Halogenation nucleophilic substitution

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. 

With the exception of the nuclear amination of 4-methylthiazole by sodium amide (341, 346) the main reactions of nucleophiles with thiazole and its simple alkyl or aryl derivatives involve the abstraction of a ring or substituent proton by a strongly basic nucleophile followed by the addition of an electrophile to the intermediate. Nucleophilic substitution of halogens is discussed in Chapter V. 

Nucleophilic substitution reactions of alkyl halides are related to elimination reactions m that the halogen acts as a leaving group on carbon and is lost as an anion The... 

Nucleophilic substitution is one of a variety of mechanisms by which living systems detoxify halogenated organic compounds introduced into the environment Enzymes that catalyze these reactions are known as haloalkane dehalogenases The hydrolysis of 1 2 dichloroethane to 2 chloroethanol for example is a biological nude ophilic substitution catalyzed by a dehalogenase... 

Unlike elimination and nucleophilic substitution reactions foimation of oigano lithium compounds does not require that the halogen be bonded to sp hybndized carbon Compounds such as vinyl halides and aiyl halides m which the halogen is bonded to sp hybndized carbon react m the same way as alkyl halides but at somewhat slowei rates... 

The Hell-Volhard-Zehnsky reaction is of synthetic value m that the a halogen can be displaced by nucleophilic substitution... 

Nucleophilic substitution by ammonia on a halo acids (Section 19 16) The a halo acids obtained by halogenation of car boxylic acids under conditions of the Hell-Volhard-Zelinsky reaction are reac tive substrates in nucleophilic substitu tion processes A standard method for the preparation of a ammo acids is dis placement of halide from a halo acids by nucleophilic substitution using excess aqueous ammonia... 

One group of aryl halides that do undergo nucleophilic substitution readily consists of those that bear a nitro group ortho or para to the halogen... 

Nucleophilic Substitutions of Benzene Derivatives. Benzene itself does not normally react with nucleophiles such as haUde ions, cyanide, hydroxide, or alkoxides (7). However, aromatic rings containing one or more electron-withdrawing groups, usually halogen, react with nucleophiles to give substitution products. An example of this type of reaction is the industrial conversion of chlorobenzene to phenol with sodium hydroxide at 400°C (8). 

It is possible to introduce sulfonic acid groups by alternative methods, but these ate Htde used in the dyes industry. However, one worth mentioning is sulfitation, because it provides an example of the introduction of a sulfonic acid group by nucleophilic substitution. The process involves treating an active halogen compound with sodium sulfite. This reaction is used in the purification of m-dinitrohen7ene. 

Fiber-Reactive Dyes. These dyes can enter iato chemical reaction with the fiber and form a covalent bond to become an iategral part of the fiber polymer. They therefore have exceptional wetfastness. Thein main use is on ceUulosic fibers where they are appHed neutral and then chemical reaction is initiated by the addition of alkaH. Reaction with the ceUulose can be by either nucleophilic substitution, using, for example, dyes containing activated halogen substituents, or by addition to the double bond in, for example, vinyl sulfone, —S02CH=CH2, groups. 

The reactivity of halogens in pyridazine N- oxides towards nucleophilic substitution is in the order 5 > 3 > 6 > 4. This is supported by kinetic studies of the reaction between the corresponding chloropyridazine 1-oxides and piperidine. In general, the chlorine atoms in pyridazine A-oxides undergo replacement with alkoxy, aryloxy, piperidino, hydrazino, azido, hydroxylamino, mercapto, alkylmercapto, methylsulfonyl and other groups. 

The most useful syntheses of pyridazines and their alkyl and other derivatives begins with the reaction between maleic anhydride and hydrazine to give maleic hydrazide. This is further transformed into 3,6-dichloropyridazine which is amenable to nucleophilic substitution of one or both halogen atoms alternatively, the halogen(s) can be replaced by hydrogen as shown in Scheme 110. In this manner a great number of pyridazine derivatives are prepared. 

Broadly speaking, nucleophilic substitution may be divided into (a) the direct displacement of hydrogen and (b) the displacement of other substituents. Displacements of type (a) are rare and are typified by the Tschitschibabin reaction. Pyrazine reacts with NaNHa/NHs to yield 2-aminopyrazine, but no yield has been quoted (46USP2394963). Generally, the synthesis of aminopyrazines, aminoquinoxalines and aminophenazines is more readily accomplished by alternative methods, particularly displacement of halogen from the corresponding halo derivatives, which are themselves readily available. 

In the case of substituted phenazine fV-oxides some activation of substituents towards nucleophilic substitution is observed. 1-Chlorophenazine is usually very resistant to nucleophilic displacements, but the 2-isomer is more reactive and the halogen may be displaced with a number of nucleophiles. 1-Chlorophenazine 5-oxide (56), however, is comparable in its reactivity with 2-chlorophenazine and the chlorine atom is readily displaced in nucleophilic substitution reactions. 2-Chlorophenazine 5,10-dioxide (57) and 2-chlorophenazine 5-oxide both show enhanced reactivity relative to 2-chlorophenazine itself. On the basis of these observations, similar activation of 5- or 6-haloquinoxaline fV-oxides should be observed but little information is available at the present time. 

In contrast, substituents in 1,2,4-triazoles are usually rather similar in reactivity to those in benzene although nucleophilic substitution of halogen is somewhat easier, forcing conditions are required. 

Halogen atoms in the 2-position of imidazoles, thiazoles and oxazoles (542) undergo nucleophilic substitution reactions. The conditions required are more vigorous than those used, for example, for a- and y-halogenopyridines, but much less severe than those required for chlorobenzene. Thus in compounds of type (542 X = Cl, Br) the halogen atom can be replaced by the groups NHR, OR, SH and OH (in the last two instances, the products tautomerize see Sections 4.02.3.7 and 4.02.3.8.1). 

Azaindolizine, 5-chloro-nucleophilic substitution, 4, 458 8-Azaindolizine, 7-chloro-nucleophilic substitution, 4, 458 Azaindolizines basicity, 4, 454 electronic spectra, 4, 445 electrophilic substitution, 4, 453 halogenation, 4, 457 hydrogen/deuterium exchange, 4, 458 NMR, 4, 447, 449 nucleophilic attack, 4, 458 protonation, 4, 453 reaction with isothiocyanates, 4, 513 reactions, 5, 267 reviews, 4, 444 UV spectra, 4, 446, 449 Azaindolizines, amino-tautomerism, 4, 452... 

---