The Hofmann Elimination

The halide anion of quaternary ammonium iodides may be replaced by hydroxide by treatment with an aqueous slurry of silver oxide. Silver iodide precipitates, and a solution of the quaternary ammonium hydroxide is formed. 

When quaternary ammonium hydroxides are heated, they undergo (3 elimination to form an alkene and an amine. 

This reaction is known as the Hofmann elimination it was developed by August W. Hofmann in the middle of the nineteenth century and is both a synthetic method to prepare alkenes and an analytical tool for structure determination. 

A novel aspect of the Hofmann elimination is its regioselectivity. Elimination in alkyltrimethylammonium hydroxides proceeds in the direction that gives the less substituted alkene. 

The least sterically hindered (3 hydrogen is removed by the base in Hofmann elimination reactions. Methyl groups are deprotonated in preference to methylene groups, and methylene groups are deprotonated in preference to methines. The regioselectivity of Hofmann elimination is opposite to that predicted by the Zaitsev rule (Section 5.10). Elimination reactions of alkyltrimethylammonium hydroxides are said to obey the Hofmann rule they yield the less substituted alkene. 

Nucleophilic substitution results when primary alkyl halides are treated with amines. 

Primary amine Primary alkyl halide Ammonium halide salt Secondary amine Hydrogen halide 

A second alkylation may follow, converting the secondary amine to a tertiary amine. Alkylation need not stop there the tertiary amine may itself be alkylated, giving a quaternary ammonium salt. 

Because of its high reactivity toward nucleophilic substitution, methyl iodide is the alkyl halide most often used to prepare quaternary ammonium salts. 

Quaternary ammonium salts, as we have seen, are useful in synthetic organic chemistry as phase-transfer catalysts. In another, more direct application, quaternary ammonium hydroxides are used as substrates in an elimination reaction to form alkenes. 

The reaction of amines with alkyl halides was seen earlier (see Section 21.7) as a complicating factor in the preparation of amines by alkylation of ammonia. 

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The Hofmann elimination route, of which many versions exist, can be carried out at much lower temperatures in conventional equipment. The PX is generated by a 1,6-Hofmaim elimination of amine from a quaternary ammonium hydroxide in the presence of a base. This route gives yields of 17—19%. Undesired polymeric products can be as high as 80% of the product. In the presence of a polymerization inhibitor, such as phenothiazine, DPXN yields can be increased to 50%. 

The yield can be raised to 28% if the Hofmann elimination is conducted in the presence of a water-soluble copper or iron compound (19). Further improvements up to 50% were reported when the elimination was carried out in the presence of ketone compounds (20). Further beneficial effects have been found with certain cosolvents, with reported yields of greater than 70% (8). 

With a regioselectivity opposite to that of the Zaitsev rule, the Hofmann elimination is sometimes used in synthesis to prepare alkenes not accessible by dehydrohalo-genation of alkyl halides. This application decreased in importance once the Wittig reaction (Section 17.12) becfflrre established as a synthetic method. Similarly, most of the analytical applications of Hofmann elimination have been replaced by spectroscopic methods. 

Quaternary ammonium hydroxides undergo elimination on being heated. It is an anti elimination of the E2 type. The regioselectivity of the Hofmann elimination is opposite to that of the Zaitsev rule and leads to the less highly substituted alkene. 

It has been noticed that the reverse reaction of Eq. (5) is a particular type of the Hofmann elimination reaction (26) via either an E2 or an ElcB mechanism. An E2 mechanism seems to be more obvious for this reaction than an ElcB mechanism, however. 

The preparation of an alkene 3 from an amine 1 by application of a /3-elimination reaction is an important method in organic chemistry. A common procedure is the Hofmann elimination where the amine is first converted into a quaternary ammonium salt by exhaustive methylation. Another route for the conversion of amines to alkenes is offered by the Cope elimination. 

The number of reaction sequences required for liberation of trimethylamine 4 indicates the degree of incorporation of a particular nitrogen into the molecular skeleton. Because of that feature, the Hofmann elimination has been used for the structural analysis of natural products, e.g. alkaloids. 

In addition to its application for structural analysis, the Hofmann elimination also is of synthetic importance. For instance the method has been used to prepare fi-cyclooctene 16, as well as higher homologs ... 

The Hofmann elimination is a classic route to olefins via alkylammonium hydroxides from amines. In the present instance it is employed in the generation of />-xylylene, a... 

The Hofmann elimination reaction is not often used today in the laboratory, but analogous biological eliminations occur frequently, although usually with protonated ammonium ions rather than quaternary ammonium salts. In the biosynthesis of nucleic acids, for instance, a substance called adenylosuccinate... 

Many of the reactions of amines are familiar from past chapters. Thus, amines react with alkyl halides in S 2 reactions and with acid chlorides in nucleophilic acyl substitution reactions. Amines also undergo E2 elimination to yield alkenes if they are first qualernized by treatment with iodomethane and then heated with silver oxide, a process called the Hofmann elimination. 

How might you use the Hofmann elimination to accomplish this reaction How would you finish the synthesis by converting cyclooctatriene into cyclooctatetraene ... 

Sulfonium compounds (—C— SR2) undergo elimination similar to that of their ammonium counterparts (17-6 and 17-7) in scope and mechanism but this reaction is not of great synthetic importance. These syn-elimination reactions are related to the Cope elimination (17-8) and the Hofmann elimination (17-6). ... 

The Hofmann elimination is useful synthetically for preparing alkenes since it gives the least substituted alkene. The reaction involves thermal elimination of a tertiary amine from a quaternary ammonium hydroxide these are often formed by alkylation of a primary amine with methyl iodide followed by reaction with silver oxide. The mechanism of the elimination is shown in Scheme 1.13 in this synthesis of 1-methyl-1-... 

The influence of hydration on the reactivity of anions is much more evident in the case of OH. In the chlorobenzene-aqueous NaOH system the hydration sphere of tetrahexylammonium hydroxide dissolved in the organic phase progressively decreases from 11 to 3.3 water molecules when the base concentration is raised from 15 to 63%. This leads to an enhanced reactivity of OH which was measured in the Hofmann elimination (Equation 3). In the examined ranges of NaOH concentrations the reactivity increased up to more than four orders of magnitude (Table I). Although the dehydration of OH is... 

The Hofmann elimination converts an amine into an alkene. The process begins by converting an amine to a quaternciry cimmonium salt (that is, it has a nitrogen atom with four bonds). The general mechanism for the elimination step is in Figure 13-40. Figure 13-41 illustrates a sample reaction scheme for the Hofmann elimination. 

The general mechanism forthe elimination in the Hofmann elimination. 

Product distribution resulting from the Hofmann elimination. 

As mentioned earlier, preparation of (Z),( )-l, 5-cyclooctadiene (31) in an optically active modification 2) first demonstrated the chiral nature of ( )-cycloalkenes. In this classical experiment, Cope and coworkers obtained ( + )-31 by the Hofmann elimination of the (-l-)-ammonium salt 30. They were also successful in obtaining (+)-31 by optical resolution of racemic 31 through complexing with a chiral Pt(II)... 

Atracurium is a synthetic bisquaternary benzylisoquinolinium compound with a novel method of metabolism, the Hofmann elimination reaction. This reaction takes place at a pH of 7.4 and a temperature of 37°C. It is thus metabolised at body temperature and pH, and has to be stored in a refrigerator. The usual intubating dose of atracurium is 0.5-0.75 mg-kg-1 (2-3xED95). The onset of action with this dose is 2-3 minutes and intubating conditions are acceptable in 90-120 seconds. Spontaneous recovery occurs reliably from an atracurium neuromuscular block, such that an intubating dose of about 0.5 mg-kg-1 can be expected to provide surgical muscle relaxation for 25-40 minutes in the normal healthy patient. Repeated administration of atracurium leads only to a small increase in the duration of action. 

A. C. Cope and E. R. Trumbull, Olefins from amines the Hofmann elimination reaction and amine... 

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