Molecular Rearrangements

Transcription

1 Ø Migration of one the molecule group from one atom to another within Ø Generally the migrating group never leaves the molecule Ø There are five types of skeletal rearrangements- 1. Electron deficient skeletal rearrangement 2. Electron rich skeletal rearrangement 3. adical rearrangement 4. earrangements on an aromatic ring 5. Sigmatropic rearrangement ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 1

2 Electron Deficient Skeletal earrangement Ø Generally it involves migration of a group from one atom to an adjacent atom, having six electrons in the valence shell Ø The molecular system may be either a cation or a neutral molecule Examples: N N N ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 2

3 Wagner- erwin earrangement Ø earrangement of alcohols under acidic condition Ø Alkyl migration occurs to give stable carbocation Ø This is the driving force for the migration of alkyl, aryl or even hydrogen atom ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 3

4 Wagner- erwin earrangement + Isoborneol amphene ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 4

5 ing Expansion Ø More stable carbocation will be generated Ø Stability of carbocations- 3 > 2 > 1 an we go from 3 to 2?? Ø ations can be made more stable if they become less strained + l l elief in strain from four to five membered ring is driving force ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 5

6 ing Expansion Li 40% 2 S Tertiary carbocation migrated to secondary ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 6

7 Pinacol-Pinacolone earrangement Pinacol 2 S 4 Pinacolone 2 Ø eason: Ø arbocation is already tertiary Ø There is no ring strain Ø Then why should it rearrange? The lone pair of electrons on the oxygen is another source to stabilize the carbocation ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 7

8 Pinacol-Pinacolone earrangement Ø Pinacol-Pinacolone rearrangement can be viewed as a push and a pull rearrangement Ø The carbocation formed as a result of loss of 2, pulls the migrating group Ø Lone pair on oxygen pushes the migrating group Preparation of Spiro System: ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 8

9 Pinacol-Pinacolone earrangement NaB 4 Epoxides : Epoxides also undergo pinacol type rearrangement on treatment with acid MgBr 2 MgBr 1) MgBr 2) Ø With a Grignard reagent, rearrangement occurs faster than addition to the epoxide ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 9

10 Pinacol-Pinacolone earrangement Ø Migrating group preference: It doesn t matter when we have symmetrical diols & epoxides It doesn t matter when we have unsymmetrical epoxides & diols 2 I 2 nly I is formed in quantitative amount because the carbocation is stabilized by two phenyl groups ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan II 10

11 Semipinacol earrangement They are nothing but pinacol rearrangement without choice s 4 Isonopinone Under normal acidic conditions ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 11

12 Semipinacol earrangement For the required product, the primary hydroxyl group needs to be made as better leaving group Tsl Py Ts a 3 Weak base Ts orey exploited a similar sequence in the synthesis of longifolene ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 12

13 Semipinacol earrangement Tsl Py Ts a 3 3 Longifolene Leaving group need not be tosylated and it can be anything which can readily leave I AgN ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 13

14 Semipinacol earrangement ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 14

15 Diazonium salts Tiffeneau-Demjanov earrangement: N 2 _ NaN 2 /l N 2 Selectivity : N 2 _ N 2 N 2 NaN 2 /l NaN 2 /l N 2 NaN 2 /l NaN 2 /l N ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 15

16 chanism : N 2 Molecular earrangements Diazonium salts N 2 Alkyl group which is anti to the leaving group, will migrate N 2 N ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 16

17 Fragmentation: Molecular earrangements Acl N N N N Ac N Stable carbocation Ø Fragmentations always require electron push and electron pull ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 17

18 An Important thod to Make igher ycloalkanes: ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 18

19 Base onditions or Nucleophilic onditions: Ms Ms 2 N Ts N Antiperiplanar bond migrates 3 Ts Base Ts 10-membered ring ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 19

20 Eschenmoser Fragmentation N NTs N N Ts Na/ 2 2 TsNN 2 PTSA Base Ts N N Ts N 2 # 3 1) NaB 4 3 / 2 S 2) PTSA N NTs Base 1) Na/ 2 2 2) TsNN 2 /PTSA ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan Base 20

21 Fragmentation of Four-mbered ing BF 3. Et 2 Ac Ac ther Examples: Ms Base Base Aldol condensation ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 21

22 ope earrangement : Sigmatropic earrangements [3,3]-Sigmatropic earrangement It is a [3,3]- sigmatropic rearrangement with only carbon atoms involved in the six membered transition state Why is it called [3,3]? The new σ bond formed has 3,3- relationship with the old σ-bond Ο ω α δ β γ ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 22

23 chanism : Molecular earrangements Sigmatropic earrangements It goes via six-membered chair-like transition state trans trans cis cis More stable conformer 3 Less stable conformer E,E-isomer E,Z Z,E Favoured Z,Z-isomer ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 23

24 Sigmatropic earrangements 1) ope: 2) xy-ope: ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 24

25 Sigmatropic earrangements 3) Anionic-xy-ope: 3 3 MM Li MM TBDMS 4) laisen earrangement of Allylvinyl Ethers: TBDMS 3 δ γ α β γ-δ-unsaturated aldehyde ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 25

26 Sigmatropic earrangements 5) laisen earrangement of Allylphenyl Ethers: 6) rtho-ester laisen earrangement: _ g(ac) 2 Et Et Et ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 26

27 Sigmatropic earrangements 7) -Allyl--TMS-Ketone Acetals: TMS TMS 8) Ester-Enolate laisen: 9) Ketene Aminals: N 2 N ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 27

28 Sigmatropic earrangements 10) Aza-laisen earrangement: N N ther Examples: 2 Et K= o 2 Et ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 28

29 Stereochemistry: Molecular earrangements Sigmatropic earrangements TMS Z-silyl ether TMS trans TMS E-silyl ether cis TMS ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 29

30 Sigmatropic earrangements [2,3]-Sigmatropic earrangement X Y harged Y X Neutral 1) Allylic Sulfoxides: S S 2) Allylic Sulfonium Ylides: S S ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 30

31 Sigmatropic earrangements 3) N-xides: N N Sommelet-auser earrangement 3 N N N 3 N 2 NaN 2 3 N ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 31

32 Sigmatropic earrangements Stevens earrangement N Na N Wittig earrangement 3 Li Li ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 32

33 Sigmatropic earrangements Ene eaction EWG EWG ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 33

34 heletropic Elimination Two bonds are broken at a single atom S 2 S 2 S 2 S ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 34

35 Elimination of arbon monoxide () Et ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 35

36 Elimination of arbon monoxide () Δ 2 2 [4+2]- ycloaddition - Aromatization ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 36

37 Dienone-enol earrangement 2 S 4 Ø an be considered as a reversal of pinacol rearrangement Ø Pinacol & semipinacol rearrangements are driven by the formation of a carbonyl group Ø In dienone-phenol rearrangement protonation of carbonyl group earranges to a tertiary carbocation Ø The driving force for this reaction is the formation of aromatic rings ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 37

38 chanism: Molecular earrangements Dienone-enol earrangement ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 38

39 Beckmann earrangement The industrial formation of nylon relies upon the alkaline polymerization of a acyclic amide known as caprolactam N n base N acid N oxime aprolactam can be produced by the action of sulfuric acid on the oxime of cyclohexanone in a rearrangement known as the Beckmann rearrangement ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 39

40 chanism: Molecular earrangements Beckmann earrangement N N 2 2 N N Ø Follows the same pattern as pinacol Ø onverts the oxime into a good leaving group Ø Alkyl/ Aryl group migrates on to nitrogen as water departs Ø The product cation is then trapped by water to give an amide ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 40

41 Beckmann earrangement Ø It can also works with acyclic oximes Ø Pl 5, Sl 2 & other acyl or sulfonyl chlorides can be used instead of acid N N 2 N Nitrilium ion Migratory Aptitude: N 2 N Al 2 3 N major N N minor ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 41

42 Beckmann earrangement In case of unsymmetrical ketone: Ø There are two groups that could migrate Ø There are two possible geometrical isomers of unsymmetrical oxime Ø When the mixtures of geometrical isomer of oximes are rearranged, mixtures of products result Ø Interestingly, the ratio of products mirrors exactly the ratio of geometrical isomers in the starting materials Ø The group that has migrated, is trans to the - group ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 42

43 Beckmann earrangement N 2 N N Al 2 3 N N 86 : 14 Steric effect 88 : ) N 2 2) ptsl N ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 43

44 chanism: '' ' Baeyer Villiger xidation Migratory Aptitude: N 2 Molecular earrangements 2 ' '' t-bu > i-pr = > Et > All 3 Acl 3 2 ' N Na L-dopa N N ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 44

45 Baeyer Villiger xidation B.V.. of Unsaturated Ketones: There are three possibilities 1) Peracids can selectively epoxidize 2) Peracids can selectively carry out B.V. 3) an carry out both reactions It is difficult to predict the outcome & it depends on- 1) Electrophilic nature of the ketone 2) Nucleophilic nature of the alkene ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 45

46 Baeyer Villiger xidation ' ' Bn mpba Bn Ø Tertiary group migrates in preference of the secondary group Ø The alkene is not as reactive as expected because of steric crowding ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 46

47 Baeyer Villiger xidation Small ring ketones will readily undergo B.V.. 2 2, Starting material configuration is retained in the product Ar 3 Ar ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 47

48 Electron-ich (Anionic) Skeletal earrangements Ø The transition state has two more electrons Ø Generally initiated by basic reagents which remove a group or an atom such as hydrogen Ø The residual anion then stabilizes itself by rearrangement Ø In the first step an acid strengthening substituent is necessary to stabilize the ionic center ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 48

49 Electron-ich (Anionic) Skeletal earrangements Stevens earrangement 3 3 N N N Proton removal is facilitated by the positive charge in the cationic substrate and also by the enolate ion formation Migrating groups are generally benzyl or allyl system 3 S S S ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 49

50 Electron-ich (Anionic) Skeletal earrangements Wittig earrangement Ø It also follows a similar pathway Ø nly difference is substrates are much less acidic than those encountered in Stevens rearrangement Ø Powerful basic reagents are required to cause the Wittig earrangement 3 2 Li ) Li 2) ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 50

51 Electron-ich (Anionic) Skeletal earrangements Sommelet-auser earrangement Nucleophilic alkylation of the aromatic rings of a benzyltrimethylammonium ion 3 N N N 3 N 2 NaN 2 3 N ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 51

52 earrangements Benzilic acid earrangement chanism: Ar Ar 6 5 K 6 5 Et, Ar Ar Ar Ar Ar Ar Formation of stable carboxylate salt is driving force for the reaction K 2 Et Application has been limited only to aromatic α-diketones ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 52

53 earrangements earrangements on an Aromatic ing 1. Fries earrangement 2. laisen earrangement 3. earrangements of Derivative of aniline earrangements of Derivatives of Aniline: N 3 l 2 l N 3 l N 3 l N 3 l l N 3 N 3 N 3 N 3 l l Friedel rafts like l ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan l 53

54 earrangements earrangements on an Aromatic ing earrangements of Derivatives of Aniline: N N N N 2 p-amino diazobenzene Diazoamino benzene It is still not clear whether it involves inter or intramolecular mechanism N N earrangement of N-thyl-N-Nitrosoamine: N N N N N N N N ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 54

55 earrangements earrangements on an Aromatic ing earrangement of N-enylhydroxylamine: N N 2 N 2 chanism N 2 N N N N N ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 55

56 earrangements earrangements on Aromatic ing earrangement of N,N-Dimethylanilinium chloride: N 3 3 N Δ 3 N 3 N 3 3 l 3 3 N N N l ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 56

57 earrangements earrangements on Aromatic ing N N 2 N 2 N hydrolysis ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 57

58 earrangements earrangements on an Aromatic ing earrangement of enylnitramine: NN 2 2 N N 2 N 2 N 2 N 2 N 2 N 2 N 2 earrangement of enylsulfamic acid: NS 3 2 N S 3 N 2 S 3 N 2 S 3 These reactions involve intramolecular pathway ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 58

59 Benzidine earrangement: earrangements earrangements on an Aromatic ing N 2 N N N N 2 2 N N 2 N ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 59

60 earrangements Some Additional Problems l l l + 2a 3 NaN l l l N l l N hydrolysis of acid derivative l l 3 l l dichloro acetic acid (l 2 ) 2 a al ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 60

61 earrangements Some Additional Problems 3 methanolic N 3 sealed tube heating N 3 2 N 3 3 N 3 ring opening vinylogous substitution 3 N 2 N ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 61

62 earrangements Some Additional Problems ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 62

63 earrangements Some Additional Problems retro Pinacol Pinacolone earrangement Pinacol Pinacolone earrangement mpba ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan

64 earrangements Some Additional Problems Acid cat. aldol condensation ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 64