Chapter 2

Conformation and
Stereochemistry
The Arrangement of
Atoms in Space
 Conformation

Conformation:

The different spatial arrangement of the atoms

that result from rotation about a single bond.
 Conformations of Alkanes:
Rotation about Carbon–Carbon Bonds
This can be contrasted, however, with rotation around the
central carbon-carbon bond in butane, in which two
methyl groups clearly overlap during a single rotation
(the van der Waals radii of the methyl hydrogen atoms
clearly overlap).
 Ethane

• eclipsed
conformation
 Ethane

• staggered
conformation
Projection Formulas of the Staggered
Conformation of Ethane

H H

H H
H H
H H
H H
H H

Newman Sawhorse
 Anti Relationships

H H

H H
H H
180° H H
H H
H H

•Two bonds are anti when the angle

between them is 180°.
 Gauche Relationships

H 60° H

H H
H H
H H
H H
H H

•Two bonds are gauche when the angle

between them is 60°.
 Different Conformations of Ethane

• A staggered conformer is more stable than an eclipsed

conformer
• Torsional strain: repulsion between pairs of bonding
electrons
 Conformations of n-Butane
• Steric strain: repulsion between the electron clouds of
atoms or groups
 Cycloalkanes: Ring Strain

• Angle strain results when bond angles deviate from the

ideal 109.5° bond angle
• The chair conformation of cyclohexane is free of strain
Ring Flipping in Cyclohexane
Drawing Cyclohexane
The Conformations of Cyclohexane
and Their Energies
Conformations of Monosubstituted
Cyclohexanes
Steric Strain of 1,3-Diaxial Interaction in
Methylcyclohexane
• The larger the substituent on a cyclohexane ring, the
more the equatorial substituted conformer will be
favored

Keq = [equatorial conformer]/[axial conformer]

 The Chair Conformers of cis-1,4-
Dimethylcyclohexane

H H

ring-flip
H CH3 H3C H

CH3 cis-1,4-dimethylcyclohexane CH3

The Chair Conformers of trans-1,4-
Dimethylcyclohexane
H CH3

H3C ring-flip H H
CH3

H CH3
trans-1,4-dimethylcyclohexane
1-tert-Butyl-3-Methylcyclohexane
 Conformations of Fused Rings

• Trans-fused cyclohexane ring is more stable than

cis-fused cyclohexane ring
 Isomers
Nonidentical compounds having the same molecular
formula
 Constitutional Isomers
Result from different in structural formula
(same molecular formula)
 Stereochemistry
Stereochemistry is the study of how the geometry affects
the properties of molecules and how they react.

Definition of stereochemistry is:

The study of the spatial arrangements of atoms in

molecules and complexes.
 Cis-Trans Isomers (Geometric isomers)

• Result from restricted rotation caused by a

double bond or by a cyclic structure
Cis-Trans Interconversion in Vision
 Stereochemical Notation

cis (identical or • trans (identical or

analogous substitutents analogous substituents
on same side) on opposite sides)
CH3(CH2)6CH2 CH2(CH2)6CO2H
C C Oleic acid
H H

• cis and trans are useful when

substituents are identical or analogous
(oleic acid has a cis double bond)
• cis and trans are ambiguous when
analogies are not obvious
 Cl Br
C C
H F

• What is needed:

1) systematic body of rules for ranking

substituents
• 2) new set of stereochemical symbols
other than cis and trans
E and Z isomers
 The E-Z Notational System
• E :higher ranked substituents on opposite sides
• Z :higher ranked substituents on same side

higher lower higher higher

C C C C

lower higher lower lower

Entgegen Zusammen
 Question: How are substituents ranked?

The Cahn-Ingold-Prelog (CIP) System

 Naming by the E,Z System
Rule 1: Consider the atomic number of the
atoms bonded directly to a specific sp2
carbon.
Rule 2: If there is a tie, consider the atoms
attached to the tie.
Rule 3: Multiple bonds are treated as attachment
of multiple single bonds.
Rule 4: Rank the priorities by mass number in
isotopes.
 Enantiomers
nonsuperimposable mirror-image molecules
Achiral compounds have superimposable mirror images

Chiral compounds have nonsuperimposable mirror

images
Drawing Enantiomers

Perspective formula

Fischer projection
A stereocenter (stereogenic center) is an atom at which
the interchange of two groups produces a stereoisomer
 Naming Enantiomers
The R,S system of nomenclature
Rank the groups (atoms) bonded to the chirality center
Orient the lowest priority (4) away from you

Clockwise = R configuration

Counterclockwise = S configuration
 Naming from the Perspective Formula
1. Rank the groups bonded to the asymmetric carbon
1

2
3

2. If the group (or atom) with the lowest priority is

bonded by hatched wedge,
3. If necessary, rotate the molecule so that the lowest
priority group (or atom) is bonded by a hatched wedge
(if R configuration then original has S configuration
(switch))

4. You can draw group 1 to group 2, passing group 4,

but never 3
 Naming from the Fischer Projection
1. Rank the groups (or atom) that are bonded to the asymmetric
carbon and draw an arrow with the highest priority to the lowest
priority
Cl

CH3CH2 CH2CH2CH3
(R)-3-chlorohexane
H
2. If the lowest priority is on a horizontal bond, the naming is
opposite to the direction of the arrow
CH3

H OH (S)-2-butanol
CH2CH 3
3. The arrow can go from group 1 to 2, passing group 4, but not
group 3
CO2H

H CH3
(S)-lactic acid
OH

A Fischer projection can only be rotated 180° in the plane

of the paper to yield the same molecule
Chiral compounds are optically active; they rotate the
plane of polarized light.

Clockwise (+) Counterclockwise (-)

Different from R,S configuration

Achiral compounds do not rotate the plane of polarized

light. They are optically inactive.
A polarizer measures the degree of optical rotation of a
compound The observed rotation (a)

a
a  =Τ
λ
lxc
[a ]T = specific rotation
T is the temp in °C
 is the wavelength
a is the measured rotation in degrees
l is the path length in decimeters
c is the concentration in grams per mL
Each optically active compound has a characteristic specific
rotation
A racemic mixture, which contains an equal amount of
the two enantiomers, is optically inactive

optical purity = observed specific rotation

specific rotation of the pure enantiomer

excess of a single enantiomer

enantiomeric excess =
entire mixture
Isomers with more than one chiral carbon: a maximum of
2n stereoisomers can be obtained
* *
CH3CHCHCH3
Cl OH

Diastereomers are stereoisomers that are not enantiomers

 Meso Compounds
Have two or more asymmetric carbons and a plane of
symmetry

They are achiral molecules

Identification of Asymmetric Carbons in
Cyclic Compounds
H
these two groups * H
are different
*
Br
CH3

H H H H
H H CH3 CH3

Br Br Br Br
CH3 CH3 H H

cis-1-bromo-3-methylcyclohexane trans-1-bromo-3-methylcyclohexane
As long as any one conformer of a compound has a
plane of symmetry, the compound will be achiral

plane of
symmetry
plane of
symmetry
The R,S nomenclature of isomers with more than one
asymmetric carbon
Reactions of compounds that contain an asymmetric
carbon.
CH2CH2CH2Cl CH2CH2CH2OH
H OH- H
CH3CH2 CH3 CH3CH2 CH3

CH CH2 CH2CH3
H2
H H
CH3CH2CH2 Pd/C CH3CH2CH2
CH3 CH3

No reaction at the asymmetric carbon; both the reagent and the

product have the same relative configuration.

If a reaction breaks a bond at the asymmetric carbon, you need to

know the reaction mechanism in order to predict the relative
configuration of the product.
 Resolution of a Racemic Mixture
(S)-base
(R)-acid (S)-acid (R,S)-salt (S,S)-salt
enantiomers diastereomers

(R,S)-salt (S,S)-salt
HCl HCl

(S)-baseH+ (S)-baseH+
+ +
(R)-acid (S)-acid
Discrimination of Enantiomers by
Biological Molecules
 Terminologies Associated with
Stereochemistry
pro-R-hydrogen

pro-S-hydrogen

Enantiotopic hydrogens have the same chemical

reactivity and cannot be distinguished by achiral agents,

but they are not chemically equivalent toward chiral

reagents
Diastereotopic hydrogens do not have the same reactivity
with achiral reagents
Atoms other than carbon can be asymmetric

CH3
CH3
Br- N+ Br-
H H N+
CH3CH2CH2 CH2CH3 CH3CH2 CH2CH2CH3

O O
P H H P
CH3CH2O OCH3 CH3O OCH2CH3
Amine Inversion
A regioselective reaction: preferential formation of one
constitutional isomer

A stereoselective reaction: preferential formation of a

stereoisomer
A stereospecific reaction: each stereoisomeric reactant
produces a different stereoisomeric product or a different
set of products

All stereospecific reactions are stereoselective

Not all stereoselective reactions are stereospecific
 Stereochemistry of Electrophilic
Addition Reactions of Alkenes

What is the absolute configuration of the product?

Addition reactions that form one asymmetric carbon
 CH3 CH3
peroxide
CH3CH2C CH2 + HBr CH3CH2CHCH2Br
*

2-methyl-1-butene 1-bromo-2-methylbutane
Addition reactions that form an additional asymmetric
carbon
Addition reactions that form two asymmetric carbons

A carbocation reaction intermediate

CH3CH2 CH2CH3 Cl
C C + HCl CH3CH2CH CCH2CH3
H3C CH3
CH3 CH3

CH3CH2 CH3 CH3CH2 CH3

H3C C C H Cl C C H
Cl CH2CH3 H3C CH2CH3

H3C CH2CH3 H3C CH2CH3

C C CH C C
H 3
H Cl
CH3CH2 Cl
CH3CH2 CH3

Two substituents added to the same side of the double bond: syn
Two substituents added to opposite sides of the double bond: anti
Addition reactions that form two asymmetric carbons
A radical reaction intermediate
Stereochemistry of Hydrogen Addition
(Syn Addition)
 Hydrogenation of Cyclic Alkenes
H H
Pt/C
+ H2 CH3 CH(CH3)2
H3C
CH(CH3)2

H3C CH(CH3)2

H H

Only cis isomers are obtained with alkenes containing

fewer than eight ring atoms
Both cis and trans isomers are possible for rings
containing eight or more ring atoms
Stereochemistry of Hydroboration–
Oxidation
Addition reactions that form a bromonium ion
intermediate (anti addition)
 Terms
Chiral
A molecule is chiral if it is not superimposable on its mirror
image.

Achiral
A molecule is achiral if it is superimposable on its mirror
image.
Meso
A molecule is meso if it is achiral and contains two or more
stereocenters.
Enantiomers
Stereoisomers that are non-superposable mirror images.
Diastereomers
Stereoisomers that are non-superposable, but are not
mirror images.
Constitutional Isomers
Isomers which contain atoms that differ in connectivity.
Non-isomers
Compounds that do not have the same molecular formula.
Superposable
A term that describes the ability to precisely overlap one
object over another. Only identical objects are
superposable, everything else is non-superposable.
Stereoisomers
Isomers which have atoms that differ only by their
orientation in space. Unlike constitutional isomers,
corresponding atoms in stereoisomers exhibit the same
connectivity.
Isomers
Compounds that have the same molecular formula.
Stereochemistry, Flow Charts