Rearrangement to electron-deficient nitrogen: - Nabagram

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).


3. Carbonyl carbon of amide if labelled with C14 then it is found that labelled C14 eliminates as 14CO2 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


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.


(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.


3) Commercial synthesis of hydrazine, β-alanine and anthranilic acid. a)

b)

c) Mechanism:

4) Synthesis of aldehyde and nitrile via Hofmann rearrangement. a)


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 of the fact transition state for SN

2 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.


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.


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)


(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.


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.


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.


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:


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 respectively in acid catalysed rearrangement is widely known as Beckmann rearrangement. This rearrangement reaction is an example of 1,2-


nucleophilic shift in which migration origin is carbon and the migration terminus is electron deficient nitrogen.

The reaction is catalysed by a wide variety of acidic reagents e.g., conc. H2SO4, HCOOH, BF3, liq. SO2, SOCl2, PhSO2Cl, SO3, PCl5, P2O5, PPA or Ac2O, DCC (N,N'-Dicyclohexylcarbodiimide; R-N=C=N-R, R=cyclohexyl). Beckmann rearrangement, in general may be represented as, The migrating group R and R’ may be alkyl, aryl or alicyclyl. Unsymmetrical oximes may remain as geometrical isomers ‘Syn and Anti’ and it is found that in the Beckmann rearrangement, the migrating group generally attains the anti-orientation with respect to the leaving group in the oxime molecule. Examples: .


Mechanism: 1) 2) Mechanistic interpretation and support of the mechanism:

1) Beckmann rearrangement may be thought as the insertion of –NH- group in between migrating alkyl or aryl (RM) and carbonyl group or simply insertion of –CONH- group in between two alkyl groups where migrating group (RM) always link to the nitrogen.


2) Protonation or esterification of hydroxyl group of oxime is essential for Beckmann

rearrangement since ionization of this leaving group is essential and is usually the RDS. It has been observed that the rate of the reaction of various oxime esters depends on the strength of the esterifying acids which are found to be in the order PhSO3H, ClCH2CO2H, CH3CO2H. The rate of the reaction also increases as the solvent polarity increases.

3) In place of oxime itself, Beckmann rearrangement may be performed with its oxime ester in neutral medium (without acid catalyst).

4) The mechanism of Beckmann rearrangement is a subject of much discussion. Different workers at different times proposed different mechanism for this rearrangement. The rearrangement pattern of Beckmann reaction depends on many parameters, as for example: (a) Whether intra- or intermolecular migration depends on structure of migrating

groups (both migrations are possible, but mostly intramolecular). (b) The migrating aptitude does not depend on the nature of the group (as in other

rearrangement) but on its stereo-chemical arrangement in the oxime. Generally, the group anti-orientation with respect to the leaving group in the oxime molecule migrates.

(c) Intramolecular rearrangement always proceeds through bridged-ion.


(d) Some Beckmann rearrangements are stereospecific and some are non

stereospecific. Stereospecificity depends on: Structure of migrating group Configuration of oximes Leaving ability of leaving groups Solvent polarity Syn- or Anti- migration (both migrations are possible).

5) Evidence in favour of intramolecular migration (synchronous migration of anti group and loss of leaving functionality) and bridged-ion intermediate. (a) When cross over experiment is performed with Beckmann rearrangement, no

cross products are found.

This observation establishes that the migrating group never detach itself from the substrate. Thus migration and loss of leaving functionality occur in a synchronous manner.

(b) Beckmann rearrangement is highly stereospecific. Intramolecular and anti migration may be justified with stereochemistry study. When Beckmann rearrangement is carried out with chiral migrating group then it is found that retention of configuration occurs during the rearrangement.

This retention of configuration of chiral group establishes that the migrating group never detach itself during the rearrangement. This retention of configuration supports the formation of a bridged-ion during the migration i.e., same orbital of chiral carbon attached to the migrating origin (C) and migrating terminus (N) during rearrangement.


(c) Bridged-ion intermediate may be further supported when the migrating group is aryl

and contains an electron releasing group in the para position; the rate of the rearrangement is accelerated.

(d) Migration of anti group and to ascertain configuration of unsymmetrical oxime are

correlated to each other. This can be understood from the following reaction scheme. Process I: Process II: In the process I, easy cyclization to form benzisoxazol derivative via activated aromatic nucleophilic substituition with base even in cold condition, showing that the aryl group lies on the same side of the C=N linkage as the –OH group. On the other hand, Beckmann rearrangement of the same produces benzamide derivative due to the migration of ‘Me’ group that is anti with respect to oxime ‘OH’ group. In the process-II, under the same condition (cold alkali treatment), it does not undergo cyclization since aryl group and oxime ‘OH’ group are in trans relation but on Beckmann rearrangement of it gives anilide derivative due to the migration of aryl group that is anti to the oxime ‘OH’ group. Thus it can be concluded anti group migrates in a Beckmann rearrangement and configuration of unsymmetrical oxime ascertained (Z-isomer gives cyclization and benzamide derivative and E-isomer gives anilide derivative with no cyclization).


Beckmann rearrangement and ‘Syn’ migration: Due to structural reasons, a few Beckmann rearrangement reactions are reported as non-stereospecific. The reason for the above observed product is that as the bulkiness of the substituents (R and R’) increases anti-aryl orientation of oxime since in the Syn-aryl configuration, the oxime is sterically congested. Therefore, the observed Beckmann rearranged products indicates the Syn-migration (i.e., alkyl migration) instead of usual anti-migration. Abnormal or Second-order Beckmann rearrangement: Certain ketoximes (oximes of α-diketones, α-keto acids, α-dialkylamino ketones, α-hydroxy ketones and oximes adjacent to a teriary centre and β-keto ethers) can be converted to nitrile by the action of proton or Lewis acids via fragmentation reactions. This happens due to the fragmentation of carbocation intermediate as formed during the course of Beckmann reaction. Fragmentation is a side reaction even with ordinary ketoximes. Now, when a particularly stable carbocation can be cleaved from the parent carbocation intermediate, may be the main reaction.


General mechanism for the abnormal or second order Beckmann rearrangement: When a mixture of oximes with a tertiary centre next to oxime is subjected to Beckmann rearrangement reaction, cross-over products are obtained showing fragmentation. The cross-products indicates formation of stable carbocations and alkyl cyanides

Me-CN and Ph-CN. Tertiary carbocation and alkyl cyanide then react via Ritter reaction. The formation of crossed-product from the mixture of oximes reveals a fragmentation-recombination mechanism i.e., intermolecular Beckmann rearrangement.


Problems: When treated with p-CH3C6H5SO2Cl in pyridine, the α- and β-benzilmonoximes undergo Beckmann rearrangement with fragmentation (known as abnormal Beckmann rearrangement) Suggest a suitable mechanism. Transformation: Transformation: Questions:

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Rearrangement to electron-deficient nitrogen: - Nabagram