Tertiary amines quaternary salt formation

Distillation of the tertiary amine before methiodide formation does not significantly affect the yield or purity of the quaternary salt. The amine boils at 91-92°/0.45 mm. 

In contrast to other methods for the methylation of primary amines, for example, the use of methyl iodide, this method leads to good yields of the iV,iV-dimethyl tertiary amines, without the formation of quaternary salt products.3 In comparison to reductive animation techniques, the reagents for the Eschweiler-Clarke reaction are cheap, and the reaction is easily scaled up.4... 

There has been a study of the mechanism of the activation of carboxylic acids to peptide formation by chloro-s -triazines in combination with tertiary amines. The first step, exemplified in Scheme 2 by the reaction of 2-chloro-4,6-disubstituted-l,3,5-triazines (18) with A -methylmorpholine, is formation of a quaternary triazinylammonium salt (20). Here there is NMR evidence for the formation at —50°C of the intermediate (19), showing that the substitution involves the two-step SnAt mechanism rather than a synchronous pathway. The subsequent reaction of (20) with a carboxylic acid yields the 2-acyloxy derivative (21), which carries an excellent leaving group for the amide-forming step. ... 

Initiation takes place by rapid reaction of an ammonium salt with the anhydride (Eq. (46)) whereby ammonium carboxylate is formed. In the propagation step, the carboxylate anion opens an epoxy ring and forms an ammonium alcoholate (Eq. (47)). The latter reacts with the anhydride to yield another ester bond, and ammonium carboxylate is recovered (Eq. (48)). Termination occurs through decomposition of the ammonium counter ion, the alkoxide anion abstracting a proton from the quaternary nitrogen with the formation of a deactivated tertiary amine. 

Electrolysis of quaternary ammonium salts in protic solvents, e.g., methanol, cleaves the C-N bond with formation of a hydrocarbon and a tertiary amine 502l... 

Demethylation of 1-methyl-3-piperideines may be accomplished with the use of the von Braun cyanogen bromide procedure.60,128 A certain drawback of this method consists in loss of half of the tertiary amine in formation of a quaternary salt (e.g., 146), in addition to the required 1-cyano derivative (e.g., 147), which is then hydrolyzed to the required secondary amine. 3-Piperideine was obtained by this procedure in the form of a stable free base.128... 

We have already encountered alkylation of amines as a side reaction in the preparation of primary amines by the ammonolysis of halides (Sec. 22.10), and as a method of synthesis of secondary and tertiary amines (Sec. 22.13). Let us look at one further aspect of this reaction, the formation of quaternary ammonium salts. 

The formation of quaternary ammonium salts, followed by an elimination of the kind just described, is very useful in the determination of the structures of certain complicated nitrogen-containing compounds. The compound, which may be a primary, secondary, or tertiary amine, is converted into the quaternary ammonium hydroxide by treatment with excess methyl iodide and silver oxide. The number of methyl groups taken up by nitrogen depends upon the class of the amine a primary amine will take up three methyl groups, a secondary amine will take up two, and a tertiary amine only one. This process is known as exhaustive methylation of amines. 

Introduction, Amines are organic derivatives of ammonia, with one, two, or three hydrogen atoms replaced by an organic radical. The three types of amines, primary (RNHj), secondary (RjNH), and tertiary (R3N), may be prepared by the reaction of mono-halides with ammonia. In the case of reactive halides, like methyl iodide, the reaction proceeds to the formation of the quaternary salt— tetramethylammonium iodide ... 

When one mole of methyl iodide and four moles of ammonia are used, the formation of primary, secondary, and tertiary amines proceeds rapidly, so that within two minutes the formation of tetramethylammonium iodide assumes the dominant role of the reaction. About seventy-five per cent of the methyl iodide is converted to the quaternary salt, while the remainder forms a mixture of the three amines. The formation of the quaternary salt can be inhibited to a large extent by the addition of an ammonium salt, such as ammonium nitrate, which reacts with the free amino group of the amine to form the ion ... 

General procedure (cf. Hagemann1150) A solution of the amine in dry ether, CHC13, or benzene is added gradually to the BrCN solution (fume cupboard ). The reaction is exothermic. The mixture of amine and BrCN (1-1.1 moles per moles of amine) may also be warmed on a water-bath. By-products, mostly precipitated when a solvent is used, may contain the hydrobromide of the tertiary amine as well as the quaternary ammonium bromide (see above), the requisite HBr being liberated by olefin formation. When no solvent is used, the reaction mixture is extracted with ether. The unused amine and the salts are removed by shaking the solution of A-substituted cyanamide with dilute aqueous acid. 

Treatment of ammonia or primary or secondary amines with alkyl halides almost always leads to a mixture of all the higher alkylation stages. Using an excess of the halide can thus afford the quaternary salt in one stage provided the formation of the hydrohalides is suppressed by addition of a base nevertheless, alkylation of a tertiary base is preferable for preparation of quaternary salts. 

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