Dr. Nabamita Basu Dept. of Chemistry, Nabagram Hiralal Paul College Rearrangement to electron-deficient nitrogen: Hofmann Rearrangement The conversion of a carboxamide to a primary amine with a C atom less by the action of alkali and halogen (chlorine or bromine) or hypohalites (NaOCl or NaOBr) is known as the Hoffmann degradation of amide. This involves a rearrangement reaction of an N-haloamide into an isocyanate which hydrolyses rapidly, under the conditions of the reaction, into a primary amine. Because of the intermediate rearrangement, the reaction is also termed as Hofmann haloamide rearrangement. Mechanism: Mechanistic interpretation and support of the mechanism: 1. The intermediate N-bromoamide has been isolated in benzene solvent and the intermediate isocyanate has been isolated in polar aprotic solvent like CHCl3. 2. Trapping of intermediate isocyanate: If the reaction is carried out in alcohol, urethane is obtained and in some cases urea derivative is also obtained. The isocyantae may also be trapped as hydantoin when it is reacted with an α-amino acid (e.g., glycine). Dr. Nabamita Basu Dept. of Chemistry, Nabagram Hiralal Paul College 3. Carbonyl carbon of amide if labelled with C14 then it is found that labelled C14 14 eliminates as CO2 in H2O. 4. Rate determining step (RDS): (a) In the Hoffmann rearrangement N-bromoamide rearranges to isocyanate in one step with a loss of bromide ion with alkyl or aryl migration. This is a slow step and proceeds through the SN2 like path. In aryl amides i.e., when the migrating group is aryl then the rate of Hofmann rearrangement gets increased by the presence of electron releasing substituents in the para position of aromatic ring. For example: The reactivity of ‘R’ is of the following order. (b) The rearrangement step is RDS since appreciable kinetic isotope effect is observed when Hofmann rearrangement is carried out using phenyl-1-C14 labelled N- bromobenzamide and that also supports the concerted mechanism. 5. The possibility of concertedness (intramolecular, one step) of the rearrangement may be justified from the following ground. (a) The possibility of the formation of nitrene (acylnitrene, isoelectric with carbene) has been rejected, because if it is formed in the intermediate, it should react with water to give hydroxamic acid which has not been detected. Therefore migration of R and leaving of bromine are concerted. (b) In the cross over experiment of Hoffmann rearrangement, no cross-products are obtained when two different amides are rearranged then it is obvious that the Dr. Nabamita Basu Dept. of Chemistry, Nabagram Hiralal Paul College rearrangement is intramolecular and migrating group never completely separates during the migration. 6. The intramlecular nature of migration may be further supported by configuration and stereochemistry (optical activity) study. (a) Configuration study (i) The retention of trans configuration of the cyclohexyl amine derivative indicates intramolecular, one step concerted nature of migration. (ii) (iii) In the above example, bicyclic amide undergoes rearrangement with retention of configuration at the migrating atom, because rigidity of the ring system prohibits inversion of configuration. Dr. Nabamita Basu Dept. of Chemistry, Nabagram Hiralal Paul College (b) Stereochemistry (optical activity) study In the above rearrangement the starting compound α-phenylpropionamide is optically active and the product amine is also optically active. In this rearrangement the migrating group is chiral and the product is optically active and therefore no racemisation occurs (since in that case zero optical rotation should be obtained) and consequently during migration, chiral group is not detached or completely free and therefore rearrangement step is intramolecular concerted process and retention of configuration is found in the product amine. Synthetic application: 1) It is difficult to synthesize such sterically hindered amine otherwise. 2) Synthesis of differently substituted aniline and pyridine. a) b) Synthesis of 3-amino pyridine is difficult otherwise it can not be produced in good yield via nitration of pyridine. Dr. Nabamita Basu Dept. of Chemistry, Nabagram Hiralal Paul College 3) Commercial synthesis of hydrazine, β-alanine and anthranilic acid. a) b) c) Mechanism: 4) Synthesis of aldehyde and nitrile via Hofmann rearrangement. a) Dr. Nabamita Basu Dept. of Chemistry, Nabagram Hiralal Paul College b) c) 5) Synthesis of anthranilic acid derivative with preferential (chemoselective) hydrolysis of phthalimide derivative. Hydrolysis of benzamide is facilitated by the substituent (either ortho or para position with respect to the amide group) that withdraw electrons from the amide linkage into the ring (opposite is the case of electron donating group). This is because 2 of the fact transition state for SN is stabilised by –M group either ortho or para position (destabilised by electron donating +M group). It is therefore, evident that in the Hoffmann rearrangement of 4-nitro phthalimide, the nitro group by withdrawing electrons at position 1, will cause preferential (chemoselective) hydrolysis of the amide linkage at this point, with subsequent rearrangement at position 2. Dr. Nabamita Basu Dept. of Chemistry, Nabagram Hiralal Paul College 6) Synthesis using intermediate isocyanate a) b) Curtius Rearrangement Curtius Rearrangement Curtius rearrangement involves pyrolysis of an acyl azide only (or in CHCl3 or EtOH solvent) that expels molecular N2 and at the same time rearranges to an isocyanate. Dr. Nabamita Basu Dept. of Chemistry, Nabagram Hiralal Paul College Mechanistic interpretation and support of the mechanism as in the Hofmann rearrangement: It is to be noted, one should not be confused with acylazide and alkyl or aryl azide. Acylazide which is the starting compound for curtius and Schmidt rearrangement goes via isocyanate intermediate under thermal condition with one step, concerted process. Alkyl or arylazide (not curtius and Schmidt starting compound which is acylazide) goes via nitrene intermediate under thermal condition with stepwise path. Examples: Synthetic application: 1) Conversion of ester into amine (a) (b) Dr. Nabamita Basu Dept. of Chemistry, Nabagram Hiralal Paul College (c) Conversion of ethylcyanoacetate derivative to amino acid 2) Conversion of substituted malonic ester into aldehyde via acylazide. 3) When α-hydroxy acylazides are heated, the intermediate isocyanate loses cyanic acid and aldehyde or ketone is formed. 4) γ or δ-hydroxy acylazides revert to the lactone through loss of hydrazoic acid. 5) Halogenated acylazides undergo rearrangement in the usual manner to isocyanate from which haloamines are obtained by hydrolysis. If the halogen is in the α-position, the resulting halogenated isocyanate is hydrolysed to an aldehyde or ketone. Dr. Nabamita Basu Dept. of Chemistry, Nabagram Hiralal Paul College 6) Curtius rearrangement is a valuable method for the synthesis of α-amino acid such as glycine, alanine, phenyl alanine and valine. Problems: Schmidt Rearrangement Schmidt rearrangement involves heating of carboxylic acid with HN3 in the presence of conc. H2SO4 to give isocyanate directly. The acylazide is not normally isolated but allowed to decompose and rearrange in the reaction mixture itself. Schmidt reaction has the advantagement over Hofmann and Curtius that it is just one laboratory step from the acid to amine but conditions are more drastic. The Schmidt reaction is only applicable if the acid does not contain groups that are sensitive to conc. H2SO4. The carbonyl compounds also undergo Schmidt reaction when treated with N3H in H2SO4. Ketones produce amides whereas aldehydes generally yield a mixture of corresponding nitrile and N-formyl derivative. Dr. Nabamita Basu Dept. of Chemistry, Nabagram Hiralal Paul College Schmidt and Beckmann rearrangement are mechanistically allied. The only difference is that Schmidt rearrangement is non-stereospecific whereas Beckmann rearrangement is stereospecific. The group anti to the hydroxyl group migrates but both are intramolecular, one step concerted process with retention of configuration of the migrating group. It is found that cyclohexanone gives same product caprolactum with Schmidt and Beckmann rearrangement. Dr. Nabamita Basu Dept. of Chemistry, Nabagram Hiralal Paul College Intramolecular Schmidt reaction: Synthetic application: 1) 2) Schmidt reaction is best for sterically hindered compounds like mesitoic acid. The AAc1 mechanism explains why good results are obtained with hindered acid. 3) It is to be noted that the reaction with ketones is virtually the insertion of –NH- group between the carbonyl group and the greater migratory aptitude of alkyl or aryl group. Problem: Dr. Nabamita Basu Dept. of Chemistry, Nabagram Hiralal Paul College Lossen Rearrangement In the Lossen rearrangement ester of hydroxamic acid is decomposed in presence of base. As the reaction is normally carried out in water the process furnishes the amine directly. - Since the leaving group leaves as carboxylate anion (ArCO2 ), the rearrangement is facilitated by the presence of electron withdrawing group in the para position of aromatic ring. In a similar reaction, aromatic acylhalides are converted to amines in one laboratory step by treatment with hydroxylamine–O–sulphonic acid. A few other Lossen rearrangements are given below. 1) 2) 3) Beckmann Rearrangement The conversion of ketoxime and aldoxime into N-substituted amide or anilide and N- substituted formamide or alkyl cyanide