Cycloaddition Reactions

CH2

CH2

+

CH2

CH2

H2C

H2C CH2

CH2

ethylen cyclobutane

X X

+

sun light

sun light

Cycloaddition reactions are the reactions of unsaturated reactants to form

stable cyclic products without elimination of small fragments. These

reactions are accompanied by the formation of 2 new σ-bonds.

2 π 2σ

a) Concerted mechanism: (one-step mechanism)

In this case the two σ-bonds are formed simultaneously and the reaction proceed via

only one step with the formation of transition state without the formation of any

intermediates.

A + B [A---------B] AB

T. S. product

This can be represented graphically as follows:

T. S

P. E

A + B

AB

Reaction coordinate

reactants

Cycloaddition reactions take place via two mechanisms:

This reaction is classified as [4 +2] or (π4 + π2) cycloaddition

reaction. Example of the different types of cycloaddition starting

with π-excessive and π-deficient – systems as follows:

In this case the two σ-bonds are formed in two steps through the

formation of two transition states and an intermediate, which may

be diradical or Zwitter ionic. The formed intermediate may be

distinguished by isolation when it is stable or by trapping.

Graphically this type may be represented as follows:

in te rme d ia teRe a c t iv e

P . EEa c t

T .S . 1T.S . 2

A B

A + B

Reaction coordinate

b) Non-concerted mechanism: - (stepwise)

T.S.1 T.S.2A + B C AB

+

+

-

Or

.

.

Cyclic product

Zwitter ionic diradical

Thus

The most common example of cycloaddition reaction is the " Diles-

Alder" reaction (reaction of diene and dienophile form cyclic product)

Cycloaddition reactions are classified as (m + p) cycloadditions where m

and p may refer to the number of atoms of each of the reactants which

participate in the ring formed or may refer to the number of p-electrons

clouds in each of the reactants as follows:

As the aromatic character of π-excessive heterocycle decreases the

reactivity of such systems to be used as reactive dienes in Diels-Alder

reactions increases thus, furan reacts with maliec anhydride and

maleimids via [4 + 2] cycloaddition to form cycloadducts. The reaction

products are mixture of exo- and endo adducts and the ratios of their

formation depend on the stability of each type under the reaction

conditions. Thus it has been found that the endo-adduct predominates at

low temperature, while the exo-adduct was the chief product at high

temperatures.

a) [4 + 2] cycloadditions of furans:

This reaction is classified as [4 +2] or (π 4 + π 2) cycloaddition reaction.

Example of the different types of cycloadditions starting with π-

excessive and π -dificient-systems as follows:

Endo-adduct predominates at lower temperature [kinetic controlled product] due to

the internal overlap interaction of the p-electron clouds of each of the furan-ring

and that of the two carbonyl groups (see overlap interaction) and the transition

state of the endo-adduct may be represented as follows:

O

O

OO

(n e w σ-b o n d s )S e c . o v e r la pin te ra c t io n

1) Furan reacts also with ethylene oxide (epoxide) as follows

2) Aromatic carbocyclic compounds can be obtained from

Diels-Alder reaction of furan via treatment with benzyne

intermediate

3) With acetylene dicarboxylic ester

CO2HN CO2H

O

OO

O

O

N O + +

NH H H

Michael-adduct

Unsubstituted pyrrole has more aromatic character than furan for this it is

less prone to reactions typical of a diene. Thus, it reacts with dieneophiles

e.g. maleic anhydrides and acetylene dicarboxylic esters via Micheal-type-

addition and not as cycloadditions

NCO2Et

CO2EtCO2Et

CO2Et

C

C+

NH

H

b) Cycloaddition of Pyroles:

N+

+C

C

CO2Et

CO2Et

N

CO2Et

N

CO2Et

CO2Et

N CO2Et

CO2Et

C2H2-

CO2Et

CO2Et

EtO2C

The reactivity of pyrrole to behaves as diene through

Diels-Alder reaction may be increased by two methods1- introducing an electron withdrawing substituent on the pyrrole-N-atom

which reduces the availability of the unshared electrons of the N-atom and so

decreases the aromatic character of the ring thus

Thus, Polysubstituted bicyclo adducts are obtained by treatment of N-

aminopyrroles with DMAD.

2- Using polysubstituted pyrrole

) Treatment of thiophene with peracids1

S

peracidS S

O

+

OO

Cycloadditionoccurs

S

S

O

O

OSulphone Sulphoxide

c) [4 + 2] Cycloadditions of thiophene:

Thiophene is the most aromatic compounds of π -excessive heterocycles with one

heteroatoms. Thus it is difficult to be used in [4 + 2] cycloaddition, the reactivity of

thiophene ring to be used as diene in cycloadditions may be increased as

follows:

S

Me

Me

Me

Me

+C

C

CN

CN

(2 + 2)

S

CN

CN

Me

Me Me

Me

(4 + 2)

S

Me

Me

Me

Me

CN

CN S

CN

CN

MeMe

Me

Me

(a)

(b)

2) Introducing electron releasing substituents and very active dienophile e.g.:

Produced (a) formed via [4 + 2]cycloaddition while the product (b) formed via

[2 + 2] cycloaddition followed by valence bond isomerization of the formed

cyclo adduct

d)[4 + 2] Cycloadditions of oxazoles

Such reactions are used for the synthesis of some important compounds

such as the synthesis of pyridoxine (vitamin B6).

Pyridoxine can be obtained also via reaction with maleic

anhydride

O

N

Me

EtO

O+

N

O

OEtMe

O

H+ / EtOH

Pyridoxine

N

Me

OEt

O

OH

O

O

O

O

O

O

N

CH2OH

OEt

Me

CH2OH

LiAlH4

N

Me

OEt

CO2H

CO2H

O

N

C6H5

+ C CH CO2H

N

C6H5

O

CO2H

O

CO2H

+

CN

3-Furic acid

Oxazoles and substituted oxazoles undergo cycloaddition of Diels-Alder

type nucleophilic reaction like furan, whereas thiazoles and imidazoles

react with dienophiles via nucleophilic addition as does pyrrole

deficient heterocycles-π] Cycloaddition of 2+ 4 [

Several six membered hetrocycles e.g. 1,2,4-triazines and 1,2,4,5-tetrazines, which have

electron attracting substituents, are very active dienes toward electron rich olephines and

acetylenes. These reactions proceed via the cycloadducts formation, which undergo

extrusion of N2 leading to the formation of other heterocycles e.g.

a) Formation of pyridines from triazines

N

N N

N+

CH2

CHPh

R

R

NN

N

N

R

R

Ph

N2- N

N

R

RPh

O

N

N

R

RPh

b) Formation of pyridazines from tetrazines

Ph

R

R

N

N

N-N2

PhR

RN

N

NH

N

N

R

R

Ph+

N

N N

N NH

OEt OEt EtOH-

triazines from tetrazines-4,2,1c) Formation of

CH2 N=N CH2 N=N CH2 N N CH2 N=N

b) Nitrilimines

R C N N R'

Dipolar cycloadditions-3,1

The [4 + 2] cycloadditions also can be carried out starting with chemical

reagents consists three atoms in the same time they have 4p-electrons

distributed over them. As examples of these compounds

a) Diazomethane CH2N2

c) Nitrileoxide

R C N O

The above compounds are neutral and can be added onto mono ene

systems (or onto one π-bond of active heterocycles) to form

cycloadducts via [4 + 2) cycloadditions. In such cases the 4π-electrons

three atoms systems are known as «1,3-dipoles » and the monoene

system is known as « Dipolarophile » and the reaction is known as

« 1,3-dipolarcycloaddition ». The process can be represented as

follows:

cyclo-adduct

ab

c

d e

ba

d e

c

4 + 2

As example of these reactions

molozonide

OO

OO

O

C C

O

4 + 2

H2H2CH2H2C

a) Addition of ozone to the olephenic systems

b) Diazomethane to ethyl acrylate

H2C

N

N

HC CH2

CO2Et

N

N

CO2Et

Thus the 1,3-dipolar-cycloaddition may be classified as [4 + 2]

cycloaddition if we use the number of p-electronspresented in the

reactions or also may be classified as [3 + 2] cycloaddition if we use

the number of atoms of each component which participate in the

formation of the cycloadduct.

The most recent 1,3-dipolaes which have been used are

Nitrileimines and nitrile-oxides.

NN

R1R N

O

R

nitrilimine nitriloxide

Nitrileimine(general formula)

Ar NH2

NaNO2 / HCl

0-5°CAr N=NCl

(CH3CO)2CHCl

Japp-Klingmann Rx.

Ar N N CH

Cl

COCH3Ar N N

Cl

COCH3CH

base

HCl-

Ar N N COCH3C

Nitrilimine can be prepared by dehydrohalogenation of hydrazonyl

halides as follows: -

On the other hand nitrile-oxide also are prepared as

follows:

Examplesof

1,3-Dipolar cycloaddition reactions

O

N

N

R1

R

O

NN

R1

R

O

N

N

R1

R

O

NN

R1

R

+

N

cyclo-adducts

NN

R

C R'N

N

N

R'

R

CH3 CH3

+N

CH3

N

NHR

R'

Michael-adducts

+

C

O

Ar

N +O O

O

N

Ar

O

NO

Ar

10% 90% yield

+

C

O

Ar

N +O O

O

N

Ar

O

NO

Ar30% 70% yield

+ X..

X

Z+ X

..

Z

X

]cycloadditions1+ 2 [

This is another type of cycloaddition reactions in which one of the

reactants is an atom or group (X) with unshared pair of electrons

when it reacts with 2π -electron system

Carbene

The carbon atom has only 6 valence electrons and is therefore considered an electrophile.

Nitrenes

The nitrogen atom has only 6 valence electrons and is therefore considered an electrophile.

NRC

R

R

As examples of one atom systems, Carbenes and

Nitrenes systems:

Carbene may be obtained as follows

diazomethane

:(1) CH2N2Sun light

CH2 + N2

methylene carbene

:(2) CH2 +CH2=C=O CO

dichlorocarbene

:(3) CHCl3 CCl3 CCl2NaOH

H2O-

Cl-

Also, nitrenes may be obtained as follows:

hydrazoic acid:(1) +HN3 HNN2

ethoxycarbonyl azide

:(2) +N2N3 NCOOC2H5 COOC2H5

ethoxycarbonyl nitrene

U.V.

Examples of [2 + 1] cycloadditions

a) For Furan

(1)When a mixture of furan and ethyl diazoacetate was subjected to UV.

radiation, an acyclic aldehyde has been obtained and its formation have been

discussed as follow:

O

+ N2 CHCO2EtU.V.

O

CHCO2Et

OHC

CO2Et

H

(2) When furan was treated with ethoxycarbonylazide under the effect of

UV, a mixture of two N-ethoxycarbonyl pyrroles has been formed. The

formation of this mixture is also discussed as follows:

O

+ N3 CO2EtU.V.

O

NCO2Et

NO

CO2Et

+

NO

CO2Et

N

CO2Et

O

Hvalence bondisomerization

b) [2 + 1] of Pyrroles

base +N N

H

CHCl3

N CHO

Cl

H(a) (b)

It was found that when pyrrole was treated with chloroform in

presence of strong base, a mixture of the pyridine (a) and the pyrrole

(b) has been formed.

The mechanism, which has been postulated for this reaction is:

(b)

(a)

H

Cl

CHO

N

CHCl3

H

N

Nbase

H

N

C

Cl

Cl

Cl-

H

N

C

Cl

Cl N CH

Cl

ClN CH

OH

OH

NaOH - H2O

(2) Pyrrole reacted with ethyl azidoformate and it give N-

ethoxycarbonyl-2-aminopyrrole

H

N+ N3 CO2Et

N

CO2Et

NH2

The formation of the reaction product can be discussed using the [4

+ 2] cycloaddition as follows

NH

N3 CO2Et

N

NH

CO2Et

Isomerization

N NH2

CO2Et

(b)(a)HCl N

NCHCl3

NN base

pyrimidinederivative

MeMe

Me N

NMe

Me

Me

+Me Me

Me

Cl

pyridazinederivative

When polysubstituted pyrrazole was treated with CHCl3 in basic medium a

mixture of (two products a) and (b) has been formed

b) [2 + 1] of Pyrazole

The formation of the product (a) can be proved as follows

(a)

H

Cl

CHCl3N

N baseCl-

MeMe

Me

N

NMe

Me

Me

NN

MeMe

Me+ CCl2H:

NN

MeMe

Me

CCl2

NN

MeMe

Me

CCl:

:N

NCCl

MeMe

Me

The formation of the product (b) can be proved as follows

NH

N

Me Me

MeN

NH

Me Me

Me

CHCl3

baseN

NHMe

ClCl

MeMe

NN

Cl

MeMe

Me- Cl