Migration to Nitrogen

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Marylou Blair
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1 Migration to itrogen ofmann rearrangement (4) is the most common rearrangement involves migration to an electron-deficient atom. The reaction accomplishes conversion of an amide to an amine possessing one less carbon atom. abr / Br Br propanamide -bromopropanamide ethylamine 2 2 abr / 2 icotinamide 3-Aminopyridine 1 The ofmann rearrangement is accomplished by allowing the amide to react with a basic solution of aqueous bromine Br Anion formation Br - Br Rearrangement Ethyl isocyanate 2 / - hydrolysis Ethylamine decarboxylation 2 1

2 The rearrangement was shown to be intramolecular when the reaction was carried out with a mixture of 3-deuteriobenzamide and 15 -benzamide. 6 4 D * 2 al / D * 2 o 6 4 D* onsistent with this result is the observation that migration proceeds with retention of configuration when chiral gr. rearranges (S)-2-phenylpropanamide abr / (S)-1-phenylethylamine 3 The urtius, Schmidt, and Lossen rearrangements are analogous to the ofmann rearrangement. urtius Rearrangement (5) ( 3 ) 2 2 l 3-methylbutanoyl chloride a 3 1) l ( 3 ) / 3 ( 3 ) ) 2 3-methylbutanoyl azide 2-methylpropylamine 70% p p ethyl p-methoxybenzoate A hydrazide 1) Benzene / 2 p ) p An acyl azide An isocyanate p-methoxyaniline 72% An acyl azide is the rearrangement precursor in the urtius and Schmidt rearrangements. 4 2

3 Schmidt Rearrangement (6) n ) 2 S 4 /benzene 2) 2 n hexanoic acid pentylamine Lossen Rearrangement (7) a / ethyl benzoate A hydroxamic acid aniline A hydroxamic acid leads to product in the Lossen rearrangement. All three methods produce isocyanates which can be isolated or hydrolyzed to amines. 5 Beckmann rearrangement (8) The mechanism of the Beckmann rearrangement follows the same pattern as a pinacol reaction. - Acid converts the oxime into a leaving group. - An alkyl group migrates on to as water departs. - The product cation is then trapped by water to give an amide. 2S4 2 alkyl migration 2 as water leaves 6 3

4 In an acyclic Beckmann rearrangement, the product cation is better represented as nitrilium ion. The mechanism involves the s lone pair to push the migrating group back on. departure of 2 pulls 2 + linear nitrilium ion 2 s lone pair pushes Which group migrates in the Beckmann rearrangement? In unsymmetrical ketones there are two groups that could migrate. There are two possible geometrical isomers of an unsymmetrical oxime. migrating gr. trans to 2 oxime formation Al 2 3 (Beckmann) 75:25 ratio of geometrical isomer 73:27 ratio of products 8 4

5 Suggest the mechanism and all products that can be formed of the following reaction. 2 Al :14 ratio of geometrical isomer 88:12 ratio of products If one of the alkyl chains is branched, more of the oxime with the gr. anti to that chain will be formed and correspondingly more of the branched group will migrate. 9 The Beckmann fragmentation When two compounds with a tertiary center next to oxime are mixed together and treated with acid. The happening is not only an intramolecular reaction, goes via a fragmentation mechanism. rearrange a mixture + cross-over compounds 10 5

6 Migration to xygen The Baeyer-Villiger rearrangement (9), a ketone is converted to an ester by reaction with the peroxy acid. The reaction is an oxidation in which an oxygen atom inserts between the ketone carbonyl and the migrating group. + F Et The common reagents are peroxytrifluoroacetic acid and m-pba (meta-chloroperbenzoic acid). 11 The reaction is believed to be initiated by formation of an adduct between the peroxy acid and the protonated ketone carbonyl gr. F F F Migration to oxygen then takes place as the carboxylate derived from the peroxy acid departs F F

7 Which group is migrates? When there is a competition between two migrating groups, Which group migrates? R F 3 3 R F 3 R F 3 by migration of : by migration of R: R R 13 R = Et i-pr t-bu Yield for migrate (%) Yield for R migrate (%) The order, with t-alkyl the best migrating, then s-alkyl closely followed by, then Et, then, follows the order in which the groups are able to stabilize a positive charge. From the previous example shows the good migrating gr. in order t-bu > s-alkyl > > Et > Primary groups are much more reluctant to undergo migration than secondary ones or aryl grs., and this makes regioselective Baeyer-Villiger reaction possible. 14 7

8 Suggest the mechanism of all products that can be formed of the Beckmann rearrangement and indicate which one is major product. i) 2 ii) Al Molecular rearrangements 1. ationic rearrangement (an e - deficient atom) Wagner-erwein rearrangement Pinacol rearrangement Wolff rearrangement (migration to carbene) ofmann rearrangement (migration to nitrogen) urtius rearrangement Schmidt rearragement Lossen rearrangement Beckmann rearrangement Baeyer-Villiger rearrangement 16 8

9 ationic Rearrangement Migration to an e - deficient center is the most common type of molecular rearrangement. Such rearrangements are usually promoted by acidic reagents or by presence of good leaving groups. Free-Radical and Anionic Rearrangement Rearrangements also follow free-radical pathways and take place through anionic intermediates. Those which occur under basic conditions generally involve negatively charged intermediates. Migrations take place to e - rich centers. 17 Free-Radical Rearrangements The free radicals generated in high-temperature processes. The free radical rearrangements is to generate the requisite precursor through an easily accessible reaction such as decarbonylation of an aldehyde. 6 5 ( 3 ) 2 2 [( 3 ) 3 ] o 6 5 ( 3 ) abstract 6 5 ( 3 ) 2 2 R i) rearrange ii). abstract 6 5 ( 3 ) ( 3 ) 2 tert-butylbenzene (43%) 2-methyl-1-phenylpropane (57%) 18 9

10 Three Steps of Free-Radical Reaction Process Initiation step ( 3 ) 3 ( 3 ) o 2 ( 3 ) ( 3 ) 2 2 Propagation step + ( 3 ) ( 3 ) ( 3 ) ( 3 ) ( 3 ) R Termination step 6 5 ( 3 ) 3 ( 3 ) 2 2 R 6 5 ( 3 ) In fact, methyl and simple alkyl groups do not normally rearrange in this type of free-radical process [( 3 ) 3 ] o 3 2 ( 3 ) 2 o rearranged product 3 2,2-dimethylbutanal 2-methylbutane Aryl is commonly the only group that exhibits a significant migratory aptitude in these neutral free-radical reactions [( 3 ) 3 ] 2 2-(1-phenylcyclopentyl)ethanal benzylcyclopentane 20 10

11 Many free-radical addition and substitution reactions lead to products with rearranged structures. Suggest a mechanism for each the following reactions. l Br 2 l 3 Br 2 l peroxides 2 Br 3 3 t-bul l 3 2 Br 2 2 l 3 + l 3 l 4 / peroxide ( 3 ) 2 l 21 ( 3 ) 3 3 Br Anionic Rearrangements Most anionic reactions begin by removal of a + by a strong base. The rearrangements of such anionic precursors may proceed by ionic or free-radical pathways. Favorskii rearrangement (10): Reaction of α-halo ketones with - or R - produce carboxylic acids or esters. a 2 5 / ( 3 ) l 1) a / 2 2)

12 chanism of the Favorskii rearrangement l + R - R l -l - α-carbanion cyclopropanone R - R - R - or ring opening to give more stable carbanion R R R 23 Reaction of 1, chlorocyclohaxanone l a 2 2 ( 3 ) 2 * 2 2 ( 3 ) 2 * 2 2 ( 3 ) 2 ( 3 ) * * * + * ( 3 ) 2-1 and -2 of cyclopentane were equally labeled with 25% 14. Ester carbonyl gr. contained 50% 14. This result is consistent with a symmetrical cyclic intermediate which can open in either direction with equal probability

13 Benzilic acid rearrangement (11) K Et 6 5 Benzil (Diphenylethanedione) ( 6 5 ) 2 ( 6 5 ) ( 6 5 ) 2 Benzilic acid (2,2-Diphenyl-2-hydroxy ethanoic acid) 1) K / Et 2) 3? ,2 Anionic rearrangements Involving movement of the migrating group to an adjacent anionic (electron rich) atom Stevens Rearrangement (12) of quarternary ammonium or sulfonium salts ( 3 ) 3 I -,,-Trimethylbenzylammonium iodine S 3 Br Benzylmethylphenacylsulfonium bromide 3 Li / Et 2 a / TF ( 3 ) 2 α-,-trimethylbenzylamine 6 5 S ,3-Diphenyl-2-methylthio-1-propanone 26 13

14 Wittig Rearrangement (13) of ethers Benzyl methyl ether 1) 6 5 Li / Et 2 / 2) enylethanol isenheimer Rearrangement (14) of amine oxides ( 3 ) ( 3 ) 2,-Dimethylbenzylamine oxide - Benzoxydimethylamine 27 The mechanism of these rearrangements is currently attracting considerable interest. A pathway involving heterolytic bond cleavage had been accepted for many years ( 3 ) 3 I - 3 Li / Et ( 3 ) 2 A nitrogen ylid ( 3 )

15 More recent evidence suggests a homolytic process involving free-radical intermediates. ( 3 ) ( 3 ) 2 Br - a / ( 3 ) ( 3 ) A nitrogen ylid ( 3 )

Mass Spec - Fragmentation

Mass Spec - Fragmentation An extremely useful result of EI ionization in particular is a phenomenon known as fragmentation. The radical cation that is produced when an electron is knocked out of a neutral