In organic chemistry, 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 a radical amine cyclization, forming a 5- (or in rare cases, 6-) membered ring. In the reaction, thermal or photochemical decomposition of N-halogenated amine 1 in the presence of a strong acid (concentrated sulfuric acid or concentrated CF3CO2H) generates a nitrogen radical intermediate. The radical then abstracts an intramolecular hydrogen atom to give a cyclic amine 2 (pyrrolidine or, in some cases, piperidine).
History
In 1878, the structure of piperidine was still unknown, and A. W. Hofmann believed it was unsaturated. Following standard analytical technique, Hofmann added hydrogen chloride or bromine to it in an attempt to induce hydrohalogenation. Instead, he produced N-haloamines and N-haloamides, whose reactions under acidic and basic conditions he investigated.
1bromo-2propylpiperidine (3) and hot sulfuric acid, followed by basic work-up, formed a tertiary amine, later identified as δ-coneceine (4).
No further examples of the reaction were reported for about 25 years. But in 1909, K. Löffler and C. Freytag extended the transformation to simple secondary amines and applied the process in their elegant synthesis of nicotine (6) from N-bromo-N-methyl-4-(pyridin-3-yl)butan-1-amine (5).
The reaction mechanism only became clear around 1950, when S. Wawzonek investigated various N-haloamine cyclizations. Noting that the hydrogen peroxide or ultraviolet light greatly improved yields, Wawzonek and Thelan suggested a free-radical mechanism. E. J. Corey et al. then examined several features of the reaction: stereochemistry, hydrogen isotope effect, initiation, inhibition, catalysis, intermediates and selectivity of hydrogen transfer. The results, presented below, conclusively supported Wawzonek and Thelan's hypothesis.
Reaction mechanism According to Wawzonek and Thelan's 1949 proposal, an acid first protonates an N-chloroamine, which, in the presence of heat, light, or other initiators, homolyzes to ammonium and chloride free radicals. The ammonium 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 ammonium radical. The alkyl chloride later cyclizes during the basic work-up to the cyclic tertiary amine.
Because the hydrogen abstraction is radical, any chiral configuration at the δ-carbon racemizes.
The reaction also has a quite large hydrogen isotope effect: in the decomposition of 10, the ratio of 1,2-dimethylpyrrolidine 11 and 1,2-dimethylpyrrolidine-2-d 12 (determined by combustion and IR spectra) suggests .
Comparable reactions at a primary carbon also give , which strongly suggests that the breaking of the C-H bond proceeds to a rather considerable extent in the transition state.
Initiation, inhibition, catalysis Molecular oxygen inhibits the reaction (trapping the radicals), but Fe2+ salts initiate it.
Further investigations demonstrated that both the rate of the ultraviolet-catalyzed decomposition of dibutylchloroamine and the yield of newly formed pyrrolidine are strongly dependent on the acidity of the reaction medium – faster and higher-yielding reaction was observed with increasing sulfuric acid concentration.
An important question in discussing the role of the acid is whether the N-haloamine reacts in the free base or the salt form in the initiation step. Based on the pKa values of the conjugate acids of 2° alkyl amines (which are generally in the range 10–11), it is evident that N-chloroamines exist largely as salts in a solution of high sulfuric acid concentration. As a result, in the case of chemical or thermal initiation, it is reasonable to assume that it is the N-chloroammonium ion which affords the ammonium free radical. The situation changes, however, when the reaction is initiated upon irradiation with UV light. The radiation must be absorbed and the quantum of the incident light must be large enough to dissociate the N-Cl bond in order for a photochemical reaction to occur. Because the conjugate acids of the N-chloroamines have no appreciable UV absorption above 225 nm, whereas the free N-chloroamine absorb UV light of sufficient energy to cause dissociation (λmax 263 nm, εmax 300), E. J. Corey postulated that in this case it is actually the small percentage of free N-chloroamine that is responsible for most of the initiation. It was also suggested that the newly generated neutral nitrogen radical is immediately protonated. However, it is important to realize that an alternative scenario might be in operation when the reaction is initiated with the UV light; namely, the free N-haloamine might not undergo dissociation upon irradiation, but it might function as a photosensitizer instead. While it was proposed that the higher acid concentration decreases the rate of the initiation step, the acid catalysis involves acceleration of the propagation steps and/or retardation of the chain termination. The influence of certain acidic solvents on the photolytic Hofmann–Löffler–Freytag reaction was also studied by Neale and co-workers.
Intermediates Isolation of 4-chlorodibutylamine from decomposition of dibutylchloroamine in H2SO4 confirmed the intermediacy of δ–chloroamines. When the acidic solution is made basic, the δ–chloroamine cyclizes to give a cyclic amine and a chloride ion.
Selectivity of hydrogen transfer In order to determine the structural and geometrical factors affecting the intramolecular hydrogen atom transfer, a number of different N-chloroamines were examined in the Hofmann–Löffler–Freytag reaction. The systems were judiciously chosen in order to obtain data on the following points: relative migration tendencies of primary (1°), secondary (2°) and tertiary (3°) hydrogens; relative rates of 1,5- and 1,6-hydrogen rearrangements; and facility of hydrogen rearrangements in cyclic systems of restricted geometry.
Investigation of the free radical decomposition of N-chlorobutylamylamine 13 allowed to determine 1° vs. 2° hydrogen migration. It was reported that only 1-n-butyl-2-methylpyrrolidine 14 was formed under the reaction conditions, no 1-n-amylpyrrolidine 15 was detected. This observation provided substantial evidence that the radical attack exhibits strong preference for the 2° over 1° hydrogen.
Tendency for 3° vs. 1° hydrogen migration was studied with n-butylisohexylamine 16. When 16 was subjected to the standard reaction conditions, rapid disappearance of 16 was observed, but no pyrrolidine product could be isolated. This result suggested that there is a high selectivity for the 3° hydrogen, but the intermediate tertiary chloro compound 17 is rapidly solvolyzed.
Similarly, no cyclic amine was observed with the reaction of n-amylisohexylamine, which demonstrates the selectivity for the 3° vs. 2° hydrogen migration.
A qualitative study of products from the Hofmann–Löffler–Freytag reaction of N-chloromethyl-n-hexylamine 18 was performed in order to evaluate the relative ease of 1,5- and 1,6-hydrogen migration. UV-catalyzed decomposition of 18 followed by basification produced a 9:1 mixture of 1-methyl-2-ethylpyrrolidine 19 and 1,2-dimethylpiperidine 20, which demonstrates that the extent of formation of six-membered rings can be appreciable.
In terms of the geometrical requirements in the intramolecular rearrangement of hydrogen, it was observed that under identical reaction conditions the UV light-catalyzed decomposition of methylcyclohexylchloroamine and N-chloroazacycloheptane proceeds far more slowly than that of dibutylchloroamine. These findings indicate that the prevailing geometries are in these two cases unfavourable for the rearrangement to occur and the Cδ–H–N bond angle required for the intramolecular hydrogen transfer cannot be easily attained.
Generally accepted mechanism It is generally accepted that the first step in the Hofmann–Löffler–Freytag reaction conducted in acidic medium is the protonation of the N-halogenated amine 21 to form the corresponding N-halogenated ammonium salt 22. In case of thermal or chemical initiation of the free radical chain reaction, the N-halogenated ammonium salt 22 undergoes homolytic cleavage of the nitrogen-halogen bond to generate the nitrogen-centered radical cation 23. In contrast, it has been argued that the UV light-catalyzed initiation involves the free form of the N-haloamine and a rapid protonation of the newly generated neutral nitrogen radical (see the section devoted to mechanistic studies for arguments supporting this statement). Intramolecular 1,5-hydrogen atom transfer produces carbon-centered radical 24, which subsequently abstracts a halogen atom from the N-halogenated ammonium salt 22. This affords the protonated δ-halogenated amine 25 and regenerates the nitrogen-centered radical cation 23, the chain carrier of the reaction. Upon treatment with base, 25 undergoes deprotonation followed by an intramolecular SN2 reaction to yield pyrrolidine 28 via intermediate 27.
The preferential abstraction of the δ–hydrogen atom corresponds to a six-membered transition state, which can adopt the unstrained cyclohexane chair-type conformation 29.
The Hofmann–Löffler–Freytag reaction is conceptually related to the well-known Barton reaction.
General features of the reaction The starting material for the Hofmann–Löffler–Freytag reaction could be N-chloro-, N-bromo-, and N-iodoamines. In case of thermal initiation, the N-chloroamines give better yields for pyrrolidines because N-bromoamines are less stable thermally than the corresponding N-chloroamines. In contrast, when the initiation is carried out by irradiation, the N-bromoamines give higher yield for pyrrolidines. The Hofmann–Löffler–Freytag reaction was originally carried out under acidic conditions, but it has been demonstrated that neutral or even weakly basic conditions might also be successfully employed. The initially formed nitrogen-centered radical abstracts a H-atom mostly from the δ-position and thus 5-membered rings are formed predominantly. Formation of 6-membered rings is also possible, but relatively rare, and in majority of cases is observed in rigid cyclic systems. The reaction can be conducted under milder conditions provided that the alkyl radical experiences some form of extra stabilization, e.g. by an adjacent heteroatom. The radical process may be initiated by heating, irradiation with light or with radical initiators (e.g. peroxides, metal salts).
Modifications and improvements Because the original strongly acidic reaction conditions are often not compatible with the sensitive functional and protecting groups of complex substrates, several modifications of the Hofmann–Löffler–Freytag reaction were introduced:
M. Kimura and Y. Ban demonstrated that adjacent nitrogen atoms can stabilize radical species generated by H-atom abstraction and permit this step to take place under weakly basic conditions They reported that far better yields are obtained on photoirradiation in the presence of triethylamine, which neutralizes the hydrogen chloride generated by cyclization. M. Kimura and Y. Ban employed the modified conditions of the Hofmann–Löffler–Freytag reaction to the synthesis of dihydrodeoxyepiallocernuine 35.
It has been demonstrated that photolysis of N-haloamides proceeds efficiently under neutral conditions. Irradiation of N-bromoamide 36 (R=tBu) gave rise to bromomethyl-cyclohexane-amide 37 which, upon treatment with base in situ afforded iminolactone 38 in 92% yield.