Stereochemistry

Stereochemistry refers to the

3-dimensional properties and
reactions of molecules. It has
its own language and terms that
need to be learned in order to
fully communicate and
understand the concepts.
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 Definitions
• Stereoisomers – compounds with the same
connectivity, different arrangement in
space
• Enantiomers – stereoisomers that are non-
superimposible mirror images; only
properties that differ are direction (+ or -)
of optical rotation
• Diastereomers – stereoisomers that are not
mirror images; different compounds
with different physical properties

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 More Definitions
• Asymmetric center – sp3 carbon with 4
different groups attached
• Optical activity – the ability to rotate the
plane of plane –polarized light
• Chiral compound – a compound that is
optically active (achiral compound will not
rotate light)
• Polarimeter – device that measures the
optical rotation of the chiral compound

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 Chirality

• “Handedness”: Right-hand glove does

not fit the left hand.
• An object is chiral if its mirror image is
different from the original object.
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 Achiral
• Mirror images that can be superposed
are achiral (not chiral).

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 Stereoisomers
Enantiomers: Compounds that are
nonsuperimposable mirror images. Any molecule
that is chiral must have an enantiomer.

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 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
(enantiomer).

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 Stereocenters
• An asymmetric carbon atom is the most
common example of a chirality center.
• Chirality centers belong to an even broader
group called stereocenters. 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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 Examples of Chirality Centers

Asymmetric carbon atoms are examples of chirality

centers, which are examples of stereocenters.

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 Achiral Compounds

Take this mirror image and try to

superimpose it on the one to the
left matching all the atoms.
Everything will match.

When the images can be superposed, the

compound is achiral.
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 Planes of Symmetry

• A molecule that has a plane of symmetry is

achiral.

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 Cis Cyclic Compounds

• Cis-1,2-dichlorocyclohexane is achiral because

the molecule has an internal plane of symmetry.
Both structures above can be superimposed
(they are identical to their mirror images).

© 2013 Pearson Education, Inc. Chapter 5 13

 Trans Cyclic Compounds

• Trans-1,2-dichlorocyclohexane does not have a

plane of symmetry so the images are
nonsuperimposable and the molecule will have two
enantiomers.

© 2013 Pearson Education, Inc. Chapter 5 14

 (R) and (S) Configuration

• Both enantiomers of alanine receive the same name in the

IUPAC system: 2-aminopropanoic acid.
• Only one enantiomer is biologically active. In alanine only the
enantiomer on the left can be metabolized by the enzyme.
• A way to distinguish between them is to use stereochemical
modifiers (R) and (S).

© 2013 Pearson Education, Inc. Chapter 5 15

 Cahn–Ingold–Prelog
Priority System
• Enantiomers have different spatial arrangements of the
four groups attached to the asymmetric carbon.
• 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.

© 2013 Pearson Education, Inc. Chapter 5 16

 (R) and (S) Configuration: Step 1
Assign Priority
• Assign a relative “priority” to each group
bonded to the asymmetric carbon.
Group 1 would have the highest priority,
group 2 second, etc.
• Atoms with higher atomic numbers
receive higher priorities.

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

© 2013 Pearson Education, Inc. Chapter 5 17

 Assign Priorities

Atomic number: F > N > C > H

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 (R) and (S) Configuration:
Breaking Ties
In case of ties, use the next atoms along
the chain of each group as tiebreakers.

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 (R) and (S) Configuration:
Multiple Bonds
Treat double and
triple bonds as if
each were a bond to
a separate atom.

© 2013 Pearson Education, Inc. Chapter 5 20

 (R) and (S) Configuration:
Step 2
• Working in 3-D, rotate the
molecule so that the lowest
priority group is in back.
• Draw an arrow from highest
(1) to second highest (2) to
lowest (3) priority group.
• Clockwise = (R),
Counterclockwise = (S)

© 2013 Pearson Education, Inc. Chapter 5 21

 Assign Priorities

Counterclockwise
(S)

Draw an arrow from Group 1 to Group 2 to Group 3 and

back to Group 1. Ignore Group 4.

Clockwise = (R) and Counterclockwise = (S)

© 2013 Pearson Education, Inc. Chapter 5 22

 Example
3
1 CH2CH3
OH
rotate
C 3 2
C 4
2 CH2CH3 CH3CH2CH2 H
CH3CH2CH2
H OH
4 1

Clockwise
(R)

When rotating to put the lowest priority group in the back,

keep one group in place and rotate the other three.

© 2013 Pearson Education, Inc. Chapter 5 23

 Example (Continued)

3
CH3

1
CH3CH2CH=CH H4
CH2CH2CH2CH3
2

Counterclockwise
(S)

© 2013 Pearson Education, Inc. Chapter 5 24

 Conformational Analysis

Newman Projections
Ring Strain
Cyclohexane Conformations

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 Views of Ethane

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 The Newman Projection

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 Rotational Conformations of Ethane

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 Definitions
• Conformations - Different spatial
arrangments that a molecule can adopt
due to rotation about sigma bonds.
• Staggered - A low energy conformation
where the bonds on adjacent atoms bisect
each other (60o dihedral angle),
maximizing the separation.
• Eclipsed - A high energy conformation
where the bonds on adjacent atoms are
aligned with each other (0o dihedral angle).

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 60 Rotation Causes Torsional
o

or Eclipsing Strain

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 Types of Strain
• Steric - Destabilization due to the repulsion
between the electron clouds of atoms or groups.
Groups try to occupy some common space.
• Torsional - Destabilization due to the repulsion
between pairs of bonds caused by the electrostatic
repulsion of the electrons in the bonds. Groups
are eclipsed.
• Angle - Destabilisation due to distortion of a bond
angle from it's optimum value caused by the
electrostatic repulsion of the electrons in the
bonds. e.g. cyclopropane

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 Definitions
• Anti - Description given to two substitutents
attached to adjacent atoms when their bonds are
at 180o with respect to each other.
• Syn - Description given to two substitutents
attached to adjacent atoms when their bonds are
at 0o with respect to each other.
• Gauche - Description given to two substitutents
attached to adjacent atoms when their bonds are
at 60o with respect to each other.

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 Potential Energy Diagram

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 Propane Conformations:
Larger Barrier to Rotation (link)

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 Butane Conformations (C2-C3)

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 Gauche Interaction in Butane

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 2 Different Eclipsed
Conformations

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 Butane has Steric and Torsional
Strain When Eclipsed

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 PE Diagram for Butane (link)

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 1-Chloropropane

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 Saturated Cyclic Compounds

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 Cyclopropane
Angle and Torsional Strain

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 Cyclobutane is not Planar

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 Cyclopentane

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 Cyclohexane

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 Chair Conformation
link to active site

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 Boat Conformation

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 Axial bonds and
Equatorial bonds

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 Rings can Flip from one Chair
Conformation to Another

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 Flipping Chair Conformations

• All axial bonds become

equatorial
• All equatorial bonds become
axial
• All “up” bonds stay up
• All “down” bonds stay down
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 axial up

eq. up

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 Axial-up becomes Equatorial-up

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© 2013 Pearson Education, Inc.
 Equatorial Conformation is
Preferred (link)

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 Axial Methyl group is Gauche to
C3 in the ring

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 Gauche Interactions are
Flagged by Parallel H’s
1,3-Diaxial Interactions

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 Equatorial Methyl Group is Anti
to C3 in the ring

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 Aromaticity

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 Aromatic
• Requirements
Structure must be cyclic with conjugated pi bonds.
• Each atom in the ring must have an unhybridized p orbital.
• The p orbitals must overlap continuously around the ring.
(Usually planar structure)
• Aromatic: the compound is more stable than its open-chain
counterpart
• Antiaromatic: cyclic, conjugated, with overlapping p orbitals
around the ring, but the energy of the compound is greater
than its open-chain counterpart.
• Nonaromatic compounds do not have a continuous ring of
overlapping p orbitals and may be nonplanar

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 Cyclobutadiene & Cyclooctatetraene

}
Cyclobutadi
ene
Aromatic?
Cyclooctatetra
ene

Observations:
•Cyclobutadiene and cyclooctatetraene are difficult to
prepare.
•Intraring bond distances in stable cyclobutadiene
derivatives are not equal.
•Resonance energy for cyclooctatetraene is very low.
•Cyclooctatetraene is not a planar molecule.
Conclusion:
Cyclic conjugation is a necessary but not sufficient
requirement for aromatic character!
What more is needed?
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Hückel’s Rule
 Hückel’s Rule - Annulenes
The year 1931! Hückel’s Discovery - An early success using
molecular orbits to understand chemistry.

Analysis of MOs for Monocyclic Conjugated Polyenes with

Regular Polygons having Planar Geometries
•Said hydrocarbons are characterized by a set of -
molecular orbitals in which:
•One (1) orbital is of lowest energy (-bonding);
•Another is of highest energy (*-antibonding);
•The rest are distributed in pairs between them (Some
-bonding, an equal number as *-antibonding, and in
some cases some nonbonding).

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 Constructing the -Orbital MO Diagrams
1. Draw the polygon representing the ring of interest with one apex at the bottom
of the drawing.
2. Place an orbital at each corner of the polygon.
3. Fill the orbitals with electrons in the usual manner.
1. Pair electrons in lower energy orbitals before filling higher energy
orbitals.
2. Closed shells are favorable (aromatic, 4n+2) unshared electrons in
orbitals are not (antiaromatic, 4n).
4 6  8
 6 7
4 5
n n n n
2 
2 
3
1 1 1
3

Cyclobutadiene Benzen Cyclooctatetraene

e

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 Interpreting the MO Figure
8
6
5
n n n n

3 2
1 1
1
Cyclobutadiene Benzen Cyclooctatetraene
Color coding of orbitals in the energy diagram: green = bonding (energy released),
e
blue = nonbonding (no change in energy), & magenta = anti-bonding (absorb energy).
•Placing electrons in bonding orbitals adds stability to the compound.
•Placing them in the nonbonding orbitals has no effect on compound’s stability.
•Placing electrons in anti-bonding orbitals decreases the stability.
•When all orbitals below the “blue” line are filled with electrons and none are in or
above the blue line the system has a “closed shell” electron configuration.

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 Hückel’s 4n+2 Rule
Monocyclic planar, fully conjugated polyenes are called
annulenes.
Among annulenes, only those possessing 4n+2  electrons, where n is an
integer, will have special aromatic stability.
– Planarity and complete conjugation are important criteria.
– The 4n+2 rule may be fulfilled for neutral or ionic moieties.

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 Cycloheptatriene & the Cycloheptatrienyl
Cation
H H H

Cycloheptatrie Cycloheptatrienyl
ne Cation
Cycloheptatriene (the tropylium cation) has a conjugated, but not a
fully conjugated structure.

The conjugation is interrupted by the presence of the sp3-hybridized

carbon atom.

Ionization of cycloheptatriene by removal of a hydride ion (H -)

converts this carbon to an sp2 hybrid and allows the conjugation of
the triene moiety to “close ends” via the empty p-orbital making a
fully conjugated system.

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 The Cycloheptatrienyl Cation -MO Diagram

There are 7 p-orbitals which give rise to seven  MOs.

•There are 3 bonding orbitals
•The remaining four orbitals are antibonding
•There are six available electrons that fill the bonding
orbitals making a closed shell
•Note 4n + 2 = 6. The cation is planar and aromatic!

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 Additional Aromatic Ions
H H H H

- +
-H +
-H-

Cyclononatetraene can form either a anion (removal of a proton) or

an cation (removal of a hydride ion).
Which if any is a viable candidate for aromatic stabilization?
Answer:
•The cation has 8  electrons and therefore is not viable.
•The anion has 10  electrons and therefore is viable.
•Propose a MO diagram for the anion that is consistent with
aromatic stabilization. Answer

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 A Couple More Examples

H H H
2-
+
-
H
H H
Cycloprope Cyclopentadie Cyclooctatetrae
nyl nyl ne
Cation Anion Dianion
Convince yourself that these ions fulfill Hückel’s 4n+2 rule!

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 Heterocyclic Aromatic Compounds
Definition: A heterocycle (heterocyclic compound) is a cyclic
compound with at least one atom other than carbon as a ring
member.
Definition: A heterocyclic compound that possesses aromatic
stability is called a heterocyclic aromatic compound,

Some Examples:

N N O S
H

Pyridi Pyrrol Fura Thiophe

ne e n ne
How do these compounds comply with Hückel’s rule?

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 Where are Those Lone Pairs?
Are the electron pair electrons  electrons or simple unshared pairs?

N N O S
H
Pyridi Pyrrol Fura Thiophe
ne pairs colored ne
e in magenta are nelectrons in p-orbitals.
Electron
Electron pairs in blue are simple unshared pairs in sp 2 hybridized
orbitals.

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 Some Interesting Heterocycles
N N N
Pyrrole based heterocycles
N O S
with a second heteroatom in H
the ring.
Imidazo Oxazole Thiazole
le
H CH3
N
NCN
Cimitidine – Have an ulcer?
N
Try this! CH2SCH2CH2NHCNHCH3

N S
Romantic night lights? Firefly
S N CO2H
Luciferin HO

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 Polycyclic Aromatic Heterocycles

Benzene fused with pyridine:

N
N

Quinoli Isoquinoli
ne ne
Benzene fused with pyrrole, furan & thiophene:

N O S
H

Indo Benzofur Benzothiophe

le an ne

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