Hexaminium salts

Upon heating with a mixture of concentrated hydrochloric acid and ethanol under reflux, the hexaminium salt 4 is cleaved into the primary amine and formaldehyde. The latter can further react with ethanol under the acidic conditions to give formaldehyde diethylacetal ... 

This method gives better yields than other methods of preparation of 2-bromoallylamine, and it is the most convenient method for the preparation of large quantities of the compound. The procedure illustrates a reaction, the so-called Delepine reaction, that has been used for the preparation of many primary aliphatic amines.8-12 A number of primary aliphatic amines have been prepared by this method without isolation of the intermediate hexaminium salt.11 Several preparations of aliphatic aldehydes via the hexaminium salt have been described in earlier volumes of this series.13... 

Dissolve 71 g. of P-methylnaphthalene in 460 g. (283 ml.) of A.B. carbon tetrachloride and place the solution in a 1 -litre three-necked flask equipped with a mechanical stirrer and reflux condenser. Introduce 89 g. of JV-bromosuccinimide through the third neck, close the latter with a stopper, and reflux the mixture with stirring for 16 hours. Filter ofiT the succinimide and remove the solvent under reduced pressure on a water bath. Dissolve the residual brown oil (largely 2-bromomethyl naphthalene) in 300 ml. of A.R. chloroform, and add it to a rapidly stirred solution of 84 g. of hexamine in 150 ml. of A.R. chloroform contained in a 2-litre three-necked flask, fitted with a reflux condenser, mechanical stirrer and dropping funnel maintain the rate of addition so that the mixture refluxes vigorously. A white solid separates almost immediately. Heat the mixture to reflux for 30 minutes, cool and filter. Wash the crystalline hexaminium bromide with two 100 ml. portions of light petroleum, b.p. 40-60°, and dry the yield of solid, m.p. 175-176°, is 147 g. Reflux the hexaminium salt for 2 hours with 760 ml. of 60 per cent, acetic acid, add 160 ml. of concentrated hydrochloric acid, continue the refluxing for 5 minutes more, and cool. Extract the aldehyde from the solution with ether, evaporate the ether, and recrystallise the residue from hot -hexane. The yield of p-naphthaldehyde, m.p. 69-60°, is 60 g. 

Cognate preparations. p-Nitrobenzaldehyde. This preparation is an example of the Sommelet reaction in which the hexaminium salt is isolated. Dissolve llg (0.13mol) of hexamethylenetetramine in 70ml of chloroform (CAUTION) and add 11.4 g (0.067 mol) of p-nitrobenzyl chloride or 14.4 g of p-nitrobenzyl bromide (Expt 6.28). Heat the mixture under reflux on a steam bath for 4 hours a precipitate gradually separates. Replace the reflux condenser by a condenser set for distillation and distil off about 35 ml of solvent. Add 35 ml of acetone, cool in ice, collect the precipitate by suction filtration and dry it in the air. Heat the hexaminium salt thus obtained under reflux for 1 hour with 100 ml of 50 per cent acetic acid then add 100 ml of water and 25 ml of concentrated hydrochloric acid and continue the refluxing for 5-10 minutes. Cool the solution in ice, collect the crystals of p-nitrobenzaldehyde and dry them in a vacuum desiccator. The yield is 6.4 g (63%), m.p. 106 °C. The p.m.r. spectrum is noted in Expt 6.117. 

In a procedure for the preparation of 2-thiophenealdehyde, the hexaminium salt is prepared in refluxing chloroform and steam distilled to effect the remaining steps... 

SuUiruted alkyl halides are convcriible into the hexaminium salts in high yield but the yield in the second step Is low, for example, 46% in the case of the salt from... 

The Sommelet reaction, also known as the Sommelet oxidation, is the oxidation of benzyl halides (1) to the corresponding aldehydes (3) using hexamethylenetetramine (HMTA) followed by hydrolysis of the hexaminium salt 2.1-3 This reaction is closely related to the Delepine amine synthesis, the Duff aldehyde synthesis, and the Krtihnke reaction (see Section 7.10.3). 

When benzyl halide 1 is treated with HMTA, the first step was the straightforward formation of hexaminium salt 2. In the presence of water, an isomer of 2, iminium 7, is hydrolyzed to give hemiaminal 8. Fragmentation of 8 affords iminium 9, which collapses to benzylamine 4 and formaldehyde. Condensation of benzylamine 4 and formaldehyde provides another key intermediate, aldimine 5. The crucial key oxidation-reduction process takes place between 4 and 5 with the exchange of two equivalents of hydride, giving rise to methylbenzylamine 10 and imine 11, which is subsequently hydrolyzed to benzaldehyde 3. 

While the aforementioned mechanism covers all the basis of experimental data, it is long and tedious. In 1961, Le Henaff simplified the mechanism to one that has been widely accepted by the chemistry community. "12 According to Le Henaff, hexaminium salt 2 isomerizes to iminium 7, which undergoes a hydride transfer to provide iminium 12. Hydrolysis of iminium 12 affords hemiaminal 13, which then delivers benzaldehyde 3 and amine 14. 

The Delepine reaction or the Del6pine amine synthesis is the closest variation of the Sommelet reaction. The Delepine amine synthesis is the acid hydrolysis of the hexaminium salt 2 with strong acid in ethanol, giving rise to benzylamine 4 with the formaldehyde being removed as volatile formaldehyde diacetal.13-15 In essence, it may be considered as half of the Sommelet reaction or the interrupted Sommelet reaction. The Delepine reaction works well for active halides such as benzyl, ally halides, and a-halo-ketones. 

According to Angyal s recommendation,1 the optimal Sommelet reaction may be run without isolation of the hexaminium salt under such conditions 0.1 mole of halomethyl compound is heated under reflux for one or two hours with 30 g of hexamine in 90 mL of 50% acetic acid, or with 16.5 g of hexamine in 90 mL of 60% ethanol. 

The antimicrobial efficacy of the amine-formaldehyde reaction products essentially corresponds to the formaldehyde content of these compounds. Known exceptions are HTA, hexahydro-oxadiazines and octahydro-s-tetrazines, which derive from ammonia respectively certain alkylolhydrazines (Paulus, 1980) here the detection of formaldehyde by the Taimenbaum methods gives a negative result, which means that these substances have no significant antimicrobial effect at neutral to alkaline pH they release formaldehyde in acidic media only. This pH dependency is broken off, if, for example, HTA is quatemized (Jacobs et al., 1916). In contrast to HTA the quaternary hexaminium salts release formaldehyde widely independent of pH and therefore may be used as preservatives also for media of neutral to alkaline pH. They are not comparable with the surface active conventional quaternary ammonium compounds (QACs see Section 16.1)... 

The 3 M NH3 and 6 m CH2O first liberated during hydrolytic cleavage at pH values > 7 will soon become rearranged to form 0 75 M hexamethylenetetramine and 1 5 M CH2O, the latter remaining available for the antimicrobial efficacy. Examination of MICs of different quaternary hexaminium salts confirms that in actual fact a mere 25% (approx.) of the hexaminium salts calculated formaldehyde content is available for the antimicrobial efficacy (see Table 23). 

Table 23. MIC of Quaternary Hexaminium Salts for Bacillus subtilis Fouild and Calculated from the CH2O Content of the Compounds...

The antimicrobial efficacy corresponds with the formaldehyde which is released and disposable from the molecule (see Section 3.3). Although there are two hex-aminium moieties in the molecule of the a.i., compared with the iV-(3-chloroallyl)-hexaminium salt one can expect an increase in efficacy of 20% only due to the considerable ascent of the molecular weight. 

The quaternary bis-hexaminium salt described here is particularly useful as a preservative in a wide variety of water based systems, e.g. polymer emulsions, latex paints, pigment and dye slurries, concrete additives, starches, thickener solutions. Addition rates 0 05-0-2%. For the rest what is mentioned before under Section 3.3 and 3.3.2 is valid. 

The AT-carboxymethyl-hexaminium salt is a zwitterionic substance that can be used as a preservative for aqueous functional fluids containing nonionic, anionic, or cationic components without deactivation or problems of incompatibility. Addition rates 0-1-0-3%. 

Other quaternary hexaminium salts (Scott Wolf, 1962)... 

Generally the activity of formaldehyde releasing compounds is reduced in alkaline media containing ammonia, because of the formation of inactive hexam-ethylene tetramine (Section 3.3.1). In the case of MCA, however, the hexamethylene tetramine formed reacts with MCA or CA to give quaternary hexaminium salts (Sections 3.3.5 and 3.3.6) which are effective, as they release formaldehyde widely independent of pH (see Section 3.3). 

The D lepine method , for primary amines, is based on the quatemisation of hexamine with an alkyl halide the resulting hexaminium salt is then decomposed with ethanolic hydrochloric acid to give the desired amine, ammonia and the carbon fi agments of the ring as diethylformed (reaction 43). 

Jacobs discovered the bactericidal effects of the quaternary hexaminium salts. 

Figure 12 Hydrolytic cleavage of quaternary hexaminium salts.

Table 25 MIC of quaternary hexaminium salts for Bacillus subtilis found and calculated from the CH2O content of the compounds...

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