1. Chapter 5 Stereochemistry at Tetrahedral Centers

2. Learning Objectives Enantiomers and the tetrahedral carbon
The reason for handedness in molecules: Chirality
Optical activity
Pasteur’s discovery of enantiomers
Sequence rules for specifying configuration
Diastereomers and Meso compounds
Racemic mixtures and the resolution of enantiomers
A review of isomerism
Chirality at nitrogen, phosphorus, and sulfur
Prochirality
Chirality in nature and chiral environments
A surprise discovery.

3. Enantiomers and the Tetrahedral Carbon
Enantiomers: Molecules that have a carbon with 4 different groups have a non-superimposable mirror image – enantiomer (opposite part or form).
The molecule or object and its mirror image are called enantiomorphs (Greek opposite forms)

4. Figure 5.2 - Attempts at Superimposing the Mirror-Image Forms of Lactic Acid
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
A object and its mirror image are called enantiomorphs (Greek opposite forms)

5. Reason for Handedness: Chirality
Chiral Molecules: Molecules that do not have a plane of symmetry and are not superimposable on their mirror image
Achiral Molecules: Molecules with a plane of symmetry that is the same as its mirror image
"chiral" comes from the Greek meaning "hand" and signifies that the molecules can have two forms differing from one another as the right hand does from the left.

6. Figure 5.3 - The Meaning of Symmetry Plane
Hands, gloves are prime examples of chiral object. They have a “left” and a “right” version
Symmetry Plane Not a Symmetry Plane
The reason for handedness in molecules: Chirality

7. Chirality Center
A point in a molecule where four different groups are attached to carbon
Chiral center is the cause of chirality or optical activity
Example: 5-bromodecane has four different groups that are bonded to C5
The reason for handedness in molecules: Chirality

8. Chirality Center
Methylcyclohexane has a symmetry plane and therefore is an achiral molecule
2-Methylcyclohexanone does not have a symmetry plane and hence chiral molecule
C2 is bonded to four different groups
The reason for handedness in molecules: Chirality

9. Worked Example Which of the following molecules are chiral? a) b)
Identify the chirality center in each a) b)
The reason for handedness in molecules: Chirality

10. Worked Example Solution:
All –CH3 and –CX3 carbons are not chirality centers
All –CH2– and –CX2– carbons are not chirality centers
All aromatic ring carbons are not chirality centers
a) b)
The reason for handedness in molecules: Chirality

11. Optical Activity
Ordinary light consists of electromagnetic waves and oscillate in an infinite number of planes at right angles to its direction of travel. When light passes through a polarizer it has just one plane and is called plane polarized light
Solutions of chiral compounds rotate plane-polarized light and the molecules are said to be optically active and the property is called optical activity. Optical activity is measured with polarimeter
Optical activity

12. Polarimeter
A polarimeter measures the rotation of plane-polarized light that has passed through a solution. The angle between the entrance and exit planes is the optical rotation.
To have a basis for comparison, define specific rotation, []D for an optically active compound
Specific rotation is that observed for 1 g/mL in solution in cell with a 1 dm path using light from sodium metal vapor (589 nm, Na D line)
1g per mL or 1 mL solution containing 1 g compound. If the wavelength of the light used is 589 nanometers (the sodium D line), the symbol “D” is used. The sign of the rotation (+ or −) is always given.
Units: deg·mL·g−1·dm−1
simply degrees

13. Table 5.1 - Specific Rotation of Some Organic Molecules
Levorotatory: Optically active substance that rotates the plane of polarization of plane-polarized light in counterclockwise direction
Dextrorotatory: Optically active substance that rotates the plane of polarization of plane-polarized light in clockwise direction
 If a chiral molecule is dextrorotary, its enantiomer (geometric mirror image) will be levorotary, and vice versa. In fact, the enantiomers will rotate plane polarized light the same number of degrees, but in opposite directions. Apart from direct measurement of the optical rotation of an actual sample,  it is not possible to determine whether a given chiral molecule will be levorotatory or dextrorotatory, directly from its absolute configuration. That is to say, both "R" and "S" stereocenters have the ability to be dextrorotatory or levorotatory. A dextrorotary compound is often prefixed "(+)-" or "d-". Likewise, a levorotary compound is often prefixed "(−)-" or "l-". The Rectus (R)- and Sinister (S)- prefixes are different from the preceding ones in that the labels R and S characterize the absolute configuration of a specific stereocenter, not a whole molecule. 

15. Worked Example
A 1.50 g sample of coniine was dissolved in ethanol to make 10 mL solution and placed in a sample cell with a 5.00 cm pathlength
The observed rotation at the sodium D line was 1.21°
Calculate the specific rotation []D for coniine
Solution:
Given: l =5.00 cm = dm;  = 1.21°;
C = 1.50g /10ml =0.150 g/mL
Optical activity

16. Worked Example
Using the formula
Optical activity

17. 9.4 Pasteur’s Discovery of Enantiomers
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

18. Sequence Rules for Specifying Configuration
A general method applies to the configuration at each chiral center
The configuration is specified by the relative positions of all the groups with respect to each other at the chiral center
The groups are ranked and compared in an established priority sequence rules
These rules are also called the Cahn–Ingold–Prelog (CIP) rules
Configuration is the relative position of the atoms or groups on a chiral center.
Configuration is the relative position of the atoms in a molecule that can be changed exclusively by cleaving and forming new chemical bonds.

19. Sequence Rules for Specifying Configuration
Look at the four atoms directly attached to the chirality center, and rank them according to atomic number
Atom with highest atomic number has highest ranking, and atom with lowest atomic number has lowest ranking
Sequence rules for specifying configuration

20. Sequence Rules for Specifying Configuration
If a decision cannot be reached by ranking the first atoms in the substituent, look at the second, third, or fourth atoms until the difference is found
Sequence rules for specifying configuration

21. Sequence Rules for Specifying Configuration
Multiple-bonded atoms are equivalent to the same number of single-bonded atoms
An aldehyde has higher ranking than an alcohol.
An aldehyde has higher ranking than an alcohol.
A ketone has higher ranking than an aldehyde.

22. Sequence Rules for Specifying Configuration
The atom with the highest atomic number is ranked1 and lowest 4
• With the lowest priority atom/group (4) pointing away, look at remaining 3 in a plane
R configuration: if the curved arrow is drawn clockwise in ordering three atoms or groups 1-3
S configuration: if the curved arrow is drawn counterclockwise in ordering three atoms or groups 1-3
Absolute configuration: Exact 3-D structure of a chiral molecule

23. Worked Example Rank the following sets of substituents: Solution:
a) –H, –OH, –CH2CH3, –CH2CH2OH
b) –SH, –CH2SCH3, –CH3, –SSCH3
Solution:
Using the sequence rules:
a) –OH, –CH2CH2OH, –CH2CH3, –H
b) –SSCH3, –SH, –CH2SCH3, –CH3
Sequence rules for specifying configuration
Highest Lowest
Highest Lowest

24. 9.6 Diastereomers
Molecules with more than one chirality center have mirror image stereoisomers that are enantiomers (2R, 3R VS. 2S, 3S)
In addition they can have stereoisomeric forms that are not mirror images, called diastereomers (2R, 3R VS. 2R, 3S or 2S, 3R)
2-amino-3-hydroxybutanoic acid (Threonine, an essential α-amino acid)
2-amino-3-hydroxybutanoic acid (Threonine, an essential α-amino acid).
Epimers: Compounds in which two diastereomers differ at only one chirality center but are the same at all others

25. Worked Example How many chirality centers does morphine have?
How many stereoisomers of morphine are possible in principle?
Diastereomers

26. Worked Example Solution: Number of chirality centers = 5
Number of stereoisomers = 2n = 25 = 32
n = # of chiral centers
Majority of the stereoisomers are too strained to exist
Diastereomers

27. 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
chiral
achiral
Tartaric acid occurs naturally in many plants, particularly grapes, bananas, and tamarinds.
180 degrees and superimpose.

28. Table 5.3 - Some Properties of the Stereoisomers of Tartaric Acid
Enantiomers have same chemical and physical properties except optical rotation. Diastereomers have different properties.

29. Worked Example Does the following structure represent a meso compound?
If so, indicate the symmetry plane
Cis-3,4-dimethylcyclopentanol

30. Worked Example Solution: The molecule represents a meso compound
The symmetry plane passes through the carbon bearing the –OH group and between the two ring carbons that are bonded to methyl groups
What if it was trans-3,4-dimethylcyclopentanol?

31. Racemic Mixtures and The Resolution of Enantiomers
A 50:50 mixture of two chiral compounds that are mirror images does not rotate light – called a racemic mixture
The pure enantiomeric compounds need to be separated or resolved from the mixture (called a racemate)
To separate components of a racemate we make a derivative of each with a chiral substance (resolving agent), the method called resolution
This gives diastereomers that are separated by their differing solubility
The resolving agent is then removed

32. A Review of Isomerism

33. Constitutional Isomers
Compounds whose atoms are connected differently
A review of isomerism

34. Stereoisomers Same connections, different spatial arrangement of atoms
Enantiomers (nonsuperimposable mirror images)
Diastereomers (all other stereoisomers)
Includes cis, trans, and configurational
A review of isomerism

35. Worked Example What kinds of isomers are the following pairs?
a) (S)-5-Chloro-2-hexene and chlorocyclohexane
b) (2R,3R)-Dibromopentane and (2S,3R)-dibromopentane
a) These two compounds are constitutional isomers (C6H11Cl)
b) The two dibromopentane stereoisomers are
diastereomers (2R,3R and 2S,3R)
A review of isomerism

36. (2R,3R)-Dibromopentane and (2S,3R)-dibromopentane

37. Chirality at Nitrogen and Phosphorus
N, P, and S are commonly found in organic compounds and can have chirality centers
Trivalent nitrogen is tetrahedral and lone pair lowest ranked
Does not form a chirality center since it rapidly flips
Individual enantiomers cannot be isolated
Rapid Inversion
Chirality at nitrogen, phosphorus, and sulfur
Trivalent: An atom that has three covalent bonds

38. Chirality at Nitrogen and Phosphorus
May apply to phosphorus but it flips slowly
Chirality at nitrogen, phosphorus, and sulfur

39. Prochirality
A prochiral molecule is a molecule that is achiral but can become chiral by a single alteration
Prochirality

40. 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 face (pronounced “ray”) if the three groups in priority sequence are clockwise, and si face (pronounced “sigh”) if they are counterclockwise.
note that the designation of the resulting chiral center as S or R depends on the priority of the incoming group.

41. Prochiral Distinctions: Faces

42. Prochirality
An sp3 carbon with two groups that are the same is a prochirality center
Two identical groups are distinguished by considering either and seeing if it were increased in priority in comparison with the other
If the center becomes R, the group is pro-R and if the center becomes S, the group is pro-S
Promoting the pro-R substituent to higher priority than the other identical substituent results in an R chirality center at the original sp3-hybridized atom, and analogously for the pro-S substituent.

43. Prochirality Biological reactions often involve prochiral compounds
Determining the stereochemistry of reactions at prochirality centers helps in the study of mechanisms in biochemical reactions
Example - Addition of water to fumarate
Prochirality

44. Worked Example
Identify the indicated faces of carbon atoms in the following molecules as Re or Si:
Prochirality

45. Worked Example Solution:
Draw the plane that includes the sp2 carbon and its substituents, and rank the substituents. The arrow that proceeds from group 1 to group 2 to group 3 is drawn
If the direction of rotation is clockwise, the face is the re face. If rotation is counter-clockwise, the face is the si face
Prochirality

46. Chirality in Nature and Chiral Environments
Stereoisomers (enantiomers) are readily distinguished by chiral receptors in nature
Pharmacological activity of some drugs depend on stereochemistry
Of the two optical isomers of ibuprofen it is the S form which is the pharmacologically active component that has anti-inflammatory effect while the R form has no anti-inflammatory effect.

47. Summary
Objects or molecules that are mirror images but not superimposable are said to be chiral
Chiral compounds can exist as a pair of non-superimposable mirror-image stereoisomers called enantiomers
Stereochemical configuration of a chirality center can be specified as either R or S by using Cahn–Ingold–Prelog rules
Diastereomers have the same configuration in at least one center and opposite configurations at the others
Epimers are diastereomers that differ in configuration at only one chirality center

48. Summary Meso compounds contain chirality centers but are achiral
50:50 mixtures of (+) and (-) enantiomers area called racemates
If a molecule can be achiral to chiral in a single chemical step, it is said to be prochiral
Prochiral sp2-hybridized atom has two faces, described as either Re or Si
An sp3-hybridized atom is a prochirality center if, by changing one of its attached atoms results in a chirality center
Atom whose replacement leads to an R chirality center is pro-R
Atom whose replacement leads to an S chirality center is pro-S