Organic Chemistry

CB1103

Asst Prof Phillip S. Grant

School of Chemical and Biomedical Engineering
Nanyang Technological University

1
 Organic Chemistry: Part 1
3. Stereochemistry (2 h)
Concepts & Chirality
Fischer Projections
Nomenclature (R/S)
Enantiomers
Diastereomers

CB1103 Chapter 3 2
 Why?
Thalidomide (1957)
Against nausea and to alleviate morning sickness in pregnant women

This drug incidents alarm us that the stereochemistry is very important in organic
chemistry.

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 3.1 Molecular Isomerism
Stereochemistry: refers to the relative spatial arrangements of atoms in a molecule;
Studies of three-dimensional structures of molecules

Isomers

Constitutional isomers Stereoisomers

(Structural isomers)
Isobutane
Diastereomers Enantiomers

Geometric Isomer Others

Cis-, trans-, isomers (2 or more chiral centers)

Constitutional isomers: differ in bonding sequence; their atoms are connected differently
Stereoisomers: same bonding sequence but different orientation of atoms in space [Configuration]
Enantiomers: nonsuperimposable mirror-image stereoisomers
Diastereomers: nonsuperimposable non-mirror-image stereoisomers

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 3.2 Chirality and Key Terminologies
Nonsuperimposable mirror-image Superimposable mirror-image

 “Handedness”: Right-hand glove does  Mirror images that can be

not fit the left hand. superposed are achiral (not chiral).
 An object is chiral if its mirror image is
different from the original object.

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 3.2 Chirality and Key Terminologies
Enantiomers: Compounds that are nonsuperimposable mirror images. Any
molecule that is chiral MUST have an enantiomer.

Chiral Carbon Atom: Also called asymmetric carbon atom.

Carbon atom that is bonded to four different groups is chiral.
Its mirror image will be a different compound (its enantiomer).

Superimposable

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 3.2 Chirality and Key Terminologies
Chiral: Stereocenter
A stereocenter (or stereogenic atom) is any atom at which the interchange of two
groups gives a stereoisomer.
Asymmetric carbons and the double-bonded carbon atoms in cis-trans isomers
are the most common types of stereocenters.

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 3.2 Chirality and Key Terminologies
Achiral: Mirror Planes of Symmetry
A molecule that has a plane of symmetry is achiral.

Cis-1,2-dichlorocyclohexane (Achiral)

Trans-1,2-dichlorocyclohexane (Chiral)

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 3.3 Fischer Projection Formulae
Flat representation of a 3-D molecule: a method to describe absolute configuration
based on the projection tetrahedral carbon atom onto a flat surface
 A chiral carbon is at the intersection of horizontal and vertical lines.
 Horizontal lines are forward, out of plane.
 Vertical lines are behind the plane.

Fisher Projection

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 3.4 Nomenclature for Chiral Centers
Cahn-Ingold-Prelog R/S Nomenclature

• Enantiomers have different spatial arrangements of the four groups

attached to the asymmetric/chiral carbon (C*).
• The two possible spatial arrangements are called configurations.
• Each asymmetric carbon atom is assigned a letter (R) or (S) based on
its three-dimensional configuration.
• Cahn–Ingold–Prelog convention is the most widely accepted system
for naming the configurations of chirality centers.

A pair of opposite configurations: R/S

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 3.4 Nomenclature
Cahn-Ingold-Prelog R/S Nomenclature

1. Assign Priority
Atoms attached to the chiral carbon are ranked / prioritized according to atomic
numbers (higher atomic no. higher priority). Highest priority = 1, lowest = 4:

I > Br > Cl > S > F > O > N > 13C > 12C > 2H > 1H
53 35 17

Atomic number: F > N > C > H

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 3.4 Nomenclature
Cahn-Ingold-Prelog R/S Nomenclature
4. Rotate
 Working in 3-D, rotate the molecule so that the lowest priority group is in back.
 Draw an arrow from highest to lowest priority group (from 1 to 2, and to 3).
 Clockwise = (R), Counterclockwise = (S)
 Sometimes it is more convenient to look with the lowest priority group nearest eye (in
front). If so the assignment is reversed. Clockwise = (S), Counterclockwise = (R)

Clockwise
(R)

Avoid rotation of molecule; pick up the view

angle to make the smallest group in back
(furthest away from you) or in front (nearest to
you)

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 3.4 Nomenclature
Cahn-Ingold-Prelog R/S Nomenclature
2. Breaking Ties
 In case of ties, use the next atoms along the chain of each group as
tiebreakers.
How to find the “next atoms”? Rank the atoms in the group linked to tie atom

 Keep working outwards from the chiral center until a priority can be reached
Compare the “next atoms” of four groups

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 3.4 Nomenclature
Cahn-Ingold-Prelog R/S Nomenclature
3. Multiple Bonds
 Multiple-bonded atoms are considered as an equivalent number of single-bonded
atom expanded by replacing the atom attached to each end of the bond

Expansion: break and duplicate

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 Example

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 3.4 Nomenclature
Fisher Projection & R/S Nomenclature
The arrow from group 1 to group 2 to group 3 appears counterclockwise in the Fischer
projection. If the molecule is turned over so the hydrogen is in back, the arrow is
clockwise, so this is the (R) enantiomer of glyceraldehyde.

When naming (R) and (S) from Fischer projections with the hydrogen on a horizontal
bond (toward you instead of away from you), just apply the normal rules backward.

 The Lowest group on a horizontal bond: Clockwise = (S), Counterclockwise = (R)

 The Lowest group on a vertical bond: Clockwise = (R), Counterclockwise = (S)

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 3.4 Fischer Projection Formulae
Fischer Rules (One chiral carbon)
 Rotation of the Fischer projection by 90° (or 270°, i.e. -90°) gives the formula for
the enantiomer
 Rotation by 180° (i.e. 2 x 90°) affords 2 sequential mirror image conversions,
which therefore MUST afford the exact same substrate.
 Exchange of a pair of substituents lead to the enantiomeric structure ⇒
exchanging two pairs of substituents gives the same chiral molecule.

R S

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 3.4 Fischer Projection Formulae
Fischer Rules
 Rotation of the Fischer projection by 90° (or 270°, i.e. -90°) gives the formula for
the enantiomer
 Rotation by 180° (i.e. 2 x 90°) affords 2 sequential mirror image conversions
which therefore MUST afford the exact same substrate
 Exchange of a pair of substituents lead to the enantiomeric structure ⇒
exchanging two pairs of substituents gives the same chiral molecule.

R R

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 3.3 Fischer Projection Formulae
Fischer Rules
 Rotation of the Fischer projection by 90° (or 270°, i.e. -90°) gives the formula for
the enantiomer
 Rotation by 180° (i.e. 2 x 90°) affords 2 sequential mirror image conversions
which therefore MUST afford the exact same substrate
 Exchange of a pair of substituents lead to the enantiomeric structure ⇒
exchanging two pairs of substituents gives the same chiral molecule.

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 3.1 Molecular Isomerism
Stereochemistry: Refers to the relative spatial arrangements of atoms in a molecule;
Studies three-dimensional structure of molecules

Isomers

Constitutional isomers Stereoisomers

(Structural isomers)

Diastereomers Enantiomers

Geometric Isomer Others

Cis-, trans-, isomers (2 or more chiral centers)

Constitutional isomers: differ in bonding sequence; their atoms are connected differently
Stereoiomsers: same bonding sequence but different orientation of atoms in space [Configuration]
Enantiomers: nonsuperimposable mirror-image stereoisomers [R/S configuration]
Diastereomers: nonsuperimposable non-mirror-image stereoisomers

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 3.5 Diastereomers
Diastereomers: Cis-Trans Isomerism on Double Bonds

These stereoisomers are not mirror images of each other, so they are not
enantiomers. They are diastereomers.

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 3.5 Diastereomers
Diastereomers (two or more chiral centers)
 When compounds have two or more chiral centers they have enantiomers,
diastereomers, or meso isomers.
 Enantiomers have opposite configurations (R/S) at each corresponding chiral carbon.
 Diastereomers have some matching, some opposite configurations.

Meso compounds: Diastereomers with 2 or more chiral centers with an internal mirror
plane. Example tartaric acid

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 1 2 3 4

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 3.4 Nomenclature for Chiral Centers
Fischer-Rosandoff Nomenclature (D/L Sugar Convention)

 The molecule is written with the longest chain placed vertically.

 The most oxidized end of the chain is placed at the top (as CHO in glucose).
 If in the projected structure, the OH group (or any negative group, X) at the bottom
most (highest-numbered) chiral centre (C-5 in glucose) is on the right hand side,
the molecule is given the D configuration and if it is on the left, the molecule is
given the L configuration
 Nomenclature mainly applied to sugar molecules but not to other unrelated
molecules.

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 3.6 Chirality and Biological Significance
Enzyme catalyzes a biological
reaction by first positioning
them at a binding site by a
combination of H-bonds, van
der Waals, ionic and other
interactions. An enzyme with
specific binding sites for 3-4
groups on a stereocentre can
distinguish between a molecule
and its enantiomer.

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 3.6 Chirality and Biological Significance

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 3.7 Optical Properties
Optical activity: ability of a compound to rotate the plane polarized light (PPL).

Enantiomers rotate the plane of polarized light in opposite directions, but same
number of degrees.

Levorotatory (l) or (-): isomer that rotates the PPL to the left.
Dextrorotatory (d) or (+): isomer that rotates the PPL to the right.

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 3.7 Optical Properties
Specific Rotation: Observed rotation depends on the length of the cell and
concentration, as well as the strength of optical activity, temperature, and
wavelength of light.

Where  (observed) is the rotation observed in the polarimeter, c is

concentration in g/mL, and l is length of sample cell in decimeters (dm).

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 3.7 Optical Properties
Racemic Mixtures: mixture of equal amounts of enantiomers (50:50).
If optically inactive reagents combine to form a chiral molecule, a racemic
mixture is formed.

• Equal quantities of d- and l-enantiomers.

• Notation: (d,l) or ()
• No optical activity.
• The mixture may have different boiling point (b. p.) and melting point (m. p.)
from the enantiomers!

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 3.7 Optical Properties
Optical Purity

• Optical purity (o.p.) is sometimes called enantiomeric excess (e.e.).

• One enantiomer is present in greater amounts.

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 3.8 Chemical Resolution of Enantiomers

In 1848, Louis Pasteur noticed that a

salt of racemic (±)-tartaric acid
crystallizes into mirror-image crystals.
Using a microscope and a pair of
tweezers, he physically separated the
enantiomeric crystals.
Pasteur had accomplished the first
artificial resolution of enantiomers.

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 3.8 Chemical Resolution of Enantiomers

Chromatographic resolutions
(analysis & preparative scale
enantioseparations)

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