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-(+)-carvone

Caraway(Dill)(Manderine Orange Peel)

R-(-)-carvone

Spearmint

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

ClBrA 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

HO

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 Concepts1. 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 Concepts5. 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 Concepts10. 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

diastereomers2. A and B are not

superimposable3. A and B are

enantiomers4. A is meso and B is

chiral5. 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 amounts2. two enantiomers in

different amounts 3. two diastereomers in

equal amounts4. two diastereomers in

different amounts5. 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 diastereomers2. 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