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Hoffmann Rearrangement

Amber Julius Aroosa Shahid Faisal Jamil


CHEM 443, January 16, 2012 Forman Christian College

Presentation Outline
Biography Major Discoveries Similar Reactions Reaction Scheme and Mechanism Examples Applications of Hoffmann Rearrangement Reaction

Biography of August Wilhelm von Hoffmann


Born 8 April 1818 Giessen, Germany Alma mater University of Gottingen Doctoral advisor Justus von Liebig Doctoral students Richard Abegg Adolf Pinner Fritz Haber Karl Friedrich von Auwers Rudolf Hugo Nietzki Ferdinand Tiemann Eugen Bamberger Died 5 May 1892 (aged 74) Berlin, Germany

Major Discoveries
Hofmann was the first to introduce molecular models into his public lectures around 1860 Hofmann elimination Hofmanns rule Hofmann rearrangement

Similar Reactions

Citrus Rearrangement

Lossen Rearrangement

Schmidt Rearrangement

Reaction Scheme

Amide reacts with Br2 and base

Rearranges to lose carbonyl carbon making chain 1 carbon shorter

Gives high yields of arylamines and alkylamines

First published 1881


Hofmann, A. W. Chem. Ber. 1881, 14, 2725.

Hoffmann Rearrangement of Amides

In the presence of a strong base, primary amides react with chlorine or bromine to form shortened amines, with the loss of the carbonyl carbon atom. This reaction, called the Hoffmann rearrangement, is used to synthesize primary and aryl amines. The Hofmann rearrangement of 10 amides provides 10 amines exclusively, with no contamination from 20 or 30 amines. This reaction also can be useful for shortening a carbon chain, which explains why it is sometimes referred to as a Hoffmann degradation.

Mechanism of the Hofmann Rearrangement: Steps 1 and 2

Mechanism of the Hofmann Rearrangement: Steps 3 and 4

Summarizing the Hoffmann rearrangement mechanism

In the Hofmann rearrangement, an unsubstituted 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. Another modification uses NBS/NaOMe. Under these conditions the product of addition to the isocyanate is the carbamate RNHCOOMe, which is easily isolated or can be hydrolyzed to the amine. Side reactions when NaOH is the base are formation of ureas RNHCONHR and acylureas RCONHCONHR by addition, respectively, of RNH2 and RCONH2 to RNCO. If acylureas are desired, they can be made the main products by using only one-half of the usual quantities of Br2 and NaOH. Another side product, but only from primary R, is the nitrile derived from oxidation of RNH2.
Source: Smith. M. B., & March . J. (2007). Marchs Advanced Organic Chemistry Reactions, Mechanisms, and Structure. 6th Edition. Chapter 18, 1.2REARRANGEMENTS. p. 1607

Examples of reactions involving Hoffmann rearrangement

Examples of reactions involving Hoffmann rearrangement (Contd.)

Several reagents can substitute for bromine. N-Bromosuccinimide and 1,8-Diazabicyclo[5.4.0]undec-7ene (DBU) can effect a Hofmann rearrangement. In the following example, the intermediate isocyanate is trapped by methanol forming a carbamate. A mild alternative to bromine is also bis(trifluoroacetoxy)iodo)benzene. (Source: http://www.kuwait-md.org/?q=node/1121)

Applications of Hoffmann rearrangement reactions


Aliphatic & aromatic amides are converted into aliphatic and aromatic amines, respectively In the preparations of Anthranilic Acid from Phthalimide Nicotinic acid is converted into 3-Amino pyridine Synthesis of Symmetrical Ureas by (Diacetoyxiodo)benzeneInduced Hoffmann Rearrangement. (Dirk Landberg, Markus Kalesse)

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