Nitrogen nucleophilic substitution

All the mechanisms so far discussed take place at a saturated carbon atom. Nucleophilic substitution is also important at trigonal carbons, especially when the carbon is double bonded to an oxygen, a sulfur, or a nitrogen. Nucleophilic substitution at vinylic carbons is considered in the next section at aromatic carbons in Chapter 13. 

Most syntheses of nitrogen heterocycles involve substitution and/or condensation reactions of nitrogen nucleophiles with difunctional halides or carbonyl compounds. Common nitrogen reagents are ... 

Many saturated nitrogen heterocycles are commercially available from industrial processes, which involve, for example, nucleophilic substitution of hydroxyl groum by amino groups under conditions far from laboratory use, e.g. 

As is broadly true for aromatic compounds, the a- or benzylic position of alkyl substituents exhibits special reactivity. This includes susceptibility to radical reactions, because of the. stabilization provided the radical intermediates. In indole derivatives, the reactivity of a-substituents towards nucleophilic substitution is greatly enhanced by participation of the indole nitrogen. This effect is strongest at C3, but is also present at C2 and to some extent in the carbocyclic ring. The effect is enhanced by N-deprotonation. 

Piperazinothiazoies (2) were obtained by such a replacement reaction, Cu powder being used as catalyst (25. 26). 2-Piperidinothiazoles are obtained in a similar way (Scheme 2) (27). This catalytic reaction has been postulated in the case of benzene derivatives as a nucleophilic substitution on the copper-complexed halide in which the halogen possesses a positive character by coordination (29). For heterocyclic compounds the coordination probably occurs on the ring nitrogen. 

Phthalimide with a of 8 3 can be quantitatively converted to its potassium salt with potassium hydroxide The potassium salt of phthalimide has a negatively charged nitrogen atom which acts as a nucleophile toward primary alkyl halides m a bimolecu lar nucleophilic substitution (Sn2) process... 

Chemical Properties. The presence of both a carbocycHc and a heterocycHc ring faciUtates a broad range of chemical reactions for (1) and (2). Quaternary alkylation on nitrogen takes place readily, but unlike pyridine both quinoline and isoquinoline show addition by subsequent reaction with nucleophiles. Nucleophilic substitution is promoted by the heterocycHc nitrogen. ElectrophiHc substitution takes place much more easily than in pyridine, and the substituents are generally located in the carbocycHc ring. 

Nitrogen nucleophiles used to diplace the 3 -acetoxy group include substituted pyridines, quinolines, pyrimidines, triazoles, pyrazoles, azide, and even aniline and methylaniline if the pH is controlled at 7.5. Sulfur nucleophiles include aLkylthiols, thiosulfate, thio and dithio acids, carbamates and carbonates, thioureas, thioamides, and most importandy, from a biological viewpoint, heterocycHc thiols. The yields of the displacement reactions vary widely. Two general approaches for improving 3 -acetoxy displacement have been reported. One approach involves initial, or in situ conversion of the acetoxy moiety to a more facile leaving group. The other approach utilizes Lewis or Brmnsted acid activation (87). 

Nucleophilic substitution reactions that occur imder conditions of amine diazotization often have significantly different stereochemisby, as compared with that in halide or sulfonate solvolysis. Diazotization generates an alkyl diazonium ion, which rapidly decomposes to a carbocation, molecular nitrogen, and water ... 

Monomeric thiazyl halides can be stabilized by coordination to transition metals and a large number of such complexes are known (Section 7.5). In addition, NSX monomers undergo several types of reactions that can be classified as follows (a) reactions involving the n-system of the N=S bond (b) reactions at the nitrogen centre (c) nucleophilic substitution reactions (d) halide abstraction, and (e) halide addition. Examples of each type of behaviour are illustrated below. 

One potential problem with this procedure is that the product can sometimes act as a nitrogen nucleophile, and multiple substitutions may then occur. It is useful, therefore, to be able to distinguish the relative nucleophilicity of different amines. 

In addition to their reactions with amines, Zincke salts also combine with other nitrogen nucleophiles, providing various A -substituted pyridine derivatives. Pyridine A -oxides result from the reaction with hydroxylamine, as exemplified for the conversion of Zincke salt 38 to the A -oxide 39 Reactions of Zincke salts with hydrazine, meanwhile, lead... 

B. Activation by Azine-Nitrogen and Other Factors in THE Nucleophilic Substitution op Azines... 

Intramolecular nucleophilic displacement of the bromo group by an azine-nitrogen occurs in the cyclization of A-2-quinaldyl-2-bromo-pyridinium bromide (248) to give the naphthoimidazopyridinium ring system. The reaction of 2-bromopyridine and pyridine 1-oxide yields l-(2-pyridoxy)pyridinium bromide (249) which readily undergoes an intramolecular nucleophilic substitution in which departure of hydrogen as a proton presumably facilitates the formation of 250 by loss of the JV-oxypyridyl moiety. 

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