Eliminations Hofmann

Elimination of the quaternary ammonium salt generally takes place by the E2 mechanism, which requires a strong base. To provide the base, the quaternary ammonium iodide is converted to the hydroxide salt by treatment with silver oxide. Heating of the quatanary ammonium hydroxide results in E2 elimination and formation of an alkene. This elimination of a quaternary ammonium hydroxide is called the Hofinann elimination. Conversion to the hydroxide salt 

The Hofmann elimination is a one-step, concerted E2 reaction using an amine as the leaving group. 

For example, when 2-butanamine is exhaustively methylated, converted to the hydroxide salt, and heated, elimination takes place to form a mixture of 1-butene and 2-butene. 

In Chapter 7, we saw that eliminations of alkyl halides usually follow the Zaitsev s rule that is, the most substituted product predominates. This rule applies because the most-substituted alkene is usually the most stable. In the Hofmann elimination, however, the product is commonly the leort-substituted alkene. We often classify an elimination as giving mostly the Zaitsev pmduct (the most-substituted alkene) or the Hofmann product (the least-substituted alkene). 

Some of the stereochemical features of the Hofmann elimination are best studied using your models. Models are essential for working problems involving this elimination, such as Problem 19-20. 

Elimination reaction of alkyl trimethyl amines proceeds with anh-stereochemistry, furmshing the least highly substituted olefins. 

Example 1, Amine released from the resin by Hofmann elimination  

Name Reactions A Collection of Detailed Mechanisms and Synthetic Applications, DOI 10.1007/978-3-319-03979-4 135, Springer International Publishing Switzerland 2014 

Upon treatment of primary amides with hypohalites, primary amines with one less carbon are obtained via the intermediacy of isocyanate. Also know as the Hofmarm degradation reactiom 

In 1851, A.W. Hofmann discovered that when trimethylpropylammonium hydroxide is heated, it decomposes to form a tertiary amine (trimethylamine), an olefin (propene), and water. Widespread use of this transformation did not occur until 1881, when Hofmann applied this method to the study of the structure of piperidines and nitrogen-containing natural products (e.g., alkaloids). The pyrolytic degradation of quaternary ammonium hydroxides to give a tertiary amine, an olefin and water is known as the Hofmann elimination. The process involves three steps 1) exhaustive methylation of the primary, secondary or tertiary amine with excess methyl iodide to yield the 

The enantioselective formal total synthesis of 4-demethoxydaunomycin was accomplished in the laboratory of M. Shibasaki. The key intermediate was prepared from an enantiomerically enriched frans- 3-amino alcohol, which was first exhaustively methylated to the corresponding quaternary ammonium salt. This salt was then treated with excess n-BuLi to afford the desired allylic alcohol in moderate yield. 

The ABCD ring system of the diterpene alkaloid atisine was constructed by T. Kametani et al using an intramolecular Diels-Alder cycloaddition reaction as the key step. The dienophile was obtained by the traditional Hofmann degradation of the corresponding dimethylamino precursor. The diene was prepared by the kinetic enolization of the cyclohexenone system with LDA. 

In the laboratory of D.S. Watt, the enantioselective total synthesis of (+)-picrasin B was achieved from (-)-Wieland-Miescher ketone. At the early stages of the synthetic effort, an exocyclic double bond was introduced in a two-step procedure by first alkylating the bicyclic conjugated TMS end ether with Eschenmoser s salt at the y-position, followed by Hofmann elimination of the dimethylamino group. 

A three-step sequence uses an amide as a protecting group. 

Amines, like alcohols, contain a poor leaving group. To undergo a P elimination reaction, for example, a 1 ° amine would need to lose the elements of NH3 across two adjacent atoms. The leaving group, NH2, is such a strong base, however, that this reaction does not occur. 

The only way around this obstacle is to convert NH2 into a better leaving group. The most common method to accomplish this is called a Hofmann elimination, which converts an amine into a quaternary ammonium salt prior to P elimination. 

The Hofmann elimination converts an amine into an alkene. 

The Hoftnaim elimination consists of three steps, as shown for the conversion of propylamine to propene. 

Chapter 2. Acids, Bases, Functional Group Exchanges 

A typical synthetic transformation using the Hofmann elimination also illustrates an alternative synthetic approach to this reaction. Reaction of iodomethane with the dimethylamino moiety in 215 leads to the trimethylammonium salt. This ammonium leaving group allows the usual Hofmann elimination sequence, with thermal syn-elimination giving the vinyl derivative, 216.203 204 j is variation is important since using an amine as a Hofmann precursor is often more convenient than relying on an Sn2 reaction of an amine and a halide to produce the requisite ammonium salt (sec. 2.1.A). 

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Two efficient syntheses of strained cyclophanes indicate the synthetic potential of allyl or benzyl sulfide intermediates, in which the combined nucleophilicity and redox activity of the sulfur atom can be used. The dibenzylic sulfides from xylylene dihalides and -dithiols can be methylated with dimethoxycarbenium tetrafiuoroborate (H. Meerwein, 1960 R.F. Borch, 1968, 1969 from trimethyl orthoformate and BFj, 3 4). The sulfonium salts are deprotonated and rearrange to methyl sulfides (Stevens rearrangement). Repeated methylation and Hofmann elimination yields double bonds (R.H. Mitchell, 1974). 

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

A novel aspect of the Hofmann elimination is its regioselectivity Elimination m alkyltrimethylammonmm hydroxides proceeds m the direction that gives the less substi tuted alkene... 

The least sterically hindered p hydrogen is removed by the base m Hofmann elim matron reactions Methyl groups are deprotonated m preference to methylene groups and methylene groups are deprotonated m preference to methmes The regioselectivity of Hofmann elimination is opposite to that predicted by the Zaitsev rule (Section 5 10) Elimination reactions of alkyltrimethylammonmm hydroxides are said to obey the Hofmann rule, they yield the less substituted alkene... 

With a regioselectivity opposite to that of the Zaitsev rule the Hofmann ehmma tion IS sometimes used in synthesis to prepare alkenes not accessible by dehydrohalo genation of alkyl halides This application decreased in importance once the Wittig reac tion (Section 17 12) became established as a synthetic method Similarly most of the analytical applications of Hofmann elimination have been replaced by spectroscopic methods... 

Hofmann elimination (Section 22 14) Conversion of a quater nary ammonium hydroxide especially an alkyltnmethyl ammonium hydroxide to an alkene on heating Elimination occurs in the direction that gives the less substituted double bond... 

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). 

Conversion of 3-chlorothietane 1,1-dioxide to the 3-(N,N-dimethylaraino) derivative followed by reduction, quaternization, and Hofmann elimination affords a convenient route to the highly reactive thiete (thiacyclobutenel... 

FIGURE 22.4 New-man projections showing the conformations leading to (a) 1-butene, and (b) frans-2-butene by Hofmann elimination of sec-butyl-trimethylammonium hydroxide. The major product is 1-butene. 

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 reactions of (174) with various amines has been studied." " Hydrolysis of the hexamine salt of (174) gave not the symmetric diamine but (184) via a cyclic intermediate. The pyrolysis of 5-methyl-2-thenyltrimethyl ammonium hydroxide (185) is claimed to give (186) through a 1,6 Hofmann elimination reaction. The Bischler-Napieralski cyclization has been applied to acetyl derivatives of 2-(2-thienyl) ethylamine and 2-(3-thienyl) ethylamine for the preparation of sulfur analogs of isoquinoline. ... 

In an alternative route, the isoxazolidine 62a (R = -pentyl R = COOEt R = Me) was directly cleaved by hydrogenolysis to the Q -methylaminolactone, which by subsequent treatment with CH3I and Hofmann elimination afforded... 

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. 

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