Elimination reactions Hofmann

3-dicarboxylic acids 8 by hydrolysis of the cyano group. Reaction of an a-halocarboxylic acid 2 with ammonia leads to formation of an a-amino acid 9  

The preparation of a-iodocarboxylic acids is of particular interest, since iodide is a better leaving group as is chloride or bromide. A similar a-iodination with a phosphorus trihalide as catalyst is not known. However the iodination can be achieved in the presence of chlorosulfonic acid mechanistically the intermediate formation of a ketene 10 by dehydration of the carboxylic acid is assumed  

The ketene as a more reactive species is iodinated by reaction with iodine. Bromine or chlorine as substituents may also be introduced by this method.  

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. 

Primary, secondary and tertiary amines can serve as starting materials. The amine, e.g. 1, is first treated with excess methyl iodide, to generate the quaternary ammonium iodide 5. Subsequent treatment with silver oxide in water gives the corresponding ammonium hydroxide 2  

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The least sterically hindered p 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. 

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. ... 

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... 

Hexamethylphosphoramide Hoffmann, Roald, 1180 Hoffmann-I.a Roche Co., vitamin C synthesis and, 773 von Hofmann. August Wilhelm, 933 Hofmann elimination reaction. 936-938... 

Hofmann elimination reactions from hi- and tri-cyclic systems can, however, be used to create internal unsaturation without loss of a trialkyl amine as shown in Scheme 1.14 for the synthesis of the hexahydrothieno [ZjJazecine. 

A selective heating in liquid/liquid systems was exploited by Strauss and coworkers in a Hofmann elimination reaction using a two-phase water/chloroform system (Fig. 2.10) [32]. The temperatures of the aqueous and organic phases under micro-wave irradiation were 110 and 55 °C, respectively, due to the different dielectric properties of the solvents (Table 2.3). This temperature differential prevented decomposition of the final product. Comparable conditions would be difficult to obtain using traditional heating methods. A similar effect has been observed by Hallberg and coworkers in the preparation of /3,/3-diarylated aldehydes by hydrolysis of enol ethers in a two-phase toluene/aqueous hydrochloric acid system [33],... 

For the syntheses of such chochins both the 1,6-Hofmann elimination reactions of suitable [2.2]paracyclophane derivatives with p-xylyl ammoniumbases (e.g. 36 and 37 — as used for the first synthesis of a [4]chochin 43 65) — and the photodesulfurization method l7,66) have proved applicable. 

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. 

In the case of phosphonium salts, some examples of decomposition by Hofmann elimination reactions are known. The phosphonium salts which normally undergo such a decomposition possess an activated hydrogen / to the phosphorus the salts 70, with a strong electron-withdrawing Z group on the carbon / to the phosphorus (reaction 202) and the a-hydroxyalkylphosphonium salts 71 (reaction 203)... 

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

The purity of purchased aqueous [(C4H9)4N]OH varies in our experience in particular, concentrated aqueous solutions of [(C4H,)4N]OH (40%, Aldrich) gradually deposit solid at the bottom of the bottle, especially when stored below 30°C [as seems advisable to prevent possible Hofmann elimination reactions producing [(C4H,)3N + 1-butene + H20], In some instances, simple warming of the bottle briefly in a steam bath redissolves the solid however, it is better (as detailed below see also p. 1695 and footnote 11 elsewhere7) to prepare fresh aqueous... 

Here, we envisage building the benzimidazole scaffold directly onto the linker and, by analogy with a regular tertiary amine synthesis on the REM linker, we can quaternize the resin-bound benzimidazole compounds by reaction with reactive bromides. The quaternary salt can then be liberated by a Hofmann elimination reaction upon treatment with base. 

The preferred order of proton removal in Hofmann elimination reactions is j8 CH3 > j8 CH2 > / CH.Ethylene is the majoralkene formed, the observed ratio of ethylene to 1-butene being 98 2. 

J. K. Crandall, M. Apparu, Base-Promoted Isomerizations of Epoxides, Org. React. 1983, 29, 345—443. A. C. Cope, E. R. Trumbull, Olefins from Amines The Hofmann Elimination Reaction and Amine Oxide Pyrolysis, Org. React. 1960, 11, 317-493. 

Explain why deuterium is lost in preference to hydrogen in this Hofmann elimination reaction ... 

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