Hinsberg procedure

Hinsberg procedure for the separation of primary, secondary and tertiary amines is given under (viii) above, and this method may be used. The following experimental details may, however, be found useful for the preparation of derivatives of primary and secondary amines. 

Benzenesulphonyl chloride reacts with primary and secondary, but not with tertiary, amines to yield substituted sulphonamides (for full discussion, see Section IV,100,3). The substituted sulphonamide formed from a primary amine dissolves in the alkaline medium, whilst that produced from a secondary amine is insoluble in alkali tertiary amines do not react. Upon acidifying the solution produced with a primary amine, the substituted sulphonamide is precipitated. The reactions form the basis of the Hinsberg procedure for the separation of amines see Section IV,100,(viii) for details. Feebly basic amines, such as o-nitroaniline, react slowly in the presence of allcali in such cases it is best to carry out the reaction in pyridine solution see Section IV,100,3. ... 

A notable utilization of the Hinsberg procedure was executed in the synthesis of a thiophene analogue of porphyrin. A previous synthesis of the tetrathioporphyrin dication of 7 found this material to be unsuitable for chemical exploration as a result of its limited accessibility and solubility. Efforts by Vogel et al. were then directed toward... 

The alkylation of diphenyl A alkylphosphinic amides via the amide anion and subsequent cleavage of the iVW-dialkylamide with toluene-p-sulphonic acid is a valuable, if not preferable, alternative to the preparation of secondary amines through the Hinsberg procedure. ... 

The separation of a mixture of amines by means of benzenesulphonyl chloride or p-toluenesulphonyl chloride (Hinsberg s procedure) is described in Section IV,100,(viii). 

Section 2 presents the Hinsberg test, a test for distinguishing between primary, secondary, and tertiary amines Section 3 gives procedures for preparation of solid derivatives for melting point characterizations and Section 4 gives spectral characteristics. Apply the procedures to known substances along with the unknown. 

Problem 23.24 The sulfonamides of big primary amines are only partially soluble in aqueous KOH. (a) In the Hinsberg test, what incorrect conclusion might you draw about such an amine (b) How might you modify the procedure to avoid this mistake ... 

Phenylenediamine has been prepared by the reduction of o-nitroaniline by means of tin and hydrochloric acid/ stannous chloride and hydrochloric acid/ sodium stannite/ zinc dust and water/ sodium hydrosuliite and sodium hydroxide, zinc dust and alcoholic alkali, and by electrolytic reduction in aqueous alcohol in the presence of sodium acetate. The present procedure is a modification of the method of Hinsberg and Konig. ... 

Two common qualitative tests for amines are the Hinsberg test and the nitrous acid test. The nitrous acid test is not included here because the N-nitroso derivatives of some secondary amines are carcinogenic. The risk of producing an as-yet-unrecognized carcinogenic material in this procedure outweighs any possible benefit of a test that can also be misleading and difficult to interpret. The modified sodium nitroprusside test has been included as an alternative. 

The procedure for the Hinsberg test must be followed as closely as possible, because it is designed to minimize compHcations that arise because of side reactions that may occur between tertiary amines and benzenesulfonyl chloride. For example, 23, the initial adduct between the chloride and the amine, is subject to an S[,j2 reaction (Secs. 14.2 and 14.4) with another molecule of amine to produce the benzenesulfonamide of a secondary amine and a quaternary ammonium salt (Eq. 25.54). Although this process is normally unimportant, particularly when excess amine is avoided, the observation of small amounts of an insoluble product formed by this pathway may erroneously cause designation of a tertiary amine as secondary. 

To summarize the discussion, tertiary amines may produce small amounts of insoluble products if the concentration of the amine in the test solution is too high and if the reaction time is too long. If the directions of the procedure are followed and care is taken not to interpret small amounts of insoluble product as a positive test for secondary amines, the Hinsberg test may be used with confidence to designate an amine as primary, secondary, or tertiary. 

Among chemical methods for the separation of amines, those of Hinsberg (reaction with / -toluenesulfonyl chloride) and of Alexander (94) (reaction with 3-nitrophthalic anhydride) are most commonly used. Tertiary amines do not react with the reagents mentioned and they can be separated after the reaction — for example, by extraction. Derivatives of primary amines with p-toluenesulfonyl chloride are soluble in alkali hydroxide solutions, in contrast to sulfonamides of secondary amines this is utilized for their separation. When primary and secondary amines are separated by reacting them with 3-nitrophthalic anhydride, use is made of the fact that only phthal-imine acids derived from primary amines can be cyclized. Practical utilization of both procedures is demonstrated by the separated of a mixture of aniline, ethylaniline, and diethylaniline. However, it should be mentioned that in a number of cases the procedures fail or do not lead to a sufficiently sharp separation. Negatively substituted amines which do not react with / -toluenesulfonyl chloride can be separated with 3-nitrophthalic anhydride. Some p-toluenesulfonamides of primary amines are poorly soluble in alkali. The derivative of primary amine with 3-nitrophthalic anhydride is cyclized merely by boiling in benzene, and the phthalimide formed is soluble in benzene and can be isolated together with the tertiary amine. 

A classical method of distinguishing between the types of amines is based on the difference in the reactivity of amines with benzenesulfonyl chloride followed by reaction vyith sodium hydroxide. The procedure is called the Hinsberg test. First, benzenesulfonyl chloride is shaken with a mixture of an amine and aqueous base. Then, the reaction mixture is examined to determine which of three possible events occurred. If the amine was tertiary, no precipitate appears, and there is no evidence of any reaction. If the amine was secondary, a water-insoluble sulfonamide forms and appears as a precipitate. Primary amines also give no evidence of a reaction because the sulfonamide is soluble in the base, but if the solution is neutralized with an acid, the neutral water-insoluble sulfonamide precipitates. Thus, the experimental results are unique for each class of amine. Infrared spectroscopy and NMR allow us to identify classes of amines (Section 23.14). 

The preparation of monoalkyl derivatives of diamines represents something of a synthetic problem. Procedure 13-3 involves acetylation of ethylenediamines under mild conditions to the monoacetyl ethyl-enediamine, protection of the second amino group by a Hinsberg reaction with benzenesulfonyl chloride, followed by N-alkylation of the acetamido group, and recovery of the iV-alkylethylenediamine by acid hydrolysis [15]. 

---