Molecular Rearrangements of Organic Reactions pps

1. MOLECULAR REARRANGEMENTS Dr. OM PRAKASH, M.P. GOVT. P. G. COLLEGE HARDOI, U. P.

2. Rearrangements •In a rearrangement reaction an atom or group moves from one atom to another in the same molecule i.e. connectivity of atoms changed within the molecule. • Most of the migrations are from an atom to an adjacent one (called 1,2-shifts), but some are over longer distances. The migrating group (W) may migrate with electron pair(nucleophilic rearrangement) or without electron pair(electrophilic rearrangement) or with one electron(free radical rearrangement) as the case may be. Dr. OM PRAKASH, M.P. GOVT. P. G. COLLEGE HARDOI, U. P.

3. NOTE- • The nucleophilic 1,2-shifts are much more common than electrophilic or free-radical 1,2-shifts. • The reason for this can be understood by a consideration of the transition states (or in some cases intermediates) involved. Scheme 2 Scheme 2 represents the transition state or intermediate for all three cases(nucleophilic, electrophilic and free radical rearrangements). Dr. OM PRAKASH, M.P. GOVT. P. G. COLLEGE HARDOI, U. P.

4. Rearrangement to Electron Deficient Carbon Carbon Migration(nucleophilic rearrangement)• Wagner-Meer-wein Rearrangement • In this rearrangement less stable carbocation is converted into more stable through the migration of Aryl, alkyl or hydrogen which leads the formation of most stable carbocation. • It is one of the simplest systems where an alkyl group migrates, with its bonding pair, to an electron-deficient carbon atom. The driving force for the rearrangement resides in the greater stability of a tertiary carbo-cation compared to that of primary carbo-cation Dr. OM PRAKASH, M.P. GOVT. P. G. COLLEGE HARDOI, U. P.

5. isoborneol camphene Meerwein rearrangement of norbornyl systems: Dr. OM PRAKASH, M.P. GOVT. P. G. COLLEGE HARDOI, U. P.

6. Features of this migration • The carbocation may be produced by a variety of ways. •Hydrogen can also migrate in this system. Dr. OM PRAKASH, M.P. GOVT. P. G. COLLEGE HARDOI, U. P. • Less stable cyclic carbocations also converted into more stable through exansion or contraction of ring.

7. Degenerate carbo-cations & rearrangements Carbocations that rearrange to give products of identical structure (e.g., 6=6’, 7= 7’) are called degenerate carbocations and such rearrangements are degenerate rearrangements. Dr. OM PRAKASH, M.P. GOVT. P. G. COLLEGE HARDOI, U. P.

8. •Aryl groups have a greater migratory aptitude than alkyl group or hydrogen due to the formation of lower-energy bridged phenonium ion

9. • Rearrangements in bicyclic systems are common. •The rearrangement is stereo-sepecific and intra- molecular. •Two or more rearrangements may take place simultaneously. Dr. OM PRAKASH, M.P. GOVT. P. G. COLLEGE HARDOI, U. P.

10. Dr. OM PRAKASH, M.P. GOVT. P. G. COLLEGE HARDOI, U. P.

11. Pinacol Rearrangement •Treatment of 1,2-diols (pinacol) with acid lead to rearrangement to give ketone. • This rearrangement fundamentally is similar to the above described Wagner-Meerwein rearrangement . •The characteristics of the Wagner-Meerwein apply to the pinacol rearrangement. Dr. OM PRAKASH, M.P. GOVT. P. G. COLLEGE HARDOI, U. P.

12. Mechanism Dr. OM PRAKASH, M.P. GOVT. P. G. COLLEGE HARDOI, U. P.

13. Migratory aptitudes of different groups The following are a few of the relative migratory aptitudes determined for aryl groups by Bachmann and Ferguson: p-anisyl, 500; p-tolyl, 15.7; m-tolyl, 1.95; phenyl, 1.00; p- chlorophenyl, 0.7; o-anisyl, 0.3. For the o-anisyl group, the poor migrating ability probably has a steric cause, while for the others there is a fair correlation with activation or deactivation of electrophilic aromatic substitution, which is what the process is with respect to the benzene ring. If other things are same normal migratory aptitude follow the order Ph> Me3C > Me2CH > CH3 Dr. OM PRAKASH, M.P. GOVT. P. G. COLLEGE HARDOI, U. P.

14. Examples Dr. OM PRAKASH, M.P. GOVT. P. G. COLLEGE HARDOI, U. P.

15. Benzilic Acid Rearrangement •1,2-Diketones that have no α-hydrogen react with hydroxide ion to give α –hydroxy-acid. • The best known example is the rearrangement of benzil to benzilic acid( benzil is PhCOCOPh; benzilic acid is Ph2COHCOOH). Dr. OM PRAKASH, M.P. GOVT. P. G. COLLEGE HARDOI, U. P.

18. Arndt-Eistert Homologation Reaction The reaction of acid chloride with diazomethane gives a diazoketone which is in the presence of silver oxide under heating proceeds the Wolff rearrangement to yield a ketene that is directly converted into an acid in the presence of water. Dr. OM PRAKASH, M.P. GOVT. P. G. COLLEGE HARDOI, U. P.

21. Halogen, Oxygen, Sulfur, and Nitrogen Migration Dr. OM PRAKASH, M.P. GOVT. P. G. COLLEGE HARDOI, U. P.

22. •In the system X-C-C-Y, an atom X with an unshared pair of electrons (X= O, N, S, Cl) can assist the heterolysis of the C-Y bond. In case of unsymmetrical system, nucleophilic attack predominates at the less substituted carbon of the bridged ion that leads to rearranged skeleton. no Dr. OM PRAKASH, M.P. GOVT. P. G. COLLEGE HARDOI, U. P.

24. Rupe Rearrangement α-acetylenic alcohols converted into α,β- unsaturated ketones. Dr. OM PRAKASH, M.P. GOVT. P. G. COLLEGE HARDOI, U. P.

28. In case of a neighbouring acetoxy group, the solvolysis is assisted via a five-membered acetoxonium ion. Dr. OM PRAKASH, M.P. GOVT. P. G. COLLEGE HARDOI, U. P.

29. REARRANGEMENT TO ELECTRON DEFICIENT NITROGEN Dr. OM PRAKASH, M.P. GOVT. P. G. COLLEGE HARDOI, U. P.

30. Hofmann Rearrangement •In the Hofmann rearrangement, an un-substituted amide is treated with sodium hypobromite (or sodium hydroxide and bromine, which is essentially the same thing) to give a primary amine that has one carbon fewer than the starting amide. • The actual product is the isocyanate, but this compound is seldom isolated since it is usually hydrolyzed under the reaction conditions. • The R group may be alkyl or aryl, but if it is an alkyl group of more than about six or seven carbons, low yields are obtained unless Br2 and NaOMe are used instead of Br2 and NaOH. Dr. OM PRAKASH, M.P. GOVT. P. G. COLLEGE HARDOI, U. P.

31. Features of this reaction • The intermediate N-halo amides have been isolated in the first step. • In the second step, N-halo amides lose a proton to the base as it is acidic. • The third step is actually two steps: (1)loss of bromide to form a nitrene. (2) followed by the actual migration, but most of the available evidence favors the concerted reaction. • The reaction is intra-molecular and stereo-specific. Dr. OM PRAKASH, M.P. GOVT. P. G. COLLEGE HARDOI, U. P.

32. Mechanism The workup can also be with alcohol or amine to give urethane or urea, respectively Dr. OM PRAKASH, M.P. GOVT. P. G. COLLEGE HARDOI, U. P.

34. Curtius Rearrangement This rearrangement describes the transformation of acyl azide into isocyanate by decomposition on heating and its application for the synthesis of primary amines, urethanes and ureas as presented in Hofmann rearrangement . Dr. OM PRAKASH, M.P. GOVT. P. G. COLLEGE HARDOI, U. P.

36. Schmidt Rearrangement Carboxylic acid reacts with hydrazoic acid in the presence of conc. H2SO4 to give acid azide which is present in the form of conjugate acid eliminates nitrogen to afford isocyanate that could be converted into amine as reported in Hofmann rearrangement The reaction is also effective with aldehydes, ketones, tertiary alcohols and substituted alkenes. Dr. OM PRAKASH, M.P. GOVT. P. G. COLLEGE HARDOI, U. P.

39. Lossen Rearrangement Ester of hydroxamic acid reacts with base to give isocyanate that could be converted into amine as shown in Hofmann rearrangement. Dr. OM PRAKASH, M.P. GOVT. P. G. COLLEGE HARDOI, U. P.

41. Beckmann Rearrangement •Oximes rearranges in acidic conditions to give amides. •The reaction is intramolecular and stereospecific: the substituent trans to the leaving groups migrates. Dr. OM PRAKASH, M.P. GOVT. P. G. COLLEGE HARDOI, U. P.

42. An interesting application of this method is the synthesis caprolactam from cyclo-hexanone oxime. Caprolactam is the substrate precursor for nylon-6 preparation. Dr. OM PRAKASH, M.P. GOVT. P. G. COLLEGE HARDOI, U. P.

45. Neber Rearrangement • a-Amino ketones can be prepared by treatment of keto-xime tosylates with a base, such as ethoxide ion or pyridine. • This reaction is called the Neber rearrangement. • The R group is usually aryl, though the reaction has been carried out with R= alkyl or hydrogen. The R’ group may be alkyl, or aryl but not hydrogen. Dr. OM PRAKASH, M.P. GOVT. P. G. COLLEGE HARDOI, U. P.

46. Mechanism The mechanism of the Neber rearrangement is via an azirine intermediate 79. •The best evidence for this mechanism is that the azirine intermediate has been isolated. •Both a syn and an anti ketoxime give the same product. •The mechanism as shown above consists of three steps. However, it is possible that the first two steps are concerted, and it is also possible that what is shown as the second step is actually two steps: loss of OTs to give a nitrene, and formation of the azirineDr. OM PRAKASH, M.P. GOVT. P. G. COLLEGE HARDOI, U. P.

47. REARRANGEMENT TO ELECTRON DEFICIENT OXYGEN Dr. OM PRAKASH, M.P. GOVT. P. G. COLLEGE HARDOI, U. P.

48. Baeyer Villiger Reaction •Treatment of ketones with peroxyacid gives ester. •The reaction is effective with acid or base and the mechanism is closely related to pinacol rearrangement. •Nucleophilic attack by the peroxyacid on the carbonyl group gives an intermediate that rearranges with the expulsion of the anion of the acid. Dr. OM PRAKASH, M.P. GOVT. P. G. COLLEGE HARDOI, U. P.

49. Mechanisms Dr. OM PRAKASH, M.P. GOVT. P. G. COLLEGE HARDOI, U. P.

50. Mechanisms • Migratory Aptitude: 3◦ > 2◦ > PhCH2 > Ph > 1◦ > Me > H. • Electron withdrawing groups in peracids and electron releasing groups in migrating group increases the rate of reaction. Dr. OM PRAKASH, M.P. GOVT. P. G. COLLEGE HARDOI, U. P.

52. Hydro-peroxide Rearrangement •Tertiary hydroperoxide with acid undergoes rearrangement to give ketone and alcohol or phenol. • The mechanism is similar to that of Baeyer-Villiger reaction. •For example, cumene forms hydroperoxide by autoxidation which rearranges in the presence of an acid to give phenol and acetone. Dr. OM PRAKASH, M.P. GOVT. P. G. COLLEGE HARDOI, U. P.

53. Dienone–Phenol Rearrangement •Cyclohexadienone derivatives that have two alkyl groups in the 4 position undergo, on acid treatment,1,2 migration of one of these groups from 64 to give the phenol. •Note that a photochemical version of this reaction has been observed Dr. OM PRAKASH, M.P. GOVT. P. G. COLLEGE HARDOI, U. P.

54. Mechanism The driving force in the overall reaction (the dienone– phenol rearrangement) is of course creation of an aromatic system. Dr. OM PRAKASH, M.P. GOVT. P. G. COLLEGE HARDOI, U. P.

55. Dakin Reaction Benzaldehyde or acetophenone bearing hydroxyl substituent in the ortho or para position proceed rearrangement to give catechol or quinol, respectively. The reaction is performed in the presence of alkaline hydrogen peroxide and the mechanism is similar to that of Baeyer-Villiger reaction. Dr. OM PRAKASH, M.P. GOVT. P. G. COLLEGE HARDOI, U. P.

58. REARRANGEMENT TO ELECTRON-RICH CARBON Electro-philic rearrangement Dr. OM PRAKASH, M.P. GOVT. P. G. COLLEGE HARDOI, U. P.

59. General This group of reaction has been less explored, and is less of synthetic importance compared to the rearrangements to electron deficient carbons. The rearrangements to electron deficient hetero atom may be generally explained as follows. Dr. OM PRAKASH, M.P. GOVT. P. G. COLLEGE HARDOI, U. P.

60. Stevens Rearrangement Quaternary ammonium salt which has β-hydrogen proceeds E2 (Hofmann) elimination with base. Dr. OM PRAKASH, M.P. GOVT. P. G. COLLEGE HARDOI, U. P.

61. Mechanism In case of quaternary ammonium salts containing β-ketone or ester or aryl group, an α- hydrogen is removed by base to give an ylide and then the rearrangement occurs. Dr. OM PRAKASH, M.P. GOVT. P. G. COLLEGE HARDOI, U. P.

63. Sommelet-Hauser Rearrangement •In the absence of β-carbonyl group, the α-hydrogen is too weakly acidic for hydroxide ion induced rearrangement. • Thus, a strong base, such as amide ion in liquid ammonia, is to be used, when the rearrangement takes a different course: instead of [1,2] shift (Steven’s rearrangement), a [3,2]-sigmatropic rearrangement takes place which is called Sommelet- Hauser rearrangement. Dr. OM PRAKASH, M.P. GOVT. P. G. COLLEGE HARDOI, U. P.

64. Mechanism There can be competition between Stevens and Sommelet-Hauser rearrangement mechanisms. Dr. OM PRAKASH, M.P. GOVT. P. G. COLLEGE HARDOI, U. P.

66. Wittig Rearrangement Ethers undergo [1,2]-sigmatropic rearrangement in the presence of strong base such as amide ion or phenyllithium to give more stable oxyanion. The mechanism is analogous to that of Stevens rearrangement Dr. OM PRAKASH, M.P. GOVT. P. G. COLLEGE HARDOI, U. P.

69. Favorskii Rearrangement α-Haloketones with base afford enolates which rearrange to give esters via cyclo-propa-nones. Dr. OM PRAKASH, M.P. GOVT. P. G. COLLEGE HARDOI, U. P.

70. Mechanism The direction of ring opening of cyclo-propa- none is determined by the more stable carbanion, formed in the reaction. Dr. OM PRAKASH, M.P. GOVT. P. G. COLLEGE HARDOI, U. P.

73. AROMATIC REARRANGEMENTS Dr. OM PRAKASH, M.P. GOVT. P. G. COLLEGE HARDOI, U. P.

74. General A number of rearrangements occur in aromatic compounds of the type X is usually nitrogen or oxygen. Both intermolecular and intra-molecular migrations are known. Dr. OM PRAKASH, M.P. GOVT. P. G. COLLEGE HARDOI, U. P.

75. Fries Rearrangement •Aryl esters with Lewis acid undergo rearrangement to give phenols having keto substituent at ortho and para positions. • The complex between the ester and Lewis acid gives an acylium ion which reacts at the ortho and para positions as in Friedel-Crafts acylation. Dr. OM PRAKASH, M.P. GOVT. P. G. COLLEGE HARDOI, U. P.

76. Mechanism In general, low temperature favors the formation of para-product (kinetic control) and high temperature lead to the formation ortho-product (thermodynamic control ) Dr. OM PRAKASH, M.P. GOVT. P. G. COLLEGE HARDOI, U. P.

77. Claisen Rearrangement Aryl allyl ethers undergo [3,3]-sigma-tropic rearrangement on being heating to allyl-phenols Dr. OM PRAKASH, M.P. GOVT. P. G. COLLEGE HARDOI, U. P.

78. Mechanism If the ortho position is blocked, rearrangement continues to give para-product. Dr. OM PRAKASH, M.P. GOVT. P. G. COLLEGE HARDOI, U. P.

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