14 Cycloaddition Reactions II Chem Reactivity 2023

National Technical University of Ukraine 1
‘Igor Sikorsky Kiev Polytechnic Institute’
Reactivity of Organic Compounds
Cycloaddition Reactions:
The Diels-Alder Reaction
Andrey O. Kushko, Ph.D.,

Senior Lecturer
Kiev-KPI-2023
2
The Diels-Alder Reaction: Introduction
The Diels–Alder Reaction is a chemical reaction
between a conjugated diene and a substituted alkene,
commonly termed the dienophile, to form a
substituted cyclohexene derivative. It is the prototypical
example of a pericyclic reaction with a concerted
mechanism. More specifically, it is classified as a
thermally allowed [4+2] cycloaddition with the
Woodward-Hoffmann symbol [4s + 2s]. It was first
described by Otto Diels and Kurt Alder in 1928. For
the discovery of this reaction, they were awarded
the Nobel Prize in Chemistry in 1950. Through the
Otto Diels (1876–1954) Kurt Alder (1902–1958) simultaneous construction of two new carbon-carbon
Nobel Prize 1950 Nobel Prize 1950
bonds, the Diels–Alder reaction provides a reliable way
to form six-membered rings with good control over the
EWG EWG regio- and stereochemical outcomes.
+
Diels, O.; Alder, K. "Synthesen in der hydroaromatischen Reihe, I.
Substituted Mitteilung: Anlagerungen von "Di-en"-kohlenwasserstoffen". Justus Liebigs
Diene Dienophile
Cyclohexene Annalen der Chemie. 1928, 460: 98–122.
3
Cycloadditions Reactions
Reading Materials:
• Pericyclic Reactions: A Mechanistic and Problem-Solving Approach, S. Kumar, V. Kumar,
and S.P. Singh, 2016 Elsevier Inc.;
• The Diels-Alder Reaction in Total Synthesis, K. C. Nicolaou, Angew Chem. Int. Ed. 2002,
41, 1668-1698.;
• Catalytic Enantioselective Diels–Alder Reactions: Methods, Mechanistic Fundamentals,
Pathways, and Applications, E. J. Corey, Angew Chem. Int. Ed. 2002, 41, 1650-1667.;
• Chemistry and Biology of Biosynthetic Diels–Alder Reactions Emily M. Stocking and
Robert M. Williams, Angew Chem. Int. Ed. 2003, 42, 3078-3115;
• Recent Advances in Natural Product Synthesis by Using Intramolecular Diels-Alder
Reactions, Tadano et al. Chem Rev. 2005, 105, ASAP.
4
Thermal Concerted [4 + 2] Cycloaddition
The archetypal Diels-Alder reaction is a [4 + 2]
cycloaddition in which a diene (the 4 component) combines
with a dienophile (the 2 component) to produce a 6-
membered ring. The process is very useful because it
generates four new sp3 carbons stereoselectively, the
geometry of both starting molecules being conserved within
the product (the reaction is stereospecific). For example, if
the dienophile bears two groups with a cis relationship, the
two groups will remain cis in the product. The net reaction
involves the loss of two  bonds and the gain of two  bonds,
which makes it about 167 kJ/mol (40 kcal/mol) exothermic.
The six-membered transition structure for the process
resembles a folded cyclohexane (boat conformation).
Note that the symmetry of the interacting orbitals permits
synchronous bond formation while the p orbitals of the 
bonds become the bonds of the product.
Pericyclic Reactions: A Mechanistic and Problem-Solving Approach, S. Kumar, V. Kumar, and S.P. Singh, 2016 Elsevier Inc.
5
The Frontier Molecular Orbital (FMO) Interactions in a
[4 + 2 ] Cycloaddition.
The orbital interaction is between the
HOMO(4) and the LUMO(2). The
symmetry properties of these orbitals are
correctly 'matched' for the simultaneous
overlap of each bonding pair, i.e. the
interacting lobes are in phase. The same is
true of the LUMO(4) and HOMO(2)
combination. For ground-state molecules, the
frontier orbitals are thus correctly matched
for synchronous bond formation, making
this a thermally allowed [4 + 2]
cycloaddition.
Frontier Molecular Orbital (FMO) Interaction Diagram for 6
1,3-Butadiene and Ethene
The complete orbital interaction

diagram is constructed by a linear
combination of the starting
systems, butadiene, and ethene.
The green arrows indicate the two
HOMO-LUMO interactions;
Note that ΔE is small because the

HOMO-LUMO energy gap is
relatively large
7
Main Features of the [4 + 2] Cycloaddition
1. The concerted (synchronous) mechanism, is compatible with orbital
symmetry requirements for bonding overlap, no polar intermediates, and reversible.
ΔG for the cycloreversion process becomes more favorable (negative) with increased
temperature because the −TΔS term dominates over the ΔH term (ΔG = ΔH − TΔS).
2. Stereoselective, endo product is favoured over exo product (kinetic control).
8
3. Matching of components, the 'normal' reaction involves electron-poor 2 and
electron-rich 4 components.
4. Regioselective, typically as shown below (X = donor, Y = acceptor).
9
5. Lewis acid catalysis can make the reaction faster and more selective
(coordinates to 2 component, lowers its LUMO energy).
10
Diels-Alder Reaction: Orbital Symmetry Considerations
The Alder Endo Rule:
The following observation illustrates an example of the Alder Rule.
disfavored favored
"Exo product" "Endo product"
Observation: The endo Diels-Alder adduct is formed faster even though the exo product is more
stable. There is thus some special stabilization in the transition state leading to the endo product
which is lacking the exo transition state.
Diels-Alder Reaction: Orbital Symmetry Considerations 11
The Alder Endo Rule: Exo TS‡

Exo TS‡
Endo TS‡
Endo TS‡
Of the two possible transition states, the one having the Secondary orbital
‘greatest accumulation of interacting double bonds will be overlap
preferred’ (The Alder Endo Rule). Secondary orbital overlap is
noted
Diels-Alder Reaction: Orbital Symmetry Considerations 12
If the symmetries of the frontier MO's of reacting partners are "properly matched" the reaction is referred to
as "symmetry-allowed". The Diels-Alder reaction is such a case. As illustrated, the HOMO and LUMO of
both the diene and dienophile, which in this case are the same, will constructively overlap as indicated in
the formation of both sigma bonds.
HOMO-2 LUMO-3
LUMO-3 HOMO-2
13
Frontier MO Explanation for the Endo Rule:
LUMO-3
Secondary (transient) orbital overlap
can also occur in the stabilization of
certain transition state geometries.
Such a transient stabilizing interaction
can occur in the endo, but not exo,
HOMO-2
transition state:
14
The Other Dimerization Possibility for Butadiene:
Is the possibility for the following

does concerted dimerization exist?
Note that the termini only match at one end for the HOMO-2
HOMO-LUMO pairing. Hence we say that the
symmetry requirements for the reaction in question
are not met. This does not mean that the reaction
will not occur, only that the reaction will not be
concerted. Such reactions are called "symmetry-
forbidden". LUMO-3
15
Diels-Alder Reaction: The Transition Structure
Transition State Modelling is Coming of Age:
The lengths of the forming C–C bonds are 1.5 times the normal bond distance. This
factor comes out of the ab initio work of Jorgensen and Houk
Jorgensen K. A., J. Am. Chem. Soc. 1993, 115, 2936-2942.; Houk, Jorgensen, J. Am. Chem. Soc., 1989, 111, 9172.;
Houk, Angew. Chem. Int. Ed. 1992, 31, 682-708
Diels-Alder Reaction: The Transition Structure 16
Bond formation is not synchronous

with substituted dienophiles
(Jorgensen)
Diene Reactivity as measured against Maleic anhydride
log k = 4.96 log k = 2.36 log k = 2.19 log k = 2.12 log k = 1.83
Sauer, Angew. Chem. Int. Ed., 1980, 19, 779-807.

17
Diels-Alder Reaction: The Transition Structure
Lewis Acid Catalysis of the reaction is possible!
The Critical Energy
Difference:
LUMO1 LUMO2
E(LUMO1) - E(HOMO2)
or
Energy
E(LUMO2) - E(HOMO1)
HOMO1
• The closer the two orbitals are in
HOMO2 energy, the better they interact;
• As E decreases for the relevant
ground-state FMOs, reaction rates
Dienophile increase
Diene
Yates, Eaton, J. Am. Chem. Soc., 1960, 82, 4436.
Diels-Alder Reaction: The Transition Structure 18
Lewis Acid Catalysis of the reaction is possible!

Ethylene and Butadiene Butadiene and Acrolein
LUMO2
LUMO1
Lewis acid catalysis not only
LUMO3
dramatically increases rates by 10+6 it
also improves reaction regiochemistry
and endo diastereoselectivity
HOMO2 HOMO3
HOMO1
E (LUMO3-HOMO1) < E (LUMO2-HOMO1) to Rate Yates, Eaton, J. Am. Chem. Soc., 1960,
Acceleration 82, 4436.
Diels-Alder Reaction: Regioselectivity 19
The 'normal' Diels-Alder matching pair is an electron-rich diene with an electron-deficient dienophile,
so the dominant FMO interaction is HOMO(4)–LUMO(2). The  orbitals of butadiene and ethene are
readily polarisable and influenced by donor or acceptor substituents. When X is a donor and Y is an
acceptor, the  MOs polarise and the orbital coefficients change as shown below. A prediction of the
regioselectivity of a cycloaddition is obtained by matching the largest coefficients in the diene HOMO
and dienophile LUMO (the greater the overlap, the stronger the covalent bonding).
Diels-Alder Reaction: Regiochemistry 20
Orientation of Reacting Partners:
4.5 : 1 , 100 °C
favored disfavored
Lewis acid catalysis improves orientation:
toluene, 120 °C 59 : 41
C6H6, SnCl4, 25 °C 96 : 4
favored disfavored
In general, 1-substituted dienes are more

regioselective than their 2-substituted counterparts Sauer, Angew. Chem. Int. Ed., 1967, 6, 16-33.
21
Diels-Alder Reaction: Regiochemistry
Lewis acid catalysis improves endo-diastereoselection:
Diene Dienophile
favored disfavored
CH2Cl2, 0 °C 80 : 20
C6H6, SnCl4, 25 °C 95 : 5
Sauer, Angew. Chem. Int. Ed., 1967, 6, 16-33.

22
Here is an interesting problem in reaction design:
favored disfavored
However, what if you need the disfavored product?

Ni(Raney)
disfavored favored
Trost B., J. Am. Chem. Soc. 1980, 102, 3554.

23
By employing a removable substituent, it is possible to access the normally disfavored
product diastereomer:
The NO2 FG completely

dominates directivity
Danishefsky, J. Am. Chem. Soc., 1978, 100, 2918.
It then can be
removed by elimination
or by reduction
Ono, Tetrahedron, 1985, 4013.

24
By employing a removable substituent, it is possible to access the normally disfavored
product diastereomer:
mixture of ring-fusion
isomers
Ono, Chem. Commun. 1982, 33-34.

25
Instructive Issues of Regiocontrol with Quinone Dienophiles:
Conditions Ratio
Orientation of Reacting Partners thermal (100 °) 50 : 50
controlled by Lewis acid structure BF3•OEt2 (-20 °) 80 : 20
SnCl4 (-20 °) <5 : 95
Reusch, J. Org. Chem. 1980, 45, 5013.

26
selection 80 : 20
selection > 95 : 5
Stoodley, Chem. Comm. 1982, 929.

27
selection > 95 :5
selection > 95 :5
Kelly, Tetrahedron. Lett. 1978, 4311.

28
Ratio: 90 : 10
Corey E. J., J. Am. Chem. Soc., 1969, 91, 5675.

29
Diels-Alder Reactions with Chiral Dienes:
X= Ratio
–OH 36 : 64
–OCH3 83 : 17
–CH3 >97 : 3
Overman, J. Am. Chem. Soc., 1988, 110, 4625.

Diels-Alder Reaction: Regiochemistry 30
Diels-Alder Reactions with Chiral Dienes:
R = Me: Ratio; 83 : 17
R = Me3Si: Ratio; 88 : 12
Comments on the Transition State
• Avoid Eclipsing allylic substituents;
• Better donor (Me) anti to forming bond;
• Avoid gauche OR interaction better than
Franck, Tetrahedron Lett. 1985, 26, 3187.;

Franck, J. Am. Chem. Soc., 1988,110, 3257.
31

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National Technical University of Ukraine 1

‘Igor Sikorsky Kiev Polytechnic Institute’

Reactivity of Organic Compounds

Andrey O. Kushko, Ph.D.,

1,3-Butadiene and Ethene

The complete orbital interaction

Note that ΔE is small because the

2. Stereoselective, endo product is favoured over exo product (kinetic control).

4. Regioselective, typically as shown below (X = donor, Y = acceptor).

"Exo product" "Endo product"

The Alder Endo Rule: Exo TS‡

The Other Dimerization Possibility for Butadiene:

Is the possibility for the following

Bond formation is not synchronous

Diene Reactivity as measured against Maleic anhydride

Sauer, Angew. Chem. Int. Ed., 1980, 19, 779-807.

Lewis Acid Catalysis of the reaction is possible!

Orientation of Reacting Partners:

Lewis acid catalysis improves orientation:

In general, 1-substituted dienes are more

Sauer, Angew. Chem. Int. Ed., 1967, 6, 16-33.

However, what if you need the disfavored product?

Trost B., J. Am. Chem. Soc. 1980, 102, 3554.

The NO2 FG completely

Danishefsky, J. Am. Chem. Soc., 1978, 100, 2918.

Ono, Tetrahedron, 1985, 4013.

Ono, Chem. Commun. 1982, 33-34.

Reusch, J. Org. Chem. 1980, 45, 5013.

Stoodley, Chem. Comm. 1982, 929.

Kelly, Tetrahedron. Lett. 1978, 4311.

Corey E. J., J. Am. Chem. Soc., 1969, 91, 5675.

Overman, J. Am. Chem. Soc., 1988, 110, 4625.

Diels-Alder Reactions with Chiral Dienes:

Franck, Tetrahedron Lett. 1985, 26, 3187.;

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