Hofmann reaction mechanism

Among the most concrete evidence obtainable about the mechanism of a reaction is that provided by the actual isolation of one or more intermediates from the reaction mixture. Thus in the Hofmann reaction (p. 122), by which amides are converted into amines,... 

In the system epoxide (epoxy resin) — anhydride, we can thus expect the presence of anhydride, epoxy- and proton donor groups. In their study of the reaction mechanism, Fisch and Hofmann 20 22-24) proposed a sequence of reactions leading to the crosslinking of epoxy resins or to the formation of linear polyesters. The first step is the reaction of the anhydride with hydroxyl groups giving a monoester (Eq.(l))... 

The conversion of an amide in this way is termed the Hofmann reaction or the Hofmann rearrangement. The mechanism of the reaction involves an intramolecular 1,2-carbon-to-nitrogen nucleophilic shift of the alkyl (or aryl) group... 

To analyze reaction mechanisms in complex catalytic systems, the application of micropulse techniques in small catalytic packed beds has been used. Christoffel [33] has given an introduction to these techniques in a comprehensive review of laboratory reactors for heterogeneous catalytic processes. Mtlller and Hofmann [59,61] have tested the dynamic method in the packed bed reactor to investigate complex heterogeneous reactions. Kinetic parameters have been evaluated by a method, which employs concentration step changes and the time derivatives of concentration transients at the reactor outlet as caused by a concentration step change at the reactor inlet. 

Amides react with alkaline hypochlorite or hypobromite solutions to form primary amines having one less carbon atom. The reaction involves the hydrolysis of an isocyanate, which is seldom isolated. Isocyanates are also intermediates in the Curtius and Lossen rearrangements (methods 447 and 448). Although diese methods have a common mechanism and intermediate, they involve three separate and distinct types of starting materials and are, therefore, treated individually. A comparison of these reactions has been made. A detailed discussion of the Hofmann reaction, which includes conditions, typical procedures, and compounds prepared thereby, has been presented. ... 

For the reaction mechanism it was suggested that the hydrochloride salts of 540 suffered Hofmann elimination to give pyrimidines 544. The 4-chloro-5-[(2-benzylamino)ethyl] pyrimidines 544 then underwent cycliza-tion to pyrrolo[2,3-[Pg.166]

The first intermediates of the Hofmann reaction are A -haloamides e.g. 1), which are subsequently converted to alkaline salts e.g. 2). Both intermediates can be isolated under carefully controlled conditions. Kinetic evidence on both the substituent and isotope effects in the Hofmann rearrangement of various IV-halobenzamides (1) in an aqueous sodium hydroxide solution strongly support a concerted mechanism, involving the bridged anion (3), shown in Scheme 6. 

Incorporation of (103, labelled as shown), into haemanthamine (106) is without loss of tritium, half of which is sited at C-2. Aromatisation of ring c via 11-oxohaemanthamine with either t-butoxide or in a Hofmann reaction gave differing tritium retentions. Consideration of the possible mechanisms involved in relation to tritium retention led to the suggestion that the tritium which is expected at C-4 might not be stereospecific. ... 

The combination of an aryl- or alkylsulfonamide, 3 equiv. PhI(OAc)2 and substoichiometric I2 is able to promote C-H animation of simple hydrocarbons in the absence of any metal catalyst [120]. These reactions are best performed neat (10-fold excess of substrate relative to RS02NH2) at 50°C and appear to operate with reasonable selectivity to give benzylic sulfonamide products. Over-oxidation to the sulfonylimine is noted in some cases. A proposed reaction mechanism posits the intermediacy of a sulfonamidyl radical, formed from the AModosulfonamide. This pathway parallels in many ways the mechanism invoked for the Hofmann-Loffler-Freytag process. 

These results imply that the a -j8 mechanism does not operate under the usual conditions for the Hofmann reaction and is only encountered in dipolar aprotic and not in protic solvents. Presumably in dipolar aprotic solvents the ylid formed is stabilised by ion pairing for sufficient time to allow the planar arrangement of the bonds (C -H, Q-Ca, C -N and N-CH2) necessary for elimination via the ylid, to be attained. 

A more elegant and convincing demonstration of the ylid mechanism is accomplished by tracer studies. In the ylid mechanism, the trimethylamine produced contains one deuterium atom per molecule if the beta hydrogen atom is labelled in the substrate (47), whereas the E2 mechanism yields unlabelled material. Analysis by mass spectroscopy or nuclear magnetic resonance affords a convenient diagnosis of mechanism. Tracer studies confirm the absence of the ylid mechanism for the Hofmann reactions of a series of quaternary ammonium salts (51) , (52) . 

The Hofmann reaction, shown in (79) (discovered 1882) gives excellent (80-90%) yields with lower alkyl and aryl amides, but side-reactions intrude with higher homologues. The discoverer elucidated the mechanism except for the details of the migration. He isolated 76, showed that the corresponding iV chloro, but not the... 

The mechanism of the Curtius rearrangement is discussed in the chapter on the Hofmann reaction (p. 268). 

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. 

In conclusion, the Hofmann-Loffler-Freytag reaction tends to give moderate and sometimes poor yields for the preparation pyrrolidines under the classic conditions. Nonetheless, the utility of this reaction to functionalize molecules via the aminyl radical mechanism plays an unique role in the tool box for the organic chemist, enabling transformations not easily achievable using other means. Furthermore, milder conditions and better yields can be achieved by taking advantages of the newer developments such as the Suarez modification. 

The so-called Hofmann-Loeffler-Freytag reaction" " of TV-chloroamines 9 proceeds by a similar mechanism, and is for example used for the synthesis of pyrrolidines 11 ... 

Figure 24.5 MECHANISM Mechanism of the Hofmann rearrangement of an amide to an amine. Each step is analogous to a reaction studied previously.

This mechanism is similar to that of the Hofmann-Loffler reaction (18-40). 

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). ... 

This reaction takes place only when the methyl group is in a favorable steric position.The mechanism is similar to that of the Hofmann-Loffler reaction. ... 

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-... 

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