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• The three-dimensional (3D) structure of a molecule can greatly affect its physical and chemical properties. Can you give some examples?

• 3D structure is critical in biochemistry. HOW?

Chapter 5: Stereochemistry

Copyright 2012 John Wiley & Sons, Inc. Klein, Organic Chemistry 1e 5 -1

• Isomers are NONIDENTICAL molecules that have the same formula.

• There are two classes of isomers:

• Draw two molecules that are constitutional isomers:

5.1 Isomers


• C–C bonds in a cyclic structure cannot freely rotate.

• The two molecules below have the same connectivity, but are NOT identical – they are called stereoisomers.

• Need to learn some new nomenclature to name them.

5.1 Stereoisomers


• To maintain orbital overlap in the pi bond, C=C double bonds cannot freely rotate.

• The two molecules below have the same connectivity, but are NOT identical – they are also called stereoisomers.

5.1 More Stereoisomers


• Identify the following pairs as either constitutional isomers, stereoisomers, or identical. EXPLAIN.

5.1 Isomers


1.

2.

3.

4.

5.

• With rings and C=C double bonds, cis and trans notation is used to distinguish between stereoisomers.

– Cis—identical groups positioned on the SAME side of a ring.

– Trans—identical groups positioned on OPPOSITE sides of a ring.

5.1 Isomers


• 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.

• Practice with SKILLBUILDER 5.1.

5.1 Isomers


E/Z Nomenclature


The cis/trans system used by Klein for naming isomers becomes problematic for

alkenes with more than two different substituents – in those cases we need to use

the E/Z notation. Z (German: zusammen) means "together" and corresponds to

the term cis; E (German: entgegen) means "opposite" and corresponds to trans.

Cl Br

Current Standard: cis/trans is used for rings, E/Z is used for alkenes

• Identify the following as either cis, trans, or neither. EXPLAIN.

5.1 Isomers


1.

2.

3.

4.

5.

• Beyond cis and trans isomers, there are many other important stereoisomers that are based on CHIRALITY:

– 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.

• You can test whether two objects are identical by seeing if they are SUPERIMPOSABLE.

• Can you be superimposed upon your mirror image?

5.2 Stereoisomers


• Some other chiral objects include gloves, shoes, cars. HOW?

• Chirality is important in molecules. – Two molecules that are mirror images have many similar properties, but their

pharmacology may be very different.

• Visualizing mirror images of molecules and manipulating them in 3D to see if they are superimposable is challenging. – Use handheld models as visual aids until you get more experience.

5.2 Stereoisomers


• Chirality most often results when a carbon atom is bonded to 4 unique groups of atoms.

• Use handheld models to prove to yourself that these two molecules are NOT superimposable.

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.

5.2 Stereoisomers


• 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.

• Make handheld models for both structures to verify that they are NONIDENTICAL mirror images.


5.2 Stereoisomers – Enantiomers


• What is the relationship between the two molecules below?

• Given that the molecules are so similar, how is it possible that our noses can distinguish between them?

5.2 Stereoisomers – Enantiomers


• Enantiomers are NOT identical, so they must have distinct 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.

5.3 Designating Configurations


• Cahn-Ingold-Prelog rules:

1.Use atomic numbers to 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




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.

– Handheld models are really helpful in this step.

– Name: S-1-chloro-1-ethoxy-propane



Practice: Complete steps 1 and 2 for the following molecule:

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



• Designate each chiral center below as either R or S.



R R

S

• 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?



1 4

2 3

Tie First layer:

Second layer:

• 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.

– Is this molecule R or S?



1 4

Tie

2 3

First layer: Second layer:

• When prioritizing for the Cahn-Ingold-Prelog rules, double bonds count as two single bonds.

• Determine whether the following molecule is R or S.



R

• Handheld molecular models can help arrange the molecule in space so the lowest priority group faces away from you.

• Here is another useful trick: Switching any two groups on a chiral center will produce its opposite configuration.

• Switching another pair of groups will produce the original configuration.



• You can use this trick to adjust any molecule so that the lowest priority group faces away from you:

• With the 4th priority group facing away, you can now easily designate the configuration as R.

• Work backwards to show how the original structure’s configuration is also R.



R S R




• The R or S configuration is used in the IUPAC name for a molecule to distinguish it from its enantiomer.



• Because the structures of enantiomers are so similar, many of their properties are identical.

• 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?

5.4 Optical Activity


• Enantiomers have opposite configurations (R vs. S), so they will rotate PLANE-POLARIZED light in opposite directions.

• What is PLANE-POLARIZED light?



• To get light waves that travel in only one plane, light travels through a filter (polarizer).

• When plane-polarized light travels through a chiral compound, the plane that the light travels on will rotate.

• Compounds that can rotate the plane of plane-polarized light are called OPTICALLY ACTIVE.



two parallel polarizing filters Crossed polarizers


Klein, Organic Chemistry 1e 5 -34

• Enantiomers will rotate the plane of the light to equal degrees, but in opposite directions. – The degree to which light is rotated depends on the sample, as well as 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:



• Consider the enantiomers of 2-bromobutane.

– 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, and 20°C.



• There is no relationship between the R/S configuration and the direction of light rotation (+/-).

• Consider the molecule below: is it R or S?

– Unless its bonds are broken, its configuration is fixed.

– It is levorotatory (-) at 20°C, and dextrorotatory (+) at 100°C.



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.

• Predict the optical rotation for a RACEMIC MIXTURE (a sample with equal amounts of two enantiomers).

The optical rotation of this mixture will be: zero

• Predict the optical rotation for a sample of 2-methylbutane.

The optical rotation of 2-methylbutane will be: zero




• 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?



% ee = 70% - 30% = 40 %

• If the mixture has an optical rotation of +4.6, use the formula to calculate the % ee and the ratio of R/S.

% ee of S isomer = 4.6 / 23.1 = 20% (S/R = 60/40)

Ratio of R/S = 40/60 = 2:3 = 0.667 SKILLBUILDER 5.5.



R S

• Categories of isomers:

• Are cis and trans isomers enantiomers or diastereomers?

5.5 Stereoisomeric Relationships


• Draw each of the four possible stereoisomers for the following compound. It is helpful to make and use handheld models.

• Pair up the isomers above in every possible combination and label the pairs as either enantiomers or diastereomers.





• Consider a cyclohexane with three distinct substituents:

– What patterns do you notice?

• 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?




max number of

possible isomers = 28 = 64

• Any compound with 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.

5.6 Symmetry and Chirality


• The molecules below have two chiral centers, but only one is a chiral molecule, and the other is an achiral molecule.

• 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 of mirror image enantiomers cancel out each others optical rotation.



• Compounds 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.



• Another example of a MESO isomer.

• Compounds of this type have less than the maximum number of stereoisomers predicted from the 2n formula.

• Draw all four expected isomers and show how two of them are identical. A handheld model might be helpful.




R

• Determine the relationship between the two compounds below.

• Analyze both molecules to see if either is a meso compound.



S

R

R

Meso

• Some compounds do NOT have a plane of symmetry and yet are still achiral.

• This molecule has chiral centers, but is

identical to its mirror image, and hence achiral.

• Draw the mirror image of the molecule above and show that it can be superimposed on its mirror image.

• Handheld models help.

• Practice with CONCEPTUAL CHECKPOINT 5.23.



• 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.

5.8 Interconverting Enantiomers


• Should the cis-1,2-dimethylcyclohexane chair conformation be chiral or achiral? YES!

– 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.



• If the chair could interconvert with its mirror image, would it be chiral?

– The freely interconverting chairs (mirror images) cancel out their optical rotation, making the compound achiral.

– This analysis is easier with a handheld model than in your head

– If the Haworth image has a mirror plane, then the chair will be able to interconvert with its enantiomer, and it will be achiral.



• To separate compounds, we exploit differences in their physical properties:

– Distillation separates compounds of different boiling points.

– Recrystallization separates compounds with different solubilities.

– Other methods of separation or purification…?

• Most such methods can not separate one enantiomer from its partner (aka resolution of enantiomers). WHY?

5.9 Resolution of Enantiomers


• In 1847, Pasteur performed the first resolution of enantiomers on a racemic mixture of tartaric acid salts.

• These enantiomers formed differently shaped crystals that were separated by hand using tweezers.

• This method doesn’t work for most pairs of enantiomers. WHY?



• Another method is to use a chiral resolving agent.

• The different physical properties of diastereomers (here as salts) allow them to be more easily separated.



• Affinity chromatography can separate compounds.

– Pack a glass column with particles of a polar solid substance.

– Pass a mixture of two compounds with different polarities 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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