Quaternization of amines

The alkylation process possesses the advantages that (a) a wide range of cheap haloalkanes are available, and (b) the substitution reactions generally occur smoothly at reasonable temperatures. Furthermore, the halide salts formed can easily be converted into salts with other anions. Although this section will concentrate on the reactions between simple haloalkanes and the amine, more complex side chains may be added, as discussed later in this chapter. The quaternization of amines and phosphines with haloalkanes has been loiown for many years, but the development of ionic liquids has resulted in several recent developments in the experimental techniques used for the reaction. In general, the reaction may be carried out with chloroalkanes, bromoalkanes, and iodoalkanes, with the reaction conditions required becoming steadily more gentle in the order Cl Br I, as expected for nucleophilic substitution reactions. Fluoride salts cannot be formed in this manner. 

The quaternization of amines is an extensively studied reaction in organic chemistry. The quaternization of piperidine can follow two distinct stereochemical pathways, axial or equatorial alkylation (70MI20700). Since the Curtin-Hammett principle is valid in this reacting system it is important to recognize that the product ratio of (87) to (89) does not directly reflect the ratio of (86) to (88). 

Organic syntheses were performed by quaternization of amines according to a new peptide procedure (10). In some instances, the amine was not available but the dimethyl amino derivative could be produced from the cyclic carbonyl using the Leukhart reaction (11). 

The quaternization of amines and phosphines with haloalkanes has been known for many years. In general, the reaction may be carried out using chloroalkanes, bromoaUcanes, and iodoalkanes, with the milder reaction conditions in the order Cl Br I, as is expected for nucleophilic substitution reactions. Fluoride salts cannot be formed in this manner. 

The quaternization of amines to the quaternary ammonium salt has proved a very useful method of converting the soft amine base to the pH insensitive quaternary ammonium salt. The amine is reacted with an appropriate measure of an alkyliodide as first described by Menshutkin (106). This reaction was systematically examined by Arcus and Hall in the 1960s as a means of quaternizing preformed polymers (107), and has emerged as a method of choice. For example, thwarted in our efforts to solubilize a high molecular weight... 

Quaternization of amines. Amines (primary, secondary, and tertiary) are efficiently quaternized by methyl iodide and potassium bicarbonate in methanol at 20°. The reagent does not attack hydroxyl or phenolic groups, amides, or amino groups protected as the BOC or CBZ derivatives. ... 

Polyamines can also be made by reaction of ethylene dichloride with amines (18). Products of this type are sometimes formed as by-products in the manufacture of amines. A third type of polyamine is polyethyleneimine [9002-98-6] which can be made by several routes the most frequently used method is the polymeriza tion of azitidine [151 -56 ] (18,26). The process can be adjusted to vary the amount of branching (see Imines, cyclic). Polyamines are considerably lower in molecular weight compared to acrylamide polymers, and therefore their solution viscosities are much lower. They are sold commercially as viscous solutions containing 1—20% polymer, and also any by-product salts from the polymerization reaction. The charge on polyamines depends on the pH of the medium. They can be quaternized to make their charge independent of pH (18). 

Besides the salts (458) and (459) previously described, aminopyrazolium salts can be obtained from the reaction between amines and chloropyrazolium salts (Section 4.04.2.3.7(ii)) or by quaternization of iminopyrazplines as in (461)—> (462) (72BSF2807). The lithium aluminum hydride reduction of the salt (462) affords mixtures of reduced and open-chain pyrazoles (Figure 23 Section 4.04.2.1.6(i)). 

A special type of ammonio group is represented by 4-( 1 -pyridinium)-pyridine and other azinium analogs. Such products often result from self-quaternization of highly reactive derivatives. A -(4-Pyridyl)-and A -(3-nitro-4-pyridyl)-pyridinium chloride hydrochlorides (121) react with aniline, chloride ion, and water to give 4-substituted pyridines plus pyridine. l-(2-Quinolyl)- and l-(4-quinolyl)-pyridinium salts undergo 2- and 4-substitution, respectively, with amines, anilines, hydroxylamine, phenols, alkoxides, mercaptans, and chloride... 

In principle, the quaternization reactions are extremely simple the amine (or phosphine) is mixed with the desired haloalkane, and the mixture is then stirred and heated. The following section refers to the quaternization of l-alkylimidazoles, as these are the most common starting materials. The general techniques are similar, however, for other amines such as pyridine [9], isoquinoline [10], 1,8-diazabi-cyclo[5,4,0]-7-undecene [11], 1-methylpyrrolidine [12], and trialkylamines [13], as... 

The C6 position of a V,./V-dialkyl-3//-azepin-2-amine, e.g. 1, displays remarkable reactivity towards electrophilic substitution, and with dimethyl(methylsulfanyl)sulfonium tetrafluorobor-ate undergoes methylsulfanylation and quaternization to yield 6-(methylsulfanyl)-3//-azepin-ium tetrafluoroborates, e.g. 2, identical to those obtained by quaternization of the free bases with trityl tetrafluoroborate.64 Basification of the salts with potassium carbonate yields the free bases, e.g. 3, which decompose during distillation or on exposure to air. 

The direct quaternization of chloromethylated polystyrenes by tertiary amines or phosphines represents the easiest way to obtain polymer-supported quaternary onium salt (12,13). A lipophilic character of quaternary cation and a topology allowing sufficient cation-anion separation also play an important role (35,36). A linear spacer chain (of about 10 carbon atoms) between the catalytic site and the polymer backbone substantially increases the reaction rates. The loading of quaternary onium groups also affects catalytic efficiency, the influence being different for directly bonded and spaced groups, e.g. 10 and 11, respectively (37). 

Molecular weights of the products as measured with vapor pressure osmometry were in good agreement with the calculated ones. Interestingly, resins based on hexahydrophthalic anhydride and diisopropanolamine with tertiary amines as functional groups are soluble in water without quaternization of the... 

Another quaternary anti arrhythmic agent is emilium tosyl-ate ( ). It is synthesized simply by quaternization of m-methoxybenzyl chloride (64) with dimethyl ethyl amine followed by ion exchange. 

Quaternary ammonium iodides are attractive choices because they generally have good activity, low cost, and solubility in the reaction and recovery processes. Simple quaternization of the wide variety of available tri(n-alkyl) amines with n-alkyl iodides allows optimization of the tetra(n-alkyl) ammonium iodide salt properties ... 

The quaternization of the nitrogen atom in these unsaturated amines alters considerably the position of the equilibrium. This fact has been taken advantage of in the synthesis (Scheme 2) of the ladybug alkaloid coccinellin (79TL1991). 

Overall, there is a slight preference for axial quaternization of piperidine derivatives (equation 28). The degradation of amines via these quaternary ammonium salts (Hofmann... 

The preparation of conjugated dienes from pyridines is exemplified by the transformation of 2-picoline into the sex pheromone (669) of Lobesia botrana, a major pest of vineyards (Scheme 154) (80TL67). Thus, the lithio salt of 2-picoline was alkylated by 2-(5-chloropentyl-oxy)tetrahydropyran, the resulting pyridine (665) N-methylated, and the pyridinium salt reduced by sodium borohydride. Quaternization of the 1,2,3,6-tetrahydropyridine (666) and Hofmann elimination gave the (7 , 9Z)-undecadien-l-ol (667) as the sole isomer. Protection of the alcohol and treatment of the corresponding ammonium salt (668) of the amine with lithium dimethylcuprate gave pure (669) after hydrolysis, acetylation and HPLC purification. 

The only drawback of strategies for the synthesis of tertiary amines that are based on the quaternization of polystyrene-bound /V-nucleophiles is that quaternizations on polystyrene only proceed sluggishly and generally require the use of highly reactive alkylating agents (methyl, allyl, or benzyl halides or sulfonates see Section 10.2). 

The quaternization of tertiary amines on cross-linked polystyrene has been investigated in detail. The most commonly used substrates in these studies have been N,N-dialkyl- 3-alanine derivatives because, after their quaternization, pure tertiary amines can be released from the support by treatment with a base (see Section 3.7). 

Table 10.16. Quaternization of support-bound tertiary amines.

As expected, carbon-13 shifts of phosphines (Table 4.49) are enhanced by increasing alkylation (a effect) and increasing number of jS alkyl carbons ([1 effect). In contrast to amines, however, quaternization of phosphines causes shieldings in a and fi posititions (Table 4.49). A particularly large a shielding is induced by quaternization of triphenylphosphine. 

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