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 - 423 ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 1
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 - 423 ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 2
Wagner- erwin earrangement Ø earrangement of alcohols under acidic condition + + 2 Ø Alkyl migration occurs to give stable carbocation Ø This is the driving force for the migration of alkyl, aryl or even hydrogen atom - 423 ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 3
Wagner- erwin earrangement + Isoborneol amphene + - 423 ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 4
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 - 423 ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 5
ing Expansion Li 40% 2 S 4 2 2 Tertiary carbocation migrated to secondary - 423 ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 6
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 - 423 ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 7
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: 2-423 ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 8
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 - 423 ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 9
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 - 423 ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan II 10
Semipinacol earrangement They are nothing but pinacol rearrangement without choice s 4 Isonopinone Under normal acidic conditions 2-423 ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 11
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 3-423 ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 12
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 3-423 ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 13
Semipinacol earrangement + 2 + 2-423 ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 14
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 2-423 ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 15
chanism : N 2 Molecular earrangements Diazonium salts N 2 Alkyl group which is anti to the leaving group, will migrate N 2 N 2-423 ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 16
Fragmentation: Molecular earrangements Acl N N N N Ac N Stable carbocation Ø Fragmentations always require electron push and electron pull 2-423 ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 17
An Important thod to Make igher ycloalkanes: - 423 ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 18
Base onditions or Nucleophilic onditions: Ms Ms 2 N Ts N Antiperiplanar bond migrates 3 Ts Base Ts 10-membered ring - 423 ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 19
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 - 423 ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan Base 20
Fragmentation of Four-mbered ing BF 3. Et 2 Ac Ac ther Examples: Ms Base Base Aldol condensation - 423 ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 21
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]? 1 1 2 2 3 3 The new σ bond formed has 3,3- relationship with the old σ-bond Ο ω α δ β γ - 423 ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 22
chanism : Molecular earrangements Sigmatropic earrangements It goes via six-membered chair-like transition state trans trans cis cis 3 3 3 More stable conformer 3 Less stable conformer E,E-isomer E,Z Z,E Favoured Z,Z-isomer - 423 ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 23
Sigmatropic earrangements 1) ope: 2) xy-ope: - 423 ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 24
Sigmatropic earrangements 3) Anionic-xy-ope: 3 3 MM Li MM 3 3 3 3 TBDMS 4) laisen earrangement of Allylvinyl Ethers: TBDMS 3 δ γ α β γ-δ-unsaturated aldehyde - 423 ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 25
Sigmatropic earrangements 5) laisen earrangement of Allylphenyl Ethers: 6) rtho-ester laisen earrangement: _ g(ac) 2 Et Et Et - 423 ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 26
Sigmatropic earrangements 7) -Allyl--TMS-Ketone Acetals: TMS TMS 8) Ester-Enolate laisen: 9) Ketene Aminals: N 2 N 2-423 ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 27
Sigmatropic earrangements 10) Aza-laisen earrangement: N N ther Examples: 2 Et K=0.25 275 o 2 Et 3 3 2 5 3 2 5 3 3 3-423 ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 28
Stereochemistry: Molecular earrangements Sigmatropic earrangements TMS Z-silyl ether TMS trans TMS E-silyl ether cis TMS - 423 ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 29
Sigmatropic earrangements [2,3]-Sigmatropic earrangement X Y harged Y X Neutral 1) Allylic Sulfoxides: S S 2) Allylic Sulfonium Ylides: S S - 423 ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 30
Sigmatropic earrangements 3) N-xides: N N Sommelet-auser earrangement 3 N 3 3 3 N 3 3 3 3 3 N 3 N 2 NaN 2 3 N 3-423 ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 31
Sigmatropic earrangements Stevens earrangement N Na N 6 5 2 Wittig earrangement 3 Li Li - 423 ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 32
Sigmatropic earrangements Ene eaction EWG EWG 2 2-423 ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 33
heletropic Elimination Two bonds are broken at a single atom S 2 S 2 S 2 S 2-423 ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 34
Elimination of arbon monoxide () Et - 423 ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 35
Elimination of arbon monoxide () Δ 2 2 [4+2]- ycloaddition - Aromatization - 2 2 2-423 ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 36
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 - 423 ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 37
chanism: Molecular earrangements Dienone-enol earrangement - 423 ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 38
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 - 423 ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 39
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 - 423 ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 40
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 - 423 ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 41
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 - 423 ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 42
Beckmann earrangement N 2 N N Al 2 3 N N 86 : 14 Steric effect 88 : 12 3 1) N 2 2) ptsl N - 423 ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 43
chanism: '' ' Baeyer Villiger xidation Migratory Aptitude: N 2 Molecular earrangements 2 ' '' t-bu > i-pr = > Et > All 3 Acl 3 2 ' N 2 2 2 Na L-dopa N 2 2 3 N 2 2-423 ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 44
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 - 423 ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 45
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 - 423 ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 46
Baeyer Villiger xidation Small ring ketones will readily undergo B.V.. 2 2, Starting material configuration is retained in the product Ar 3 Ar - 423 ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 47
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 - 423 ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 48
Electron-ich (Anionic) Skeletal earrangements Stevens earrangement 3 3 N 6 5 2 2 3 N 3 6 5 2 6 5 6 5 3 3 N 6 5 2 6 5 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 2 2 6 5 6 5 3 S 2 6 5 6 5 3 S 6 5 2 6 5-423 ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 49
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 6 6 5 5 6 5 3 3 6 5 3 2 2 2 2 1) Li 2) 3 2 2 2-423 ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 50
Electron-ich (Anionic) Skeletal earrangements Sommelet-auser earrangement Nucleophilic alkylation of the aromatic rings of a benzyltrimethylammonium ion 3 N 3 3 3 N 3 3 3 3 3 N 3 N 2 NaN 2 3 N 3-423 ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 51
earrangements Benzilic acid earrangement chanism: Ar Ar 6 5 K 6 5 Et, 6 5 6 5 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 - 423 ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 52
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 - 423 ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan l 53
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 - 423 ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 54
earrangements earrangements on an Aromatic ing earrangement of N-enylhydroxylamine: N N 2 N 2 chanism N 2 N N N N N 2 + - 423 ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 55
earrangements earrangements on Aromatic ing earrangement of N,N-Dimethylanilinium chloride: N 3 3 N 3 275 0 Δ 3 N 3 N 3 3 l 3 3 N N N 2 3 3 l 3 3 3-423 ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 56
earrangements earrangements on Aromatic ing N N 2 N 2 N 3 3 3 3 3 hydrolysis 3 3 3 3 - + 3-423 ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 57
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 - 423 ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 58
Benzidine earrangement: earrangements earrangements on an Aromatic ing N 2 N N N N 2 2 N N 2 N 2-423 ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 59
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 + 2 2 + al 2 + 2-423 ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 60
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 3-423 ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 61
earrangements Some Additional Problems 3 3 3 3 3 3 3 3 3-423 ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 62
earrangements Some Additional Problems retro Pinacol Pinacolone earrangement Pinacol Pinacolone earrangement mpba 3 3-423 ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 3 3 3 3 63
earrangements Some Additional Problems 3 3 3 3 Acid cat. aldol condensation 3 2 3 2 3 3 3 3-423 ourse on rganic Synthesis; ourse Instructor: Krishna P. Kaliappan 64