Hoffmann RearrangementAmber Julius

Aroosa Shahid

Faisal Jamil

CHEM 443, January 16, 2012Forman 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 studentsRichard 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• Hofmann’s rule• Hofmann rearrangement

Similar Reactions

Citrus Rearrangement

Lossen Rearrangement

Schmidt Rearrangement

Reaction Scheme

• First published 1881Hofmann, A. W. Chem. Ber. 1881, 14, 2725.

Amide reacts with Br2 and base

Rearranges to lose carbonyl carbon making chain 1 carbon shorter

Gives high yields of arylamines and alkylamines

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). March’s Advanced Organic Chemistry Reactions, Mechanisms, and Structure. 6th Edition. Chapter 18, 1.2-REARRANGEMENTS. 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-7-ene (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)benzene-

Induced Hoffmann Rearrangement. (Dirk Landberg, Markus Kalesse)