Amine with alkyl halides

Amines are powerful nucleophiles which react under neutral or slightly basic conditions with several electron-accepting carbon reagents. The reaction of alkyl halides with amines is useful for the preparation of tertiary amines or quaternary ammonium salts. The conversion of primary amines into secondary amines is usually not feasible since the secondary amine tends towards further alkylation. 

Ju and Varma envisioned that the nucleophilic substitution reaction of alkyl halides with amines may be accelerated by microwave energy because of their polar nature [88]. An environmentally friendly synthesis of tertiary amines via direct JV-alkylation of primary and secondary amines by alkyl halides under microwave irradiation was developed (Scheme 21), that pro-... 

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... 

Synthesis of primary amines from alkyl halides with hexamelhylenetelramines. 

Primary amines through reaction of alkyl halides with hexamethylenetetramine... 

Nitriles are similar in some respects to carboxylic acids and are prepared either by SN2 reaction of an alkyl halide with cyanide ion or by dehydration of an amide. Nitriles undergo nucleophilic addition to the polar C=N bond in the same way that carbonyl compounds do. The most important reactions of nitriles are their hydrolysis to carboxylic acids, reduction to primary amines, and reaction with organometallic reagents to yield ketones. 

Azide synthesis (Section 24.6) A method for preparing amines by S 2 reaction of an alkyl halide with azide ion, followed by reduction. 

A convenient way of obtaining secondary amines without contamination by primary or tertiary amines involves treatment of alkyl halides with the sodium or calcium salt of cyanamide NH2—CN to give disubstituted cyanamides, which are then hydrolyzed and decarboxylated to secondary amines. Good yields are obtained when the reaction is carried out under phase-transfer conditions. The R group may be primary, secondary, allylic, or benzylic. 1, co-Dihalides give cyclic secondary amines. 

Unsymmetrical secondary aliphatic amines have been prepared by reaction of alkyl halides with benzylidene amines and subsequent hydrolysis 814 by reaction of alkyl halides with alkyl amines 5 by reduction of amine-aldehyde adducts 8-8 and by dealkylation of tertiary amines with dibenzoyl peroxide. ... 

By heating an alkyl halide with an alcoholic solution of ammonia in a sealed tube, a mixture of amines is formed by nucleophilic substitution reaction. 

Gabriel Synthesis The reaction of an alkyl halide with potassium phthalimide to form, after hydrolysis, a primary amine. 

In addition to alkylation with alkyl halides, electrophilic amination has been achieved with di-(/< /r-butyl) azodi-carboxylate <2004HCA1016>, and reactions with aldehydes have generated alcohol derivatives <1999JOC8668, 2003TL671>. Dialkylation at the 5-position has also been achieved <1998TA3881>. 

Bis-iV-alkylated complexes of Me2-9 and Me2-ll, as well as the tetra-methylated Ni(II)cyclam (NinTMC) derivatives, have been synthesized by the deprotonation of secondary amines followed by alkylation (34, 47,48). When EtI or other alkyl halide with /3-hydrogen was added to the deprotonated Ni(II) complex of cyclam or 11, HX elimination occurred instead of SN2 reaction. Therefore, ethylene gas was produced instead of -ethylated complex formation when EtI was added to the deprotonated complex of cyclam or 11. However, in the case of 8, bis- -ethylated Ni(II) complex was isolated. This may be because HX elimination is slower than SN2 reaction. The - -alkylated Ni(II) complexes of 9 (Me2-9 and Et2 9) and Me2-ll were stable against ligand dissociation in acidic aqueous solutions. The -alkylated complexes were dealkylated when the complexes were heated in aqueous solutions (34, 47). 

The quaternary ammonium compounds (qv) are manufactured by the reaction of an alkyl halide with a tertiary amine. The alkyl halide may be short-chain, long-chain, or benzyl. Selection of a long-chain alkyl group yields structures with variable composition and greatly adds to the chemical complexity inherent in this group. Investigation of structure-activity relationships has led to claims for superior efficacy or compatibility, most notedly with anionic surfactants in disinfectant-detergent cleaner systems, of closely related compounds in the family. 

Alkyl halides with (3-hydrogens generally undergo only elimination reactions under the conditions of the vinyl substitution (100 C in the presence of an amine or other base). Exceptions are known only in cases where intramolecular reactions are favorable. Even alkyl halides without (3-hydrogens appear not to participate in the intermolecular alkene substitution since no examples have been reported, with the exception of reactions with benzyl chloride and perfluoroalkyl iodides. 

Recently, organic carbamates have been synthesized by the reaction of amines and alkyl halides with scC02 in the presence of potassium carbonate and an onium salt (Bu4N)Br [52]. In order to ascertain the carbonyl-active species (carbonate or C02 ), the reaction was carried out also with potassium phosphate instead of the carbonate salt the similar results obtained confirmed that scC02 acted in the process not only as a solvent but also as a carboxylating agent. 

A one-pot PTC reaction procedure for the overall conversion of an alkyl halide into a primary amine via an azide is particularly illustrative.204 Thus the reduction of the azide is effected by the addition of sodium borohydride to a reaction mixture arising from the PTC displacement reaction of an alkyl halide with sodium azide (the preparation of 1-octylamine, Expt 5.193). The reaction appears to be applicable to primary and secondary alkyl halides, alkyl methane-sulphonates and benzylic halides. 

A C—N disconnection of a primary amine gives rise to the carbocation and amide anion synthons. It might be predicted therefore that treatment of an alkyl halide with ammonia (reagents equivalent to the above synthons) under pressure would constitute a suitable synthesis of a primary amine. In practice, however, the yield is poor since a mixture of all three classes of amines, together with some of the quaternary ammonium salt, is obtained, owing to more ready further alkylation of the sequentially formed products. 

Merker, R. L. Scott, M. J. The reaction of alkyl halides with carboxylic acids and phenols in the presence of tertiary amines./. Org. Chem. 1961, 26, 5180-5182. 

So the reaction of an alkyl halide with NaSH or Na2S cannot usually be made to stop after one alkylation as the anion of the first product is at least as nucleophilic as HS or S2. This is obvious in reactions with Na2S. Less obviously with NaSH the first reaction 18 gives the thiol 19 but this is in equilibrium with RS- and a second displacement 20 gives the sulfide 21. We shall see shortly how to get round this problem. A more important example—the failure of the alkylation of ammonia to give a useful amine synthesis—has chapter 8 to itself. 

Oxidation-reduction (redox) reactions, along with hydrolysis and acid-base reactions, account for the vast majority of chemical reactions that occur in aquatic environmental systems. Factors that affect redox kinetics include environmental redox conditions, ionic strength, pH-value, temperature, speciation, and sorption (Tratnyek and Macalady, 2000). Sediment and particulate matter in water bodies may influence greatly the efficacy of abiotic transformations by altering the truly dissolved (i.e., non-sorbed) fraction of the compounds — the only fraction available for reactions (Weber and Wolfe, 1987). Among the possible abiotic transformation pathways, hydrolysis has received the most attention, though only some compound classes are potentially hydrolyzable (e.g., alkyl halides, amides, amines, carbamates, esters, epoxides, and nitriles [Harris, 1990 Peijnenburg, 1991]). Current efforts to incorporate reaction kinetics and pathways for reductive transformations into environmental exposure models are due to the fact that many of them result in reaction products that may be of more concern than the parent compounds (Tratnyek et al., 2003). 

The overall reaction involves replacing the halogen atom of the alkyl halide with an NH, unit. Another method is the Gabriel synthesis of amines. This involves treating phthalimide with KOH to abstract the N-H proton. The N-H proton of phthalimide is more acidic (pK9) than the N-H proton of an amide since the anion formed can be stabilised by resonance with both neighbouring carbonyl groups. The phthalimide ion can then be alkylated by treating it with an alkyl halide in nucleophilic substitution. 

Subsequent hydrolysis releases a primary amine (Following fig.). Still other possible method is to react an alkyl halide with ammonia, but this is less satisfactory because overalkylation is possible. The reaction of an aldehyde with ammonia by reductive animation is another method of obtaining primary amines. 

Alternate routes to amine derivatives have been developed in the intervening years. The production of dimethylamines can be accomplished by the routes shown in eqs 6.1.4-6.1.7. [8]. Both routes involve the reaction of an alkyl halide with dimethylamine. The first route is the conversion of a fatty alcohol to fatty chloride using phosphorous trichloride. The alkyl chloride is reacted with dimethylamine giving the alkyl dimethylamine [9, 10] ... 

Reaction of alkyl halides with dimethvl hydrazine184 and by initial formation of azides followed by reaction with borohydride185 also gives routes for their interconversion into amines. 

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