Third Year Organic Chemistry Course
CHM3A2
Frontier Molecular Orbitals and
Pericyclic Reactions
Part 2(ii):
Cycloaddition Reactions
Cycloaddition reactions are intermolecular pericyclic processes involving
the formation of a ring from two independent conjugated systems through
the formation of two new -bonds at the termini of the -systems.
The
reverse process is called cycloreversion or is referred to as a retro-reaction.
HOMO – y2
Suprafacial
Suprafacial
Sub
Sub
LUMO – y2
CHM3A2
– Introduction to FMOs –
– Learning
Objectives Part 2(ii) –
Cycloaddition Reactions
After completing PART 2(ii) of this course you should have an understanding of, and be able to demonstrate, the
following terms, ideas and methods.
(i)
A cycloaddition reaction involves the formation of two  bonds between the termini of two independent systems, resulting in ring formation - or the reverse process.
(ii)
Cycloaddition reactions are stereospecific (e.g. cis/trans isomers). The stereospecificity being afforded by
the suprafacial or antarafacial nature of the approach of the two -units in the transition state.
(iii)
The suprafacial or antarafacial process involved in the  bond making process is controlled by the
HOMO/LUMO interactions of the two -systems in the transition state.
(v)
Cycloaddition reactions can be regioselective. The regioselectivity cannot be predicted from the simple
treatment given to frontier molecular orbitals in this course. However, generalisations can be made from
looking at classes of substituents (C, Z, X) which are in conjugation with the -systems, which allow us to
predict the regioselectivity in an empirical manner.
The Questions FMO Theory Can Answer
150°C
85%
10 days
0%
165°C
78%
900 atm
17 hours
FMO Theory Explains Difference in Rates of Cycloadditions
CHO
150°C
O
O
O
O
0.5 hours
CHO
20°C
68 hours
MeO
MeO2 C
CO 2Me
25°C
4 hours
O OMe
O
MeO
O
90%
92%
OMe
O
80%
FMO Theory Explains Stereospecificity of Cycloadditions
CO 2Me
25°C
CO 2Me
CO 2Me
25°C
OMe
OMe
O
O
O
O
OMe
OMe
OMe
OMe
O
O
O
MeO2 C
O
OMe
OMe
FMO Theory Explains Regiochemistry of Cycloadditions
OMe
OMe
O
O
19
(±)
CO 2Me
20°C
1 year
64%
OMe
O
O
(±)
OMe
1
Analysing Cycloaddition Reactions
Interaction of the termini of
the two -systems
Interaction of the termini of
the two -systems
The interaction is between the
HOMO of one -system with the
LUMO of the second -system, such
that the energy difference is least.
Terminology
SUPRAFACIAL
New bonds to the same
side of the -system
n
ANTARAFACIAL
New bonds to the opposite
side of the -system
n
4n+2  Electron
Cycloaddition
Transition States
Suprafacial-Suprafacial Interaction:
4n+2  Electron Transition States
HOMO
Suprafacial
Number of -electrons
in each component
Xs + Ys
n
suprafacial
In-phase
Suprafacial
LUMO
n
Diels-Alder Cycloaddition Reaction:
6 -Electron Transition State
Suprafacial
y2 HOMO
4s + 2s
Suprafacial
y2 LUMO
4n  Electron
Cycloaddition
Transition States
Suprafacial-Antarafacial Interaction:
4n  Electron Transition States
HOMO
n
Suprafacial
Xs + Ya
n
Antarafacial
antarafacial
LUMO
Why Ethene Does Not Dimerise:
4 -Electron Transition State
Suprafacial
y1 HOMO
2s + 2s
y2 LUMO
Suprafacial
Why Ethene Does Not Thermally Dimerise:
4 -Electron Transition State
Suprafacial
y1 HOMO
2s + 2s
In-phase
y2 LUMO
Out-of-phase
Suprafacial
Can not react via suprafacial/suprafacial Interaction
How About a Suprafacial/Antarafacial Interaction?
Suprafacial
y1 HOMO
2s + 2a
y2 LUMO
Antarafacial
How About a Suprafacial/Antarafacial Interaction?
Suprafacial
y1 HOMO
2s + 2a
y2 LUMO
Antarafacial
In principle, suprafacial/antarafacial is possible by FMO
theory, however, it is geometrically impossible
The Diels-Alder Reaction: In Detail
The Diels-Alder reaction is an extremely well studied cycloaddition reaction,
The reason for this is that careful design of the diene component and the ene
component (the dienophile) has led to a great insight into the reaction
mechanism.
Diels-Alder Reaction Transition State Geometry
Suprafacial
Diene
EWG
EWG
HOMO – y2
EWG
EWG
EWG
EWG
MESO
Dieneophile
LUMO – y2
Suprafacial
4s + 2s
Suprafacial
Diene
HOMO – y2
EWG
EWG
EWG
Dieneophile
One of two equally
likely transition states
See Next 2 Slides…
EWG
EWG
EWG
EWG
EWG
LUMO – y2
Suprafacial
4s + 2s
i.e. enantiomers
Enantiomer Formation
EWG
EWG
Top
Top
Bottom
Bottom
A pair of Enantiomers
EWG
EWG
EWG
EWG
Enantiomer Formation
EWG
EWG
Top
Top
EWG
EWG
EWG
Bottom
Bottom
EWG
A pair of Enantiomers
EWG
EWG
EWG
EWG
Normal Electron Demand in Diels-Alder Cycloaddition Reactions
EWG
Diene
EDG
EWG
Dieneophile
EWG
EDG
EWG
Diene
Dieneophile
Raising and Lowering the Energy of HOMO and LUMOS
Energy
LUMO
Z = EWG
X = EDG
LUMO
LUMO
HOMO
X
HOMO
HOMO
Z
Diene HOMO/Dienophile LUMO: Normal Electron Demand
165°C
CHO
900 atm
17 hours
78%
150°C
O
0.5 hours
90%
LUMO
LUMO
LUMO
LUMO
HOMO
HOMO
HOMO
HOMO
Z
Regiochemistry Issues in the Diels-Alder Reaction
C/Z/X
C/Z/X
C/Z/X
C/Z/X
X
X
Except
X
C = Extending Conjugation
Z = Electron Withdrawing Group
X = Electron Donating Group
X
X/Z/C
X/Z/C
C/Z/X
X
X
Except
C = Extending Conjugation
Z = Electron Withdrawing Group
X = Electron Donating Group
C/Z/X
X
X
Substituents and Desymmetrisation of Orbitals
Z
O
Z
O
X
OMe
OMe
X
Low Energy
Transition State
High Energy
Transition State
X
X
Small/Small
Large/Large
Coefficient
interaction
Z
X
Small/Large
Large/Small
Z
Despite
more
pronounced steric
interactions
X
Z
Z
Rules for Cycloadditions
Number of -Electrons
Thermal
Photochemical
___________________________________________________________________
4n
sa
ss
4n + 2
ss
(aa)
sa
___________________________________________________________________
s = suprafacial
a = antarafacial
Photochemical cycloaddition reactions are dealt with in CHM3A2
in year 3
CHM3A2
– Introduction to FMOs –
– Summary
Sheet Part 2(ii) –
Cycloaddition Reactions
Cycloaddition reactions are intermolecular pericyclic processes involving the formation of a ring from two independent
conjugated systems through the formation of two new -bonds at the termini of the -systems. The reverse process is
called cycloreversion or is referred to as a retro-reaction.
By far the best known example of a cycloaddition is a Diels-Alder reaction. The reverse process is known as a retro-DielsAlder reaction.
Perhaps the simplest approach for assessing the feasibility of a particular cycloaddition uses frontier molecular orbital
theory. In the concerted cycloaddition of two polyenes, bond formation at each terminus must be developed to some
extent in the transition state.
Thus, orbital overlap must occur simultaneously at both termini.
For a low energy
concerted process - an allowed reaction - to be possible, such simultaneous overlap must be geometrically feasible and
must also be potential bonding.
There are two stereochemically different ways in which new bonds can be formed – either to the same face of the -bond,
i.e. in a suprafacial way, or to opposite faces, i.e. in an antarafacial way. The same definitions apply to longer  systems.
Suprafacial, suprafacial (ss) approach of two polyenes is normally sterically suitable for efficient-orbital overlap. The vast
majority of concerted additions involves the ss approach.
However, this type of overlap will only be energetically
favourable when the HOMO of one component and the LUMO of the other component can interact in a bonding fashion at
both termini. Thus, these orbitals must be of the correct phase of symmetry. In the Diels-Alder reaction of a diene with a
monoene, the HOMO and LUMO of each reactant are of the appropriate symmetry so that mixing of these orbitals will result
in simultaneous potential bonding character between the terminal atoms.
In contrast, a similar ss approach of two olefins does not lead to a stabilising interaction since the HOMO and LUMO are of
incompatible phase for simultaneous bonding interaction to occur at both termini. Thus, the initial approach of reactants
for a concerted ss addition is favourable for a Diels-Alder reaction - which is therefore an allowed process - but not for
olefin dimerisation, which is therefore disallowed.
Exercise 1: 4n+2  Cycloadditions
MeO2C
relative rate = 1
CO2Me
Explain the difference in the rates of reaction of
the two reaction shown right.
MeO2C
relative rate >> 1
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
Answer 1: 4n+2  Cycloadditions
MeO2C
relative rate = 1
CO2Me
CO2Me
Explain the difference in the rates of reaction of
the two reaction shown right.
MeO2C
CO2Me
relative rate >> 1
CO2Me
CO2Me
CO2Me
The difference in rates is a result of at least 2 factors.
Factor 1: The HOMO of cyclopentadiene is raised relative to
the HOMO of butadiene as a result of the bridging methylene
units +I inductive effect, thus the energy difference between the
diene HOMO and dieneophile LUMO is the least with
cyclopentadiene, and results in the greatest HOMO/LUMO
interaction (i.e. DE2<<DE1).
Factor 2: Butadiene does not exist
preferentially in the reactive cis
conformation,
thus
the
concentration
of
reactive
conformations of butadiene is
always low.
Reactive
Conformation
MeO2C
CO2Me
LUMO
LUMO
DE2
DE1
HOMO
HOMO
HOMO
1%
LUMO
99%
In contrast, the bridging methylene
unit in cyclopentadiene forces the
diene moiety to exist exclusively in
the reactive conformation.
Reactive
Conformation
Locked
Exercise 2: 4n+2  Cycloadditions
Ph
Utilise FMOs to predict stereochemical outcome of
the Diels-Alder reaction shown right
Ph
Ph
CO2 Me
CO2 Me
CO2 Me
CO2 Me
Ph
Answer: 4n+2  Cycloadditions 2
Ph
Utilise FMOs to predict stereochemical outcome of
the Diels-Alder reaction shown right
Ph
Ph
MeO2C
Ph
HOMO
y2 of Butadiene moiety
CO2Me
Ph
Ph
H
MeO2C
H
CO2Me
LUMO
y2 of Ene moiety
Ph
CO2 Me
CO2 Me
CO2 Me
CO2 Me
Ph
Ph
MeO2C
Ph
CO2Me
MESO
Exercise 3: 4n+2  Cycloadditions
Predict the cycloaddition products formed from the following pairs of starting materials. State the
number of  electrons involved and use the ns/na descriptor to describe each reaction.
CO2Me
N
20°C
 e's
N
CO2Me
CO2Me
4°C, 3d
 e's
CO2Me
20°C, 3d
O
 e's
Answer 3: 4n+2  Cycloadditions
Predict the cycloaddition products formed from the following pairs of starting materials. State the
number of  electrons involved and use the ns/na descriptor to describe each reaction.
20°C
CO2Me
CO2Me
N
N
10  e's
N
CO2Me
N
CO2Me
8s + 2s
CO2Me
CO2Me
4°C, 3d
±
10  e's
CO2Me
CO2Me
8s + 2s
20°C, 3d
O
10  e's
4s + 6s
O
Meso
Exercise 4: 4n+2  Cycloadditions
CO2Me
Utilse FMOs to rationalise the
stereochemical outcome of the
cycloaddition reaction shown
right
4°C, 3d
CO2Me
±
CO2Me
CO2Me
Answer 4: 4n+2  Cycloadditions
CO2Me
Utilse FMOs to rationalise the
stereochemical outcome of the
cycloaddition reaction shown
right
4°C, 3d
CO2Me
±
CO2Me
CO2Me
y4 Octatetraene (3 nodes, 9/4)
HOMO
CO2Me
y2 Ene
LUMO
s/s
H
MeO2C
H
CO2Me
CO2Me
CO2Me
Enantiomers
CO2Me
MeO2C
CO2Me
CO2Me
s/s
H
H
CO2Me
Exercise 5: 4n+2  Cycloadditions
Propose an arrow pushing mechanism for the reaction shown right
Utilse FMOs to rationalise the stereochemical outcome.
Identify a regioisomer of the product.
O
O
210°C
24 hrs
90%
O
±
Answer 5: 4n+2  Cycloadditions
O
O
O
Propose an arrow pushing mechanism for the reaction shown right
210°C
Utilse FMOs to rationalise the stereochemical outcome.
24 hrs
90%
Identify a regioisomer of the product.
Enantiotopic
hydrogen
O
The reaction
requires forcing
conditions
because the
HOMO/LUMO
gap is large
O H
"Diene"
O
H
O
O
O
Regioismer, not formed
because coefficient overlap not
maximised
Dieneophile
y2 HOMO
y2 LUMO
Enantiotopic
Hydrogen will go up
H
O
O
H
O
Enantiotopic
Hydrogen will go
down
±
O
y2 LUMO
y2 HOMO
Exercise 6: 4n+2  Cycloadditions
Propose
an
arrow
pushing
mechanism,
reagents
and
byproducts for the reaction shown right. Additionally, identify
any driving forces which make the reaction proceed from
starting material to product.
N
N
CO2Me
CO2Me
Answer 6: 4n+2  Cycloadditions
Propose
an
arrow
pushing
mechanism,
reagents
and
byproducts for the reaction shown right. Additionally, identify
any driving forces which make the reaction proceed from
CO2Me
N
N
CO2Me
starting material to product.
N2 gas liberation:
Strong driving force
N
N
N
N
A retro-Diels-Alder
Rearomatisation:
Strong driving force
CO2 Me
CO2 Me
CO2 Me
CO2 Me
A Diels-Alder