Cycloaddition Reactions 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. CH2
CH2
sun light
H2C
CH2
H2C
CH2
+ CH2
CH2 ethylen
cyclobutane X
X
sun light
+
2π
2σ
Cycloaddition reactions take place via two mechanisms: a) Concerted mechanism: (one-step mechanism) In this case the two Ďƒ-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]
reactants
AB
T. S.
product
This can be represented graphically as follows: T. S P. E A+B AB
Reaction coordinate
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:
b) Non-concerted mechanism: - (stepwise) In this case the two Ďƒ-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:
T .S .
1
T .S .
2
Eact P. E
R e a c t iv e in t e rm e d ia t e
A + B AB
Reaction coordinate
A + B
T.S.1
C
T.S.2
AB
Thus
+
Cyclic product
.
+
Or -
Zwitter ionic
. diradical
The most common example of cycloaddition reaction is the " DilesAlder" 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:
a) [4 + 2] cycloadditions of furans: 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.
This reaction is classified as [4 +2] or (π
4
+ π 2) cycloaddition reaction.
Example of the different types of cycloadditions starting with πexcessive 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
( n e w Ďƒ- b o n d s )
S e c . o v e r la p in te r a c tio n O O
O
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
b) Cycloaddition of Pyroles: 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-typeaddition and not as cycloadditions O O
+ N H
O O
N H
O
+
O
N H
CO2H CO2H
Michael-adduct
+ N H
C CO2Et C CO2Et
N H
CO2Et CO2Et
The reactivity of pyrrole to behaves as diene through Diels-Alder reaction may be increased by two methods 1- 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
CO2Et N
+ N CO2Et
+
C C
CO2Et CO2Et
CO 2Et N
CO2Et CO2Et
CO2Et
EtO2C -C
2H2
N CO2Et
2- Using polysubstituted pyrrole Thus, Polysubstituted bicyclo adducts are obtained by treatment of Naminopyrroles with DMAD.
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:
1) Treatment of thiophene with peracids O S peracid S S
O
Sulphone
+
S O
O
Sulphoxide
Cycloaddition occurs S O
O
2) Introducing electron releasing substituents and very active dienophile e.g.: S Me Me
Me
+ Me
S
Me
C
CN
C
CN
(4 + 2)
CN
Me Me
Me
(a)
(2 + 2)
Me Me
Me Me
S
CN
CN CN
Me
CN
Me Me
CN S
Me
(b)
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
O
O Me
N
N
+ EtO
O
O OEt
O
Me
O
O
OH CH2OH N
CO2H
N
H+ / EtOH
N
LiAlH4 Me
CH2OH OEt Pyridoxine
O
O CO2H
Me OEt
Me OEt
O
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 C6H5
C6H5
N N
O
+
H
C
C
CO2H
O CO2H
CN
CO2H
+ O 3-Furic acid
[4 + 2] Cycloaddition of π-deficient heterocycles 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
b) Formation of pyridazines from tetrazines N R Ph N N
N N
N
CH2
R
Ph
N
CH
+
N
R
Ph - N2
N N
R
R
O
R
R
Ph N N R
c) Formation of 1,2,4-triazines from tetrazines N R
R
N
N
N
N R
NH
+ Ph
OEt
N
N N
R
NH R
OEt
-N
2
- EtOH
N
N
N Ph
Ph R
1,3-Dipolar cycloadditions 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 CH2 N=N
CH2 N=N
CH2 N
b) Nitrilimines
R
C
N
N
C
N
O
c) Nitrileoxide
R
R'
N
CH2 N=N
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:
b
b
a d
c e
4 + 2
c
a d
e
cyclo-adduct
As example of these reactions a) Addition of ozone to the olephenic systems
O
O
O
O H2C
CH2
4+2
O
O
H2C
C H2
molozonide
b) Diazomethane to ethyl acrylate
N H2C
N
N N
HC CO2Et
CH2 CO2Et
Thus the 1,3-dipolar-cycloaddition may be classified as [4 + 2] cycloaddition if we use the number of p-electrons presented 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. R1
N N
nitrilimine
N
R O
nitriloxide
R
Nitrilimine can be prepared by dehydrohalogenation of hydrazonyl halides as follows: -
Ar
NH2
NaNO 2 / HCl 0-5째C
base
Ar
- HCl
Ar
N
N
Ar
C
N H
COCH3
Nitrileimine (general formula)
N
C Cl
N=NCl
COCH3
(CH3 CO)2 CHCl Japp-Klingmann Rx. Ar
N
N
CH COCH3 Cl
On the other hand nitrile-oxide also are prepared as follows:
Examples of 1,3-Dipolar cycloaddition reactions R N
N R
N
N O
O
R1
R1
R N
N R
N
N O
R1
O
R1
R'
R'
N R
+
N N
N N
N CH3
C R'
N
+ R
N CH3
CH3
Michael-adducts
cyclo-adducts
+
O
N O
N O
O
+
O
+
Ar
90% yield
Ar
Ar
N O
N
O
10%
C O
Ar
Ar
C
NHR
O
30%
N O
O
+
N
O
70% yield
Ar
[2 + 1]cycloadditions 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 2Ď€ -electron system
+
..
X
X
..
+ Z
X
X Z
As examples of one atom systems,
Carbenes and
Nitrenes systems:
Carbene The carbon atom has only 6 valence electrons and is therefore considered an electrophile.
R C R
Nitrenes The nitrogen atom has only 6 valence electrons and is therefore considered an electrophile.
R
N
Carbene may be obtained as follows
(1)
CH2N2
Sun light
(3)
CH2=C=O
CHCl3
+
N2
methylene carbene
diazomethane
(2)
: CH2
NaOH -H O 2
: CH2
CCl3
+ - Cl
CO
: CCl2 dichlorocarbene
Also, nitrenes may be obtained as follows:
(1)
HN3
HN :
+
N2
hydrazoic acid
(2)
N3
COOC2H5
ethoxycarbonyl azide
U.V.
N2
+
: N COOC H 2 5 ethoxycarbonyl nitrene
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: H
U.V. + N2
CHCO2Et
O
CO2Et
CHCO2Et O
OHC
(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:
U.V. + N3
+
CO2Et
N
O
CO2Et
valence bond isomerization
H NCO2Et O O
O
N CO2Et
N CO2Et
O
b) [2 + 1] of Pyrroles 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.
Cl
CHCl3 N
base
+ N
N
(a)
H (b)
H
CHO
The mechanism, which has been postulated for this reaction is:
Cl
CHCl3 base
N
C Cl
N H
H
N H
Cl
N (a)
Cl C
Cl
- Cl
N
Cl NaOH CH Cl
OH N
CH OH
-HO 2
N H (b)
CHO
(2) Pyrrole reacted with ethyl azidoformate and it give Nethoxycarbonyl-2-aminopyrrole
+
N3
CO2Et
N H
NH2 N CO2Et
The formation of the reaction product can be discussed using the [4 + 2] cycloaddition as follows NH N3 N H
CO2Et
Isomerization N
CO2 Et
N CO2Et
NH2
b) [2 + 1] of Pyrazole When polysubstituted pyrrazole was treated with CHCl3 in basic medium a mixture of (two products a) and (b) has been formed
Me Me
Me CHCl3
Me
N H
N
base
Me Me
Cl N
N (a)
Me
Me
+ Cl
pyrimidine derivative
Me
N (b)
N
pyridazine derivative
The formation of the product (a) can be proved as follows Me
Me
Me CHCl3
Me
N
N
base
Me
Me
Me N
N
Me - Cl
+ :CCl2H
Me
N
H
N
CCl2 Me Me
Me Me
Me
N N (a)
Me
Cl
Me
N
Me
N CCl
Me N
N:
:CCl
The formation of the product (b) can be proved as follows Me
Me
Me
Cl
CHCl3 N
Me N H
Cl
Cl
Me Me
Me
Me
Me
NH
Me N
base
NH
Me N
- Cl Me
N N