Ammonium salts, nucleophilic

There are two generally accepted mechanisms of degradation of neat ammonium salts -nucleophilic substitution and elimination reaction [14, 15], In the former, nucleophilic attack on the R4N+ moiety by, for example, chloride ion leads to the formation of RCl and R3N, which is essentially the reverse reaction of most quaternary ammonium syntheses (Scheme 2.1). 

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. 

Because of its high reactivity toward nucleophilic substitution methyl iodide is the alkyl halide most often used to prepare quaternary ammonium salts... 

Ammonia can act as a nucleophile toward primary and some secondary alkyl halides to give primary alkylamines Yields tend to be modest because the primary amine IS itself a nucleophile and undergoes alkylation Alkylation of ammonia can lead to a mixture containing a primary amine a secondary amine a tertiary amine and a quaternary ammonium salt... 

Alkylation (Section 22 12) Amines act as nucleophiles toward alkyl halides Pri mary amines yield secondary amines secondary amines yield tertiary amines and tertiary amines yield quaternary ammonium salts... 

Ammonium ion, JV-(2-thenyl)-N-benzyldimethyl-Stevens and Sommelet rearrangement, 4, 800 Ammonium salts, diallyldialkyl-polymerization, 1, 293 Ammonium salts, 2-pyrrolylmethyl-nucleophilic substitution abnormal, 4, 244 Sommelet rearrangement, 4, 244 Ammonium salts, trimethyl(l,3,5-triazinyl)-applications, 3, 525 Amobarbital, 3, 150 Amodiaquine, 1, 145 Amolanone applications, 4, 708... 

Phase transfer catalysts were used for nucleophilic displacement reactions of activated leaving groups by hydroxyfurazanyl anions. For example, tetrachloro-pyrazine was found to react with hydroxyfurazans in benzene/Na2C03/tetraalkyl-ammonium salts giving products of mono- or disubstitution (Scheme 173) (94MI1). The course of the reaction depends on the ratio of the reactants and the nature of the ammonium salt. 

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-... 

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. 

In this method, a catalyst is used to carry the nucleophile from the aqueous into the organic phase. As an example, simply heating and stirring a two-phase mixture of 1-chlorooctane for several days with aqueous NaCN gives essentially no yield of 1-cyanooctane. But if a small amount of an appropriate quaternary ammonium salt is added, the product is quantitatively formed in about 2 h." There are two principal types of phase-transfer catalyst. Though the action of the two types is somewhat different, the effects are the same. Both get the anion into the organic phase and allow it to be relatively free to react with the substrate. 

Other nitrogen compounds, among them hydroxylamine, hydrazines, and amides (15-9), also add to alkenes. Even with amines, basic catalysts are sometimes used, so that RNH or R2N is the actual nucleophile. Tertiary amines (except those that are too bulky) add to Michael-type substrates in a reaction that is catalyzed by acids like HCl or HNO3 to give the corresponding quaternary ammonium salts. " ... 

In the synthesis of DMC fiom the transesterification of EC and methanol, quaternary ammonium salt catalysts showed good catalytic activity. The main byproduct was ethylene glycol. The quaternary salt with the cation of bulkier alkyl chain laigth and witii more nucleophilic anion showed better reactivity. Hi temperature and large amount of catalyst increased the conversion of EC. The EC conversion and DMC selectivity increased as the pressure of CO2 increased from 250 to 350 psig. 

The Delepine reaction Involves nucleophilic displacement of active halides by hexamethylenetetramine, followed by hydrolysis of Intermediate quaternary ammonium salt to release the amine. 

Benzylic quaternary phosphonium and ammonium salts are dealky-lated by mild heating and/or nucleophilic anions, particularly iodide (9) and thiolate (10), but also hydroxide (11). Most N-benzyl-pyridinium or quaternary aryl ammonium compounds are particularly susceptible (12). Decompositions of this sort have seriously limited the usefulness of solid phase-transfer catalysts derived from (chloromethyl)polystyrene (13, 14). 

Secondary amines, such as pyrrolidine, must be alkylated with care too polar a solvent leads to participation of a second nearby polymer-bound alkylant in the formation of a quaternary ammonium salt, along with the desired immobilized trialkyl amine. The exception, as seen above, is diisopropylamine, which refuses to displace tosylate even in the refluxing pure amine, or in hot dimethyl-formamide or other polar solvent, while metal diisopropylamide is notorious as a powerful non-nucleophilic base. However, carboxamide is not difficult to form from (carboxymethyl)polystyrene, again using toluenesulfonyl chloride as condensing agent this can then be reduced to (diisopropyl-ethylaminoethyl)polystyrene, which is of interest as a polymer-bound non-nucleophilic base. ... 

Uncatalyzed amidations of acids have been realized under solvent-free conditions and with a very important microwave effect [67 a]. The best results were obtained by use of a slight excess of either amine or acid (1.5 equiv.). The reaction involves thermolysis of the previously formed ammonium salt (acid-base equilibrium) and is promoted by nucleophilic attack of the amine on the carbonyl moiety of the acid and removal of water at high temperature. The large difference in yields (MW > A) might be a consequence of interaction of the polar TS with the electric field (Eq. (15 a) and Tab. 3.6). 

Catalysis, enzymatic, physical organic model systems and the problem of, 11,1 Catalysis, general base and nucleophilic, of ester hydrolysis and related reactions, 5,237 Catalysis, micellar, in organic reactions kinetic and mechanistic implications, 8,271 Catalysis, phase-transfer by quaternary ammonium salts, 15,267 Catalytic antibodies, 31,249... 

Partitioning of carbocations between addition of nucleophiles and deprotonation, 35, 67 Perchloro-organic chemistry structure, spectroscopy and reaction pathways, 25, 267 Permutational isomerization of pentavalent phosphorus compounds, 9, 25 Phase-transfer catalysis by quaternary ammonium salts, 15, 267 Phosphate esters, mechanism and catalysis of nucleophilic substitution in, 25, 99 Phosphorus compounds, pentavalent, turnstile rearrangement and pseudoration in permutational isomerization, 9, 25... 

The reaction of 5-[2-(iV,./V-dimethylamino)ethyl]-l,2,4-oxadiazole with methyl iodide forms the quaternary ammonium salt 170 (Scheme 22), which undergoes elimination in the presence of base (diisopropylethylamine (DIEA), TEA, l,8-diazabicyclo[4.3.0]undec-7-ene, etc.) to form an intermediate 5-vinyl-l,2,4-oxadiazole 171, which undergoes in situ Michael addition with nucleophiles to furnish the Michael adducts 172. As an example, also shown in Scheme 22, 3-hydroxy-pyrrolidine allows the synthesis of compound 172a in 97% yield. Mesylation followed by deprotonation of the 1,2,4-oxadiazole methylene at C-5 enables Sn2 displacement of the mesylate to give the 5-azabicycloheptyl derivative 173, which is a potent muscarinic agonist <1996JOC3228>. 

Triorganostannyl anions are excellent nucleophiles in SrnI processes with aromatic substrates,86 and arylstannanes can be prepared from the photostimulated reactions of Ph3SnNa or Me3SnNa (from R3SnCl + Na) and aryl halides in DMSO, or of aryl amines, via their ammonium salts,88 in liquid ammonia, or of phenols, via their phosphates, in liquid ammonia.89 Examples are given in Equations (11)—(13). 

The hydration number (the number of water molecules intimately associated with the salt) of the quaternary ammonium salt is very dependent upon the anion. The change in the order of reactivity is thus believed to be due to the hydration of the anion the highly hydrated chloride and cyanide ions are less reactive than expected, and the poorly hydrated iodide fares better under phase transfer conditions than in homogeneous reactions. Methanol may specifically solvate the anions via hydrogen bonding, and this effect is responsible for the low reactivity of more polar nucleophiles in that solvent. 

The ammonium catalyst can also influence the reaction path and higher yields of the desired product may result, as the side reactions are eliminated. In some cases, the structure of the quaternary ammonium cation may control the product ratio with potentially tautomeric systems as, for example, with the alkylation of 2-naph-thol under basic conditions. The use of tetramethylammonium bromide leads to predominant C-alkylation at the 1-position, as a result of the strong ion-pair binding of the hard quaternary ammonium cation with the hard oxy anion, whereas with the more bulky tetra-n-butylammonium bromide O-alkylation occurs, as the binding between the cation and the oxygen centre is weaker [11], Similar effects have been observed in the alkylation of methylene ketones [e.g. 12, 13]. The stereochemistry of the Darzen s reaction and of the base-initiated formation of cyclopropanes under two-phase conditions is influenced by the presence or absence of quaternary ammonium salts [e.g. 14], whereas chiral quaternary ammonium salts are capable of influencing the enantioselectivity of several nucleophilic reactions (Chapter 12). 

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