Molecular rearrangement

Molecular rearrangement

1. Prof. Rakesh D. Amrutkar Assistant Professor 16/09/2017 1 Mahatma Gandhi Vidyamandir's Samajshri Prashantdada Hiray College of Pharmacy, Malegaon MOLECULAR REARRNGEMENT

2. CONTENTS : Molecular Rearrangement Classification of Molecular Rearrangement Carbonium ion /Carbon deficiency Rearrangement Pinacole – Pinacolone Rearrangement Wagner- meerwein rearrangement Benzilic acid rearrangement Wolf rearrangement Nitrogen deficiency Rearrangement Schmidt Rearrangement Curtius Hoffmann Beckmann Lossen 16/09/2017 2

3. REARRANGEMENT REACTION  The reactions which proceed by a rearrangement or reshuffling of the atoms groups in the molecule to produce a structural isomer of the original substance are called Rearrangement reactions.   Most are migrations from an atom to an adjacent one (called 1,2-shifts),but some are over longer distances. 16/09/2017 3

4. Classification : Intermolecular rearrangement : Reactions which involve migration o f group between two molecules. In which the migration group gets completely detached and is later on reattached are called intermolecular rearrangements . Eg : Aromatic rearrangements Intra molecular rearrangement : Reactions which involve rearrangement with in the same molecule Those rearrangements in which the migration group is never fully detached from the system Eg: Nucleophillic rearrangement Electrophillic rearrangement Free radical rearrangement 16/09/2017 4

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6. NUCLEOPHILLIC REARRANGAMENT : Migrating group migrating towards electro defficient atoms. ELECTROPHILIC REARRANGEMENT: migrating group migrates towards electron rich centre. FREE-RADICAL REARRANGEMENT: those reactions in which migrating group moves to a free-radical centre. AROMATIC REARRANGEMENT : Migrating towards aromatic nucleus. 16/09/2017 6

7. NUCLEOPHILIC REARRANGEMENT Migrating group migrates from a carbon atom to an adjacent electron deficient atom which is generally C, N, O. rearrangement to electron deficient CARBON atom( carbonium ion rearrangement) Eg : Pinacole-pinacolone rearrangement Wagner- meerwein rearrangement Benzilic acid rearrangement rearrangement to electron deficient NITROGEN atom E.g.: Schmidt rearrangement. Hofmann rearrangement rearrangement to electron deficient OXYGEN atom E.g.: Baeyer villager reaction Cumene hydroperoxide rearrangement 16/09/2017 7

8. CARBONIUM ION REARRANGEMENT: In this case electron deficient atom is carbon the intermediate is known as carbonium ion rearrangement. And the reaction of this class is known as carbonium ion Rearrangement. with change in c-skeleton with out change in skeleton E.g.; Pinacole-pinacolone rearrangement E.g.: allycyclic rearrangement Wagner- meerwein rearrangement Benzilic acid rearrangement Wolf rearrangement 16/09/2017 8

9. PINACOLE-PINACOLONE REARRANGEMENTS The conversion of pinacols(1,2-glycols) to ketones or aldehydes means of acids is known as pinacol rearrangements. MECHANISM : The reaction involves four steps:- 1. protonation of hydroxyl group 2. Loss of water to form a carbocation 3. 1,2-shift of :H, :R or : Ar to form a more stable cation 4. Loss of H+ to form the final product 16/09/2017 9

10. Mechanism: . 16/09/2017 10

11. FEATURES OF PINACOLE REARRANGEMENT: 1). Stability of carbonium ion : when there is a choice as which hydroxyl group will be preferentially removed i.e.,when two oh groups are different then that oh group will be removed which produces the more stable cation 16/09/2017 11

12. 2). MIGRATORY APTITUDE : When each of the carbon atoms of the glycol as an aryl and alkyl group, the more Nucleophilic (potentially electron-rich) aryl group preferentially migrates. When the migratory competition is between two aryl groups, then the one which Is better nucleophile (more powerful electron donor towards carbon) migrates Preferentially. 16/09/2017 12

13. 3) INTRA MOLECULAR MIGRATION : The migrating group migrates with in the molecule, that is it never becomes free from the rest of the molecule as it retains its configuration in the product. 4) TRANS MIGRATION : The migrating group migrates to the opposite side of the leaving group which has important consequences in alicyclic system 16/09/2017 13

14. APPLICATIONS: 1.SYNTHESIS OF CARBONYL COMPOUNDS FROM ALKENES Isobutyraldehyde may prepared on large scale from isobutylene 16/09/2017 14

15. 2.RING EXPANSION OF CYCLIC KETONES Cylohexanone can be converted to cycloheptanone in good yield cycloheptanone 16/09/2017 15

16. 3.KETONES FROM CYCLIC DIOLS Pinacol rearrangement has been employed to prepare ketones which are otherwise Inaccessible to synthesis 16/09/2017 16

17. Benzillic acid Rearrangement 16/09/2017 17

18. 16/09/2017 R.D.Amrutkar SPH Pharmacy,Malegaon 18 A hydroxide anion attacks one of the ketone groups.( nucleophilic addition ). 2) Alkyl group attack on the second carbonyl group in a concerted step with reversion of the hydroxyl group back to the carbonyl group. 3) This sequence resembles a nucleophilic acyl substitution.

19. The reaction is a representative of 1,2-rearrangements. These rearrangements usually have migrating carbocations but this reaction is unusual because it involves a migrating carbanion. A hydroxide anion attacks one of the ketone groups in   1  in a nucleophilic addition to the hydroxyl anion  2 . The next step requires a bond rotation to conformer  3  which places the migrating group R in position for attack on the second carbonyl group in a concerted step with reversion of the hydroxyl group back to the carbonyl group. 16/09/2017 19 The carboxylic acid in intermediate  4  is less basic than the hydroxyl anion and therefore proton transfer takes place to intermediate  5  which can be protonated in acidic workup to the final α- hydroxy –carboxylic acid  6 .

20. Migrations to Electron-Deficient Carbons Wagner- Meerwein Rearrangements 1,2-Shifts of migrating groups to empty orbitals in carbo - cations or toward partially empty orbitals in developing c arbocations are t he most common rearrangements of o rganic molecules. Especially, migration of hydrogen atom or alkyl or aryl groups in carbocations are called “ Wagner- Meerwein Rearrangements ”

21. Wagner Meerwein : Tert-amyl & Neo- pentyl comp. alcohol , halide Highly branched : Sub, Add, elim. i.e. Dehydration, dehydrohalogenation 16/09/2017 R.D.Amrutkar SPH Pharmacy,Malegaon 21

22. Mechanism: 1) Formation of Carbonium ion by protonation 2 ) Rearrangement of Carbonium ion 3 ) Migration of Nucleophiles 4) Deprotonation 16/09/2017 R.D.Amrutkar SPH Pharmacy,Malegaon 22

23. 16/09/2017 23 Wolf Rearrangement

24. 16/09/2017 R.D.Amrutkar SPH Pharmacy,Malegaon 24 Wolff : α - diazoketones upon treatment with silver oxide and water gives carboxylic acid Mechanism

25. Migration to N + 16/09/2017 R.D.Amrutkar SPH Pharmacy,Malegaon 25

26. Curtius : Acyl azide to isocynate to amine Mechanism 16/09/2017 R.D.Amrutkar SPH Pharmacy,Malegaon 26

27. Hoffmann : Amide to amine with one carbon less 16/09/2017 R.D.Amrutkar SPH Pharmacy,Malegaon 27

28. Lossen: Decomposition of Hydroxamic acid to primary amine by using base. 16/09/2017 R.D.Amrutkar SPH Pharmacy,Malegaon 28 Mechanism

29. Beckmann: Oxime to amide Mechanism 16/09/2017 R.D.Amrutkar SPH Pharmacy,Malegaon 29

30. Features : 1) Trans migration, Stereospescific 2) Acyl derivative of oxime 3) Rate of reaction depends upon ionization rate of acyl derivative 4) The migrating “C” retains configuration. 5) Breaking of C-C and Formation of C-N bond occurs synchronously 6) Not intramolecular reaction, Carbonium ion forms and then attack of hydroxyl ion . i.e complete loss of oxime “O” 16/09/2017 R.D.Amrutkar SPH Pharmacy,Malegaon 30

31. SCHMIDT REARRANGEMENT Carboxylic acids react with hydrazoic acid in presence of concentrated sulphuric acid to give amine directly, the reaction is known as Schmidt reaction. RCOOH+N3H H2SO4 R-NH2 +CO2+ N2 Schmidt reaction also occurs between ketones or aldehydes and hydrazoic acid. 16/09/2017 31

32. Mechanism : Mechanism involves following steps : 1.elimination of nitrogen. 2.formation of intermediate. 3.intermediate undergo rearrangement to form isocyanate. 4.hydrolysis of isocyanate to form amine & co 2 Transformation occurs more rapidly with out heating with sterically hindered acids(mesitoic acid) 16/09/2017 32

33. MECHANISM: 16/09/2017 33

34. The reaction with acids i.e.benzoic acid,which require heating for the removal of nitrogen from acid azide proceed as below 16/09/2017 34

35. REACTION WITH KETONES : 16/09/2017 35

36. MECHANISM FOR ALDEHYDES: aldehyde 16/09/2017 36

37. IF ‘H’ MOVES: 16/09/2017 37

38. APPLICATIONS: PREPARATION OF AMINES : Primary amines are obtained in good yield directly from acids. a) b) 16/09/2017 38

39. PREPARATION OF a AMINOACIDS : 16/09/2017 39

40. PREPARATION OF LACTONES: Cyclic ketones react to give lactones 16/09/2017 40

41. 16/09/2017 R.D.Amrutkar SPH Pharmacy,Malegaon 41 Rearrangements to electron deficient oxygen atom Bayer Villager oxidation : Oxidation of ketone to ester in presence of peracid

42. 16/09/2017 R.D.Amrutkar SPH Pharmacy,Malegaon 42 Oxidizing agent : Peroxytrifluroacetic acid , Permonosulphuric acid (Caro’s acid), Perbenzoic acid, Peracetic acid , BF 3 -H 2 O 2 Mechanism Migratory aptitude: Tert-alkyl > Sec-alkyl, aryl, benzyl> pri-alkyl> methyl

43. 16/09/2017 R.D.Amrutkar SPH Pharmacy,Malegaon 43 Condensed cyclic ketone, migration of lesser aptitude group takes place and forms abnormal lactones' Why? Due to steric interaction Bulky per acid molecule attacks carbonyl group from the side apposite to bridge. Migration of bridge ‘C’ forms twisted boat, if 10 ‘C’ forms Chair form

44. 16/09/2017 R.D.Amrutkar SPH Pharmacy,Malegaon 44 Dakin oxidation : The replacement of aldehyde group of o/p- hydroxyl or o-amino Benzaldehyde by hydroxyl group in presence of alkaline hydrogen peroxide Note : This is only for aromatic Aldehyde /Ketone having o/p –OH/NH 2

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46. Reactions & Reagents By O.P.Agarwal Published by Krishna Prakashan Media, Pg.No . 514 to537. Advanced organic chemistry by Jerry march,4 th Edition, Published By John Willey & Sons Pvt.Ltd . Pg. No. 1051 to1157 Reactions and rearrangements by S N Sanyal , 4 th Edition Published By Bharati Bhawan , Pg. No.158 to 172 Adavanced organic chemistry by Bhal and Bhal , Published By Chand & Company Ltd. Pg. No. 98 Reactions and reagents By G.R.Chatwal Published by Himalaya publishing house, Pg. No.702 to717 &731 to 732. REFERENCES 16/09/2017 46

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