Alkylation with amines and ammonium salts

J. H. Brewster, E. L. Eliel, Carbon-Carbon Alkylations with Amines and Ammonium Salts , Org. React. 1953, 7, 99-197 [covers Michael Additions Starting from /3-(Dialkylamino) ketones, -esters or Nitriles],... 

These correlations are often confirmed by experiment. For example, for the reaction of alkyl halides with amines (quaternary ammonium salts are formed), a linear increase in E is observed with increasing both the product iiaI b nd e". The plots of the type AE A[(e - l)/(2e + 1)] and AE A(e ) at sufficiently high e (e > 3) virtually coincide. Therefore, when based on experimental data only, we cannot distinguish these two models of transition state. Note that the transition state can be considered as a sum of two dipoles if the distance between polar groups exceeds their sizes. And vice versa, if polar groups in the transition state are very close, they can... 

We ve already studied the two most general reactions of amines—alkylation and acylation. As we saw earlier in this chapter, primary, secondary, and tertiary amines can be alkylated by reaction with a primary alkyl halide. Alkylations of primary and secondary amines are difficult to control and often give mixtures of products, but tertiary amines are cleanly alkylated to give quaternary ammonium salts. Primary and secondary (but not tertiary) amines can also be acylated by nucleophilic acyl substitution reaction with an acid chloride or an acid anhydride to yield an amide (Sections 21.4 and 21.5). Note that overacylation of the nitrogen does not occur because the amide product is much less nucleophilic and less reactive than the starting amine. 

H). On the other hand, the synthesis of unsymmetricaUy iV,iV -substituted congeners is less straightforward as a functionalised imidazole has to be isolated prior to alkylation or arylation. Two main methods are available for imidazole functionaU-sation deprotonation with metalUc Na or K leading to an imidazoUde (I) followed by reaction with RX or reaction of glyoxal with a primary amine, an ammonium salt and formaldehyde (J). Al-functionalised imidazole can then be alkylated or... 

Figure 5-26. The alkylation of a primary amine gives mixtures of mono- and disubstituted products, together with the quaternary ammonium salt. This occurs because the electron releasing effects of the alkyl groups are such that the introduction of more alkyl groups makes the nitrogen more nucleophilic.

Chlorobenzene is employed in the synthesis of certain amino-containing vat dye intermediates. When reacted with phthalic anhydride, the product is 2-chloroanthraquinone, which, with ammonia, is converted readily into 2-aminoanthraquinone (61). Other routes include replacement of halogen by amino groups, with ammonia or ammonium salts of urea, and alkyl- and aryl amines to afford secondary amines. Modification of the amino group by alkylation, with dimethyl sulfate, alkyl halides or esters of toluenesul-fonic acids, is of synthetic value. Arylation of the amino groups is of importance only in the reaction between aminoanthraquinones and nitro- or chloroanthraquinones to yield dianthraquinonylamines, or anthrimides48. For example, the reaction between 62 and 63 yields 64, which can then be converted into carbazole 65, Cl Vat Brown R (Scheme 14). Amination of haloanthraquinones such as l-amino-4-bromoanthraquinone-2-sulfonic acid (bromamine acid) (66), prepared from 1-aminoanthraquinone, is of industrial use. 

In processes of producing alkylamines, and particularly methyl-amines, by reacting the corresponding alkyl chlorides, halides, hydroxides and so forth, with ammonia or ammonium salts such as ammonium chloride, the reaction product usually contains substantial quantities of all three of the primary, secondary and tertiary amines, even though the temperature, pressure, proportions and other reaction conditions may be controlled so as to give rise to a preponderance of one of said amines. 

Sulfonium and ammonium salts are prepared readily by alkylation of sulfides or amines. For example, allylation of the amine 318 gave the intermediate ammonium salt 319 (3.205). Deprotonation to the ylide with sodium hydride was followed by [2,3]-sigmatropic rearrangement at room temperature to give the peni-cilhn derivative 320. In a synthesis of y-cyclocitral, the sulfonium salt 321 was prepared by alkylation of 1,3-dithiane and was converted to the ylide 322 and hence the rearranged product 323 (3.206). 

A dealkylation reaction can be defined as the removal of an alkyl group, and its subsequent replacement by hydrogen, or the removal of an alkyl group from an ammonium salt with the formation of an amine, e.g. 

Other routes construct the heterocycle in a one-pot reaction (routes B, C). 1-Substituted imidazoles are formed when an aqueous solution of glyoxal is treated with alkyl amine, formaldehyde, and ammonium salt (route B). The reaction proceeds in acidic media [26]. When 2equiv of the primary amine... 

The efficiency of a surfactant in platelet exfoliation and interfacial bonding should be considered as the main criterion for its selection. However, it is advisable to select a surfactant with respect to its thermal stability a well. The number and length of alkyl chains, type of counterion, and class of amine (or ammonium salt) - primary, secondary, or tertiary - were considered important parameters influencing the thermal stability of nanocomposites. 

More exotic thioureas were the products of interesting reactions of isothiocyanates with ketimines, enamines imino-esters/ amidines, amidrazones, and substituted ammonium salts. Some selenoureas have been synthesized by the reaction of isoselenocyanates with amines, and the phosphorus compounds (300) were obtained analogously by treatment of w-mercaptoalkylphenylphosphines with phenyl isothiocyanate. The action of primary amines on (300) resulted in the formation of N-alkyl-lsT-phenylthioureas in high yields with simultaneous regeneration of the w-mercaptoalkylphenylphosphine. ... 

Salt formation with Brmnsted and Lewis acids and exhaustive alkylation to form quaternary ammonium cations are part of the rich derivati2ation chemistry of these amines. Carbamates and thiocarbamates are formed with CO2 and CS2, respectively the former precipitate from neat amine as carbamate salts but are highly water soluble. 

The nitrogen of aHphatic and aromatic amines is alkylated rapidly by alkyl sulfates yielding the usual mixtures. Most tertiary amines and nitrogen heterocycles are converted to quaternary ammonium salts, unless the nitrogen is of very low basicity, eg, ia tn phenylamine. The position of dimethyl sulfate-produced methylation of several heterocycles with more than one heteroatom has been examined (22). Acyl cyanamides can be methylated (23). Metal cyanates are converted to methyl isocyanate or ethyl isocyanate ia high yields by heating the mixtures (24,25). 

Low surface energy substrates, such as polyethylene or polypropylene, are generally difficult to bond with adhesives. However, cyanoacrylate-based adhesives can be effectively utilized to bond polyolefins with the use of the proper primer/activa-tor on the surface. Primer materials include tertiary aliphatic and aromatic amines, trialkyl ammonium carboxylate salts, tetraalkyl ammonium salts, phosphines, and organometallic compounds, which are initiators for alkyl cyanoacrylate polymerization [33-36]. The primer is applied as a dilute solution to the polyolefin surface, solvent is allowed to evaporate, and the specimens are assembled with a small amount of the adhesive. With the use of primers, adhesive strength can be so strong that substrate failure occurs during the course of the shear tests, as shown in Fig. 11. 

Ammonia and other amines are good nucleophiles in SN2 reactions. As a result, the simplest method of alkylamine synthesis is by Sn2 alkylation of ammonia or an alkylamine with an alky) halide. If ammonia is used, a primary amine results if a primary amine is used, a secondary amine results and so on. Even tertiary amines react rapidly with alkyl halides to yield quaternary ammonium salts, R4N+ X-... 

Benzylic quaternary ammonium salts, when treated with alkali metal amides, undergo a rearrangement called the Sommelet-Hauser rearrangementSince the product is a benzylic tertiary amine, it can be further alkylated and the product again subjected to the rearrangement. This process can be continued around the ring until an ortho position is blocked. ... 

The alkyl halide (ethyl bromide in the above equation) can react further with the primary amine produced to give a secondary amine and with that to form a tertiary amine and finally a quaternary ammonium salt. Quaternary ammonium hydroxides are very strong bases like sodium hydroxide. Tetramethylammonium hydroxide is a very important chemical used in the manufacture of semiconductors and other electronic industry products. 

Certain quaternary ammonium salts will alkylate [Co (DMG)2py] . The addition of PhCH2NMc3 I to a solution of the complex in methanol gives the PhCH2Co complex in 45% yield. The reaction works more slowly with dimethylpiperidinium iodide to give the CH3—Co complex 15). There is no alkylation with tertiary amines alone 164), but in the presence of equimolar amounts of dimethylacetylenedicarboxylate certain aliphatic tertiary amines can alkylate [Co (DMG)2py] in methanol solution. The reaction also produces the enamine derivative of a maleic ester, and the mechanism appears to involve addition of the amine to the triple bond to form an ammonium salt, which can then attack the Co(I) derivative (75). 

A thio-substituted, quaternary ammonium salt can be synthesized by the Michael addition of an alkyl thiol to acrylamide in the presence of benzyl trimethyl ammonium hydroxide as a catalyst [793-795]. The reaction leads to the crystallization of the adducts in essentially quantitative yield. Reduction of the amides by lithium aluminum hydride in tetrahydrofuran solution produces the desired amines, which are converted to desired halide by reaction of the methyl iodide with the amines. The inhibitor is useful in controlling corrosion such as that caused by CO2 and H2S. 

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