Chapter 5: Stereochemistry
Chapter 5: Stereochemistry
• The three‐dimensional (3D) structure of a molecule can greatly affect its physical and chemical properties. Can you give some examples?
• For pharmaceuticals, slight differences in 3D spatial arrangement can make the difference between targeted treatment and undesired side effects. WHY?
• 3D structure is critical in biochemistry. HOW?
• Isomers that have the same connectivity between atoms but different 3D spatial arrangement of their atoms are called STEREOISOMERS.
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5.1 Isomers
5.1 Isomers
• Isomers are NONIDENTICAL molecules that have the same formula.
• There are two classifications of isomers:
• Draw a pair of molecules that are constitutional isomers.
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• C–C bonds that are constrained in a cyclic structure cannot freely rotate.
• Although the two molecules below have the same connectivity, they are NOT identical. • The naming system we have learned thus far would give them the same name, but they are NOT identical, so we need to learn additional nomenclature.
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5.1 Isomers
5.1 Isomers
• To maintain orbital overlap in the pi bond, C=C double bonds cannot freely rotate.
• Identify the following pairs as either constitutional isomers, stereoisomers, or identical. EXPLAIN. 1.
4.
• Although the two molecules below have the same connectivity, they are NOT identical.
2.
OH
OH
5.
HO
OH
3.
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5.1 Isomers
5.1 Isomers
• With rings and C=C double bonds, cis and trans notation is used to distinguish between stereoisomers.
• Cis—identical groups are positioned on the SAME side of a C=C double bond.
• Trans—identical groups are positioned on OPPOSITE sides of a C=C double bond.
– Cis—identical groups are positioned on the SAME side of a ring.
– Trans—identical groups are positioned on OPPOSITE sides of a ring.
• Practice with SKILLBUILDER 5.1.
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5.1 Isomers
5.
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5.2 Stereoisomers
• Some other chiral objects include gloves. HOW?
– Think of some other examples of chiral everyday objects.
• Chirality is important in molecules. – If two molecules are mirror images, they will have many similar properties, but because they are not identical, their pharmacology may be very different.
• Visualizing mirror images of molecules and manipulating them in 3D space to see if they are superimposable can be VERY challenging.
– It is highly recommended that you use handheld models as visual aids until you get more experience.
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• Beyond cis and trans isomers, there are many other important stereoisomers.
• To identify such stereoisomers, we must be able to identify CHIRAL molecules.
• You can test whether two objects are identical by seeing if they are SUPERIMPOSABLE. • Can you be superimposed upon your mirror image?
3.
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– 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.
2.
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5.2 Stereoisomers
• Identify the following as either cis, trans, or neither. EXPLAIN. 1.
4.
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5.2 Stereoisomers
• Chirality most often results when a carbon atom is bonded to 4 unique groups of atoms.
• Make a handheld model to prove to yourself that they are NOT superimposable.
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5.2 Stereoisomers
• When an atom such as carbon forms a tetrahedral center with four different groups attached to it, it is called a chiral center (aka stereocenter or stereogenic
center).
• Analyze the attachments for each chiral center below.
5.2 Stereoisomers
• Identify all of the chiral centers (if any) in the following molecules.
• Practice with SKILLBUILDER 5.2.
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5.2 Stereoisomers – Enantiomers
• Some stereoisomers can also be classified as ENANTIOMERS.
• Enantiomers are TWO molecules that are MIRROR IMAGES but are NONIDENTICAL and NONSUPERIMPOSABLE.
• For the pair below, draw in the missing enantiomer.
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5.2 Stereoisomers – Enantiomers
• What is the relationship between the two molecules below?
Cl
• Make handheld models for both structures to verify that they are NONIDENTICAL mirror images.
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• Practice with SKILLBUILDER 5.3.
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5.3 Designating Configurations
• Enantiomers are NOT identical, so they must not have identical names.
• How would you name these molecules?
• Their names must be different, so we use the Cahn‐
Ingold‐Prelog rules to designate each molecule as either R or S.
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• Given that the molecules are so similar, how is it possible that our noses can distinguish between them?
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5.3 Designating Configurations
• Cahn‐Ingold‐Prelog rules: 1. Using atomic numbers, prioritize the four groups attached to the chiral 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
Counterclockwise = S
• A handheld model can be very helpful visual aid for this process.
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5.3 Designating Configurations
• Cahn‐Ingold‐Prelog rules: 5.3 Designating Configurations
• Cahn‐Ingold‐Prelog rules: 1. Using atomic numbers, prioritize the four groups attached to the chiral center. The higher the atomic number, the higher the priority.
2. Arrange the molecule in space so the lowest priority group faces away from you.
– Prioritize the groups on this molecule:
– This is the step where it is most helpful to have a handheld model.
Cl
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5.3 Designating Configurations
1. Using atomic numbers, prioritize the four groups attached to the chiral center.
2. Arrange the molecule in space so the lowest priority group faces away from you.
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5.3 Designating Configurations
• Cahn‐Ingold‐Prelog rules: 3. Count the group priorities 1…2…3 to determine whether the order progresses in a clockwise or counterclockwise direction.
• Complete steps 1 and 2 for the following molecule.
4. Clockwise = R Counterclockwise = S
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5.3 Designating Configurations
• Designate each chiral center below as either R or S.
Cl
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5.3 Designating Configurations
• When the groups attached to a chiral center are similar, it can be tricky to prioritize them.
• Analyze the atomic numbers one layer of atoms at a time.
– Is this molecule R or S?
4
First layer:
O
1
Tie
NH3
O
Second layer:
2
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3
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5.3 Designating Configurations
5.3 Designating Configurations
• Analyze the atomic numbers one layer of atoms at a time.
• The priority is based on the first point of difference, NOT THE SUM of the atomic numbers.
• When prioritizing for the Cahn‐Ingold‐Prelog rules, double bonds count as two single bonds.
– Is this molecule R or S?
4
1
First layer:
Second layer:
Tie
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2
3
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• Determine whether the following molecule is R or S.
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5.3 Designating Configurations
5.3 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 chiral 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:
– Switching two groups on a chiral center will produce its opposite configuration.
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• 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.
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5.3 Designating Configurations
• Practice with SKILLBUILDER 5.4. Copyright 2012 John Wiley & Sons, Inc.
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5.3 Designating Configurations
• The R or S configuration is used in the IUPAC name for a molecule to distinguish it from its enantiomer.
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5.4 Optical Activity
5.4 Optical Activity
• Because the structures of enantiomers are so similar, many of their properties are identical.
• Enantiomers have opposite configurations (R vs. S), so they will rotate PLANE‐POLARIZED light in opposite directions.
• What is PLANE‐POLARIZED light?
• If you have a sample of a chiral compound, how can its enantiomeric purity be assessed? – In other words, how can one enantiomer be distinguished from another?
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5.4 Optical Activity
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5.4 Optical Activity
• To get light waves that travel in only one plane, light travels through a filter.
• When plane polarized light is directed through a sample of a PURE chiral compound, the plane that the light travels on will rotate. • Compounds that can rotate the plane or plane‐
polarized light are called OPTICALLY ACTIVE.
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5.4 Optical Activity
•
Enantiomers will rotate the plane of the light to equal degrees, but in opposite directions.
–
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5.4 Optical Activity
• Consider the enantiomers of 2‐bromobutane.
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 (T) and the wavelength of light (λ) can also affect rotation and must be reported with measurements that are taken.
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– R and S refer to the configuration of the chiral center.
– (+) and (‐) signs refer to the direction that the plane of light is rotated.
– The optical activity was measured at 589 nm, which is the sodium D line wavelength.
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5.4 Optical Activity
5.4 Optical Activity
• There is no relationship between the R/S configuration and the direction of light rotation (+/‐).
• Should the chiral center below be designated R or S?
• The magnitude and direction of optical rotation cannot 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.
– It is levorotatory (‐) at 20°C, while at 100°C, it is dextrorotatory (+).
• Predict the optical rotation for a RACEMIC MIXTURE (a sample with equal amounts of two enantiomers).
• Predict the optical rotation for a sample of 2‐
methylbutane.
• Practice with SKILLBUILDER 5.5.
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5.4 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?
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5.5 Stereoisomeric Relationships
• Categories of isomers:
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5.4 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.
• Practice with SKILLBUILDER 5.5.
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5.5 Stereoisomeric Relationships
• Draw each of the four possible stereoisomers for the following compound. It might be helpful to also make a handheld model for each isomer.
OH
• Are cis isomers and trans isomers enantiomers or diastereomers?
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• Pair up the isomers in every possible combination and label the pairs as either enantiomers or diastereomers.
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5.5 Stereoisomeric Relationships
• Consider a cyclohexane with three substituents:
5.5 Stereoisomeric Relationships
• The number of possible stereoisomers for a compound depends on the number of chiral centers (n) in the compound.
• What is the maximum number of possible cholesterol isomers?
– What patterns do you notice?
• Practice with SKILLBUILDER 5.7.
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5.6 Symmetry and Chirality
• Any compound with only ONE chiral center will be chiral and have an optical rotation.
• However, compounds with an even number (2, 4, 6, etc.) of chiral centers may or may not be chiral.
• Identify each chiral center for both molecules below.
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5.6 Symmetry and Chirality
• Molecules with an even number of chiral
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.
• When a compound is identical to its mirror image, it is NOT chiral. It is achiral.
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5.6 Symmetry and Chirality
•
Both molecules have two chiral centers, but only one is a chiral
molecule, and the other is achiral.
•
•
•
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.
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5.6 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 2n formula.
• Draw all four expected isomers and show how two of them are identical. A handheld model might be helpful.
• Practice with SKILLBUILDER 5.8.
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5.6 Symmetry and Chirality
• Determine the relationship between the two compounds below.
• Analyze both molecules to see if either of them is a meso compound.
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5.7 Fischer Projections
• Fischer projections can also be used to represent molecules with chiral centers.
5.6 Symmetry and Chirality
• Some compounds do NOT have a plane of symmetry and yet are still achiral. • The molecule to the right has chiral centers, yet because it is identical to its mirror image, it is not chiral.
• Draw the mirror image of the molecule above and show that it can be superimposed on its mirror image.
• Having handheld models to work with can simplify this challenging task.
• Practice with CONCEPTUAL CHECKPOINT 5.23.
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5.7 Fischer Projections
• Fischer projections can be used to quickly draw molecules with multiple chiral centers.
– Horizontal lines represent attachments coming out of the page.
– Vertical lines represent attachments going back into the page.
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5.7 Fischer Projections
• Fischer projections can also be used to quickly assess stereoisomeric relationships.
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5.8 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 must be optically active and unable to interconvert with their mirror image.
• Practice with SKILLBUILDER 5.9.
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5.8 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 CANNOT be found in the chair conformation.
• Which conformation better represents the molecule’s actual structure?
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5.8 Interconverting Enantiomers
• If the chair could interconvert with its mirror image, would it be chiral?
– The freely interconverting mirror images cancel out their optical rotation making it 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. Copyright 2012 John Wiley & Sons, Inc.
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5.9 Resolution of Enantiomers
• In 1847, Pasteur performed the first resolution of enantiomers from a racemic mixture of tartaric acid salts.
• The different enantiomers formed different shaped crystals that were separated by hand using tweezers.
• This method doesn’t work for most pairs of enantiomers. WHY?
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5.8 Interconverting Enantiomers
• Should the cis‐1,2‐dimethylcyclohexane chair conformation be chiral or achiral?
– It is not superimposable on its chair mirror image.
– Is has two chiral centers and no plane of symmetry.
• Recall that chairs can flip their conformation by rotating single bonds and interconvert readily at room temperature.
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5.9 Resolution of Enantiomers
• To separate compounds from one another, most methods take advantage of the differences in physical properties of the compounds to be separated:
– Distillation separates compounds with different boiling points.
– Recrystallization separates compounds with different solubilities.
– Can you think of more methods of separation or purification?
• Such methods often don’t work to separate one enantiomer from its partner. WHY?
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5.9 Resolution of Enantiomers
• Another method is to use a chiral resolving agent.
• The differing physical properties of diastereomers
allow them to be more easily separated.
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5.9 Resolution of Enantiomers
• Affinity chromatography is often used to separate compounds.
– For example, a glass column or tube can be packed with particles of a polar solid substance.
– If a mixture of two compounds with different polarities are passed through the column, what will happen?
• A pair of enantiomers will not have different polarities, so how might such chromatography be modified to resolve the enantiomers in a racemic mixture?
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