Hofmann–Löffler 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 latershown 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. More detailed mechanistic studies were conducted by E. J. Corey et al., who examined several features of the reaction relevant to the mechanism: stereochemistry, hydrogen isotope effect, initiation, inhibition, catalysis, intermediates and selectivity of hydrogen transfer. The results, presented below, pointed conclusively to a free-radical chain mechanism involving intramolecular hydrogen transfer as one of the propagation steps. In order to determine, whether the replacement of hydrogen in the cyclization of N-haloamines proceeds with retention, inversion, or equilibration of configuration, deuterated amine 9 was synthesized. Chlorination of 9 followed by thermal decomposition of its N-chloro derivative 10 in sulfuric acid at 90 °C produced optically inactive 1,2-dimethylpyrrolidine. This experimental observation was a strong evidence in favor of intermediacy of a species with an sp2-hybridized δ-carbon. The hydrogen isotope effect for the replacement of δ-H in the decomposition of 10 was determined by analyzing the mixture of 1,2-dimethylpyrrolidine 11 and 1,2-dimethylpyrrolidine-2-d 12 for deuterium content. Combustion analysis of the mixture of deuterated and undeuterated 1,2-dimethylpyrrolidines gave the value of 0.78 atom of deuterium per molecule, which corresponds to an isotope effect (kH/kD) of 3.54. The value of the isotope effect was verified by an independent method of deuterium analysis which relied on the comparison of the intensity of the C-D stretching absorptions in the infrared spectra of mixed 1,2-dimethylpyrrolidines from the cyclization of 10 with the pure sample of 1,2-dimethylpyrrolidine-2-d 12; the IR-based analysis produced kH/kD of 3.42, which is in agreement with the combustion analysis.Studies performed to determine kH/kD for cyclization to a primary carbon also gave kH/kD>>1, which strongly suggested that the breaking of the C-H bond proceeds to a rather considerable extent in the transition state. It was observed that N-chlorodi-n-butylamine was stable in 85% H2SO4 at 25 °C in the dark, but it began to disappear soon after irradiation with UV light. The reaction was found to have an induction period of about 12 minutes after the start of irradiation, but it was almost completely eliminated when the reaction was carried out under nitrogen atmosphere; under oxygen-free conditions a significant increase in the rate of the light-catalyzed decomposition of N-haloamines was reported. These observations provided a strong evidence for the inhibition of the reaction by molecular oxygen.