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5. Stereochemistry5. Stereochemistry
Why this Chapter?Why this Chapter?
Handedness is important in organic and biochemistry
Molecular handedness makes possible specific interactions between enzymes and substrates
2
StereochemistryStereochemistrySome 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. The property is commonly called “handedness”
Organic molecules (including many drugs) have handedness that results from substitution patterns on sp3 hybridized carbon
p. 290
5.1 Enantiomers and the Tetrahedral Carbon5.1 Enantiomers and the Tetrahedral Carbon
In Muscle Tissue
In Sour Milk
4
EnantiomersEnantiomersEnantiomers 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
5
Examples of EnantiomersExamples of EnantiomersMolecules that have one carbon with 4 different
substituents have a nonsuperimposable mirror image – enantiomer
Build molecular models to see this
Carvones:Carvones:S-(+)-carvoneS-(+)-carvone
Caraway(Dill)(Manderine Orange Peel)
Caraway(Dill)(Manderine Orange Peel)
R-(-)-carvoneR-(-)-carvone
SpearmintSpearmint
7
5.2 Chirality5.2 ChiralityMolecules 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)
8
ChiralityChiralityIf an object has a plane of symmetry it is
necessarily the same as its mirror imageThe lack of a plane of symmetry is called
“handedness”, chiralityHands, gloves are prime examples of
chiral object◦They have a “left” and a “right” version
9
Plane of SymmetryPlane of Symmetry
There is no mirror plane for a hand
The plane has the same thing on both sides for the flask
10
Chirality CentersChirality CentersA 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
11
Chirality Centers in Chiral MoleculesChirality Centers in Chiral MoleculesGroups 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
p. 293
Examples:Examples:
p. 293
p. 294
Learning Check:Learning Check:
Label the chiral centers.
p. 294
Solution:Solution:
Label the chiral centers.
*
* *
*
**
*
How many possible stereoisomers? (2n)
2n = 21 = 2 2n = 23 = 8 2n = 23 = 8
Which of the following molecules Which of the following molecules possesses a plane of symmetry?possesses a plane of symmetry?
1 2 3 4 5
20% 20% 20%20%20%
1. A only2. B only3. C only4. A and C5. B and C
CH3
ClBr
CH3
Cl
ClBr
A B C
Which of the following statements about Which of the following statements about enantiomers is enantiomers is falsefalse??
1 2 3 4 5
20% 20% 20%20%20%1. They have identical melting points.
2. They have identical boiling points.
3. The magnitude of their specific rotations is identical.
4. They have identical densities.
5. They react at the same rate with optically active reagents.
How many stereogenic centers are How many stereogenic centers are present in the following molecule?present in the following molecule?
1 2 3 4 5
20% 20% 20%20%20%
1. 02. 13. 24. 45. 7
OH
O
19
5.3 Optical Activity5.3 Optical ActivityLight restricted to pass through a plane is
plane-polarizedPlane-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 Jean-Baptiste Biot in the early 19th century
20
Optical ActivityOptical ActivityLight passes through a plane polarizerPlane polarized light is rotated in
solutions of optically active compounds
Measured with polarimeterRotation, in degrees, is []Clockwise rotation is called
dextrorotatoryAnti-clockwise is levorotatory
21
Measurement of Optical RotationMeasurement of Optical RotationA polarimeter measures the rotation of plane-
polarized that has passed through a solutionThe source passes through a polarizer and
then is detected at a second polarizerThe angle between the entrance and exit
planes is the optical rotation.
22
Specific RotationSpecific RotationTo have a basis for comparison, define
specific rotation, []D for an optically active compound
[]D = observed rotation
(pathlength x concentration)
= = degrees (l x C) (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 nm)
The specific rotation, [], of a sample is defined for each chiral molecule (the value is solvent dependent):
Specific rotation is a physical constant for a substance as is melting point, boiling point, density, etc.
[ ]
where [ ] = specific rotation
t = temperature in degrees Celsius
= wavelength of incident light
(D = 589 nm, the yellow D line from Na)
ot
l c
= observed optical rotation in degres
l = sample container length in dm
c = concentration (g/ml)
24
Specific Rotation and MoleculesSpecific Rotation and MoleculesCharacteristic 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
25
5.4 Pasteur’s Discovery of Enantiomers5.4 Pasteur’s Discovery of EnantiomersLouis 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
26
5.5 Sequence Rules for Specification of 5.5 Sequence Rules for Specification of ConfigurationConfigurationA general method applies to the
configuration at each chirality center (instead of to 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 applied to the configuration, according to a rule
27
Sequence Rules (IUPAC)Sequence Rules (IUPAC)Rule 1:• Assign each group priority according to the Cahn
Ingold-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”)
•CounterclockCounterclockwise is wise is designated S designated S (from Latin word for “left” sinister)
28
Rule 2: If decision can’t be reached by ranking the first
atoms in the substituents, look at the second, third, or fourth atoms until difference is found
Rule 3:Multiple-bonded atoms are equivalent to the
same number of single-bonded atoms
Fig. 9-8, p. 299
Examples:Examples:
Fig. 9-8, p. 299
Examples:Examples:
What are the absolute configurations of the What are the absolute configurations of the chiral centers in the molecule shown below?chiral centers in the molecule shown below?
1 2 3 4 5
20% 20% 20%20%20%
1. 1: R, 2: R2. 1: R, 2: S3. 1: S, 2: S4. 1: S, 2: R5. because of the ring
structure, the compound does not have chiral centers
H
O
HO12
32
5.6 Diastereomers5.6 DiastereomersMolecules 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
33
Diastereomers
p. 304
EpimersEpimers
Despite its name, ascorbic acid (vitamin C) is not a Despite its name, ascorbic acid (vitamin C) is not a carboxylic acid, but rather has the structure shown carboxylic acid, but rather has the structure shown below. How many stereoisomers of this compound below. How many stereoisomers of this compound are possible?are possible?
1 2 3 4 5
20% 20% 20%20%20%
1. 12. 23. 34. 45. 8
OHO
HOO
HO OH
ascorbic acid
What is the relationship between the two What is the relationship between the two compounds shown below?compounds shown below?
1 2 3 4 5
20% 20% 20%20%20%Br
HClF
F
ClBrH
1. they are identical2. they are constitutional
isomers3. they are
nonsuperimposable mirror images of each other
4. they are different conformations of the same compound
5. they have different atom connectivity
Which of the Which of the structures above are structures above are identical?identical?
1 2 3 4 5
20% 20% 20%20%20%
1. A and C only2. B and D only3. A and D only4. B, C, and D only5. all are the same
A B C D
38
5.7 Meso Compounds5.7 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
Table 9-3, p. 306
MesoEnantiomers
40
5.8 Racemic Mixtures and The 5.8 Racemic Mixtures and The Resolution of EnantiomersResolution of Enantiomers
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 or 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
41
Resolution of EnantiomersResolution of Enantiomers
Inseparable by normal extraction techniques due to identical chemical properties
42
Resolution of EnantiomersResolution of Enantiomers
Separable by normal extraction techniques due to different chemical properties
43
5.9 A Review of Isomerism5.9 A Review of Isomerism
The flowchart summarizes the types of isomers we have seen
44
Constitutional IsomersConstitutional IsomersDifferent order of connections gives different carbon
backbone and/or different functional groups
45
StereoisomersStereoisomersSame connections, different spatial arrangement of atoms
◦ Enantiomers (nonsuperimposable mirror images)◦ Diastereomers (all other stereoisomers)
Includes cis, trans and configurational
46
Stereochemistry of Reactions: Addition Stereochemistry of Reactions: Addition of Hof H22O to AlkenesO 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 H2O to 1-butene
47
Achiral Intermediate Gives Achiral Intermediate Gives Racemic ProductRacemic Product
Addition via carbocationTop and bottom are equally accessible
48
Stereochemistry of Reactions: Addition of Stereochemistry of Reactions: Addition of HH22O to a Chiral AlkeneO to a Chiral Alkene
What is the sterochemical result of the addition of H2O to a chiral alkene R-4-methyl-1-hexene
Product has 2 chiral centers
Fig. 9-16, p. 313
50
5.10 Chirality at Nitrogen, Phosphorus, 5.10 Chirality at Nitrogen, Phosphorus, and Sulfurand SulfurN, P, S commonly found in organic compounds, and
can have chirality centersTrivalent nitrogen is tetrahedralDoes not form a chirality center since it rapidly flips Individual enantiomers cannot be isolated
51
Also applies to phosphorus but it flips more slowly
p. 315
53
5.11 Prochirality5.11 ProchiralityA molecule that is achiral but that can
become chiral by a single alteration is a prochiral molecule
54
Prochiral Distinctions: FacesProchiral Distinctions: FacesPlanar faces that can become tetrahedral are
different from the top or bottomA 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
55
Prochiral distinctions, paired atoms or groupsProchiral distinctions, paired atoms or groupsAn sp3 carbon with two groups that are the
same is a prochirality centerThe 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 pro-S if the center becomes S
56
Prochiral Distinctions in NatureProchiral 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
Example: addition of water to fumarate
p. 317
ExamplesExamples
p. 317
Learning Check:Learning Check:Identify the indicated H’s as Pro R or Pro S
p. 317
Solution:Solution:Identify the indicated H’s as Pro R or Pro S
Pro S Pro R Pro R Pro S
p. 318
Learning Check:Learning Check:Identify the indicated faces as Re or Si
p. 318
Solution:Solution:Identify the indicated faces as Re or Si
Re Re
Si Si
p. 318
Learning Check:Learning Check:Lactic acid in tired muscles results from reduction (addition of H) of pyruvate from the Re face. What is the stereochem of the product?
p. 318
Solution:Solution:
CH3C
CO2-
H OH
Lactic acid in tired muscles results from reduction (addition of H) of pyruvate from the Re face. What is the stereochem of the product?
(S)-
64
5.12 Chirality in Nature and 5.12 Chirality in Nature and Chiral EnvironmentsChiral Environments
Stereoisomers are readily distinguished by chiral receptors in nature
Properties of drugs depend on stereochemistryThink of biological recognition as equivalent to
3-point interactionSee Figure 9-17
p. 318
p. 319
p. 321
p. 321
Important ConceptsImportant Concepts
1. Isomers - Same molecular formula – different compounds.
• Constitutional – Individual atoms are connected differently• Stereoisomers – Same connectivity – different 3D
arrangement.• Mirror-Image Stereoisomers – Related as image – mirror
image.
2. Chiral Molecule - Not superimposable on its mirror image.
3. Stereocenter – Carbon atom bearing 4 different substituents.
4. Enantiomers – Two stereoisomers, each a non-superimposable mirror images of the other.
Important ConceptsImportant Concepts
5. Racemate – A one to one mixture of enantiomers.
6. Mirror Plane – Chiral molecules cannot contain a mirror plane.
7. Diastereomers – Stereoisomers not related to each other as mirror images (ie. cis/trans).
8. Two Stereocenters In A Molecule – Create up to 4 stereoisomers: 2 diastereomerically related pairs of enantiomers. If the 2 stereocenters generate a mirror plane in the molecule, the molecule is known as a meso compound and is achiral.
9. Physical Properties of Stereoisomers – Most are the same except for the rotation of plane polarized light. One enantiometer rotates the plane of polarization to the right, the other to the left. This rotation is expressed as the specific rotation, [].
Important ConceptsImportant Concepts
10. Absolute Configuration - Determined by x-ray diffraction. Assignment of R or S, as determined by the Cahn, Ingold, and Prelog sequence rules.
11. Stereoselectivity - Preference for the formation of one stereoisomer when several are possible.
12. Resolution – Separation of enantiomers.• Reaction with a pure enantiomer of a second chiral
compound and separation of the diastereomers.• Chiral chromatography.
Which statement about chirality and optical Which statement about chirality and optical activity is activity is falsefalse??
1 2 3 4 5
20% 20% 20%20%20%1. If a solution shows optical activity, it must have a compound present whose mirror image is not superimposable on the compound itself.
2. Molecules with plane of symmetry will show no optical activity.
3. The angle of rotation of plane-polarized light depends on how many chiral molecules does the light interact with while passing through the sample.
4. Enantiomers will always have opposite signs of optical rotation.
5. The R enantiomers are dextrorotatory.
Which of the above Which of the above molecules are molecules are achiralachiral??
1 2 3 4 5
20% 20% 20%20%20%
1. A and C2. A and E3. B and C4. B and D5. D and E
E
OH OH
OHOH
A B C D
H
CH3
HO
HO
CH3
H
How many stereoisomers exist for the How many stereoisomers exist for the molecule shown below?molecule shown below?
1 2 3 4 5
20% 20% 20%20%20%
1. 12. 23. 34. 45. 8
HOOC COOH
OH
OH
OH
How many How many mesomeso dibromocyclopentanes, Cdibromocyclopentanes, C55HH88BrBr22, are , are there?there?
1 2 3 4 5
20% 20% 20%20%20%
1. 02. 13. 24. 35. 4
An aqueous solution of A (one stereoisomer) and B An aqueous solution of A (one stereoisomer) and B (one stereoisomer) shows no optical activity. A and (one stereoisomer) shows no optical activity. A and B are stereoisomers. Which statement cannot be B are stereoisomers. Which statement cannot be true?true?
1 2 3 4 5
20% 20% 20%20%20%
1. A and B are diastereomers
2. A and B are not superimposable
3. A and B are enantiomers
4. A is meso and B is chiral
5. A and B are E and Z isomers
How many stereoisomers exist for 5-How many stereoisomers exist for 5-methylhepta-2,3-diene? methylhepta-2,3-diene?
1 2 3 4 5
20% 20% 20%20%20%
1. 12. 23. 34. 45. 8
EE-3-Hexene reacts with one equivalent of -3-Hexene reacts with one equivalent of HBr. If there are no carbocation HBr. If there are no carbocation rearrangements, how many different rearrangements, how many different isomeric products (including stereoisomers) isomeric products (including stereoisomers) will form?will form?
1 2 3 4 5
20% 20% 20%20%20%
1. 12. 2 3. 3 4. 45. 5
What is the relation between the What is the relation between the following two compounds?following two compounds?
1 2 3 4 5
20% 20% 20%20%20%
1. diastereomers2. enatiomers3. identical4. constitutional
isomers5. meso
Br
BrBr
Br
Which is the Which is the bestbest accounting for the accounting for the stereochemistry of the product formed by addition stereochemistry of the product formed by addition of HCl to (of HCl to (RR)-4-chloro-1-pentene?)-4-chloro-1-pentene?
1 2 3 4 5
20% 20% 20%20%20%
1. two enantiomers in equal amounts
2. two enantiomers in different amounts
3. two diastereomers in equal amounts
4. two diastereomers in different amounts
5. three stereoisomers, two of them in equal amounts
How many different How many different mesomeso compounds will be compounds will be produced by the following reaction (assuming produced by the following reaction (assuming there are no carbocation rearrangements)?there are no carbocation rearrangements)?
1 2 3 4 5
20% 20% 20%20%20%
1. 1 2. 2 3. 3 4. 4 5. 5
Br
HBr
Which of the following structures represents the Which of the following structures represents the lowest-energy form of (1lowest-energy form of (1SS, 3, 3SS)-3-)-3-chloromethylcyclohexane?chloromethylcyclohexane?
1 2 3 4 5
20% 20% 20%20%20%1. 2.
3.
4. 5.
Enantiomers have identical chemical and physical properties Enantiomers have identical chemical and physical properties in achiral environments, while diastereomers have different in achiral environments, while diastereomers have different properties in chiral and achiral surroundings. What can be properties in chiral and achiral surroundings. What can be deduced based on the observation that A smells like citrus deduced based on the observation that A smells like citrus fruits, while B has an odor of pine trees?fruits, while B has an odor of pine trees?
1 2 3 4 5
20% 20% 20%20%20%
1. A and B are diastereomers
2. A and B are an exception to the rule and do not have the same properties.
3. The sense of smell cannot be used to deduce anything about the stereochemistry of A and B.
4. The receptors responsible for smell are chiral
5. As can be observed by looking into a mirror, our noses are chiral
H H
A B
How many prochirality centers does 1-How many prochirality centers does 1-butanol (CHbutanol (CH33CHCH22CHCH22CHCH22OH) have?OH) have?
1 2 3 4 5
20% 20% 20%20%20%
1. none2. 13. 24. 35. 4