Cycloaddition

Definition
• Cycloaddition is the formation of two sigma bonds between the
termini of two isolated pi systems to form a cyclic product without
elimination of any fragment
• Cycloaddition is a process in which two or more reactants combine
to form a stable cyclic molecule during which no small fragment is
eliminated and s bonds are formed but not broken.
• Such reactions are generally inter molecular but intramolecular
cycloaddition is also known.

2
• The addition is generally cis addition or supra-supra addition (i.e. addition
to the same side of the double bonds)
• However there are other processes where trans addition or supra-antara
addition occurs to maintain orbital symmetry
• Cycloaddition reactions are also highly stereospecific. Stereospecificity is
controlled by mode of attack (s,s or s,a)
• Selection rule for cycloaddition correlates mode of attack under thermal
and photochemical conditions for different systems.

m+n No. of p D hn
bonds
4q even (s,a) or (a,s) s,s
q = 1,2,3…

4q+2 odd s,s (s,a) or (a,s)

q = 0,1,2,3…

m and n are number p of electrons in the two p systems

The frontier molecular orbitals of both reactants must be
considered: the HOMO and LUMO
Rules for Cylcoadditions - Suprafacial Cycloadditions

The terminal p lobes of the two reactants must have the

correct symmetry for bonding to occur
Suprafacial cycloadditions take place when a bonding
interaction occurs between lobes on the same face of one
reactant and lobes on the same face of the other reactant
Rules for Cylcoadditions - Antarafacial Cycloadditions

These take place when a bonding interaction occurs between

lobes on the same face of one reactant and lobes on
opposite faces of the other reactant (not possible unless a
large ring is formed)
 Stereochemistry of Cycloadditions

HOMO of one reactant combines with LUMO of other

Possible in thermal [4 +2] cycloaddition
 [2+2] Cylcoadditions

Only the excited-state HOMO of one alkene and the LUMO

can combine by a suprafacial pathway in the combination of
two alkenes
 Formation of Four-Membered Rings

Photochemical [2 + 2] cycloaddition reaction occurs smoothly

Cycloadditions are classified according to the number of
p electrons that interact in the reaction
 Diels-Alder Reaction
• Method for synthesis of 6-membered ring
• One-step, concerted reaction
• Termed [4+2] cycloaddition reaction where 4p and 2p
Otto Diels electrons react. Kurt Alder
s
+ p
s

Diene – electron-rich nucleophile

electron-donating groups make it more reactive.

H3C

H3C
MeO
 Diels–Alder Reactions
The Diels–Alder cycloaddition reaction is a pericyclic process
that takes place between a diene (four p electrons) and a
dienophile (two p electrons) to yield a cyclohexene product
Stereospecific with respect to substituents
The Diels-Alder Reaction
•The Diels-Alder reaction is an addition reaction between a 1,3-
diene and an alkene (called a dienophile), to form a new six-
membered ring.

•Three curved arrows are needed to show the cyclic movement

of electron pairs because three p bonds break and two s bonds
and one p bond form.
•Because each new s bond is ~20 kcal/mol stronger than a p
bond that is broken, a typical Diels-Alder reaction releases ~40
kcal/mol of energy.
Some examples of Diels-Alder reactions are shown below:
 Examples of Diels-Alder Reactions

N H
H3C C H H3C
C C C N
+
H3C C H3C C H
H H
H

diene dienophile Diels-Alder adduct

O OCH3 O
C
C OCH
C C 3
+
C C
C C OCH
3
O OCH3 O
All Diels-Alder reactions have the following
features in common:

1. They are initiated by heat; that is, the Diels-Alder

reaction is a thermal reaction.
2. They form new six-membered rings.
3. Three p bonds break, and two new C—C s bonds and
one new C—C p bond forms.
4. They are concerted; that is, all old bonds are broken
and all new bonds are formed in a single step.
Predict the products.

+ heat

COOH COOH

+ heat
CO2CH3

CO2CH3
Mechanism of Diels-Alder:
one-step, simultaneous (concerted) bond-making and
bond-breaking involving 6 p electrons
Several rules govern the course of the Diels-Alder
reaction.
1. The diene can react only when it adopts the s-cis
conformation.

This rotation is prevented in cyclic alkenes. When the two

double bonds are constrained to an s-cis conformation, the
diene is unusually reactive. When the two double bonds are
constrained in the s-trans conformation, the diene is
unreactive.
s-cis conformation
2. Electron-withdrawing substituents in the dienophile increase the reaction
rate.
•In a Diels-Alder reaction, the conjugated diene acts as a nucleophile and the
dienophile acts as an electrophile.
•Electron-withdrawing groups make the dienophile more electrophilic (and
thus more reactive) by withdrawing electron density from the carbon-carbon
double bond.
•If Z is an electron-withdrawing group, then the reactivity of the dienophile
increases as follows:
•A carbonyl group is an effective electron-withdrawing group because it
bears a partial positive charge (+), which withdraws electron density from
the carbon—carbon double bond of the dienophile.
•Some common dienophiles are shown below:

acrylonitrile
Dienes:

MeO MeO

S O O

Dienophiles:
N N N
H H H C H H C H H C
C C C C C
C C C C C
H H H H C C H C H C
N N N N

O
O O
F
O OCH3

O
3. The stereochemistry of the dienophile is retained.
syn stereochemistry
 What about the diene?
CH3 CH 3
CO2CH3
CO2CH 3
+
CO2CH 3
CH3 CO2CH3 CH 3
trans, trans cis
CH 3
CO2CH3
CO2CH 3
CH3
+ CO2CH 3
CH3 CO2CH3 CH 3

cis, trans trans

severe steric crowding

s-cis CH 3 CH3 s-trans - much more stable

CH 3 H3C

cis, cis
Unreactive!!!! Why?
 Conclusion:

Diels-Alder is stereospecific with respect to the diene.

trans, trans  cis product

trans, cis  trans product
cis, trans  trans product
cis, cis  unreactive
Predict the products.

CO2CH3
CO2CH3
CO2CH3
heat
+ +

CO2CH3
CO2CH3
CO2CH3

O O O
H H

heat
+ +

H H
O O O

These two cis products are identical.

•A cyclic dienophile forms a bicyclic product.
•A bicyclic system in which two rings share a common C—C bond is called a
fused ring system. The two H atoms of the ring fusion must be cis, because
they were cis in the starting dienophile
•A bicyclic system of this sort is said to be cis-fused.
4. When endo and exo products are possible, the endo product is
preferred.

•Consider the reaction of 1,3-cyclopentadiene with ethylene. A

new six-membered ring forms and above the ring there is a one
atom “bridge.”
•Thus, the product is bicyclic, but the carbon atoms shared by
both rings are non-adjacent.
•A bicyclic ring system in which the two rings share non-adjacent
carbon atoms is called a bridged ring system.
Fused and bridged bicyclic ring systems compared
•When cyclopentadiene reacts with a substituted alkene as the dienophile
(CH2=CHZ), the substituent Z can be oriented in one of two ways in the
product.
•The terms endo and exo are used to indicate the position of Z.
•In a Diels-Alder reaction, the endo product is preferred, as shown in the
two examples below. The transition state leading to the endo product allows
more interaction between the electron rich diene and the electron-
withdrawing substituent Z on the dienophile, an energetically favorable
arrangement.
 Endo Rule
when substituted bicyclic structures form ,the endo
product is favored over the exo product.

+
CHO H CHO
OHC H

Endo Exo
favored
 Endo Rule
If the electron-withdrawing group(s) on the dienophile have a pi bond,
there is secondary overlap with the p orbitals of C2 and C3 in the
diene.

More stable transition state

Explanation of Endo Rule: There are two possible pproaches
between the diene and dienophile in this reaction.
H
H
HOMO H H
H H
diene
H
H H
H
H H
H H
H
H
O
LUMO H
H

dienophile O
H
H

Additional interaction
lowers Ea – reacts faster

H CHO
OHC H
Endo - major Exo - minor
 O
O O O
C
O
O C
exo product O
O
O
O
O
O + O O
O C O
O C O
O O
endo product
exo product more stable by 1.9 kcal/mol
Ea lower for the endo product by 3.8 kcal/mol
E O O

O
O 3.8 kcal/mol

O
O
O
O

C O
C
O O O
1.9 kcal/mol
O O
O + O C
O
C
O O
Reaction progress
Predict the products.

+ heat

CO2CH3
CO2CH3

CO2CH3

+ heat
CO2CH3
CO2CH3
CO2CH3
The Diels-Alder Reaction—Retrosynthetic Analysis
To draw the starting materials from a given Diels-Alder adduct:
•Locate the six-membered ring that contains the C=C.
•Draw three arrows around the cyclohexane ring, beginning with the p bond
and two s bonds, and forming three p bonds.
•Retain the stereochemistry of substituents on the C=C of the dienophile; cis
substituents on the six-membered ring give a cis dienophile.
Predict the starting materials.

CO2CH2CH3 CO2CH2CH3

Cl Cl
O

O Cl
+ O

O Cl

O
O
The Retro Diels-Alder Reaction

•The formation of dicyclopentadiene is so rapid that it takes only a few

hours at room temperature for cyclopentadiene to completely dimerize.
•When heated, dicyclopentadiene undergoes a retro Diels-
Alder reaction, and two molecules of cyclopentadiene are re-
formed.
•If the newly produced cyclopentadiene is immediately treated
with a different dienophile, it reacts to form a new Diels-Alder
adduct with this dienophile.
•This is how cyclopentadiene used in Diels-Alder reactions is
produced.
 Regiospecificity
The 6-membered ring product of the Diels-Alder reaction will
have electron-donating and electron-withdrawing groups
1,2 or 1,4 but not 1,3.

H H D
D
C
C
W W
H
H H
not
C D W
C
W W
H
D D
 CH2=CH2
C C 2 LUMO
E
HOMO
C C 
1

LCAOs MOs

C C C C 4 CH2=CHCH=CH2

 LUMO
C C C C 3
E
HOMO
C C C C 2

C C C C 
1
LCAOs MOs
 MO’s must overlap smoothly

H W H
C D C W
C C H
H H
H

Conservation of
Orbital Symmetry
Which orbitals? thermal = HOMO + LUMO
HOMO = highest occupied molecular orbital
LUMO = lowest unoccupied molecular orbital

HOMO LUMO

LUMO HOMO

symmetry
allowed
supra-supra
Frontier Orbital Analysis of a [4 + 2]
Cycloaddition Reaction
Correlation Diagram of Diels Alder reaction
 Correlation Diagram of Diels Alder reaction

• In the correlation diagram symmetries associates with the

MOs of reactants in the bonding and antibonding state as well
as MOs of products in the bonding and antibonding state are
considered.
• There is a perfect correlation and conservation of symmetries
of MOs of the reactants and products. Also there is no
crossover of any kind between bonding and antibonding
state.
• Hence it is a symmetry allowed reaction and takes place
thermally
 Symmetry-Allowed Reaction

• Diene contributes
electrons from its
highest energy
occupied orbital
(HOMO).
• Dienophile receives
electrons in its lowest
energy unoccupied
orbital (LUMO).
 “Symmetry Forbidden” Cycloaddition

[2 + 2] cycloaddition of two
ethylenes to form
a
cyclobutene has anti-
bonding overlap of HOMO
and LUMO
A [2 + 2] Cycloaddition Reaction
 Photochemical Induction

Absorption of correct energy photon will promote

an electron to an energy level that was previously
unoccupied.
 [2 + 2] Cycloaddition

Photochemically
allowed, but
thermally
forbidden.
 Frontier MO Analysis of the
[2 + 2] Cycloaddition Reaction
Regiochemical Predictions

O-Me O-Me Me-O O-Me Me-O

hn
+ and / or

O-Me
Woodward – Hofmann Rules for Cycloadditions:

[i+j] Thermal Photochemical

4n
supra-supra supra-supra
forbidden allowed
supra-supra supra-supra
4n + 2
allowed forbidden
 [4+4]
+

HOMO =  2
forbidden!

LUMO = 
3
 [4+4]
+

[4+2]
 [4+4]
+
hv

HOMO* =  3
allowed
LUMO = 
3