Stereochemistry
Based 9. on McMurrys Organic Chemistry, 6th edition
2002 Ronald Kluger Department of Chemistry University of Toronto
Stereochemistry
Some objects are not the same as their mirror
images (technically, they have no plane of symmetry) A right-hand glove is different than a left-hand glove (See Figure 9.1) 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
These are stereoisomers called enantiomers
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9.1 Enantiomers and the Tetrahedral Carbon
Enantiomers are molecules that are not the same as
their mirror image They are the same if the positions of the atoms can coincide on a one-to-one basis (we test if they are superimposable, which is imaginary) This is 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 Build molecular models to see this
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Mirror-image Forms of Lactic Acid
When H and
OH substituents match up, COOH and CH3 dont when COOH and CH3 coincide, H and OH dont
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9.2 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 (See Figure 9.4 for examples)
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Chirality
If an object has a plane of symmetry it is necessarily
the same as its mirror image The lack of a plane of symmetry is called handedness, chirality Hands, gloves are prime examples of chiral object They have a left and a right version
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Plane of Symmetry
The plane has the same
thing on both sides for the flask There is no mirror plane for a hand
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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
anystructural 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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9.3 Optical Activity
Light restricted to pass through a plane is plane-
polarized 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 Phenomenon discovered by Biot in the early 19th century
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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
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Measurement of Optical Rotation
A polarimeter measures the rotation of plane-
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
rotation of plane polarized light Operator lines up polarizing analyzer and measures angle between incoming and outgoing light
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Specific Rotation
To have a basis for comparison, 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)
See Table 9.1 for examples
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Specific Rotation and Molecules
Characteristic property of a compound that is
optically active the compound must be chiral The specific rotation of the enantiomer is equal in magnitude but opposite in sign
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9.4 Pasteurs Discovery of Enantiomers (1849)
Louis Pasteur discovered that sodium 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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Relative 3-Dimensionl Structure
The original method
was a correlation system, classifying related molecules into families focused on carbohydrates Correlate to D- and L-glyceraldehyde D-erythrose is the mirror image of Lerythrose This does not apply in general
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9.5 Sequence Rules for Specification of Configuration
A general method applies to the configuration at each
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 chirality 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 to applied the configuration, according to a rule
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Sequence Rules (IUPAC)
Assign each group priority
according to the CahnIngold-Prelog scheme With the lowest priority group pointing away, look at remaining 3 groups in a plane Clockwise is designated R (from Latin for right) Counterclockwise is designated S (from Latin word for left) McMurry Organic Chemistry 6th edition Ch 9 (c) 2003
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R-Configuration at Chirality Center
Lowest priority group is pointed away and direction of
higher 3 is clockwise, or right turn
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Examples of Applying Sequence Rules
If lowest priority is back,
clockwise is R and counterclockwise is S
R = Rectus S = Sinister
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9.6 Diastereomers
Molecules with more
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 See Figure 9-10
2R,3R
2S,3S
2R,3S
2S,3R
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9.7 Meso Compounds
Tartaric acid has two chirality centers and two diastereomeric
forms One form is chiral and the other is achiral, but both have two chirality 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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9.8 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
Cholesterol has eight chirality centers
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9.9 Physical Properties of Stereoisomers
Enantiomeric molecules differ in the direction in which
they rotate plane polarized but their other common physical properties are the same Daistereomers have a complete set of different common physical properties
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9.10 Racemic Mixtures and Their Resolution
A 50:50 mixture of two chiral compounds that are
mirror images does not rotate light called a racemic mixture (named for racemic acid that was the double salt of (+) and (-) tartaric acid The pure compounds need to be separated ot resolved from the mixture (called a racemate) To separate components of a racemate (reversibly) we make a derivative of each with a chiral substance that is free of its enantiomer (resolving agent) This gives diastereomers that are separated by their differing solubility The resolving agent is then removed
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9.11 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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9.12 Stereochemistry of Reactions: Addition of HBr to Alkenes
Many reactions can produce new chirality centers
from compounds without them What is the stereochemistry of the chiral product? What relative amounts of stereoisomers form? Example addition of HBr to 1-butene
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Achiral Intermediate Gives Racemic Product
Addition via carbocation Top and bottom are equally accessible
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Mirror Image Transition States
Transition states are mirror images and product is
racemic
Br
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9.13 Stereochemistry pf Reactions: Addition of Br2 to Alkenes
Stereospecific
Forms racemic mixture Bromonium ion leads to trans addition
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Addition of Bromine to Trans 2Butene
Gives meso product (both are the same)
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9.14 Stereochemistry of Reactions: Addition of HBr to a Chiral Alkene
Gives diastereomers in
unequal amounts. Facial approaches are different in energy
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9.15 Chirality at Atoms Other Than Carbon
Trivalent nitrogen is tetrahedral Does not form a chirality center since it rapidly flips Also applies to phosphorus but it flips more slowly
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9.16 Chirality in Nature
Stereoisomers are readily distinguished by chiral
receptors in nature Properties of drugs depend on stereochemistry Think of biological recognition as equivalent to 3-point interaction See Figure 9-19
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9.17 Prochirality
A molecule that is achiral but that can become chiral
by a single alteration is a prochiral molecule
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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
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Prochiral distinctions, paired atoms or groups
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 was increased in priority in comparison with the other If the center becomes R the group is pro-R and proS if the center becomes S
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Prochiral Distinctions in Nature
Biological reactions often involve making distinctions
between prochiral faces or or groups Chiral entities (such as enzymes) can always make such a distinction Examples: addition of water to fumarate and oxidation of ethanol
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