The Hofmann rearrangement (Hofmann degradation) is the

organic Organic may refer to: * Organic, of or relating to an organism, a living entity * Organic, of or relating to an anatomical organ Chemistry * Organic matter, matter that has come from a once-living organism, is capable of decay or is the product ...

reaction of a primary

amide In organic chemistry, an amide, also known as an organic amide or a carboxamide, is a chemical compound, compound with the general formula , where R, R', and R″ represent any group, typically organyl functional group, groups or hydrogen at ...

to a primary

amine In chemistry, amines (, ) are organic compounds that contain carbon-nitrogen bonds. Amines are formed when one or more hydrogen atoms in ammonia are replaced by alkyl or aryl groups. The nitrogen atom in an amine possesses a lone pair of elec ...

with one less

carbon Carbon () is a chemical element; it has chemical symbol, symbol C and atomic number 6. It is nonmetallic and tetravalence, tetravalent—meaning that its atoms are able to form up to four covalent bonds due to its valence shell exhibiting 4 ...

atom. The reaction involves

oxidation Redox ( , , reduction–oxidation or oxidation–reduction) is a type of chemical reaction in which the oxidation states of the reactants change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is ...

of the nitrogen followed by rearrangement of the carbonyl and nitrogen to give an

isocyanate In organic chemistry, isocyanate is the functional group with the formula . Organic compounds that contain an isocyanate group are referred to as isocyanates. An organic compound with two isocyanate groups is known as a diisocyanate. Diisocyan ...

intermediate. The reaction can form a wide range of products, including

alkyl In organic chemistry, an alkyl group is an alkane missing one hydrogen. The term ''alkyl'' is intentionally unspecific to include many possible substitutions. An acyclic alkyl has the general formula of . A cycloalkyl group is derived from a cy ...

and

aryl In organic chemistry, an aryl is any functional group or substituent derived from an aromatic ring, usually an aromatic hydrocarbon, such as phenyl and naphthyl. "Aryl" is used for the sake of abbreviation or generalization, and "Ar" is used ...

amines.

The reaction is named after its discoverer,

August Wilhelm von Hofmann August Wilhelm von Hofmann (8 April 18185 May 1892) was a German chemist who made considerable contributions to organic chemistry. His research on aniline helped lay the basis of the aniline-dye industry, and his research on coal tar laid the g ...

, and should not be confused with the

Hofmann elimination Hofmann elimination is an elimination reaction of an amine to form alkenes. The least stable alkene (the one with the fewest substituents on the carbons of the double bond), called the Hofmann product, is formed. This tendency, known as the Hofm ...

, another

name reaction A name reaction (or named reaction) is a chemical reaction named after its discoverer(s) or developer(s). Among the tens of thousands of organic reactions that are known, hundreds of such reactions are typically identified by the eponym. Well-know ...

for which he is

eponymous An eponym is a noun after which or for which someone or something is, or is believed to be, named. Adjectives derived from the word ''eponym'' include ''eponymous'' and ''eponymic''. Eponyms are commonly used for time periods, places, innovati ...

Mechanism

The reaction of

bromine Bromine is a chemical element; it has chemical symbol, symbol Br and atomic number 35. It is a volatile red-brown liquid at room temperature that evaporates readily to form a similarly coloured vapour. Its properties are intermediate between th ...

with

sodium hydroxide Sodium hydroxide, also known as lye and caustic soda, is an inorganic compound with the formula . It is a white solid ionic compound consisting of sodium cations and hydroxide anions . Sodium hydroxide is a highly corrosive base (chemistry), ...

forms

sodium hypobromite Sodium hypobromite is an inorganic compound with the chemical formula . It is a sodium salt of hypobromous acid. It consists of sodium cations and hypobromite anions . It is usually obtained as the pentahydrate, so the compound that is usually c ...

in situ is a Latin phrase meaning 'in place' or 'on site', derived from ' ('in') and ' ( ablative of ''situs'', ). The term typically refers to the examination or occurrence of a process within its original context, without relocation. The term is use ...

'', which transforms the primary

into an intermediate isocyanate. The formation of an intermediate

nitrene In chemistry, a nitrene or imene () is the nitrogen analogue of a carbene. The nitrogen atom is uncharged and valence (chemistry)#monovalent, monovalent, so it has only 6 electrons in its valence level—two covalent bonded and four non-bonded e ...

is not possible because it implies also the formation of a

hydroxamic acid In organic chemistry, hydroxamic acids are a class of organic compounds having a general formula bearing the functional group , where R and R' are typically organyl groups (e.g., alkyl or aryl) or hydrogen. They are amides () wherein the nitroge ...

as a byproduct, which has never been observed. The intermediate isocyanate is hydrolyzed to a primary amine, giving off

carbon dioxide Carbon dioxide is a chemical compound with the chemical formula . It is made up of molecules that each have one carbon atom covalent bond, covalently double bonded to two oxygen atoms. It is found in a gas state at room temperature and at norma ...

#Base abstracts an acidic N-H proton, yielding an anion. #The anion reacts with bromine in an α-substitution reaction to give an ''N''-bromoamide. #Base abstraction of the remaining amide proton gives a bromoamide anion. #The bromoamide anion rearranges as the R group attached to the carbonyl carbon migrates to nitrogen at the same time the bromide ion leaves, giving an isocyanate. #The isocyanate adds water in a nucleophilic addition step to yield a

carbamic acid Carbamic acid, which might also be called aminoformic acid or aminocarboxylic acid, is the chemical compound with the formula . It can be obtained by the reaction of ammonia and carbon dioxide at very low temperatures, which also yields ammoni ...

(aka urethane). #The carbamic acid spontaneously loses CO₂, yielding the amine product.

Variations

Several reagents can be substituted for bromine.

Sodium hypochlorite Sodium hypochlorite is an alkaline inorganic chemical compound with the formula (also written as NaClO). It is commonly known in a dilute aqueous solution as bleach or chlorine bleach. It is the sodium salt of hypochlorous acid, consisting of ...

lead tetraacetate Lead(IV) acetate or lead tetraacetate is an metalorganic compound with chemical formula , often abbreviated as , where Ac is acyl. It is a colorless solid that is soluble in nonpolar, organic solvents, indicating that it is not a salt. It is de ...

, ''N''-bromosuccinimide, and (bis(trifluoroacetoxy)iodo)benzene have all been used for Hofmann rearrangements. The intermediate

can be trapped with various

nucleophile In chemistry, a nucleophile is a chemical species that forms bonds by donating an electron pair. All molecules and ions with a free pair of electrons or at least one pi bond can act as nucleophiles. Because nucleophiles donate electrons, they are ...

s to form stable

carbamate In organic chemistry, a carbamate is a category of organic compounds with the general Chemical formula, formula and Chemical structure, structure , which are formally Derivative (chemistry), derived from carbamic acid (). The term includes orga ...

s or other products rather than undergoing decarboxylation. In the following example, the intermediate isocyanate is trapped by

methanol Methanol (also called methyl alcohol and wood spirit, amongst other names) is an organic chemical compound and the simplest aliphatic Alcohol (chemistry), alcohol, with the chemical formula (a methyl group linked to a hydroxyl group, often ab ...

In a similar fashion, the intermediate isocyanate can be trapped by ''tert''-butyl alcohol, yielding the ''tert''-butoxycarbonyl (Boc)-protected amine. The Hofmann Rearrangement also can be used to yield carbamates from α,β- unsaturated or α- hydroxy amides or nitriles from α,β-

acetylenic In organic chemistry, the term acetylenic designates *A doubly unsaturated position (''sp''-hybridized) on a molecular framework, for instance in an alkyne such as acetylene Acetylene (Chemical nomenclature, systematic name: ethyne) is a chemi ...

amides in good yields (≈70%).

Applications

* The preparation of

anthranilic acid Anthranilic acid is an aromatic acid with the formula C6H4(NH2)(CO2H) and has a sweetish taste. The molecule consists of a benzene ring, ''ortho''-substituted with a carboxylic acid and an amine. As a result of containing both acidic and basic f ...

from

phthalimide Phthalimide is the organic compound with the formula C6H4(CO)2NH. It is the imide derivative of phthalic anhydride. It is a Sublimation (phase transition), sublimable white solid that is slightly soluble in water but more so upon addition of bas ...

* The conversion of

Nicotinamide Nicotinamide (International nonproprietary name, INN, British Approved Name, BAN ) or niacinamide (United States Adopted Name, USAN ) is a form of vitamin B3, vitamin B3 found in food and used as a dietary supplement and medication. As a suppl ...

into

3-Aminopyridine 3-Aminopyridine is an aminopyridine. It is a colorless solid. Preparation 3-Aminopyridine is prepared by heating nicotinamide with sodium hypobromite ( Hofmann rearrangement), which is in turn prepared ''in situ'' by the reaction of sodium hy ...

* In the synthesis of

gabapentin Gabapentin, sold under the brand name Neurontin among others, is an anticonvulsant medication primarily used to treat neuropathic pain and also for partial seizures of epilepsy. It is a commonly used medication for the treatment of neuropath ...

, beginning with the mono-amidation of 1,1-cyclohexane diacetic acid anhydride with

ammonia Ammonia is an inorganic chemical compound of nitrogen and hydrogen with the chemical formula, formula . A Binary compounds of hydrogen, stable binary hydride and the simplest pnictogen hydride, ammonia is a colourless gas with a distinctive pu ...

to 1,1-cyclohexane diacetic acid mono-amide, followed by a Hofmann rearrangement

References

Bibliography

* * {{DEFAULTSORT:Hofmann Rearrangement Rearrangement reactions Degradation reactions Name reactions

Mechanism

Variations

Applications

See also

References

Bibliography