Hofmann-Löffler reaction
| Hofmann–Löffler–Freytag reaction | |
|---|---|
| Named after |
August Wilhelm von Hofmann Karl Löffler Curt Freytag |
| Reaction type | Ring forming reaction |
The Hofmann–Löffler reaction (also referred to as Hofmann–Löffler–Freytag reaction, Löffler–Freytag reaction, Löffler–Hofmann reaction, as well as Löffler's method) is an organic reaction in which a cyclic amine 2 (pyrrolidine or, in some cases, piperidine) is generated by thermal or photochemical decomposition of N-halogenated amine 1 in the presence of a strong acid (concentrated sulfuric acid or concentrated CF3CO2H). The Hofmann–Löffler–Freytag reaction proceeds via an intramolecular hydrogen atom transfer to a nitrogen-centered radical and is an example of a remote intramolecular free radical C–H functionalization.
In 1878, the structure of piperidine was still unknown, and A. W. Hofmann made attempts to add hydrogen chloride or bromine to it in the belief that the compound possessed unsaturation (i.e. he performed standard alkene classification test reactions). In the course of his studies, A.W. Hofmann synthesized a number of N-haloamines and N-haloamides and investigated their reactions under acidic and basic conditions. He reported that the treatment of 1-bromo-2-propylpiperidine 3 with hot sulfuric acid, followed by basic work-up, resulted in the formation of a tertiary amine, which was later shown to be δ-coneceine 4.
Although the Hofmann–Löffler–Freytag reaction was to become a general and expeditious process for the formation of pyrrolidines, it was not until about 25 years after Hofmann's work that further examples of the reaction appeared in the literature. In 1909, K. Löffler and C. Freytag extended the scope of this transformation to simple secondary amines and demonstrated the synthetic utility of the process as exemplified by their elegant synthesis of nicotine 6 from N-bromo-N-methyl-4-(pyridin-3-yl)butan-1-amine 5.
Although the reaction was first reported in 1883, its mechanistic details were not fully understood until the late 1950s. The mechanism of the Hofmann–Löffler–Freytag reaction was first investigated by S. Wawzonek, who studied cyclization reactions of various N-halogenated amines. In 1949, Wawzonek and Thelan reported that a solution of N-chloro-N-methylcyclooctylamine 7 in sulfuric acid when irradiated with ultraviolet light in the presence of chlorine or when treated with hydrogen peroxide in the dark gave up to 24% yield of N-methylgranatinine 8, much more than is formed in the absence of light and peroxide. Based on this evidence, they correctly proposed that the reaction proceeds via a radical chain reaction pathway. More specifically, Wawzonek and Thelan suggested that the N-chloroamine is first protonated with the acid and then undergoes homolytic cleavage under the influence of heat, light, or other initiators to afford amminium and chloride free radicals. The amminium radical intramolecularly abstracts a sterically favored hydrogen atom to afford an alkyl radical which, in a chain reaction, abstracts chlorine from another N-chloroammonium ion to form an alkyl chloride and a new amminium radical. The alkyl chloride is later cyclized under the influence of alkali and the cyclic tertiary amine results.
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