

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Chirality
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Chirality
A molecule is chiral if its two mirror-image
forms are not superimposable in three dimensions.
The word chiral is derived from the Greek word
cheir, meaning hand.
Chirality most often occurs in molecules that
contain a carbon that is attached to four
different groups.
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Enantiomers
Stereoisomers that are related as an object and
its nonsuperimposable mirror image are classified
as enantiomers.
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Rotating Molecules in Space
To check whether the representations are
superposable first rotate the molecule around so
that the H is in the same direction.
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Rotating molecules in Space
After rotation of B check if it is superposable
with A. The H and the F are superposable but the
Br and Cl are not. So, non-superposable mirror
images that are enantiomers.
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Chirality Center
Molecules of the general type CWXYZ are chiral
when w, x, y, and z are different.
2-Butanol is chiral four different groups on C-2.
2-Propanol is achiral two of the groups on C-2
are the same.
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Common Chiral Molecules
Linalool, a pleasant smelling oil from oranges.
Limonene, a constituent of lemon oil. C-4 is the
chirality center.
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Chirality with Isotopes
Achiral alkanes can be transformed into chiral
molecules by replacing H with deuterium (D) or
tritium (T) as shown in this molecule
Isotopic labelling can be used to learn
information about the mechanism of reactions.
For example
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Symmetry in Achiral Compounds
A molecule that has either a plane of symmetry
or, a center of symmetry will be superposable on
its mirror image and therefore achiral.
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Plane of Symmetry
A plane of symmetry bisects a molecule so that
one half of the molecule is the mirror image of
the other half. This achiral molecule,
chlorodifluoromethane, has the plane of symmetry
shown.
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Center of Symmetry
A point is a center of symmetry if any line drawn
from it to some element of the structure will,
when extended an equal distance in the opposite
direction, encounter an identical element.
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Optical Activity
A sample is optically active if it rotates the
plane of polarized light.
To be optically active, the sample must contain a
chiral substance and one enantiomer must be
present in excess of the other.
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Optical Activity
The direction and magnitude of rotation are cited
as a, the observed rotation.
Mixtures of enantiomers are characterized by
the enantiomeric excess (ee). ee ( major
enantiomer) ( minor enantiomer)
If ee 100 the sample is enantiopure. A 11
mixtures of enantiomers are called racemic
mixtures. Racemic mixtures are optically
inactive.
All achiral substances are optically inactive.
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Specific Rotation
Specific rotation a is the rotation adjusted
for concentrationand the length of the sample
cell.
a can be used to determine the sample purity.
Enantiomers have a of equal magnitude but
oppositesign.
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Absolute Configuration
The exact three-dimensional spatial arrangement
of substituents at a chirality center is its
absolute configuration.
Cannot decide which is ()-2-butanol, or
(-)-2-butanol!
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Relative Configuration
Compounds have the same relative configuration if
the configuration of the chirality center is the
same. In these reactions the reactant and
product have the same relative configuration
because the reactions do not affect the chirality
center.
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From Relative Configuration to Absolute
Configuration
Absolute configuration of a salt of () tartaric
acid was determined in 1951 by X-ray
crystallography. The absolute configurations of
all compounds related to ()-tartaric acid were
then known.In this way the absolute
configuration of the enantiomers of 2-butanol are
known.
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The Cahn-Ingold-Prelog Rules

• 1. Rank the substituents at the chirality center
  according to rules used in E-Z notation.highest
  -OH gt CH2CH3 gt CH3 gt H lowest
• 2. Orient the molecule so that lowest-ranked
  substituent points away from you and ignore the
  lowest-ranked substituent.

becomes
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The Cahn-Ingold-Prelog Rules

• 3. If the order of decreasing precedence traces a
  clockwise path, the absolute configuration is R.
  If the path is counterclockwise, the
  configuration is S.

becomes
So the name is (S)-2-Butanol.
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Names of Enantiomers
The pair of enantiomers differ only in the
arrangement of atoms in space so the name only
differs in the R/S assignment.
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Chirality Center in a Ring
Remember a CC double bond is treated like two
bondsto a C.
and the configuration is R
()-4-methylcyclohexene
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Fischer Projections

• For a Fischer projection the molecule is oriented
  so that the vertical bonds at the chirality
  center are directed away from you and the
  horizontal bonds point toward you.
• The chirality center is at the center of a cross
  and notspecified.

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Fischer Projections

• The molecule is oriented so that the lowest
  numbered carbon is at the top of the chain.

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Properties of Enantiomers

• Some enantiomers have different odors. Each
  enantiomer reacts with the receptors in the nose
  differently. This is chiral recognition which
  is common in nature where receptors interact
  with only one enantiomer.

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Chiral Drugs

• Many drugs have a chirality center, two examples
  are ibuprofen and thalidomide. Often only one
  enantiomer is active.

(S)-Ibuprofen has pain-relieving properties while
the (R)-enantiomer does not. (R)-Thalidomide
was used for its anti-nausea properties. The
(S)-enantiomer caused birth defects.
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Chirality Axis

• A chirality axis is an axis about which a set of
  atoms or groups is arranged so that the spatial
  arrangement is notsuperposable on its mirror
  image.Substituted biaryls like biphenyl may
  have chirality axes and exist as two
  non-superposable enantiomers.

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Chirality Axis

• Unsubstituted biphenyl (A, B, X, Y H) is
  nonplanar but can rotate about the C-C single
  bond to interchange between conformations
  rapidly. With substituents A, B, X, Y the
  conformations are locked and cannot interchange.

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Chirality Axis

• The compound below was demonstrated to exist as
  two enantiomers with a chirality axis in 1922!

These isomers are known as atropisomers, from the
Greek a meaning not and tropos meaning turn.
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Chirality Axis

• Many compounds with chiral axes are incorporated
  intometal catalysts. These catalysts mediate
  reactions that are enantiospecific and yield
  predominantly one enantiomer as product. Binap
  is one example used in chiral drug synthesis.

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Reactions that Create Chiral Centers

• Many of the reactions we have examined so far
  often form chiral centers.

The central carbon of the epoxide is a chirality
center with four different groups attached.
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Reactions that Create Chiral Centers

• The alkene is planar so the peroxyacid attacks
  the alkenefrom the top or the bottom.

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Reactions that Create Chiral Centers

• Addition of HBr to an alkene can generate a
  chirality center.

Chlorination of alkanes can generate a chirality
center.
Both reactions form a 11 mixture of enantiomers
whichis a racemic mixture.
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Reactions that Create Chiral Centers
Optically inactive starting materials can give
optically active products only if they are
treated with an optically active reagent or if
the reaction is catalyzed by an optically active
substance.In nature the chiral catalyst is an
enzyme.
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Molecules with two Chirality Centers
Consider 2,3-dihydroxybutanoic acid.

• Carbons 2 and 3 are chirality centers. Each
  stereocentercould be R or S so there are four
  possible stereoisomers(2R, 3R) (2S, 3S) (2R,
  3S) (2S, 3R).

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Stereoisomers of 1,2-Dihydroxybutanoic acid
Stereoisomers I and II are enantiomers of each
other
Stereoisomers III and IV are enantiomers of each
other
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Stereoisomers of 1,2-Dihydroxybutanoic acid
Stereoisomers I and III are diastereomers of each
other.
Diastereomers are stereoisomers that are not
enantiomers.Pairs of diastereomers I and
III I and IV II and III II and IV.
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Stereoisomers of 1,2-Dihydroxybutanoic acid
Enantiomers Are mirror images of each
other. With two stereocenters in a molecule the
enantiomer has the configuration changed at both
stereocenters. Enantiomers have equal and
opposite specific rotations.
Diastereomers Are stereoisomers that are not
mirror images. With two stereocenters in a
molecule a diastereomer has the configuration
changed at only one stereocenter. Diastereomers
will have different magnitude and direction
specific rotations.
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Fischer Projections of 1,2-Dihydroxybutanoic Acid
Setting up the Fischer ProjectionDraw the
structure so that the lowest numbered carbon is
at the top. Arrange horizontal bonds to be facing
towards you. Then flatten the molecule and draw
it out.
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Fischer Projections of 1,2-Dihydroxybutanoic Acid
Fischer Projection of compounds with multiple
stereocenters simplifies identification of
enantiomers and diastereomers.
Erythreo isomers have like substituents on the
same side. Threo isomers have like substituents
on opposite sides.
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Physical Properties of Diastereomers
Physical properties of enantiomers are identical
except for the rotation of plane polarized
light. Diastereomers may differ in any physical
property, for example
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Stereoisomers of 1-bromo-2-chlorocyclopropane
Two stereocenters in a ring may also give rise to
four stereoisomers which can be grouped as two
pairs of enantiomers.
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Symmetric Molecules with two Chirality Centers

• 2,3-Butanediol has two chirality centers that are
  equivalently substituted.

There are only three stereoisomers not four.
Why?
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Stereoisomers of 2,3-Butanediol

• These are the three stereoisomers.

Compound (c) has a plane of symmetry and is
superposable on its mirror image. This is a
molecule with chirality centers that is achiral
(not chiral) and is named a meso form. It
issuperposable on its mirror image so there are
only three stereoisomers.
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Stereoisomers of 2,3-Butanediol

• These stereoisomers can be shown as Fischer
  projections.

The dashed line represents the plane of symmetry.
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Stereoisomers of 1,2-dibromocyclopropane

• This molecule has three stereoisomers. The cis
  compoundhas a plane of symmetry and is a meso
  compound.

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Molecules with Multiple Chirality Centers

• A molecule with n stereocenters can have a
  maximum of 2n stereoisomers.

This carbohydrate has 4 stereocenters and no
planes of symmetry so there are 24 16
stereoisomers.
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Molecules with Multiple Chirality Centers

• Steroids also contain multiple stereocenters.

Cholic acid shown here has 11 stereocenters and
potentionally 211 or 2048 stereoisomers. Only
one has been isolated from natural sources.
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Alkenes and Chirality Centers

• Molecules that include both an alkene and a
  chirality centermay exist as 4 stereoisomers
  (R,E), (R,Z), (S,E) and (S,Z).For example
  3-penten-2-ol

-enantiomers-
-enantiomers-
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Reactions that Produce Diastereomers

• Reaction of 2-butene with bromine yields
  2,3-dibromobutanewhich has two identically
  substituted chirality centers.
• The product can therefore exist as a pair of
  enantiomers and a meso compound.

The actual product formed depends on the
stereochemistry of the alkene and the anti
addition of bromine.
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Effect of Alkene Stereochemistry

• Anti addition of bromine to the (E) stereoisomer
  yields the meso product.

meso-2,3-dibromobutane
meso-2,3-dibromobutane
A single achiral product is formed!
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Effect of Alkene Stereochemistry

• Anti addition of bromine to the (Z) stereoisomer
  yields a (11) racemic mixture of enatiomers.

(2S,3S)-2,3-dibromobutane
(2R,3R)-2,3-dibromobutane
A 11 (racemic) mixture of enantiomers is formed.
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Generating a Second Chirality Center

• Hydrogenation of the alkene below yields two
  stereoisomers.The major product corresponds to
  hydrogenation from the least hindered side of
  the alkene.

The reaction is stereoselective one
stereoisomer is formed as the major product.
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Resolution with Tartaric Acid

• The first resolution was carried out by Louis
  Pasteur in 1848using tartaric acid.

Pasteur separated a salt of a rare racemic
mixture of tartaric acid based using a
micrsocope and tweezers.
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Resolution of Enantiomers

• Enantiomers only differ in the rotation of plane
  polarized light but diastereomers may differ in
  other physical properties and may be separated.
  The strategy (1) Transform the mix of
  enantiomers into a mix of diastereomers as a
  salt for separation.(2) Separate the
  diastereomeric mixture(3) Reform the separated
  enantiomer.

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Resolution of Enantiomers
Graphical representation.
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Forming Diasteromeric Salts

• Enantiomers are transformed into diastereomeric
  salts by acid-base reactions.

The compounds used for resolution are generally
derivedfrom natural sources, for example
(S)-malic acid fromapples.
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Dissociating the Diastereomeric Salts

• After separation of the diastereomeric salts the
  separatedsalts are treated with base to
  regenerate the enantiomer

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Kinetic Resolution

• Kinetic resolution depends on the different rates
  of reactions of two enantiomers with a chiral
  compound (enzyme).

One enantiomer of the ester is hydrolyzed
preferentially. The product of that reaction is
isolated as a pure enantiomer while the
unreacted enantiomer can be isolated as well.