Hofman rearrangement

Hoffman Rearrangement is used to convert an unsubstituted amide into a primary amine with one carbon atom less than the amide.

1. Module : Reaction Mechanism Name Reactions HOFMANN REARRANGEMENT BY Dr. M. T. Bachute DEPARTMENT OF CHEMISTRY K. B. P. Mahavidyalaya , Pandharpur

2. The rearrangement which converts an AMIDE to a n AMINE with one carbon atom less by the action of alkaline hypohalite or bromine in alkali is known as Hofmann rearrangement or reaction . Amides which do not have a substitution on the NITROGEN display molecular rearrangement to primary amines. In this rearrangement, the carbonyl carbon atom of the amide is lost and the R group of amide gets attached to the nitrogen of the amine.

3. The reaction is as follows :- O || R-C-NH 2 + Br 2 + 4NaOH R-NH 2 + 2NaBr + Na 2 CO 3 + 2H 2 O An amide 1 amine Hofmann Rearrangement H 2 O MECHANISM :- The reaction is believed to proceed through following steps--- Step 1: Bromination of nitrogen. Step 2: Extraction of H + by OH - & rearrangement of anion. Step 3: Hydrolysis.

4. O O || || R-C-NH 2 + Br 2 R-C-NH-Br An amide N- bromamide .. O O || ||(-) R-C-NH-Br + OH - R-C-N-Br + H 2 O N- bromamide Bromamide anion (UNSTABLE) .. .. O O || || R-C-N-Br R-C-N + Br - Acyl nitrene .. .. .. .. O || R-C-N R-N=C=O Isocyanate .. .. .. Actual rearrangement Electron deficient .. ..

5. R-N=C=O + H 2 O R-NH 2 + CO3 2 - Isocyanate Amine Carbonate ion .. .. 2OH - The Hofmann rearrangement involves a 1,2-shift of group with its electron pair to an electron-deficient NITROGEN.

6. STEREOCHEMISTRY :- An interesting stereochemical observation is that if the migrating group (R) is chiral , its configuration is retained in the product amine. Thus this rearrangement is INTRAMOLECULAR , the migrating group does not become free , but remains attached with the substrate in some way e.g. via bridged transition state.

7. That the rearrangement is intramolecular has been supported by following evidences:-- 1.When the HR is carried out with mixture of m- deuteriobenzamide & benzamide , only m- deuterioaniline & aniline are formed. This shows that the rearrangement is intramolecular , if it is intermolecular then the cross-products such as aniline & m- deuterioaniline are formed. D CONH 2 + CONH 2 D D NH 2 NH 2 NH 2 NH 2 m- deuteriobenzamide benzamide Intramolecular Intermolecular m- deuterioaniline aniline Cross-products not formed HR

8. 2.When optically active α - phenylpropionamide undergoes HR, then α - phenylethylamine having the same configuration is formed. CH 3 O CH 3 || H C C NH 2 H C NH 2 C 6 H 5 C 6 H 5 Br 2 KOH α - Phenylpropionamide α - Phenylethylamine

9. RATE OF HOFMANN REACTION:- In Hofmann rearrangement, N- Bromamide rearranges to isocyanate is one step with a loss of bromide ion.This is a slow step. Further, in arylamides,i.e ., when the migrating group is aryl, then the rate of Hofmann reaction gets increased by presence of electron-releasing substituents in the aromatic ring. For e.g.,in the case of substituted benzamide as :-- CONH 2 G NH 2 G OBr -

10. The reactivity of G is of the following order :--- OCH 3 > CH 3 > H > Cl > NO 2 3. In the preparation of anthranilic acid from phthalamide 2. Preparation of aldehyde APPLICATIONS :- 1. Synthesis of 1 aliphatic & aromatic amines

11. APPLICATIONS:- 1. Synthesis of 1 aliphatic & aromatic amines:- The HR is useful for conversion of carboxylic acids & their derivatives into 1 amines having one carbon atom less than the starting material. COOH COOH Br Br Br CONH 2 NH 2 Benzoic acid P- Bromoaniline Br 2 FeBr 3 i) SOcl 2 ii) NH 3 Br 2 KOH

12. i) Preparation of methylamine, aniline, benzylamine, etc. :- CH 3 CONH 2 CH 2 NH 2 C 6 H 5 CONH 2 C 6 H 5 NH 2 C 6 H 5 CH 2 CONH 2 C 6 H 5 CH 2 NH 2 H 2 N.CO.NH 2 H 2 N-NH 2 UREA HYDRAZINE Br 2 / KOH

13. ii) Preparation of β - aminopyridine :- It is prepared from the nicotinamide , because it cannot be produced in good yield via the nitration of pyridine. Br 2 / KOH (65-70%) iii) Preparation of amino acids ;- β - Alanine is prepared (45% yield) by treating succinimide with bromine & aq.caustic potash, reaction takes place through the haloamide of succinic acid.

14. CH 2 -CO CH 2 CONH 2 CH 2 NH 2 CH 2 -CO CH 2 COO - CHCOO - NH OH - Br 2 KOH β - Alanine iv) Synthesis of anthranilic acid :- Anthranilic acid is basic starting material for preparation of ortho-disubstituted benzene derivatives. C C O O || || O C C NH || O COOH CONH 2 O || COOH NH 2 Phthalic anhydride Phthalimide Anthranillic acid NH 3 - H 2 O Cl 2 NaOH HR Succinimide

15. 2. Preparation of aldehyde:- Hofmann reaction is used to convert α , β - unsaturated acids & α - hydroxy acid amides into aldehyde. R.CH=CH.CONH 2 R.CH=CH.NHCOCH 3 R-CHO Cl 2 /NaOH HCl

16. REFERENCES:- Organic chemistry by MORRISON & BOYD ; 6 th edition ; 874-877. Reaction mechanism & reagents in organic chemistry by GURDEEP R.CHATWAL ; 725-729. Advanced organic chemistry by JERRY MARCH ; 4 th edition ; 1090-1091. Organic name reactions and molecular rearrangement by GURDEEP RAJ .

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