Stereochemistry

1
 Isomerism

Isomerism is a term used to describe the spatial relationship between

two (or more) molecules

• it is not relevant to a single molecule, but rather a comparison

between two or more molecules

2
 Isomers

Constitutional isomers are compounds with the same molecular

formula, but which differ in connectivity.
C7H16O

Stereoisomers are compounds which have the SAME atom connectivity

but differ only in 3-D shape/arrangement. They are different
compounds!

3
 Stereoisomers
- Cis- / trans- isomers are an example of stereoisomers that have
different spatial arrangements. The substituents are locked into position
because of a ring or double bond (no free rotation at 25C).
- Cis- / trans – nomenclature is used to distinguish between disubstituted
cycloalkanes or alkenes, substituted with identical substituents

cis-1,2-dimethylcyclohexane trans-1,2-dimethylcyclohexane

cis-2-butene trans-2-butene

Images accessed on Sept. 16, 2022 Credit”

Xin Liu, Organic Chemistry I, CC BY -NC-SA 4.0, via Pressbooks: https://kpu.pressbooks.pub/organicchemistry /chapte r/5- 2-geo metric -isomer -and -e-z- naming -system/
4
Xin Liu, Organic Chemistry I, CC BY -NC-SA 4.0, via Pressbooks: https://kpu.pressbooks.pub/organicchemistry /chapte r/4- 4-substit uted-cyclo hexanes/
 Elements of Symmetry: Chirality

All objects and molecules can be classified as being either:

1. Chiral
2. Achiral (non-chiral)

Achiral objects
• have a plane of symmetry (an imaginary plane passing through an
object such that one half is the mirror image (reflection) of the other half)
• Have superimposable mirror images. (To be superimposable, the mirror
image is indistinguishable when placed on top of the object)

Chiral objects
• lack a plane of symmetry
• Do not have superimposable mirror images (i.e the object shows
“handedness”).
5
 Plane of Symmetry
A plane of symmetry is an imaginary plane passing through an object
such that one half is the mirror image of the other half:

Planes of symmetry

Image accessed on Sept. 16, 2022: Credit: “Introduction to Crystals, CC BY-NC-SA, via LibreTexts : https ://chem.libretexts.org/Bookshelves/General_Chemistry/Book%3 A_Chem1_(Lower)/07 %3A_ Solids_and_Liquids/7 .06%3 A_In troduction_ to_C rys tals
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 Plane of Symmetry
A plane of symmetry is an imaginary plane passing through a
molecule, such that one half is the mirror image of the other half:

Planes of symmetry in H 2O

Image accessed on Sept. 16, 2022: Credit: “Fourier Transform Infrared Spectroscopy (FTIR)”, CC BY-NC-SA, via LibreTexts : https://chem.libretexts.org/Courses/University_of_California_Davis/CHE_115%3 A_Instru mental_ Analysis_ -_Lab_Manual/Lab_3 %3A_ Four ier_Transform_ Infrared
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 Achiral Objects
The flask is achiral (has a plane of symmetry). Its mirror image is
superimposable:

8
Image accessed on Sept. 16, 2022: Credit: “Chirality in Organic Chemistry”, CC BY-NC-SA, via LibreTexts : https://chem.libretexts.org/Bookshelves/General_Chemistry/Map %3 A_Chemistry_ -_The_Central_ Science_(Brown_et_al.) /24%3 A_Chemis tr y_of_Life-_Organic_and_B iological_Chemistry/24 .07 %3A_Chirali ty_in_Organic_Chemistry
 Chiral Objects: Hands
Hands are chiral (Greek: cheir – hand): They lack planes of symmetry
and their mirror images are not superimposable.

9
Image accessed on Sept. 16, 2022: Credit: “Chirality in Organic Chemistry”, CC BY-NC-SA, via LibreTexts : https://chem.libretexts.org/Bookshelves/General_Chemistry/Map %3 A_Chemistry_ -_The_Central_ Science_(Brown_et_al.) /24%3 A_Chemis tr y_of_Life-_Organic_and_B iological_Chemistry/24 .07 %3A_Chirali ty_in_Organic_Chemistry
 Stereocenters

In organic chemistry, a tetrahedral carbon bonded to four different

substituents is the main (but not only) cause for a molecule being chiral.

Stereocenter / stereogenic center / chiral centre / chirality centre:

A tetrahedral carbon with four different groups bonded to it

1 chiral centre

No chiral centre
10
Images accessed on Sept. 22, 2022: Carol Higginbotham, Introductory Organic Chemistry, CC BY-NC-SA 4.0, via Pressbooks : https://openoregon.pressbooks.pub/introductoryorganic/chapter/identifying -chiral-carbons/
Stereocenters: Consequences of a
Tetrahedral Carbon

109.5o

11
 Stereocenters: Consequences of a
Tetrahedral Carbon
CH3X

12
 Stereocenters: Consequences of a
Tetrahedral Carbon
CH3X

13
 Stereocenters: Consequences of a
Tetrahedral Carbon
mirror
CH3X : Identical molecules

2 different substituents (3 H and 1X)

14
 Stereocenters: Consequences of a
Tetrahedral Carbon
CH2XY

15
Stereocenters: Consequences of a
Tetrahedral Carbon

Mirror image
16
 Stereocenters: Consequences of a
Tetrahedral Carbon
CH2XY : Identical Molecules

3 different substituents (2H, 1X, 1Y)

17
 Stereocenters: Consequences of a
Tetrahedral Carbon
CHXYZ

4 different substituents (1H, 1X, 1Y, 1Z) on the tetrahedral carbon

18
Stereocenters: Consequences of a
Tetrahedral Carbon

Mirror image

19
Stereocenters: Consequences of a
Tetrahedral Carbon

20
Stereocenters: Consequences of a
Tetrahedral Carbon

21
 Stereocenters: Consequences of a
Tetrahedral Carbon
4 different substituents generate molecules that are non superimposable
mirror images of each other.

The pair are enantiomers and said to have different configurations.

22
 Enantiomers
Chiral and achiral are used to describe a molecule or object. A chiral
molecule has a tetrahedral carbon that has four different substituents
around it. Those substituents can be arranged in two different ways
resulting in 2 compounds that are non-superimposable mirror images of
each other, called enantiomers. Enantiomers as a term is used to describe
the pair of stereoisomers.

Enantiomers are a pair of molecules:

• whose mirror-images are
not superimposable
• that are chiral

Mirror behind

• A foolproof method for identifying chiral molecules is to build models of

the molecule and its mirror image. If the models are non-
superimposable, then the molecule is chiral and can exist as a pair of
enantiomers. Note: A chiral molecule will have only one enantiomer.
Image and Text: accessed and adapted slightly on Sept. 22, 2022: Credit;
Christ Schaller, “Enantiomers “, :”, CC BY-NC, via LibreTexts : https://chem.libretexts.org/Bookshelves/Organic_Chemistry/Supple mental_ Modules_(Organic_Chemistry)/Funda mentals /Isomerism_ i n_Organic_Compounds/Enan tio mers
“Chiral Molecules “, CC BY-NC-SA, via LibreTexts : https://chem.libretexts.org/Courses/Kenyon_College/Chemistry_231_and_232_ -_Kenyon_College_(Getzler_Hof ferberth_and_Hunsen)/5%3 A_S tereoisomers/5.1 %3 A_Chiral__Molecules
Tim Soderberg, “Chirality and Stereoisomers”, CC BY-NC-SA, via LibreTexts : https://chem.libretexts.org/Bookshelves/Organic_Chemistry/Book%3 A_Organic_Chemistry_with_a_ Biological_E mphasis_v2.0_(Soder berg)/03 %3A_Confor mations_and_ Stereochemistry/3 .04 %3A_Chirali ty_and_stereoisomers
23
 Achiral (Not Chiral) Molecules:
superimposable on its mirror image
Rotate about C-H bond

Identical structures

• The molecule contains only 3 different substituents (1H, 2Cl and

1F). The molecule and its mirror image are superimposable and
thus the molecule is achiral.
• The compounds are NOT a pair of enantiomers
24
Image and text accessed and adapted on Sept. 16, 2022: Credit: “Chirality in Organic Chemistry”, CC BY-NC-SA, via LibreTexts : https://chem.libretexts.org/Bookshelves/General_Chemistry/ Map%3 A_Chemistry_ -_The_Central_ Science_(Brown_et_al .)/24 %3A_Chem istr y_of_Life-_Organic_and_ Biological_Chemis try/24.07 %3A_Chirali ty_in_Organic_Chemistry
 Enantiomers: non superimposable on
its mirror image
Rotate about C-H bond

Non identical
structures

• The molecule contains 4 different substituents (1H, 1Cl, 1Br and

1F). The molecule and its mirror image are non-superimposable
and thus the molecule is chiral.
• The molecule and its mirror image are a pair of enantiomers
25
Image accessed and text adapted on Sept. 16, 2022: Credit: “Chirality in Organic Chemistry”, CC BY-NC-SA, via LibreTexts : https://chem.libretexts.org/Bookshelves/General_Chemistry/ Map%3 A_Chemistry_ -_The_Central_ Science_(Brown_et_al .)/24 %3A_Chem istr y_of_Life-_Organic_and_ Biological_Chemis try/24.07 %3A_Chirali ty_in_Organic_Chemistry
 In class problem

Describe the relationship(s) between these two molecules. They are

________.

A. Stereoisomers
B. Enantiomers
C. Identical molecules
D. Constitutional isomers
E. Conformers
F. Isomers
Im a g e ac ce sse d an d p ro bl e ma da pte d wit h p ermi ss io n on Se pt. 1 6, 20 22 : Credit
J a m e s As he nh urst, “Typ es o f Isom ers: Con stit uti on al Is ome rs, Stere oi so mers, Ena ntio me rs , a nd Di as te reo mers ”, vi a Ma steri ng Org an ic Ch emi stry: h t p s:// www.mas te rorga ni cc he mi stry .c om/2 01 8/09 /1 0/typ es-o f-i so mers /
“M o l e c ul e Ch ira li ty: En an ti o mers”, CCBY-NC-SA, vi a Li bre Te xts: h t p s:// ch em.l ib retex ts .o rg/Cou rse s/Sie na _He ig hts_ Uni ve rsi ty /T es ti n g/07 %3 A_ Cha pte r_ 7_ Chi ral i ty /7 .01 %3A_ _Mo l ecu l e_ Chi ral it y% 3A_ En an tio mers
NEUROti k e r, Pub l ic do ma in , vi a Wik im ed ia Co mmo ns : https /: /com mon s.wik im ed ia .o rg/wi ki /F i le :M il ch s%C3 %A4 ure_ Ena nti ome ren pa ar.svg
26
 Properties of Enantiomers
Molecules A and B are optically active, they rotate plane polarized light:

A B

Compound bp oC Solubility []D

A 99.5 12.5 +13.8
B 99.5 12.5 -13.8

• Enantiomers have the same physical properties except the way they
rotate plane polarized light.
27
 Enantiomers

Enantiomers:

1. are stereoisomers
2. are different compounds
3. Differ in way they react in a chiral environment, and may have
different biological properties (see later on)
4. Have identical physical properties except that they rotate plane
polarized light in opposite directions (+ or -).
• Because of this, enantiomers cannot be separated from
each other by physical means such as distillation or
crystallization.
• Compounds that lead to a net rotation of a plane of
polarized light are said to have optical activity or to be
optically active.

28
Text accessed and adapted on Oct. 12, 2022: Credit: “Biochemistry of enantiomers”, CC BY-NC-SA, via LibreTexts : https://chem.libretexts.org/Courses/Brevard_College/CHE_201%3A_Organic_Chem istry_I/05 %3A_ Stereochem istry/5.09 %3A_ Biochemis try _of_Enan tiomers
 Plane-polarized light

Light is characterized as a wave with oscillating electric and magnetic fields.

The fields are perpendicular to each other and to the direction of
propagation.

Ordinary light: light vibrating in all planes perpendicular to its direction of

propagation.
Plane-polarized light: light vibrating only in parallel planes.
Image accessed on Sept. 16, 2022: Credit: David Harvey, “Overview of Spectroscopy”, CC BY-NC-SA, via LibreTexts : https://chem.libretexts.org/Under_Construction/Purgatory/ Book%3 A_Analy tical_Chemistry_2.0_(Harvey)/10_Spectroscopic_Methods /10 .1%3 A_Overview_of_Spectroscopy "
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Generating Plane-
polarized light

In ordinary (non polarized) light, there are many waves randomly oriented to
each other. Polarizing filters allow light waves of only one electric field
direction to pass through. All the light waves that pass through have their
direction of vibration aligned parallel.

Polarizing
filter (0°)
Non polarized light Plane-polarized light
• Electric field vectors • electric field vectors in
are in all directions single direction
30
Image accessed on Sept. 16, 2022: Credit: Xin Liu, Organic Chemistry I, CC BY-NC-SA 4.0, via Pressbooks: https://kpu.press books.pub/organicchemistry/c hapter/5-3-chirality/
 Aligned Polarizing Filters

Non polarized Polarizing Plane-polarized Polarizing Plane-polarized

light filter (0°) light filter (0°) light
• If you put two polarizing filters one after the other lined parallel, polarized
light passes through two filters perfectly aligned. You will see light pass
through.
31
Image accessed on Sept. 16, 2022: Credit: Douglas College Physics 1207, OpenStax , CC BY 4.0, via Pressbooks : https://pressbooks.bccampus.ca/introductorygeneralphysics2phys1207opticsfirst/chapter/27 -8-polarization/
 Non-Aligned Filters

No Light
passes
through!

Non polarized Polarizing Plane-polarized Polarizing

light filter (0°) light filter (90°)

• If you put two polarizing filters one after the other 90 degrees to
each other, polarized light does not pass through two filters.
You won’t see light pass through.
32
Image accessed on Sept. 16, 2022: Credit: Douglas College Physics 1207, OpenStax , CC BY 4.0, via Pressbooks : https://pressbooks.bccampus.ca/introductorygeneralphysics2phys1207opticsfirst/chapter/27 -8-polarization/
Plane Polarized Light: Demonstration

33
Plane Polarized Light: Demonstration

Polarizing filters

34
 Plane Polarized Light: Demonstration

Both filters oriented at 0°

35
 Plane Polarized Light: Demonstration

focus on the front filter

Both filters oriented at 0°

36
 Plane Polarized Light: Demonstration

focus on the back filter 0°

37
Plane Polarized Light: Demonstration

10°

38
Plane Polarized Light: Demonstration

20°

39
Plane Polarized Light: Demonstration

30°

40
Plane Polarized Light: Demonstration

40°

41
Plane Polarized Light: Demonstration

50°

42
Plane Polarized Light: Demonstration

60°

43
Plane Polarized Light: Demonstration

70°

44
Plane Polarized Light: Demonstration

80°

45
 Plane Polarized Light: Demonstration

90°

When the polarizers are crossed, there is no light transmission.

46
 Plane Polarized Light: Demonstration

0°

When the polarizers are uncrossed, there is maximal light transmission.

47
 Plane Polarized Light: Demonstration

-90°

The polarizers can be crossed in either the +90° or -90° direction

48
Plane Polarized Light: Demonstration

0°

49
 Polarimeter: Angle of rotation

Movable analyzing filter

Sample tube containing

chiral molecule

• A polarimeter measures the rotation of plane polarized light in the

presence of a chiral compound.
• Without sample, light is observed at the end of the polarimeter when
Sodium lamp
the analyzing filter and the polarizing filters are set to 0°.
• In the presence of a chiral sample, the sample rotates plane
polarized light and as such, the light that passed through the
polarimeter is diminished.
• The angle by which the analyzing filter has to be rotated so that the
light is bright (light passes through) again is called the angle of
rotation for the optically active compound.
Image and text accessed on Sept. 16, 2022: Credit:
David Klein, Organic Chemistry I, John Wiley & Sons, 2021
“isomers of Organic Compounds”, CC BY-NC-SA, via LibreTexts : https ://chem.libretexts.org/Bookshelves/General_Chemistry/Book%3 A_General_Chem istry%3A_ Principles_Pa tterns_and_Applica tions_(Averi ll)/23 %3A_Organic_Compounds /23.03 %3A_ Isomers_of_Organic_Compounds
50
 Plane-polarized light: right and left CPL
• The polarizing filter generates plane polarized light which is a net sum
of left and right circularly polarized light (CPL)
• Right and left circularly polarized light are mirror images of each other.

Right-CPL Left-CPL

Direction of
propagation

Plane polarized light

Images and text adapted on Sept. 17, 2022:

Credit: Jona, CC BY-SA 4.0, via Wikimedia Commons: https://commons.wikimedia.org/wiki/F ile:Coil_ illustrat ion.svg https ://
51
Credit: John D. Roberts and Marjorie C. Caserio, “Plane-Polarized Light and the Origin of Optical Rotation”, CC BY-NC-SA, via LibreTexts : https://chem.libretexts.org/Bookshelves/Organic_Chemistry/Book%3 A_Basic_Principles_o f_Organic_Chemistry_%28Roberts_and_Caserio%29 /19%3 A_More_on_ Stereochemis try/19.01 %3A_ Plane -Polarized_Ligh t_and_the_Orig in_of_Op tical_Rota tion
 Plane-polarized light
• A pure chiral molecule will interact with either the right or the left CPL,
not both. The enantiomer will interact with the other CPL in the
opposite direction.
• The net effect of the interaction of plane polarized light with a pure
chiral compound is that the plane of polarization is rotated. It is rotated
in the opposite direction with its enantiomer.

Image accessed on Sept. 17, 2022: Credit: Xin Liu, Organic Chemistry I, CC BY-NC-SA 4.0, via Pressbooks: https://kpu.press books.pub/organicchemistry/c hapter/5-3-chirality/ 52
 The Polarimeter: chiral molecule
°

Pure Chiral molecule:

Plane polarized light Enantiomer 1 Rotated light

Rotate plane polarized light in

clockwise (+) direction:
Note:
i. +
• Chiral compounds are
optically active ii. Dextrorotatory
• Achiral compounds are iii. d
optically inactive.

53
Image adapted on Sept: 17, 2022: Tim Soderberg, “Optical Activity”, CC BY-NC-SA, via LibreTexts : https://chem.libretexts.org/Courses/SUNY_Oneonta /Chem_221 %3A_Organic_Chem istry_I_(Benne tt)/1 %3 ALecture_Textbook/03 %3A_Con form a tions_and_Stereochem istry/3.06 %3A_ Optical_ Activity
 The Polarimeter: chiral molecule
-°

Pure Chiral molecule:

Plane polarized light Enantiomer 2 Rotated light

Rotate plane polarized light in

counter-clockwise (-) direction:
i. -
ii. Levorotatory
iii. l

54
Image adapted on Sept: 17, 2022: Tim Soderberg, “Optical Activity”, CC BY-NC-SA, via LibreTexts : https://chem.libretexts.org/Courses/SUNY_Oneonta /Chem_221 %3A_Organic_Chem istry_I_(Benne tt)/1 %3 ALecture_Textbook/03 %3A_Con form a tions_and_Stereochem istry/3.06 %3A_ Optical_ Activity
 The Polarimeter: Racemic Mixture
°

Racemic Mixture: 50:50 Mixture of two enantiomers. One half of the sample rotates
the light in one direction, one half in the other so there is no net rotation

-°

Plane polarized light Rotated light

Net rotation of plane polarized light is 0
e.g.. 50% rotates: +
50% rotates -
overall 0.0
Image adapted on Sept: 17, 2022: Tim Soderberg, “Optical Activity”, CC BY-NC-SA, via LibreTexts : https://chem.libretexts.org/Courses/SUNY_Oneonta /Chem_221 %3A_Organic_Chem istry_I_(Benne tt)/1 %3 ALecture_Textbook/03 %3A_Con form a tions_and_Stereochem istry/3.06 %3A_ Optical_ Activity
55
 The Polarimeter
The polarimeter is a device for measuring the extent of rotation of plane
polarized light caused by a sample

1 dm in
length

Sample goes in this tube 56

 Recap: Observed rotation
• Observed rotation (): the number of degrees by which a compound
rotates the plane of polarized light.
• dextrorotatory (+): refers to a compound that rotates the plane of
polarized light to the right/droit
• levorotatory (-): refers to a compound that rotates the plane of polarized
light to the left.
+
-

Electric vectors of Direction of the Plane of polarization Plane of polarization

a beam of electric vector of rotated rotated clockwise:
unpolarized light. plane polarized counterclockwise: angle of rotation =
light. angle of rotation = -  +
57
levorotatory dextrorotatory

57
 Racemic Mixtures

• A racemic mixture contains equal numbers of molecules of two

enantiomers

• A racemic mixture shows NO optical rotation.

 there is an equal concentration of molecules that rotate a plane
polarized light both clockwise and counterclockwise
 Sometimes indicated by prefix (±) to indicate equal number of +
dextrorotatory and equal number of - levorotatory

58
 Optical Rotation: 

How much the plane of polarized light is rotated depends on:

1. The particular optically active compound being studied
2. Its concentration
3. The length of the tube which contains the sample (e.g. 1 dm)
4. The wavelength of the plane-polarized light: usually 589 nm, sodium D
line
5. The temperature
6. What it is dissolved in (i.e. solvent)

• Once the optical rotation for one enantiomer is known, the other
enantiomer will have the same degree of rotation, but in the opposite
direction, as long as they are pure.

59
 Specific Rotation
The specific rotation of a compound is calculated using this formula:

Temperature C
Experimentally observed
optical rotation (degrees)
∝
Specific Rotation = []t =
D 𝑙𝑐

D line of sodium
spectrum: 589 nm Tube concentration
length in in g/mL
decimeters
• Specific rotation is a physical property that is characteristic of a chiral
compound, as long as the temperature, wavelength and solvent (if applicable)
are held constant.
• Units for specific rotation is deg∙cm 2∙g-1 but usually expressed without units.
• The specific rotation of a compound is reported with its concentration, and
solvent. 60
 Problem
A solution (100 mL) of 16.5 g of
levorotatory camphor in ethanol has an
optical rotation of -7.29 at 20C, using
a 10-cm sample tube and a sodium
lamp. What is the specific rotation?

= chiral centre
camphor

t ∝ ∝
Specific Rotation = [] D= = []20 =
𝑙𝑐 D 𝑙𝑐
= −7.29
16.5 𝑔
1𝑑𝑚 𝑥
100 𝑚𝐿

= -44.2 (at c = 0.165 g/mL; ethanol)

61
 Specific Rotation: 2-Butanol
Specific rotation: is the observed rotation of the plane of polarized light
when a sample is placed in a tube 1.0 dm in length and at a
concentration of 1 g/mL.

(sign of the
rotation is in
brackets)
before the
(+)-2-butanol (-)-2-butanol
name
𝛼 𝐷
25 + 13.52 𝛼 25
𝐷 -13.52

For a pair of pure enantiomers, the value of the specific rotation of each
is the same, but opposite in sign.
Data obtained on Dec. 21, 2022: Credit:
National Center for Biotechnology Information (2022). PubChem Compound Summary for CID 84682, (R) -(-)-2-Butanol: https ://pubchem.ncbi.nlm.nih.gov/co mpound/R_-_-_-2-Butanol
62
National Center for Biotechnology Information (2022). PubChem Compound Summary for CID 444683, (S) -(+)-2-butanol: https://pubchem.ncbi.nlm.nih.gov/co mpound/ S_-_-2-butanol
 Enantiomeric Excess (ee)
• If one enantiomer of a pair is present in a sample to a greater extent,
there is an excess of one enantiomer compared to the other.
• Enantiomeric excess is the difference in the number of moles of each
enantiomer in a mixture compared to the total number of moles of both
in that mixture (it is expressed as a percentage) or in other words, the
fractional excess of one enantiomer over the other.
• Equivalent to optical purity
% 𝑒𝑛𝑎𝑛𝑡𝑖𝑜𝑚𝑒𝑟𝑖𝑐 𝑒𝑥𝑐𝑒𝑠𝑠 = % 𝑜𝑛𝑒 𝑒𝑛𝑎𝑛𝑡𝑖𝑜𝑚𝑒𝑟 − % 𝑜𝑡ℎ𝑒𝑟 𝑒𝑛𝑎𝑛𝑡𝑖𝑜𝑚𝑒𝑟

𝑚𝑜𝑙𝑒𝑠 𝑜𝑓 𝑜𝑛𝑒 𝑒𝑛𝑎𝑛𝑡𝑖𝑜𝑚𝑒𝑟 −𝑚𝑜𝑙𝑒𝑠 𝑜𝑓 𝑜𝑡ℎ𝑒𝑟 𝑒𝑛𝑎𝑛𝑡𝑖𝑜𝑚𝑒𝑟

= x 100
𝑡𝑜𝑡𝑎𝑙 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑚𝑜𝑙𝑒𝑠 𝑜𝑓 𝑡ℎ𝑒 𝑒𝑛𝑎𝑛𝑡𝑖𝑜𝑚𝑒𝑟𝑖𝑐 𝑝𝑎𝑖𝑟

Example:
If a mixture contains 75% of one enantiomer and 25% of the other, the enantiomeric
excess would: .

Enantiomeric excess = % enantiomer 1 - % enantiomer 2

= 75% - 25%
= 50% 63
Text adapted on Dec. 21, 2022: Credit: John D. Roberts and Marjorie C. Caserio, “Enantiomeric Purity”, CC BY-NC-SA, via LibreTexts : https://chem.libretexts.org/Bookshelves/Organic_Chemistry/Book%3 A_Basic_Principles_o f_Organic_Chemistry_(Roberts_and_Caser io)/19%3A_ More_on_S tereochemistry/19.04 %3 A_Enan tiomeric_Puri ty
 Optical Purity
• If one enantiomer of a pair is present in a sample to a greater extent,
the mixture will show an optical rotation corresponding to the
percentage of the species that is present in excess.

• Thus % enantiomeric excess (% ee) or % optical purity is determined

by:

% 𝑜𝑝𝑡𝑖𝑐𝑎𝑙 𝑝𝑢𝑟𝑖𝑡𝑦 (𝑜𝑟 % 𝑒𝑛𝑎𝑛𝑡𝑖𝑜𝑚𝑒𝑟𝑖𝑐 𝑒𝑥𝑐𝑒𝑠𝑠)

𝑚𝑒𝑎𝑠𝑢𝑟𝑒𝑑 𝑠𝑝𝑒𝑐𝑖𝑓𝑖𝑐 𝑟𝑜𝑡𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝑡ℎ𝑒 𝑚𝑖𝑥𝑡𝑢𝑟𝑒
= 𝑥 100
𝑠𝑝𝑒𝑐𝑖𝑓𝑖𝑐 𝑟𝑜𝑡𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝑡ℎ𝑒 𝑝𝑢𝑟𝑒 𝑒𝑛𝑎𝑛𝑡𝑖𝑜𝑚𝑒𝑟

e.g.
% ee = 100%
 The solution contains 100% of one enantiomer
 It is optically pure
 It is enantiomerically pure.
64
 Problem

What is the percent optical purity of the sample when the measured
specific rotation is []25D = +50 and an optically pure sample has []
25 = +100 ?
D

𝑚𝑒𝑎𝑠𝑢𝑟𝑒𝑑 𝑠𝑝𝑒𝑐𝑖𝑓𝑖𝑐 𝑟𝑜𝑡𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝑡ℎ𝑒 𝑚𝑖𝑥𝑡𝑢𝑟𝑒

% 𝑜𝑝𝑡𝑖𝑐𝑎𝑙 𝑝𝑢𝑟𝑖𝑡𝑦 = 𝑥 100
𝑠𝑝𝑒𝑐𝑖𝑓𝑖𝑐 𝑟𝑜𝑡𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝑡ℎ𝑒 𝑝𝑢𝑟𝑒 𝑒𝑛𝑎𝑛𝑡𝑖𝑜𝑚𝑒𝑟
+50
= x 100
+100
= 50% (or 50% enantiomeric excess)

Problem taken (text adapted) on Sept. 19, 2022: Credit: Xin Liu, Organic Chemistry I, CC BY-NC-SA 4.0, via Pressbooks : https://kpu.pressbooks.pub/organicchemistry/chapter/5 -3-chirality//
65
 Problem
What is the ratio of the two enantiomers (+)/(-) when the enantiomeric
excess is 50 % d configuration?

Method 1: Solved by simple algebra

Let x = enantiomer not in excess (l)

Let y = enantiomer in excess (d) Two equations, two unknowns
x + y = 100%  both x and y can be solved!
y – x = 50% Equation to calculate % ee

Add up the two equations:

x + y + y – x = 100% + 50%
2y = 150%
y = 75%

Since x + y = 100 %  x = 100% – y  x = 100% - 75% = 25%

𝑦 75 3
Ratio = = =
𝑥 25 1
66
Problem taken with permission and text modified on Dec. 21, 2022: Credit: James Ashenhurst, “Stereochemistry and Chirality”, via Mastering Organic Chemistry: https://www.masterorganicchem istry.co m/2017 /02/24 /o ptical- purity-an d-enant io meric-excess/
 Problem
What is the ratio of the two enantiomers (+)/(-) when the enantiomeric
excess is 50 % d configuration?
Method 2: Solved intuitively

If 50% is optically pure (d or +) then the remaining 50% must be racemic

(+/- or d/l)
 this would give: 25% d(+) and 25% l(-).

%d %l
50% dl 25 25
50% d 50
TOTAL 75

75 3
Ratio = =
25 1
67
Problem and image taken on Sept. 19, 2022: Credit: Xin Liu, Organic Chemistry I, CC BY-NC-SA 4.0, via Pressbooks : https://kpu.pressbooks.pub/organicchemistry/chapter/5 -3-chirality/
 Problem

Consider the following: Assume you isolated a sample of cane sugar. The
specific rotation [] 25D was +22.2. If the specific rotation of pure cane
sugar (d configuration) is +66.6, what is the optical purity of the sample?

𝑚𝑒𝑎𝑠𝑢𝑟𝑒𝑑 𝑠𝑝𝑒𝑐𝑖𝑓𝑖𝑐 𝑟𝑜𝑡𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝑡ℎ𝑒 𝑚𝑖𝑥𝑡𝑢𝑟𝑒

% 𝑜𝑝𝑡𝑖𝑐𝑎𝑙 𝑝𝑢𝑟𝑖𝑡𝑦 = 𝑥 100
𝑠𝑝𝑒𝑐𝑖𝑓𝑖𝑐 𝑟𝑜𝑡𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝑡ℎ𝑒 𝑝𝑢𝑟𝑒 𝑒𝑛𝑎𝑛𝑡𝑖𝑜𝑚𝑒𝑟
+22.2
= x 100
+66.6
= 33.3% (or 33.3% enantiomeric excess)

68
 Problem
1. What is the percentage of (d)- cane sugar molecules and (l)- in
the sample on the previous question?
2. Based on the answer from part (1), verify that the specific
rotation is in fact +22.2

69
Problem adapted on Dec. 21, 2022: Credit: “Optical Activity”, CC BY-SA, via LibreTexts : https://chem.libretexts.org/Bookshelves/Organic_Chemistry/Organic_Chemistry_(LibreTexts)/05%3 A_S tereochemistry_at_ Tetrahed ral_Centers/5 .03%3 A_Op tical_Activi ty
 Problem
1
Let x = l enantiomer
Let y = d enantiomer, the one in excess, since the rotation is positive
x + y = 100%
y – x = 33.3%

Two equations, two unknowns  both x and y can be solved!

Add up the two equations:
x + y + y – x = 100% + 33.3%
2y = 133.3%
y = 66.65%

Since x + y = 100%  x = 100% – y  x = 100% - 66.65% = 33.35%

Thus 33.35% l and 66.65% d
has opposite specific rotation
2 Specific rotation
= (fraction of d × [] 25D of pure d) + (fraction of l × [] 25D of pure l)
= (0.6665 × (+66.6)) + (0.3335 × (-66.6))
= + 44.39 – 22.21
= +22.2
70
Problem adapted on Dec. 21, 2022: Credit: “Optical Activity”, CC BY-SA, via LibreTexts : https://chem.libretexts.org/Bookshelves/Organic_Chemistry/Organic_Chemistry_(LibreTexts)/05%3 A_S tereochemistry_at_ Tetrahed ral_Centers/5 .03%3 A_Op tical_Activi ty
 Importance of Chirality
• Many (if not most) naturally occurring compounds exist as a single
enantiomer.
• Enantiomers differ in the way they react in a chiral environment.
• Biological systems are chiral environments and can distinguish
between one enantiomer and its mirror image. Thus, mirror images
can behave quite differently under biological conditions.
enantiomers

The natural world is chiral!

Enzymes and receptors are

chiral and only react with
molecules that match their
chirality

71
Image and text accessed and adapted on Sept. 19, 2022: Credit: “Isomers of Organic Compounds” CC BY -NC-SA, via LibreTexts: https://chem.libretexts.org/Bookshelves/Gener al_Chemistry /Book% 3A_General_Che mistry% 3A_Principles_Patter ns_and_Applicatio ns_(Averill)/2 3% 3A_Organic_Com pounds/ 23.03% 3A_Isom ers_of _Orga nic_Compou nds
 Naturally Occurring Enantiomers
• Biological receptors (such as those in our noses) are chiral and
discriminate between enantiomers:

e.g. Carvone

(S)-Carvone (R)-Carvone
(+) - enantiomer (-) - enantiomer

Caraway Seeds Spearmint

72
 Enzymes
• Enzymes are made up of amino acids which are chiral (except for
Glycine since R = H) and as a result are chiral compounds.
• Think of enzymes as hands; one hand will interact with one enantiomer
more than the other
• Therefore, enantiomers of drugs can have different effects in the body,
because they are acted upon differently by enzymes and receptors

An amino acid

73
Image accessed on Sept. 19, 2022L CreditL Original: Unknown Vector: -- πϵρήλιο, Public domain, via Wikimedia Commons: https://commons.wikimedia.org/wiki/File:Chiral ity_with_hands.svg
 Thalidomide
• In the late1950s, the racemic
form of thalidomide was
prescribed as a sedative and as
a ‘treatment’ for morning
sickness for pregnant women.
Some women who took the drug
(containing both enantiomers)
delivered children with severe
birth defects. It was shown that
one enantiomer of thalidomide
produced the desired effects,
while the other enantiomer was a
teratogen.
• Because of this tragedy, things
Had the Caused changed. Drugs today are most
desired effect birth often produced optically pure,
defects one enantiomer only.

Im a g e s a cce ss ed a nd te xt a da pted on Se pt. 1 9, 2 02 2: Cre di t:

“Ste re o i s ome ris mi n Org an ic Co mpo un ds ”, CC BY-NC-SA, vi a L ib reTex ts : http s://c he m.l i bre te xts.org /Bo oks he lv es /Ge ne ral _Ch emi stry/Ma p%3 A_Ge ne ral _Ch emi stry_ (Pe tru cc i_ et_a l .)/26 %3 A_ Stru cture _o f_ Or ga ni c_ Comp ou nd s/26 .4 %3 A_Stereo i som eri sm_ in _Org an ic _Co mpo un ds
No t s p e ci fie d a t the s ou rc e. Upl oa de d to fl i ckr by Oti s His to ric al Arc hi ve s Natio na l Mu se um o f Hea l th a nd Med ic in e., CC BY 2 .0, v ia Wi ki med i a Comm on s; h t p s:// co mmo ns.wi ki med i a.org /wi ki /Fi l e:NCP14 05 3.jp g# fil el i nk s
Xi n L i u , “Op tic al Ac ti vi ty”, CC BY-NC-SA, vi a L ib reTex ts : h t ps :/ /ch em.l ib retex ts .o rg/Boo ksh el ve s/Orga ni c_ Che mis try /Organ ic _Ch emi stry_ I_ (Li u)/05 %3 A_ Ste reo ch emi stry/5.04 %3 A_Op ti ca l_ A ctiv it y
74
Fu s e 8 0 9, Pub li c do ma in , vi a Wik im ed ia Co mmo ns : http s://c ommo ns .wi ki me di a.o rg /wik i/ Fil e:Tha li d omi de -race ma te 2DCSD.svg
 Stereocenters
• A tetrahedral atom that is bonded to four different substituents is a
stereogenic center (or stereocenter or chiral center). A molecule
with a stereocenter has stereoisomers.

• Four different groups can be arranged around a tetrahedral carbon

atom in two different ways such that the two forms are non-
superimposable mirror images (i.e. enantiomers). Since they are
different compounds, they have different IUPAC names

• The actual orientation in space of groups around a stereocenter is

called the absolute configuration. The absolute configuration is
used when providing an IUPAC name

Note that configuration is different from conformation:

 changing configuration requires breaking bonds
 changing conformation requires rotating bonds
75
Absolute Configuration

76
 Absolute Configuration:
How Can We Denote This Arrangement?

 Cahn-Ingold-Prelog Rules
….incorporated into the IUPAC rules for nomenclature 77
 Cahn-Ingold-Prelog Rules: Overview
1. Assign priority to the four groups attached to the stereocenter based on
atomic number.
2. Visualize the molecule with the lowest priority group away from you
(labelled 4)
3. Trace the remaining three groups Clockwise (R)- or Counterclockwise
(S) starting from the highest (labelled 1) to lowest priority group
(labelled 3)

2 3 3 2

(S) Rotate counter- (R) Rotate

clockwise clockwise
78
Image adapted on Sept. 19, 2022: Credit: Absolute Configuration and the (R) and (S) System, CC BY-NC-SA, via LibreTexts : https://chem.libretexts.org/Courses/Sacramento_City_College/ SCC%3A_Che m_420_ -_Organic_Chemistry_I /Text /06%3 A_S tereochemistry_at_Te trahedral_Centers/6 .03%3 A_Absolu te_Configurat ion_and_the_(R)_and_(S)_Syste m
Cahn-Ingold-Prelog Rules: R and S configuration

4 1

79
Cahn-Ingold-Prelog Rules: R and S configuration

4
1

80
Cahn-Ingold-Prelog Rules: R and S configuration

4
1

81
Cahn-Ingold-Prelog Rules: R and S configuration

clockwise
2 1
(R) - configuration

(Rectus = right)

82
Cahn-Ingold-Prelog Rules: R and S configuration

clockwise counter-clockwise

(R) - configuration (S) – configuration

Rectus = Right Sinister = Left
83
 Detailed Cahn-Ingold-Prelog Rules: R/S configuration

Same rules apply when assigning E and Z configurations of alkenes.

Assign priority to the 4 substituents/groups attached to the carbon.
1. Rank atoms attached to the carbon on the basis of atomic number.
The atom with the highest atomic number has the highest priority and
the lowest atomic number has priority 4.
1
(Cl > O > C > H)
4 2
3
2. For isotopes, the atom with greater atomic mass has higher priority.
 greater No. neutrons (greater atomic mass), greater priority

4 2
(Cl > 13C > 12C > H)
1
3
Image accessed and adapted on Sept. 19, 2022: Credit:
3.6 Cahn-Ingold Prelog Rules”, CC BY-NC-SA, via LibreTexts: https://chem.libretexts.org/Co urses/ Purd ue/ Purd ue%3A_Che m_26505 %3A_Organ ic_Che mistry_ I_(Li pton)/C hapter_3._ Stereoche mistry /3.6_Cah n-In go ld_Pre lo g_Rules
Xin Lui, Organic Chemistry I, CC BY-NC-SA 4.0, , via Pressbooks : https://kpu.pressbooks.pub/organicchemistry/chapter/5 -3-chirality -and-optical-activity/
84
 Detailed Cahn-Ingold-Prelog Rules: R/S configuration
3. If the atoms directly attached to the carbon are of equal rank, the tie is
broken by looking at the atoms attached to the ‘tied’ atoms. Make a list of
decreasing atomic number. If they are identical, look at the next atom in
the chain until the tie is broken (first point of difference). The one with the
greatest atomic number is attached to the group with the greatest priority.

2
O
4 H Carbon attached to O, H, H
H
1
C
3
H Carbon attached to C, H, H
H

2 O
H Carbon attached to O, H, H
4
H
1 C
Both carbons attached to C, H
3 Carbon attached to C, H, H
H, H thus check next atom H 85
Text adapted on Dec. 19, 2022: Credit: David Klein, Organic Chemistry 4 th Edition, John Wiley & Sons, 2021
 Detailed Cahn-Ingold-Prelog Rules: R/S configuration
4. Substituents that have multiple bonds are treated as if they have
multiple single bonds. A carbon involved in a double bond is treated as
if it was bound to the same atom twice via two separate single bonds.

Carbon attached to O, O, C

4
1 H
H
3 H

Carbon attached to
C Carbon 2 H, H, H
H attached to
H C, H, H

Image and problem taken and text adapted on Dec. 21, 2022: Credit:
3.6 Cahn-Ingold Prelog Rules”, CC BY-NC-SA, via LibreTexts: https://chem.libretexts.org/Co urses/ Purd ue/ Purd ue%3A_Che m_26505 %3A_Organ ic_Che mistry_ I_(Li pton)/C hapter_3._ Stereoche mistry /3.6_Cah n-In go ld_Pre lo g_Rules
David Klein, Organic Chemistry 4 th Edition, John Wiley & Sons, 2021
Xin Liu, Organic Chemistry I, CC BY-NC-SA 4.0, via Pressbooks : https://kpu.pressbooks.pub/organicchemistry/chapter/5 -3-chirality -and-optical-activity/
86
 Detailed Cahn-Ingold-Prelog Rules: R/S configuration
A carbon involved in a triple bond is treated as if it was bound to the same
atom three times via 3 separate single bonds

3
4

1
2

5. Visualize the molecule with the lowest priority group away from you
(labelled 4)
6. Trace the remaining three groups Clockwise (R)- or Counterclockwise
(S) starting from the highest (labelled 1) to lowest priority group
(labelled 3)
Image and text adapted on Dec. 22, 2022: Credit:
3.6 Cahn-Ingold Prelog Rules”, CC BY-NC-SA, via LibreTexts: https://chem.libretexts.org/Courses/Purdue/Pur due% 3A_Chem_26 505% 3A_Organic_Ch emistry_ I_(Lipt on)/Cha pter_ 3._Stere ochemist ry/3.6_Ca hn-In gold_Prelog_Rules
David Klein, Organic Chemistry 4th Edition, John Wiley & Sons, 2021
John D. Roberts and Marjorie C. Caserio, “The R,S Convention for Designating Stereochemical Configurations”, CC BY-NC-SA, via LibreTexts: https://chem.libretexts.org/Bookshelves/Orga nic_Chemistry /Book% 3A_Basic_Principles_of_Orga nic_Chemistry _(Robe rts_and _Caserio) /19% 3A_More _on_Ster eochemist ry/19. 06% 3A_The_RS_Conven tion_fo r_Designating _Stereoch emical_Configu rations
87
IUPAC system of naming compounds noting
the stereochemistry: absolute configuration
6. Apply the same rules for naming alkanes without stereogenic centres except
now the absolute configuration (R/S) is included at the beginning of the name.
R or S is written in capital letters, in italic and placed in brackets followed by a
hyphen. If there is more than one chiral centre, you must include the location of
the chiral centres on the parent chain, i.e. (2R, 6S)-.

Text adapted on Dec. 19, 2022: Credit: “ Absolute configuration”, CC BY-SA 3.0, via Wikipedia: https://en.wikipedia.org/wiki/Absolute_configurat ion
88
 Problem
Assign the absolute configuration of the chiral centre in the following molecule.

2
4
3
Turn wheel clockwise

Images accessed and adapted on Sept. 19, 2022: Credit:

William Reusch, “Configurational Nomenclature”, CC BY-NC-SA, via LibreTexts : https://chem.libretexts.org/Bookshelves/Organic_Chemistry/Supplemen tal_Modu les_(Organic_Chemistry)/Chirality/ Stereoisomers/Chiral ity_and_Sym metry/Con figurationa l_Nomenclature
89
“Absolute Configuration and the (R) and (S) system”, CC BY-NC-SA, via LibreTexts : https://chem.libretexts.org/Courses/Sacramento_City_College/ SCC%3A_Che m_420_ -_Organic_Chemistry_I /Text /06%3 A_S tereochemistry_ at_Te trahedral_Centers/6 .03%3 A_Absolu te_Configurat ion_and_the_ %28R%29_and_ %28S %29_ System
 Problem
Assign the absolute configuration of the chiral centre in the following molecule.

1
1 4
R

2
3 2
4
3
Turn wheel clockwise
O O
H O 4th priority doesn’t
H O have to be a H!

Images accessed and adapted on Sept. 19, 2022: Credit:

William Reusch, “Configurational Nomenclature”, CC BY-NC-SA, via LibreTexts : https://chem.libretexts.org/Bookshelves/Organic_Chemistry/Supplemen tal_Modu les_(Organic_Chemistry)/Chirality/ Stereoisomers/Chiral ity_and_Sym metry/Con figurationa l_Nomenclature
90
“Absolute Configuration and the (R) and (S) system”, CC BY-NC-SA, via LibreTexts : https://chem.libretexts.org/Courses/Sacramento_City_College/ SCC%3A_Che m_420_ -_Organic_Chemistry_I /Text /06%3 A_S tereochemistry_ at_Te trahedral_Centers/6 .03%3 A_Absolu te_Configurat ion_and_the_ %28R%29_and_ %28S %29_ System
 In class problem
How many stereocentres are in the molecule below?

Problem and Image accessed and adapted on Sept. 19, 2022: Credit: Tim Soderberg, “Naming chiral centers: the R and S system”, CC BY-NC-SA, via LibreTexts : https://chem.libretexts.org/Courses/Westminster_College/CHE_261_ -_Organic_Chem istry_I/07 %3A_ Stereochem istry/7.02 %3A_Na ming_chiral_centers%3 A_the_R_and_S_system
91
 In class problem
What is the absolute configuration at each stereocentre?

Problem and Image accessed and adapted on Sept. 19, 2022: Credit: Tim Soderberg, “Naming chiral centers: the R and S system”, CC BY-NC-SA, via LibreTexts : https://chem.libretexts.org/Courses/Westminster_College/CHE_261_ -_Organic_Chem istry_I/07 %3A_ Stereochem istry/7.02 %3A_Na ming_chiral_centers%3 A_the_R_and_S_system
92
Absolute Configuration: Nomenclature

• When using the Cahn-Ingold-Prelog Rules, each name corresponds

to a unique structure that can be reproduced from the name alone.

93
 Problem

Draw the three dimensional structure for:

(S)-1-bromo-3-chloro-2-methylpropane

94
 Problem
1. Draw molecule without specifying stereochemistry

1-bromo-3-chloro-2-methylpropane

2. Identify stereocentre

3. Assign priorities to the four substituents

1 4

3 2 95
 Problem
4. Determine which way you need to rotate
Molecule is: (S)-1-bromo-3-chloro-2-methylpropane
 rotate counterclockwise.
5. Draw ‘blank canvas- tetrahedral carbon, with a bond pointing directly
in the back

6. Place the fourth priority substituent in the back

7. Place the other three substituents 123 around the carbon so that
the ‘wheel’ rotates counter-clockwise Note: Follow same
1 procedure for multiple
stereogenic centres (later on
2 S in course) except start with a
3 zig-zag.
96
 Stereochemistry: d(+) or l(-) vs R or S
• The designation of R or S, the absolute configuration for a
compound has NOTHING to do with the sign of rotation of plane
polarized light d(+) or l(-).
• The absolute configuration CANNOT be determined from the sign of
its optical rotation. It is assigned using Cahn-Ingold-Prelog rules.
• However, if the sign of rotation of one pure enantiomer is known, the
other pure enantiomer will have the opposite sign of rotation.
• Isomerization to the other enantiomer would occur if the 3D
arrangement of any of two of its bonds are exchanged

97
Images accessed on Sept. 27, 2022: Credit: Xin Liu, Organic Chemistry I, CC BY-NC-SA 4.0, via Pressbooks : https://kpu.pressbooks.pub/organicchemistry/chapter/5 -3-chirality/
Fischer Projections: Convert 3D image into 2D
Extremely useful for sugars, but can be used for other molecules as well
(such as amino acids)!

Look
Ξ
this way

• Look at the central carbon (pink sphere). Position the molecule

so that the horizontal bonds (red and green) are pointing
towards you and the vertical bonds (blue and yellow) are
pointing away from you

98
Image and text accessed and slightly adapted on Sept. 19, 2022: Credit: “Fischer Projections”, CC BY-NC-SA, via LibreTexts : https://chem.libretexts.org/Bookshelves/Organic_Chemistry/Supple menta l_Modules_(Organic_Chemistry)/Chirali ty/Fischer_Proje ctions
Fischer Projections: Convert 3D image into 2D
• Flatten the molecule on the paper. The result is a cross shape
Fisher Projection

99
Image and text accessed and slightly adapted on Sept. 19, 2022: Credit: “Fischer Projections”, CC BY-NC-SA, via LibreTexts : https://chem.libretexts.org/Bookshelves/Organic_Chemistry/Supple menta l_Modules_(Organic_Chemistry)/Chirali ty/Fischer_Proje ctions
 Allowed Manipulations of a Fisher Projection

1. You can rotate a Fisher Projection by 180 only since it retains the
configuration.
rotation by 90 inverts the configuration

2. You can keep the position of one substituent in the Fisher Projection
constant and rotate the other three substituents either clockwise or
counter-clockwise without changing the configuration of the chiral
centre.

Text accessed and adapted on Sept. 20, 2022: Credit: Xin Liu, Organic Chemistry I, CC BY-NC-SA 4.0, via Pressbooks : https://kpu.pressbooks.pub/organicchemistry/chapter/5 -5-fisher-projection/
100
 Assigning R and S configurations with
a Fisher Projection

1. Use the Cahn-Ingold-Prelog rules to assign priorities to the four

substituents on the chiral centre.
2. Place the lowest priority group in the vertical position (either one).
Follow the allowed manipulation rules to do so if necessary.
3. If the priorities of the three remaining substituents (1-2-3) is clockwise
assign R
4. If the priorities of the three remaining substituents (1-2-3) is counter
clockwise assign S

101
Text accessed and adapted on Sept. 20, 2022: Credit: Xin Liu, Organic Chemistry I, CC BY-NC-SA 4.0, via Pressbooks: https://kpu.pressbooks.pub/organicc hemistr y/chapter/5-5-fis her-projec tion/
 Allowed movements in a Fisher Projection
4
4
2
S S 1
1

3 2 3
identical
3

S Rotate 180 1 S S
2

4

Keep CH3 4
stationary and 1 3
S S
rotate other three
substituents 2
counter-clockwise
Images adapted and problem accessed and adapted on Sept. 20, 2022: Credit: Xin Liu, Organic Chemistry I, CC BY-NC-SA 4.0, via Pressbooks : https://kpu.pressbooks.pub/organicchemistry/chapter/5 -5-fisher-projection/
102
 Rotating a Fisher Projection by 90 is not allowed
4 Rotate 2
clockwise
2 3
S S 1 90 R 4

1
3
Keep Br stationary
enantiomers and rotate other 3
Keep CH3 substituents
4 stationary and counter-clockwise
rotate other 3 4

1 substituents
R 2 2 R 3
clockwise

3 1

Enantiomers have the opposite absolute

configuration (one has R, one has S)
103
Image and problem accessed on Sept. 20, 2022: Credit: Xin Liu, Organic Chemistry I, CC BY-NC-SA 4.0, via Pressbooks: https://kpu.press books.pub/organicchemistry/c hapter/5-5-fisher-projecti on/
 In class problem
What is the absolute configuration of the following molecule?

104
Problem taken on Sept. 19, 2022: Credit: Xin Liu, Organic Chemistry I, CC BY-NC-SA 4.0, via Pressbooks : https://kpu.pressbooks.pub/organicchemistry/chapter/5 -5-fisher-projection/
 Amino Acids
• Amino acids (and sugars, but we won’t deal with them) can have either
D or L stereochemistry.
• In nature, only L- enantiomers of amino acids are found (shown below)
• D/L is assigned by position of amino group in Fisher Projection
• If the amino group is on the left when the carboxylic acid is up and the R
group is down in the vertical positions as depicted below, the amino acid
is L.

L-amino acid D-amino acid

105
Text adapted with permission on Dec. 22, 2022: Credit: James Ashenhurst, “D and L Notation For Sugars”, via Mastering Organic Chemistry: https://www.masterorganicchemistry.com/2017/05/24/d -and-l-sugars/
 Amino Acids
3 R group: 2
CH3 R group:
1 1 CH2SH

4 4
3

2
L-alanine L-cysteine
(S)-Configuration (R)-Configuration
• In Nature, only L- enantiomers are found
• Whether the L-amino acids are R or S (or even achiral) depends on the
substituents (based on Cahn-Ingold Prelog Rules)
• L-cysteine is of the R-configuration (side chain –CH2SH)
• L-alanine is of the S-configuration (side chain –CH3)
• L-glycine is achiral (side chain –H)
Images accessed on Dec. 21, 2022: Credit:
106
Benjah-bmm27, Public domain, via Wikimedia Commons: https://commons.wikimedia.org/wiki/File :L -alanine-3D-balls.png
Compounds with multiple stereocentres

107
 Enantiomers
Enantiomers are pairs of stereoisomers that :
• Have the same molecular formula
• Have the same connectivity
• Have different arrangement of atoms in space
• And are non superimposable mirror images of each other
• Same physical properties except they rotate plane polarized light in
opposite directions
• Can have multiple chiral centres

Enantiomers with multiple chiral centres: All of the chiral centres are
opposite in configuration

(2R,3R)-2,3-dichlorobutane (2S,3S)-2,3-dichlorobutane
108
Im a g e an d tex t ac ce sse d on Se pt. 2 0, 20 22 : Cre di t:
Ch ri s Sc h al le r, :Ena ntio me rs ”, CC BY-NC-SA, vi a L ib reTex ts : http s://c he m.l i bre te xts.org /Bo oks he lv es /Org an ic _Ch emi stry/Sup pl eme nta l_ Mod ul e s_(Org an ic _Ch emi stry)/Fu nd ame nta ls /I so meri sm_ i n_ Org an i c_Co mp ou nd s/En an tio mers
“M e s o Comp ou nd s”, CC BY-NC-SA, v ia L i breTe xts: h t p s:// ch em.l ib retex ts .o rg/Cou rse s/Uni ve rs it y_ of_ Alb erta_ Au gu stan a_ Cam pu s/AUCHE_ 25 0%3A_Sy nthe si s_ I/ 06 %3 A_Stereo ch emi stry/6.0 6%3 A_Me so _Co mpo un ds
 Diastereomers
Diastereomers are pair of stereoisomers that : Note: Cis and trans
• Have the same molecular formula alkenes are
• Have the same connectivity diastereomers.
• Have different arrangement of atoms in space
• Are not mirror images of each other
• Are not enantiomers
• Have different physical properties

Diastereomers with multiple chiral centres: At least one (but not all) of
the chiral centres are opposite in configuration

(2R,3R)-2,3-dichlorobutane (2R,3S)-2,3-dichlorobutane
Im a g e an d tex t ac ce sse d on Se pt. 2 0, 20 22 : Cred it :
Ti m So d erbe rg, “Stere oc he mis try o f Al ken es :”, CCBY-NC-SA, vi a Li bre Te xts: h t p s:// ch em.l ib retex ts .o rg/Boo ksh el ve s/Orga ni c_ Che mi stry /Bo ok %3A_ Orga ni c_ Che mis try _wi th _a _Bi ol o gi ca l_ Emph as is _v2 .0_ (So de r be rg )/0 3% 3A_ Con fo rmati on s_a nd _Stere oc he mis try /3 .1 0% 3A_ Ste re oc he mi stry _o f_ al ke ne s
109
“Di a s te re ome rs: CC BY-NC-SA, v ia li bre te xs : http s://c he m.l i bre te xts.org /Bo oks he lv es /Org an ic _Ch emi stry/Orga ni c_ Che mis try _(Li b re Texts)/ 05 %3 A_Stereo ch emi stry_ at_Te tra he dral _ Cen te rs/5.06 %3 A_ Di aste re om ers
“M e s o Com po un ds”, CCBY-NC-SA, vi a Li bre Te xts: http s://c he m.l i bre te xts.org /Co urse s/Uni ve rsi ty _o f_ Alb erta_ Aug us ta na _Ca mpu s/AUCHE_2 50 %3A_ Synth esi s_ I/0 6% 3A_Stere oc he mis try /6 .0 6% 3A_ Mes o_ Comp ou nd s
 Meso-Compounds
Meso compounds are a special class of stereoisomers:
• They have more than one chiral center.
• It is superimposable on its mirror image
• It has an internal plane of symmetry that divides the molecule in half.
• The chiral centres have the same substituents but of the opposite
configuration (i.e. one has the R configuration and the other S). The
stereochemistry cancels out and the molecule is overall optically
inactive (it does not rotate plane polarized light). One can see it as a
‘racemic mixture’ within one molecule!
• Despite having chiral centres, a meso compound is achiral due to a
plane of symmetry!

Internal Plane of symmetry

Identical
(2S,3R)-2,3-dichlorobutane (2R,3S)-2,3-dichlorobutane
Molecules
Image and text accessed on Sept. 20, 2022: “ Meso Compounds”, CC BY-NC-SA, via LibreTexts : https://chem.libretexts.org/Courses/University_of_Alberta_Augustana_Ca mpus/AUCHE_250 %3 A_Synthesis_I /06%3 A_S tereochemistry/6 .06%3 A_Meso_Compounds
110
 Meso-Compounds

• Meso compounds contain a plane of symmetry that divides the

molecule into half.
• It is sometimes easier to identify a meso by a Fisher Projection

rotate

Image and text accessed on Sept. 20, 2022: Credit:

William Reusch, “Meso Compunds ”, CC BY_NC_SA, via LibreTexts : https://chem.libretexts.org/Bookshelves/Organic_Chemistry/Supp lemen tal_Modules_(Organic_Chemistry)/Chirali ty/ Stereoisomers/Chirali ty_and_Sym metry/ Meso_Compounds
111
“Meso Compounds”, CC BY-NC-SA, via LibreTexts : https://chem.libretexts.org/Bookshelves/Organic_Chemistry/Supple menta l_Modules_(Organic_Chemistry)/Chirali ty/Meso_Compounds
 meso compounds: tartaric acid

mirror
S R
Internal
R S plane of
symmetry

B A
• The mirror image of (S,R) tartaric acid is (R,S) tartaric acid.
• Rotating A 180 gives you B
superimposable on its mirror image (therefore identical)!
 So a meso compound does not have an enantiomer!
• An internal plane of symmetry exists in A & B

Image and text accessed with permission on Sept. 20, 2022: Credit:
William Reusch, “Meso Compunds ”, CC BY_NC_SA, via LibreTexts : https://chem.libretexts.org/Bookshelves/Organic_Chemistry/Supp lemen tal_Modules_(Organic_Chemistry)/Chirali ty/ Stereoisomers/Chirali ty_and_Sym metry/ Meso_Compounds
112
James Ashenhurst, “The Meso Trap”, via Mastering Organic Chemistry: https://www.masterorganicchemistry.com/2011/01/12/the - meso-trap/
 Meso- Compounds: Nomenclature
• These structures are identical (a meso form) so which name should
be used?
Flip it around
2 (rotate 180°
around axis
3 perpendicular to 2 3
C-C bond)

(2S,3R)-2,3-dichlorobutane (2R,3S)-2,3-dichlorobutane

• These two compounds are identical. When naming meso-

compounds, the stereocenter with the lower number is
designated as having the R configuration.

113
 Stereoisomers: Multiple Chiral Centres
Mirror Plane

Enantiomers

Diastereomers
Diastereomers Diastereomers

Enantiomers

• A compound with n stereocenters has a maximum of 2n different stereoisomers:

• Enantiomer pairs: all of the chiral centers are of the opposite configuration
• Diastereomer pairs: at least one - but not all of the chiral centers are of opposite
configuration
• Keep in mind an internal plane of symmetry may exist – Meso compound causes the
‘enantiomeric pair’ to be a single compound. A compound has only 1 mirror image, so it only
has 1 enantiomer) but can have more than one diastereomer
114
Te x t a n d Imag e ac ce sse d on Se pt. 2 1, 20 22 : Cred it :
Da v i d Kl e in , Orga ni c Ch emi stry I. Jo hn Wil e y &Son s, 20 21
“De te rm i n in g Num be ro f Ste reo is ome rs: CC BY-NC-SA, v ia Li bre Te xts: h t ps :/ /ch em.l ib retex ts .o rg/Cou rses /Pro vi de nce _Co l le ge /Org an ic _Ch emi stry_ I/ 0 7%3 A_Stere och em is try/7 .0 5% 3A_De termi ni ng _Nu mb ers_ of_Stere oi so mers
Ti m So d erb erg , “Com pounds with multip le chiral c enters ”, CCBY-NC-SA, vi a Li bre Te xts: http s://c he m.l i bre te xts.org /Bo oks he lv es /Org an ic _Ch emi stry/Boo k%3 A_Orga ni c_ Che mi stry_wi th_ a_ Bio lo gi ca l _Emp ha si s_v 2.0_ (Sod erbe r g)/03 %3 A_ Con forma ti on s_ an d_ Ste reo che mi stry/3.07 %3 A_ Com po un ds_ wi th _mu l ti pl e _ch i ra l _ce nte rs
 Stereochemistry: Cyclic Compounds Case 1
One has to be careful in naming cyclic molecules cis and trans.
They can refer to two enantiomeric compounds
One would predict by 2n rule: 22 = 4 maximum stereoisomers

Trans compounds are

a pair of enantiomers

Cis and trans

compounds are diastereomers
diastereomers

cis compounds are a

pair of enantiomers

115
Pro b l e m an d im ag es a cce sse d o n Sep t. 22 , 20 22 : Cred it : Xi n Li u, Orga ni c Che mi stry I, CC BY-NC-SA 4.0, vi a Press bo ok s: https :/ /kpu .pres sb oo ks.pu b/o rg an i cch emi stry/ch ap te r/5 -6-co mp ou nd s-wit h -m ore-tha n-o ne -chi ral i ty -cen ters/
 Stereochemistry: Cyclic Compounds Case 2
• In the following case, the 2 cis compounds are a single meso compound 
3 stereoisomers exist instead of 22. Thus the 2n rule predicts the maximum
number of stereoisomers that can exist.

Chiral enantiomers

(1R,2R)-1,2-dibromocyclopentane (1S,2S)-1,2-dibromocyclopentane

 diastereomers diastereomers

≡
• Identical, not
Not chiral enantiomers
• Superimposable
mirror image
(1R,2S)-1,2-dibromocyclopentane 116
Problem accessed on Sept. 22, 2022: Credit: Xin Liu, Organic Chemistry I, CC BY-NC-SA 4.0, via Pressbooks: https://kpu.pressbooks.pub/organicche mistry/cha pter/ 5-6-c ompou nds-with- more -than -one -chirality-ce nters/
 Special situations of Chirality: atropisomers
• A molecule can be chiral even if it does not possess any chiral centres.
• If steric hindrance prevents a s bond from rotating, conformational
enantiomers may result, which are called atropisomers.
• The molecule shown below is not planar (aromatic rings are ~
perpendicular)
• At room temperature, there is not enough energy for rotation around
the s bond due to steric hindrance and the conformations are distinct.

mirror

O 2N CO2H

O 2N CO2H

conformational enantiomers
Images and tex t adapted on Dec .. 21, 2022; Credit:
Stev en Langdon , “Introduc tion to Organic Chemis try ”, CC BY-NC-SA 4.0, v ia Pres s book s: https ://openpres s .us as k .c a/intro-organic-c hemis try /c hapter/4-3/
117
Roland Mattern, Public domain, v ia Wik imedia Commons ; https ://c ommons .wik imedia.org/wik i/F ile: Atropis omer .s v g
 on your own
Problem: Special situations of Chirality: Allenes
(a) Explain why compound A (an allene) is chiral?
(b) Explain why compound B is achiral.
A B

mirror
(a)

sp hybridized
• It is chiral because it is not superimposable on its mirror image. This molecule is
not planar but it has a twist (due to overlap of the two sets of p orbitals on the sp
hybridized carbon which are 90 º degrees from each other).

• It is achiral because there is a plane of

(b)
symmetry (sliced vertically through Cl-C-CH3
bond)

Confirm for yourself by building models.

Pro b l e m ta ke n an d ad ap ted a nd i ma ge s ad ap te d wi th pe rm is si on o n Sep t. 22 , 2 02 2: Cred i t:
J a m e s As he nh urst, “Ch ira l All e ne s An d Ch ira l Axe s”, vi a Ma steri ng Org an i c Che mis try : https :/ /www.ma stero rga ni cch em is try.co m/20 15 /0 1/1 3/ch ira l-a l en es -an d-ch ira l-a xe s/
118
Ffg a m e ra, Pu bl i c do mai n , vi a Wik ime di a Co mmo ns: h ttp s:// co mmo ns .wi ki me di a.org /wi ki /Fi l e:All e ne s_c hi ral i ty _d ep ic ti on .pn g
“Ch i ra l Mo l ecu l es”, CCBY-NC-SA, vi a Li bre Te xts: h t p s:// ch em.l ib retex ts .o rg/Cou rse s/Ke ny on _Co l e ge /Ch emi stry_ 23 1_ an d_ 23 2_ -_Ken yo n_ Col l eg e_ (Ge tzl er_Ho ffe rbe rth _a nd _Hu nse n)/5% 3A_ Ste re oi so me rs /5 .1%3 A_Ch ira l_ _M ol ec ul es
on your own
Atoms other than carbon can be chiral centres

Atoms other than carbon can be chiral centers: Nitrogen, Phosphorus,

Sulfur
 Tetrahedral group electron geometry
 4 different substituents,
 non superimposable on mirror image

A lone pair is also considered a

substituent, but lowest priority by
Cahn-Ingold-Prelog Rules 119
Image adapted and text accessed on Sept. 27, 2022: “Chirality at Nitrogen, Phosphorus and Sulfur”, CC BYNC -SA, vi LibreTexts : https://chem.libretexts.org/Bookshelves/Organic_Chemistry/Organic_Chemistry_(LibreTexts)/05%3 A_S tereochemistry_at_ Tetrahed ral_Centers/5 .10%3 A_Chirali ty_at_Nitrogen_ Phosphorus_and_Sulfur
on your own
Stereoisomers: Summary

• For a molecule with 1 stereocenter: 21 = 2 stereoisomers are

possible.

• For a molecule with 2 stereocenters, a maximum of 22 = 4

stereoisomers are possible.

• For a molecule with n stereocenters, a maximum of 2n

stereoisomers are possible.

Note the special case for meso compounds (where there is

internal plane of symmetry).

120
on your own
Summary of Isomerism
• Constitutional isomers have the same molecular formula but differ
in their connectivity.

• Conformational isomers have the same connectivity but differ in

their rotation about a sigma bond

• Stereoisomers have the same connectivity but differ in their

arrangement in space.

• Enantiomers are nonsuperimposable mirror image stereoisomers.

• Diastereomers are stereoisomers that are not enantiomers.

• Meso- compounds have chiral atoms but overall are achiral due to
an internal mirror plane of symmetry.

121
on your own
Summary: Symbols/Notation

Symbol Meaning/Use

* Stereocentre
+, - dextrorotatory, levorotatory (direction in which
plane polarized light is rotated)
d, l dextrorotatory, levorotatory (direction in which
plane polarized light is rotated)
R, S Absolute configuration based on Cahn-Inglold-
Prelog rules and set of priorities
D, L Used to indicate the stereochemistry of an
amino acid or sugar

Remember: R/S and d/l are independent of each other. A compound with absolute
configuration R can rotate plane polarized light to the right (d) or left (l) and the
same holds true for a compound with absolute configuration S.

122
Text accessed and adapted on Sept. 21, 2022: Credit: Xin Liu, Organic Chemistry I, CC BY-NC-SA 4.0. via Pressbooks : https://kpu.pressbooks.pub/organicchemistry/chapter/5 -3-chirality/
 on your own Flowchart: Most common types of isomers

Molecular Formula

Differ by Yes
rotation of a s
bond?
No

Constitutional Conformational
Conformers

Configurational Geometric (cis /trans)
Disubstituted cycloalkane
Restricted rotation
(R,S); (d,l); (+,-); (D,L)
yes
Cis and trans alkenes are not
mirror images of each other,
thus by definition,
diastereomers

trans, cis
Z, E
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 How do you separate Enantiomers?
Enantiomers have the same physical properties (bp, mp) in achiral
environment (water, ethanol etc).
 Cannot be separated by a standard laboratory techniques (e.g.
extraction, distillation).

Diastereomers have different physical properties (even in achiral

environment)
 Can be separated by standard laboratory techniques

Strategy to separate enantiomers:

 One can convert enantiomers to diastereomeric salts. The addition of a
chiral centre allows the compounds to be separated
 The separation of a mixture of enantiomers is called the resolution of a
racemic mixture
 Biological resolution involves ‘feeding’ a racemic mixture to a biological
system (e.g. enzyme) which only converts one enantiomer to another
product leaving behind the other enantiomer unchanged.

124
Te x t a d ap te d o n sl ig htl y (te xt e ss en ti al l y ta ke n as o bta in ed )o n Sep t. 21 , 2 02 2: Cred i t: : Chri s Sch al le r, “ Di aste re om ers an d Op ti ca l Re sol u ti on ”, CC BY-NC-SA, vi a L ib reTex ts : h t ps :/ /ch em.l ib retex ts .o rg/Boo ksh el ve s/Orga ni c_ Che mis try /Su pp le men tal _Mo du l es_ (Orga ni c_ Che mis try )/ Fun da men tal s/Is ome ris m_i n _Orga ni c_ Com po un ds/Di as te reo mers_ an d_ Opti ca l_ Res ol uti on
 Resolution of Racemates

• The most widely used technique of resolution depends on the

reaction of a chiral acid (resolving agent) with a racemic base or the
reaction of a chiral base with a racemic acid.

• The result is a pair of diastereomeric salts, which can be separated

based on their different physical properties (such as solubility) and
standard laboratory techniques (e.g. filtration).

• Treating the separated diastereomeric salts with base generates the

original enantiomers (but this time as separate compounds and not in
a racemic mixture).

125
Text adapted on Sept. 21, 2022: Credit:: Chris Schaller, “ Diastereomers and Optical Resolution”, CC BY-NC-SA, via LibreTexts : https://chem.libretexts.org/Bookshelves/Organic_Chemistry/Supplemen tal_ Modules_(Organic_Chemistry)/Fundamen tals/ Isomerism_in_Organic_Compounds /Diastereomers_and_Optical_Resolut ion
 Resolution: Diasteriomeric Salts

* *
+ **

(2R,3R)-2,3-dihydroxybutanedioic acid
(R)-(-)-amphetamine (S)-(+)- (+)-tartaric acid – chiral resolving agent
Racemic mixture []D= 0
CH3CH2OH (separated by filtration)

+
+
+

(R)(2R,3R) salt
(S)(2R,3R) salt
More soluble Less soluble - crystal form 126
 Resolution: Diasteriomeric Salts

(S)(2R,3R) salt
Filter out the less soluble crystals

KOH / H2O
K+

K+

soluble in water insoluble in water

(S)-(+)-amphetamine []D = +40 127
 In class problem

Determine which if any of the following compounds are optically active?

A B C D

128
Pro b l e m ad ap te d wit h p ermi sso n a nd i ma ge s ob ta in ed wit h p ermi ssi o n o n De c. 2 1, 20 22 : Cre di t:
J a m e s As he nh urst, “The M eso Tra p”, v ia M aste rin g Orga ni c Che mi stry : https://www.ma stero rg an i cch emi stry.co m/20 11 /0 1/12 /th e-me so -trap /
“M e s o Com po un ds”, CCBY-NC-SA, vi a Li breTe xts: http s://c he m.l i brete xts.org/Bo oks he lv es /Organ ic _Ch emi stry/Orga ni c_ Che mis try _(Li b re Texts)/05 %3 A_Stereo ch emi stry_ at_Te trahe dr al _ Cen te rs/5.07 %3 A_ Me so_ Com po un ds
 In class problem
How would you classify these two structures:

A. Identical compounds (Note: identical compounds will have same

IUPAC name)
B. Diastereomers
C. Enantiomers
D. Constitutional isomers
E. Meso compounds

129
Problem taken and adapted slightly on Sept. 21, 2022: “4.3 Diastereomers ”, CC BY-NC-SA, via LibreTexts : https://chem.libretexts.org/Courses/Purdue/Purdue_Chem_26100 %3A_ Organic_Chemistry_I_(Wenthold) /Chapter_04 %3A_ Stereochemistr y/4 .3_Diastereomers
 In class problem
How would you classify these two structures:

A. Identical compounds
B. Diastereomers
C. Enantiomers
D. Constitutional isomers
E. Meso compounds

130
Problem taken on Sept. 21, 2022: “4.3 Diastereomers”, CC BY-NC-SA, via LibreTexts: https://chem.libretexts.org/Courses/Purdue/Purdue_Chem_26100%3A_Organic _Chemistr y_I_(Wenthol d)/Chapter _04%3A_Stereochemistr y/4.3_Diastereomers