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CBMS304/CBMS804; Advanced Organic

and Biological Chemistry B, Topic 2
Pericyclic Reactions
No intermediates
No electrophile or nucleophile
Rate not dependant on solvent
Two or more bonds are broken simultaneously
Catalysed by light or heat
Are reversible

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electrocyclic
re actions
1 new o-bonds
1 less t-bonds
ring closing:
HOMO of t
ring opening:
HOMO of o,
LUMO of t
disrotatory conrotatory
thermal photoc hemic al

sigmatropic
re arrangements
0 new o-bonds
0 less t-bonds
bonds shifted
H-shift
C-shift
HOMO of o,
LUMO of t
suprafacial antarafacial
thermal photoc hemical
MAP FOR 331 CONCEPT

cycloadditions
2 new o-bonds
2 less t-bonds
[4n + 2]t
electrons
[4n]t
electrons
secondary orbital overlap
= exo or endo TS
photoc hemic al thermal
HOMO + LUMO
regioselec tivity based
on electronegativity
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Bonding in carbon compounds
Valence bond model
Equates covalent bonds with the sharing of two electrons
Thus H should form 1 bond and O 2 etc.
1s
2s
2p
{
Lewis rule of eight
Aufbau principle
Pauli exclusion principle

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Valence Bond Theory
Thus Oxygen should form two bonds
And Nitrogen three bonds
But why does carbon form four bonds?
O N
H
H H H H
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Hybridisation
Carbon should form two bonds but it usually forms
four
sp
3

C
C H
H
H
H
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Pauling theory of hybridisation
Mathematical combination of s and p orbitals gives
sp
3
hybrids
This explains four equivalent bonds and tetrahedral
geometry
+ 3
4
s
p
sp
3

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Does H
2
+
exist? Correlation Diagrams
H:H H.H
+
?
Rule #1: Conservation of Orbital Number
H.H
+
H H
H:H
+
-

+
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Why is O
2
paramagnetic?
Rule #2: Sigma (o) Orbitals are Always the Lowest
Energy [and Sigma* (o*) the Highest]
Rule #3: pi (t) Orbitals are Higher in Energy than o
but pi* (t*) are Lower than o*

O O
O
2p 2p
O

O O

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Ethylene (or is it ethene)?
Rule #2: Sigma (o) Orbitals are Always the Lowest
Energy [and Sigma* (o*) the Highest]
Rule #3: pi (t) Orbitals are Higher in Energy than o
but pi* (t*) are Lower than o*
C
sp
2
sp
2

C
t-
o-
o
t

C C
H
H
H
H
LUMO
HOMO
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Frontier Molecular Orbitals
Highest Occupied Molecular Orbital (HOMO) and
Lowest Unoccupied Molecular Orbital (LUMO)
are the orbitals that can either donate or receive
electrons from another molecule and thus are the
most important
The HOMO of one reactant interacts with the LUMO
of the other
ie a filled orbital of one and an empty orbital of
another are the closest in energy
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NH
3
+ H-Cl NH
4
Cl
Is something as simple as the reaction of ammonia
with hydrochloric acid describable with a correlation
diagram?
NH
3
HCl
o*
n
NH
4
+

sp
3

HOMO
LUMO
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Reaction of ethylene and bromine
The HOMO of ethylene is the t-bond
The LUMO of Bromine in the o* orbital
t-
o-
o
t
LUMO
HOMO
o
o-
LUMO
HOMO
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Guidelines to Constructing Molecular
Orbitals in Conjugated Systems
With n p-orbitals you get n +-orbitals (Rule #1)
The energy of the +-orbital increases with the number of nodes
(Rule #5)
Nodes MUST be symmetrically placed
Bonding (t) orbitals have energies less than an isolated p-orbital
Non-bonding (n) orbitals have the same energy as an isolated p-
orbital
Antibonding (t*) orbitals have greater energy than an isolated p-
orbital
Rotation (or reflection) about the centre of the conjugated system
produces an image with phases reversed (A) or the same (S)
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The Allyl system
A
S
A
0
2
1
nodes
QuickTime and a
GIF decompressor
are needed to see this picture.
QuickTime and a
GIF decompressor
are needed to see this picture.
QuickTime and a
GIF decompressor
are needed to see this picture.
t
t*
n
Bonds

2



0



+2
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The Butadiene system
C
2



S


A


S


A
mirror


A


S


A


S
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The Cyclobutadiene System
Bonds

3


1


+1


+3
Bonds

4





0






+4
Nodes

3


2


1


0
Nodes

4





2






0
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The Cyclohexatriene System
Bonds
5


3


1


+1


+3


+5
Nodes
5


4


3


2


1


0
Nodes Bonds
6 6




4 2



2 2





0 6
A

S

A

S


A

S
A



S A


S A



S
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Pericyclic reactions
Concerted reactions proceed with no intermediate
E.g. S
N
2 reactions
C Br
H
H
H
HO

C Br
H
H H
HO C HO
H
H
H
Br

Pericyclic reactions are concerted reactions with a

cyclic transition state
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Examples
Cycloadditions


1,-3-dipolar additions


Electrocyclic reactions


Sigmatropic rearrangements

O
O
O
O
O
O
O
O
+
A
O
O
O
O
H
H
hv
Ph N N N
A
N
N
N
Ph
O
OH
A
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Cycloadditions

cycloadditions
2 new o-bonds
2 less t-bonds
[4n + 2]t
electrons
[2n + 2]t
electrons
secondary orbital overlap
= exo or endo TS
HOMO + LUMO
regioselec tivity based
on electronegativity
thermal photoc hemic al
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Cycloaddition Reactions: Mechanism
The simplest example is the photolysis of ethylene: A
[2t+2t]-cycloaddition
1. Arrow pushing
Electrons can go either way
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Cycloaddition Reactions: Mechanism
Consider two ethylenes approaching each other and the t-
orbitals slowly become o-orbitals
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Cycloaddition Reactions: Mechanism
2. Correlations Diagrams
2 t-bonds are converted to two o-bonds
t-



t
o-







o
S S
A A
S A
A S
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Cycloaddition Reactions: Mechanism
2. Correlations Diagrams
Photochemically allowed: Excited state goes to excited state
t-



t
o-







o
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Cycloadditions: Mechanism
3. Frontier Molecular Orbital (FMO) approach
t-



t
HOMO
LUMO
X
HOMO
LUMO
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Cycloadditions: [4t+2t]-Cycloaddition
Also known as the Diels-Alder reaction
Involves a 4-electron system (diene) and
A 2-electron system (dienophile)
3 t-bonds become 2 o-bonds and one new t-bond
Need to consider only the orbitals that change.
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Cycloadditions: [4t+2t]-Cycloaddition
Also known as the Diels-Alder reaction
t
1
-

t
2
-


t
2


t
1

m
1

A


S

A


S
A



S
S A


A


S



S A
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Cycloadditions: [4t+2t]-Cycloaddition
FMO model
t
1
-

t
2
-


t
2


t
1

LUMO

HOMO
LUMO


HOMO
LUMO

HOMO
HOMO

LUMO
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Cycloadditions: [4t+2t]-Cycloaddition
Aromatic TS Rule
Add up the number of electrons involved in the transition
state (TS)
If the TS is aromatic then the reaction is thermally allowed
(4n+2) electrons is the magic number because it allows
electron delocalisation and REDUCTION in overall energy

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Secondary Effects: Secondary Orbital
Overlap
Notice that in the Diels-Alder reaction the dienophile
approaches the diene from one face: Suprafacial.
Qui ckTi me and a
GIF decompres sor
are needed to see this pi c ture.
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Secondary Effects: Secondary Orbital
Overlap
What happens if the dienophile is more than just an alkene?
For the dimerisation of cyclopentadiene, you can have endo
or exo attack
exo endo
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Secondary Effects: Secondary Orbital
Overlap
The two orientations end up with different stereochemistries
exo
endo
H
H
H
H
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Secondary Effects: Secondary Orbital
Overlap
Frontier molecular orbital analysis
t
1
-

t
2
-


t
2


t
1

LUMO

HOMO
exo
endo
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DNA damage; an example of [2t+2t]-
cycloaddition
Two thymidine bases can react when one is excited
photochemically.
HN
N
N
NH
O
O
O
O
HN
N N
NH
O O
O O
H H
280 nm
240 nm
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Not all cycloadditions are endo
[6t+4t]-cycloadditions
O
O
O
O
Exo





Endo
X
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Secondary effects: Regioselectivity
If the diene and dienophile are substituted many
products are possible
OCH
3
OHC
OCH
3
OCH
3
CHO
OCH
3
CHO
OCH
3
CHO CHO
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Secondary effects: Regioselectivity
[4t+2t]-cycloaddition, therefore thermally allowed
Aldehyde has a double bond that is conjugated with
the dienophile so it is really a diene too
Substituents on the diene and dienophile can
polarise the pi-system to favour one orientation over
another
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Secondary effects: Regioselectivity
Resonance effects can explain the regioselectivity
OCH
3
H
O
OCH
3
H
O
OCH
3
H
O
OCH
3
H
O
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Secondary effects: Regioselectivity
Secondary orbital overlap explains the stereoselectivity
O
H
O
H
H
3
CO
H
3
CO
HOMO


LUMO
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Secondary effects: Regioselectivity
Only one product is formed
OHC
OCH
3
OCH
3
CHO
OCH
3
CHO
OCH
3
CHO
OCH
3
CHO
OHC
OCH
3
OCH
3
CHO
OCH
3
CHO
OCH
3
CHO
OCH
3
CHO
OHC
OCH
3
OCH
3
CHO
OCH
3
CHO
OCH
3
CHO
OCH
3
CHO
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1,3-dipolar addition
Another example of [4t+2t]-cycloaddition
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1,3-dipolar addition
Correlation diagram is constructed as usual
t-







t
o- o-
1




n





o o
1

S

A

A


S

S
S A




S


S A
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1,3-dipolar addition
FMO analysis
Take the HOMO and LUMO of two reactants
See if the orbitals overlap constructively or not
anion

HOMO

LUMO
cation

HOMO

LUMO
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1,3-dipolar addition
Ozonolysis of an alkene is an example of 1,3-dipolar
addition
The malozonide is the product of the addition which
quickly rearranges to the ozonide
O
O
O
O
O O

O
O O
O
O O
malozonide
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Larger rings
Explain the following reaction:
1. Draw arrows to explain the mechanism
2. Use frontier molecular orbitals to determine if the
reaction is allowed or forbidden
3. Identify the HOMO and LUMO of each reactant
4. Does the HOMO of one overlap with the LUMO of the
other in a constructive fashion?
A
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Larger rings
LUMO of the hexatriene has 3 nodes
HOMO of alkene has none
A
LUMO

HOMO
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Larger rings
For larger rings, the ends can be flexible
A
suprafacial
antarafacial
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Summary
Cycloadditions involve the conversion of two t-
bonds to two o-bonds
They can be allowed (thermal) or forbidden (requires
electronic excitation of one reactant)
Allowed reactions involve [4n+2] electrons
Photochemical reactions require [4n] electrons
Exo and Endo products are determined by
secondary orbital overlap
Regiochemistry is determined by electronic effects
Reactions are typically suprafacial but larger rings
can react in an antarafacial way
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Summary
Adding two more electrons reverse the rules
Catalysing with UV-light reverses the rules
Going from suprafacial to antarafacial reverses the rules

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Summary

cycloadditions
2 new o-bonds
2 less t-bonds
[4n + 2]t
electrons
[2n + 2]t
electrons
secondary orbital overlap
= exo or endo TS
HOMO + LUMO
regioselec tivity based
on electronegativity
thermal photoc hemic al
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Electrocyclic Reactions

electrocyclic
re actions
1 new o-bonds
1 less t-bonds
ring closing:
HOMO of t
ring opening:
HOMO of o,
LUMO of t
disrotatory conrotatory
thermal photoc hemic al
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Electrocyclic Reactions
Involve the conversion of two t-bonds into a o-bond
and a new t-bond
What happens if the butadiene is substituted? If this
is like the other pericyclic reactions the reaction
should go with stereospecificity
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Cycloaddition Reactions
The reverse reaction (ring opening) is possible
because it is an equilibrium system
R
R
H
H
R
R
H
H
trans
cis
Conrotatory
R
R
H
H
H
R
H
R
cis
cis
Disrotatory
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Disrotatory vs Conrotatory
Look at the reaction in more detail
Disrotation


Conrotation
mirror
axis
of
rotation
Disrotatory Conrotatory
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Conrotatory and Disrotatory
QuickTime and a
GIF decompressor
are needed to see this picture.
QuickTime and a
GIF decompressor
are needed to see this picture.
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Disrotatory Correlation Diagram
R
R
H
H
R
R
H
H
R
R
H
H
R
R
H
H
R
H
R
H
R
H
R
H
R
H
R
H
R
H
H
energy
S
S
A
A
S
A
S
A
R
Thermally
forbidden
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Conrotatory Correlation Diagram
Thermally
allowed
R
R
H
H
R
R
H
H
R
R
H
H
R
R
H
H
R
R
H
H
R
R
H
H
R
R
H
H
R
R
H
energy
S
A
S
A
A
S
A
S
H
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R
R
H
H
FMO approach
R
R
H
H
R
R
H
H
R
R
H
H
R
R
H
H
HOMO
HOMO
LUMO R
R
H
H
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Biosynthesis of vitamin D
An example of a biological electrocyclic reaction
HO
HO
H H
H
HO
H H
ergosterol
lumisterol
previtamin D
3
hv
hv
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Biosynthesis of vitamin D
Looking at just the reacting ring
H
H
H
H
HOMO
LUMO
H
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Biosynthesis of vitamin D
Provitamin D
2
is converted spontaneously to vitamin D
HO
H
provitamin D
2
HO
H
vitamin D
2
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Sigmatropic Rearrangements

sigmatropic
re arrangements
0 new o-bonds
0 less t-bonds
bonds shifted
H-shift
C-shift
HOMO of o,
LUMO of t
suprafacial antarafacial
thermal photoc hemical
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Sigmatropic Rearrangements
Nomenclature
1
2
3
1'
2'
3'
1
2
3
1'
2'
3'
One sigma bond is destroyed and a new one made
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1
2
3
1'
2'
3'
1
2
3
1'
2'
3'
Sigmatropic Rearrangements
Nomenclature, [3, 3]-sigmatropic shift
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Cope Rearrangement
HOMO of o and LUMO of t-bonds
HOMO
LUMO
LUMO
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Name this reaction
HOMO
LUMO
1
2
3
4
5
1'
6
new t-bond
new o-bond
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Charged species
Name this sigmatropic rearrangement
O
Ph
O
Ph
base
O
Ph
1
2
3
1'
2'
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Biosynthesis of vitamin D
Provitamin D
2
is converted spontaneously to vitamin D
HO
H
provitamin D
2
HO
H
vitamin D
2
H
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[1,7]-migrations should be forbidden
So why does it proceed spontaneously in the
biosynthesis of vitamin D?
suprafacial antarafacial
HOMO
LUMO
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Last silde
How many peaks does this compound have in its
1
H
NMR spectrum?
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Where is Macquarie University???
Sydney, Australia