CYCLOADDITION REACTIONS

Presented by:
CH.RAGHUNATH
HT NO. 20004P-1028
M. Pharmacy I Semester
Dept. Of Pharmaceutical Chemistry
University College Of Pharmaceutical Sciences 1

Kakatiya University, Warangal.

 CYCLOADDITION REACTIONS

Reaction in which two ring bonds are formed, and no small molecules are
eliminated in the process , are called cycloaddition reaction. This reaction
provide useful synthetic routes to a wide range of heterocycles, especially
those containing four, five, or six atoms in the ring.

Types of cycloaddition reaction are

a) 1,3-dipolar cycloaddition
b) Hetero-diels-alder reaction
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c) [2+2] cycloaddition
The most important types of cycloaddition reaction are:-

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 1,3-DIPOLAR CYCLOADDITION

The 1,3 –dipolar cycloaddition is a chemical reaction between a 1,3-dipole and a

dipolarophile to form a five membered ring.

Mechanistic investigation and synthetics application were established in the 1960s,

primarily through the work of rolf huisgen. Hence, the reaction is sometimes
referred to as the huisgen cycloaddition.

 Currently, 1,3-dipolar cycloaddition is an important route to the regio-and

stereoselective synthesis of five-membered heterocycles.
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 REACTION
 The 1,3-dipolar cycloaddition is a chemical reaction between a 1,3-dipole and a
dipolarophile to form a five membered ring.

 1,3-dipole: a three atoms, π –electron system with four delocalised π-electrons.

 Dipolarophile: usually olefins, acetylenes or other multiple bonds.

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 1,3- DIPOLES

•  
 1,3- dipole is a three atoms π-electron system with four electrons delocalised
over the three atoms.
The name ‘1,3- dipole’ was coined because it is impossible to write electron-
paired resonance structures for these species without incorporating charges.
1,3- dipole species contain a heteroatom as the central atom and can be
formally sp or sp2 hybridized.
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 DIPOLAROPHILES

 The compounds that can react with these dipoles in cycloaddition reactions are
called dipolarophiles.

 These contain unsaturated functional groups such as

C═C C═N C═O C═S

C≡C C≡N

Some examples of dipolarophiles are ᵅ,ᵝ unsaturated aldehydes, ketones and

esters, allylic halides, allylic alcohols, alkenes, alkanes, vinylic ethers etc., 8
 MECHANISM
 Mechanism of 1,3-dipolar cycloaddition reactions is that they are concerted
processes(with no intermediates) that proceed through unsymmetrical transition
states in which the formation of one of the σ-bond is more advanced than the other.

 2π electrons of the dipolarophile and 4ᴨ electrons of dipolar compound participate

in a concerted pericyclic shift.

 The addition is stereo conservative (superficial) and the reaction is (p2s+p4s)

cycloaddition.

 ‘Thermally allowed’ process on the basis of woodward-hoffmann rules. 9

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 REACTIVITY
The reactivity of 1,3- dipoles towards different dipolarophiles often varies
considerably .
Based on FLEKING’S explanation, regioselectivity and reactivity in concerted 1,3-
dipolar cycloaddition reactions can be interpreted by using frontier molecular
orbitals (FMO) theory.
The theory proposes that reaction is favoured if there is a favourable interaction
between a filled π orbitals of one reactant and an empty π* of the other.
Hence the interaction dominated by the highest occupied π orbitals(homo) and the
lowest unoccupied π orbitals(lumo) of the two reactants.

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 FRONTIER MOLECULAR ORBITAL THEORY

Cycloaddition can be explained using frontier molecular orbital(fmo) theory.

Frontier molecular orbitals (fmo) of the 1,3-dipole and the dipolarophile overlap in the
symmetry – allowed π4s+π2s manner.
 Such orbitals overlap can be achieved in three ways:type1,2and3.

Type 1 :
The dipole has a high-lying homo which overlaps with lumo of the dipolarophile.
A dipole of this class is referred to as a homo-controlled dipole or a nucleophilic dipole,
which includes azomethine ylide, carbonyl ylide, nitrile ylide, azomethine imine, 12

carbonyl imine, and diazoalkane.

Electron-withdrawing groups(ewg) on the dipolarophile would accelerate the reaction by
the lowering the LUMO, while electron-donating groups (EDG) would decelerate the
reaction by raising the HOMO.

Type 2 :
 homo of the dipole can pair with lumo of the dipolarophile; alternatively , homo of the
dipolarophile can pair with lumo of the dipole. This two-way interaction arises because the
energy gap in either direction is similar.
 A dipole of this classis referred to as a homo-lumo controlled dipole or an ambiphilic
dipole, which includes nitrile imide, nitrone, carbonyl oxide, and nitrile oxide, and azide.
Any substituent on the dipolarophile would accelerate the reaction by lowering the energy.
 The two interacting orbitals; i.E; an electron withdrawing groups(ewg) would lower the
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LUMO while an electron donating group (EDG) would raise the HOMO.
 For example, azides react with various electron –rich and electron poor
dipolarophile with similar reactivities.

 Type 3 :
The dipole has a low-lying lumo which overlaps with homo of the dipolarophile.
A dipole of this class is referred to as a lumo-controlled dipole or an electrophilic
dipole, which includes nitrous oxide and ozone.
 Electron withdrawing group (ewg) on the dipolarophile decelerate the reaction,
while electron donating group (edg) accelerate the reaction.

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 Thus reactions are favoured if one component is strongly ‘nucleophilic ‘ and other
is strongly ‘electrophilic’.

The orbital energies are determined both by the nature of the skeletal atoms in the
two components and by their substituents.

The more electrophilic dipolarophile have the lower energy lumo values where as
the more nucleophilic species have higher energy homo value.

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 STEREOSPECIFICITY
1,3-dipolar cycloadditions are always stereospecific with respect to the dipolarophile.
Cis –substituents on the dipolarophilic alkene end up cis and trans-substituents end
up trans in the resulting five membered heterocyclic compounds.
The stereochemistry of the dipole is not of major concern because only few dipoles
could form stereogenic centre ,and resonance structures allow bond rotation which
scrambles the stereochemistry.
Regioselectivity
For asymmetric dipole-dipolarophile pairs, two regioisomeric products are
possible.Both electronic/stereo electronic and steric factors contribute to the
regioselectivity of 1,3-dipolar cycloaddition.
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 SYNTHETIC APPLICATION
 1,3-dipolar cycloaddition are important routes towards the synthesis of many
important 5-membered heterocycles such as triazoles, furans, isoxazoles,
pyrolidines, oxcycles and others.
 These reactions are tremendously useful also because they are stereospecific,
diastereoselective and regioselective.
 Several examples are provided below:
1. Nitrones
2. Azomethine ylides
3. Carbonyl ylides
4. Ozone 20
 NITRONES
• Many nitrones are isolable and stable compounds, especially those with c-aryl
substituents.
• Cyclic nitrones avoid geometrical isomers, and generally give better selectivity.
• Most common method for generating the nitrones
1. Condensation of N- alkyl hydroxyl amines with aldehydes or ketones

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2. Oxidation of an N,N- disubstituted hydroxylamine:

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 AZOMETHINE YLIDES
• Azomethine ylides have become one of the most investigated classes of 1,3-
dipoles.
• 1,3- dipolar cycloaddition between an azomethine ylide and an alkene furnishes an
azacyclic structures, such as pyrrolidine.This strategy has been applied to the
synthesis of spirotryprostatin A.
• Methods for generating the azomethine ylides:

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 CARBONYL YLIDES
• Cycloaddition involving carbonyl ylides have extensively been employed to generate
oxygen-containing five membered cyclic molecules.
• Several methods exist for generating carbonyl ylides, which are necessary
intermediates for generating oxygen- containing five membered ring structures, for
[3+2] cycloaddition reaction.
• Synthesis of carbonyl ylides from hydroxypyrones via proton transfer.

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 OZONE
• Ozonolysis is a very important organic reaction. Alkenes and alkynes can be cleaved
by ozonolysis to give aldehyde, ketone or carboxylic acid products.

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 HETERO-DIELS-ALDER REACTIONS

The cycloaddition of conjugated dienes to activated olefins and acetylenes commonly known
as the diels-alder reaction ,used for the construction of six-membered carbocyclic compounds.

 It is preparative value lies in the high stereo- and regioselectivity with which the adduct are
formed, and in the range of substituents which the reaction partners can bear. The selectivity of
the reaction can be accounted for, as with 1,3-dipolar addition , by means of frontier orbital
theory.

The majority of all-carbon diels-alder reactions involve the interaction of a nucleophilic diene
with an electrophilic dienophile.
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 The majority of all-carbon diels-alder reactions involve the interaction of a
nucleophilic diene with an electrophilic dienophile.
In terms of frontier orbitals, the dominant interaction is that between the homo of
the diene and the lumo of dienophile. The reactions show high selectivity, with
products arising from endo transition states being kinetically favoured.
 The diels alder reaction is, in general, facilitated by the presence of electron-
donating substituents, e.g. Alkyl groups, in the diene, and by the presence of
electrone-withdrawing groups in the alkene ( the dienophile), e.G. The C=O groups

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Examples of diels-alder cycloaddition with hetero-dienophiles

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Examples of diels-alder cycloaddition with hetero-dienes

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 [2+2]
CYCLOADDITION
Several four-membered heterocycles can be prepared by [2+2] cycloaddition
reaction but most of the reactions are not general.
The range of substituents which can be incorporated is limited, and the inherent
instability of many four-membered heterocycles means that side reactions often
compete or predominate.
 The most important of these are cycloreversion and expansion to give six-
membered rings

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 [2+2] Cycloaddition reaction-

competing reactions in [2+2] additions.

(A) cycloaddition to starting materials;
(B) cycloaddition with dismutation.
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Chlorosulphonyl isocyanate [example (i)] is a particulary good reagent for the formation of
β-lactams because it adds to a wide range of nucleophilic olefins, and because the
chlorosulphonyl group is readily removed from the cycloadducts by hydrolysis.
Addition to olefins are generally highly stereoselective, but the reaction rates are much
greater in polar than in nonpolar solvents. The most likely mechanism for addition is
stepwise one, in which a dipole intermediate is formed but which rapidly collapses to give
the azetidinone

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Stepwise mechanism for chlorosulphonyl isocyanate addition
Reagents for the synthesis of four-membered heterocycles by [2+2] addition

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It also possible to form four-membered rings by photochemical [2+2] addition. The most important
such process in heterocyclic chemistry is the paterno-buchi reaction, which is the photoaddition of
olefins to aldehydes or ketones.
Oxetanes are formed by the addition of the excited-state carbonyl compound to olefins. The products
in this case can be rationalized as being formed through diradical intermediates, with that from the
mor stable diradical predominating.

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The paterno-buchi reaction
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