For PG students of Chemistry, Applied Chemistry

1. Dr. Harish Chopra
Professor
Department of Chemistry
SLIET, LONGOWAL

2. 1,3-dipolar cycloaddition reaction, like the Diels–
Alder reaction, is a 6 electron pericyclic reaction,
but it differs from the Diels–Alder reaction in that
the 4 component, called the 1,3-dipole, is a three-
atom unit containing at least one heteroatom
and which is represented by a zwitterionic octet
structure. The 2 component, here called the
dipolarophile (rather than the dienophile), is a
compound containing a double or triple bond.
The product of the reaction is a five-membered
heterocyclic compound.

3. A typical example is the well-known reaction between
ozone (the 1,3-dipole) and an alkene (the
dipolarophile) to give an ozonide, formed by
rearrangement of the initially formed cycloadduct.
Dipolarophile Adduct Ozonide
1,3-Dipole

4. 1, 3-Dipoles are classified into THREE categories:
 Type (a): 1, 3-Dipoles with a double bond and non-
bonding pair of electrons on central atom. E.g.: azides,
diazoalkanes, nitrile ylides etc.
 Type (b): 1, 3-dipoles with non-bonding pair of
electrons on central atoms. E.g.: nitrones, ozone, azoxy
compounds, azomethine ylides etc.
 Type (c): 1, 3-Dipoles with a double bond. E.g.:
ketonitrenes, methylenes, ketomethylenes etc
Some 1,3-dipoles, such as azides and diazoalkanes,
are relatively stable, isolable compounds; however,
most are prepared in situ in the presence of the
dipolarophile.

6. MECHANISM
Two mechanisms originally proposed for the 1,3-dipolar
cycloaddition:
1. Concerted pericyclic cycloaddition mechanism
2. Stepwise diradical intermediate mechanism
However, pericyclic mechanism is now generally accepted—
the 1,3-dipole reacts with the dipolarophile in a concerted,
often asynchronous, and symmetry-allowed π4s + π2s fashion
through a THERMAL six-electron Huckel aromatic
transition state. But, a few examples do exist involving a
stepwise mechanism for the catalyst-free 1,3-dipolar
cycloaddition reactions of thiocarbonyl ylides, and nitrile
oxides

7. PERICYCLIC MECHANISM
The following observations support the concerted pericyclic mechanism,
and refute the stepwise diradical or the stepwise polar pathway:
1. Substituent effects: Different substituents on the dipole do not
exhibit a large effect on the cycloaddition rate, suggesting that the
reaction does not involve a charge-separated intermediate.
2. Solvent effects: Solvent polarity has little effect on the cycloaddition
rate, in line with the pericyclic mechanism where polarity does not
change much in going from the reactants to the transition state.
3. Stereochemistry: 1,3-dipolar cycloadditions are always stereospecific
with respect to the dipolarophile (i.e., cis-alkenes giving syn-
products), supporting the concerted pericyclic mechanism in which
two sigma bonds are formed simultaneously.
4. Thermodynamic parameters: 1,3-dipolar cycloadditions have an
unusually large negative entropy of activation similar to that of
the Diels-Alder reaction, suggesting that the transition state is highly
ordered, which is a signature of concerted pericyclic reactions.

8.  Transition state is not very polar
 Not strongly affected by solvent polarity
 In most cases, reaction is a concerted [4πs + 2πs]
Cycloaddition

9. THOERY: A normal 1,3-dipolar reaction involves 4-π
electrons from 1,3-dipole and two electrons from
dipolarophile, and in such cases the main interaction is that
between the highest occupied molecular orbital (HOMO) of
the 1,3-dipole and the lowest unoccupied molecular orbital
(LUMO) of the dipolarophile. Reactants approach each
another in parallel planes to permit interaction between the
HOMO and LUMO orbitals. The smaller the energy
difference between these frontier orbitals, the better these
orbitals interact and therefore the more readily the reaction
occurs.
(HOMO) 
(LUMO)
1,3-Dipole
Dipolarophile



E



 
1,3-Dipole
Dipolarophile
(HOMO)
(LUMO)

10. FMO Approach: Effective Frontier MO overlap can be
achieved in three ways: type I, II and III. The dominant
pathway is the one which possesses the smallest HOMO-
LUMO energy gap.
1,3-Dipole Dipolarophile
(HOMO)
(LUMO)
(HOMO)
(LUMO)
Type I: RED path
Type II: Both RED and BLUE path
Type III: BLUE path

11. Type I: 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, carbonyl imine and diazoalkane. These
dipoles add to electrophilic alkenes readily. Electron-
withdrawing groups (EWG) on the dipolarophile would
accelerate the reaction by lowering the LUMO, while electron-
donating groups (EDG) would de-accelerate the reaction by
raising the HOMO. E.g., Diazomethane reacts with the
electron-poor ethyl acrylate more than a million times faster
than the electron rich butyl vinyl ether.

12. Type II Overlap: HOMO of the dipole can pair with LUMO
of the dipolarophile; or 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 type is called as a HOMO-LUMO-controlled
dipole or an ambiphilic dipole, which includes nitrile
imide, nitrone, carbonyl oxide, nitrile oxide, and azide. An
EWG would lower the LUMO while an EDG would raise the
HOMO. E.g., The reactivity of azides is similar with various
electron-rich and electron-poor dipolarophiles.

13. Type III : 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. EWGs on the dipolarophile de-accelerate
the reaction, while EDGs accelerate the reaction. E.g., ozone
reacts with the electron-rich 2-methylpropene about 100,000
times faster than the electron-poor tetrachloroethene.
This type resembles the inverse electron-demand Diels-Alder
reaction, in which the diene LUMO combines with the
dienophile HOMO.

14. 1,3-dipolar cycloadditions usually result in retention of
configuration with respect to both the 1,3-dipole and the
dipolarophile. 1.3-Dipolar cycloaddition is a syn-addition
with respect to Dipolarophile. E.g., 1,3-Dipolar addition of
cis- and trans-stilbene to diphenylnitrilimine takes place in
a SYN manner.
STEREOSPECIFICITY
C
N
N
Ph Ph
+ trans-Stilbene cis-Stilbene
N
N
Ph Ph
Ph Ph
HH
N
N
Ph Ph
Ph H
PhH
Diphenyl-
nitrilimine
Phenyldiazomethane
N
N
Ph
MeOOC COOMe
CH3H
H
C
N
+
N
Ph
H
- H CH3
MeOOC COOMe
+
N
N
Ph
MeOOC COOMe
CH3H
H
+

15. Similarly, 1.3-Dipolar cycloaddition of 4-Nitrophenylazide
is also a syn-addition with respect to Dipolarophile.
N
N
+
N
O2N
-
HCH3
OC3H7H
HH
OC3H7CH3
4-Nitrophenylazide
N
N
N
HH
CH3 OC3H7
O2N
N
N
N
HCH3
H OC3H7
O2N
STEREOSPECIFICITY

16. STEREOCHEMISTRY
Electron
Rich end
Electron
Deficient
end
N
N
+
N
O2N
-
R
Electron
Rich end
1,3-Dipole
Dipolarophile
N
N
N
O2N
R
N
N
+
N
O2N
- R
+

17. 1,3-Dipolar cycloadditions can be controlled to achieve a
diastereoselective reaction. The metals can chelate to the
dipolarophile and the incoming dipole and direct the
cycloaddition selectively on one face. E.g., in addition of nitrile
oxide to an enantiomerically pure allyl alcohol in the presence
of a magnesium ion. The most stable conformation of the
alkene places the hydroxyl group above the plane of the alkene.
The magnesium then chelates to the hydroxyl group and the
oxygen atom of nitrile oxide. The cycloaddition thus comes
from the TOP FACE SELECTIVELY.

18. 1,3-dipolar cycloaddition with nitrile oxides is a widely used
masked-aldol reaction. Cycloaddition between a nitrile oxide
and an alkene yields the cyclic isoxazoline product, whereas
the reaction with an alkyne yields the isoxazole. Both
isoxazolines and isoxazoles can be cleaved by hydrogenation to
reveal aldol-type β-hydroxycarbonyl or Claisen-type β-
dicarbonyl products, respectively.
Nitrile Oxides
N
O
R
R R
N
+
O
-R
R
R
OH
R
R
R
O
H2, Raney Ni
H3O+
dihydroisoxazole
derivative
OH
R
R
R
NH2
LiAlH4

19. Nitrile Oxides

20. Nitrile Oxides
Intra-molecular 1,3-dipolar cycloaddition reactions take place
readily and some useful applications of this chemistry in
synthesis have been reported. In the synthesis of the
antitumor agents sarcomycin [D, where R=H], dehydration of
the nitro-alkene (A) gave the isoxazoline (B) via the
intermediate nitrile oxide. Hydrogenolysis with Raney nickel in
aqueous acetic acid then led to the b-hydroxy ketone (C),
which was dehydrated to the ethyl ester of sarcomycin (D), R=
Et
(B)(A) (C) (D)

21. In the synthesis of calicheamicin, intramolecular
cycloaddition of the nitrile oxide, generated from the oxime
(A) by in situ chlorination with sodium hypochlorite and
elimination, gave the two isoxazolines (B) and (C). The
isoxazoline (B) was later oxidized to the isoxazole, which was
ring-opened (using aqueous Mo(CO)6) to give an amino
aldehyde, used in a second ring-forming step to prepare the
required enediyne aglycon of calicheamicin.
Nitrile Oxides
(B)(A) (C)

22. The intermolecular cycloaddition of nitrile oxides or
nitrones, two of the most frequently used 1,3-dipoles, to
monosubstituted or 1,1- disubstituted alkenes (except highly
electron-deficient alkenes), the oxygen atom of the 1,3-dipole
becomes attached to the more highly substituted carbon atom
of the alkene double bond. E.g., 5-substituted isoxazolidine (B)
is generated from the cycloaddition of the cyclic nitrone (A)
with propene. Reductive cleavage of the cycloadduct then gave
the alkaloid sedridine. In this cycloaddition reaction the
‘EXO’ product is favoured.
Nitrile Oxides & Nitrones
(A) (B)
(Sedridine)
Alkaloid

23. Intra-molecular cycloaddition reactions of nitrones have been
used widely in synthesis. The required unsaturated nitrones
can be obtained by oxidation of N-alkenyl-hydroxylamines or
by condensation of an aldehyde with an N-substituted
hydroxylamine. Thus, the cis-bicyclic isoxazolidine (B) was
obtained by reaction of 5-heptenal with N-
methylhydroxylamine, by way of the intermediate nitrone (A)
Nitrones
(B)(A)

24. Cycloaddition of azomethine ylides and an alkene or alkyne
leads to formation of a pyrrolidine or dihydropyrrole ring
respectively and the latter can be converted easily to a pyrrole
ring which is commonly found in natural products and
biologically active compounds. In the presence of a
dipolarophile, cycloaddition of the azomethine ylide occurs
stereo-specifically and regio-selectively. E.g., cycloaddition
of the azomethine ylide (B), generated from the aziridine (A),
gave predominantly the pyrrolidine (C).
Azomethine Ylides
(B)(A) (C)

25. The carbonyl ylide as 1,3-dipole has received considerable
interest recently and has been formed from cyclization of an
electrophilic rhodium carbenoid onto a nearby carbonyl
group. Cycloaddition with an alkyne or alkene dipolarophile
then gives the dihydro- or tetrahydrofuran product. E.g., the
carbonyl ylide (B), formed from the diazo compound (A) and
rhodium(II) acetate, reacts with dimethyl
acetylenedicarboxylate to give the bridged dihydrofuran (C)
Carbonyl Ylides
(B)(A) (C)

26. The 1,3-Dipolar cycloaddition reaction generally does not
proceed readily under mild conditions. A Copper-catalyzed
Azide-Alkyne Cycloaddition (CuAAC), which proceeds very
readily in mild, including physiological, conditions
(neutral pH, room temperature and water solution) has been
developed. The reaction is so versatile that it is termed
the "Click" chemistry. Although copper(I) is toxic, many
protective ligands have been developed to both reduce
cytotoxicity and improve rate of CuAAC, allowing it to be used
in in vivo studies.
Copper Catalysis

27. Resources /Further Reading
1. Modern Methods of Organic Synthesis, W.
Carruthers; Cambridge Press UK
2. Pericyclic Reactions, Ian Fleming, Oxford University
Press, UK
3. NPTEL Lectures and Videos
4. https://en.wikipedia.org/wiki/1,3-Dipolar_cycloaddition

28. Thank You