pericyclic reaction

Pericyclic reaction

National Institute of Pharmaceutical Education and Research (NIPER), SAS Nagar Punjab-160062

Presented By Shantanu guptaM. Tech.(2nd sem)

Department of Pharmaceutical Technology (Process Chemistry )

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FLOW OF PRESENTATION Introduction 1

Classification 2

Mechanism 3

Example 4

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IntroductionPericyclic reactions are "Any concerted reaction in which bonds are formed or broken in a cyclic transitions state”. (electrons move around in a circle). i.e. there is a single transition state from start to finish, in contrast to a stepwise reaction.

Transition state

reaction co-ordinate

Energy

startingmaterial

product

Concerted reactionTransition states

reaction co-ordinate

Energy

startingmaterial product

Multistep reaction

inter-mediate inter-

mediate

.Angew. Chem. Int. Edit. 1969, 8(5),343-348.

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. Pericyclic reactivity can be understood interms of frontier molecular orbital (FMO) theory and the outcome of reactions can be predicted using the Woodward-Hoffmann rules.. Pericyclic reactions require light or heat and are completely stereospecfic; that is, a single stereoisomer of the reactant forms a single stereoisomer of the product.

Properties of pericyclic reactions:

(a) Little, if any, solvent effect (b) No nucleophiles or electrophiles involved.(c ) Not generally catalysed by Lewis acids.(d) Highly stereospecific. (e) Often photochemically promoted.

Classification:1. Cycloaddition reaction .2. Electrocyclic ring closing and ring opening reaction3. Sigmatropic Rearrangements4. Cheletropic5. Group Transfer

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Cycloaddition reaction • A cycloaddition is a pericyclic chemical reaction, in which

"two or more unsaturated molecules (or parts of the same molecule) combine with the formation of a cyclic adduct in which there is a net reduction of the bond multiplicity." The resulting reaction is a cyclization reaction. Designated as [A+B].

• A and B refers to number of atoms containing π-electrons• Three important classes of cycloaddition reactions(i) Diels-Alder reaction(iii) [2+2] Cycloaddition(ii) [1,3]-Dipolar cycloaddition

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Diels-Alder Reaction

•Reaction between a conjugated diene and dienophile.• Highly effective method for the formation of cyclohexene ring

•Discovered by Professor Otto Diels and his student KurtAlder in 1928 and received Nobel prize in 1950

+

diene dienophile

J. Am. Chem. Soc.; 2005; 127(43) pp 15002 - 15003;

hv

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1) Diene must be in the s-cis conformation:

s-cis s-trans

This will react: But not this:

(ends are toofar apart)

2) Dienophiles with electron-withdrawing groups (EWG) react faster:

Me Me

CO2MeO

OMe

CO2MeO

OMe

O

OMeCO2Me

slow

fast

This is because the electron- withdrawing group reduces the LUMO energy and improves the overlap with the orbitals in the diene.

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3) The reaction is stereospecfic:

MeO2C CO2MeCO2Me

CO2Me

MeO2C

CO2MeCO2Me

CO2Me

4) Endo-product often favoured:

O

O

O O

O

O

+

Two isomers can be formed:

OO

OENDOMAJOR

HH

EXOMINOR H

H

OO

O

In a kinetically controlled (product is fastest to form, irreversible) the ENDO is favoured but for reversible reactions (thermodynamic control) the EXO may dominate e.g. with furan.

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FMO Theory• Cycloaddition can be explained using frontier molecular orbital (FMO) theory.• Frontier Molecular Orbital Theory was developed in the 1960s by Kenichi

Fukui who recognised that chemical reactivity can often be explained in terms of interacting Highest Occupied MOs (HOMOs), Lowest Unoccupied MOs (LUMOs)

• The alkene (dienophile) component has two electrons is a "single" π-bond. FMO theory, here, identifies the HOMO and LUMO components of this system:

The Journal of Chemical Physics 20 (4): 722.

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•Likewise, the diene which has four electrons in is conjugated π-system can have its HOMO and LUMO identified within FMO theory:

The Journal of Chemical Physics 20 (4): 722.

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• If we examine the phases at the ends (terminis) of the diene and dieneophile we find that the LUMO/HOMO interactions are phase matched:

•In the FMO diagrams above, the sizes or coefficients, are all the same size, butusually they are of different sizes. The rule is that the coefficients match as well: small with small and large with large.•Thus, the regioselectivity of the cycloaddition can be explained

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[2+2] Cycloaddition reaction

The [2+2] photocycloaddition is a cycloaddition-type reaction – it generally entails the formation of new molecules by the reaction of two unsaturated molecules via two atoms from each molecules (hence "[2 + 2]").

Polym. Int. 58 (7): 720

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1,3 dipolar cycloaddition reaction

R N O

RO

N

R

R

•These are 3 atom 4 electron diene which react with dienophile and form 5-member ring•This is called 1,3 dipole and this cycloaddition reaction called as 1,3 dipolar cycloaddition reaction

R N O

R

O

N

R

R

Mechanism

J. Clayden, N. Greeves, S. Warren, P. Wothers, Oxford, chapter 34, p 867

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•Molecular rearrangements in which a σ-bonded atom or group, flanked by one or more π-electron systems, shifts to a new location with a corresponding reorganization of the π-bonds are called sigmatropic reactions. The total number of σ-bonds and π-bonds remain unchanged. Diffenent type of sigmatropic rearrangement reaction are-

Sigmatropic Rearrangements

•(3,3)-sigmatropic rearrangement• (2,3)-sigmatropic rearrangement •(1,5)-sigmatropic rearrangement

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Claisen rearrangement or (3,3)-sigmatropic rearrangement

O OHheat

• This is a example of (3,3)-sigmatropic rearrangement•This is one-step mechanism without ionic intermediate or any charge •Similar like a Cycloaddition reaction

J. Clayden, N. Greeves, S. Warren, P. Wothers, Oxford, chapter 35, p 897

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Electrocyclic Reactions An electrocyclic reaction is a reversible reaction that involves ring

closure of a conjugated polyene to a cycloalkene, or ring opening of a cycloalkene to a conjugated polyene.

For example, ring closure of 1,3,5-hexatriene forms 1,3-cyclohexadiene, a product with one more ! bond and one fewer " bond than the reactant. Ring opening of cyclobutene forms 1,3-butadiene, a product with one fewer ! bond and one more " bond than the reactant.

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EXAMPLE OF PERICYCLIC REACTION

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Synthesis of citral

J. Clayden, N. Greeves, S. Warren, P. Wothers, Oxford, chapter 34, p 897-930

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Fischer indole synthesis

NH

NH2 ONH

N

NH

NH

H

NHNH

H

NH2NH

NH NH2

NH NH3

NH

NH

H

H

[3,3]-sigmatropicrearrangement

hydrazine cyclohexanone

J.J. Li, Name Reactions, 4th ed, p 245

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Pericyclic Reactions in Biological Systems

J. Am. Chem. Soc.; 2005; 127(43) pp 15002 - 15003;

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Oxidation of 3-alcohol to carbonyl compund


OHR CrO3

H

O R

OR

CrO

OOH

CrO3

[3,3]-sigmatropicrearrangement O R

CrO OOH

H

H

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Synthesis of substituted alcohol

Ph

O

Ph

OBuLi

Ph

OH

Ph

OH

[2,3]-sigmatropicrearrangement

benzyl allyl ether


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Diels-Alder reactions: Alkaloid synthesis:

NH

O

OBn Bn=CH2Ph

CHO

+

NH

CHOO

OBn

P

O

nPr

O

MeOMeO

base(Wadsworth-Emmons)

NH

O

OBn

Diels-Alder

O

nPr

H2, Pd/C(removes CO2Bnand reduces alkene)

NH2

O

nPr H+ (catalytic)

N

H

HnPr

not isolated

NaBH4

(reduces C=N NH

H

H H

Pumiliotoxin C('poison arrow' toxin)

regio and stereo-controlledcarbamate

J. Org. Chem., 2013, 78 (19), pp 9738–9747

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Synthesis of intermediate of estrone

O

O

heat

O

OH3CO H3CO

O

HO

H

H H

estrone

Diels-alder product

benzoquinone7-methoxy-4-vinyl-1,2-

dihydronaphthalene


Diels-Alder reactions for the synthesis of carbohydrate

O

OMe

Me3SiO

O

OMe

Me3SiO

O

OMe

Me3SiO

+

Danishefskydiene.

A novel approach to the synthesis ofcarbohydrates.

BnO BnO BnO

2-(benzyloxy)acetaldehyde


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Thank you

pericyclic reaction

Science

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