Halogen by nucleophiles

Monohalogcno compounds are more likely to be accessible when imidazoles with an electron-withdrawing substituent are halogenated, by nucleophilic methods (see Section 7.3.1), and via oiganolithium derivatives (see Section 7.2.2), Alternatively, it may be possible to polyhalogenate, then selectively reduce one or more of the halogen substituents. 

Many reactions of Pd(II) salts, useful for organic synthesis, have been described 103-107) Most of those involving olefins can be explained by the insertion reaction. The most remarkable property of Pd(II) is the substitution of vinyl hydrogen or halogens by nucleophiles. The usefulness of this reaction is apparent from the consideration that addition to olefins is common in usual organic reactions but no displacement reaction of olefinic hydrogen is possible. By coordination with palladium salts, nucleophilic displacement on olefins be-... 

Only limited work has been done on the displacement of halogen by nucleophiles in this ring system, partly because the requisite displacements have usually been carried out on the pyridine precursors of the ring system. Acid hydrolysis of 6-chloropyrido[2,3-b]pyrazine provides the... 

Reaction of the dichloride with sodium phenoxide gives the product from double displacement of halogen by nucleophilic substitution. 

The slow step in base-promoted a-halogenation is removal of an a-hydrogen by base to form an enolate anion, which then reacts with halogen by nucleophilic displacement to form the final product. This procedure for a-halogenation produces HX as a by-product, and in order to keep the solution basic, it is necessary to add slightly more than one mole of base per mole of aldehyde or ketone. Because base is a reactant required in equimolar amounts, we say that this reaction is base-promoted rather than base-catalyzed. 

Halogenobenzimidazoles undergo SNAr-displacement of halogen by nucleophiles Hke alkoxides, thiolates, or amines. However, SuAr proceeds more slowly than with 2-halogeno-benzoxazoles and -benzothiazoles. 

Displacement of Halogen by Nucleophiles Phase-transfer Methods, Catalysis of the Su reactions of alkyl halides [equation (17)] by phase-transfer methods has... 

In addition, A-cyclohexylisocyanide dichloride (cyclohexylcarbonimidic dichloride, A -dichloromethylenecyclohexanamine), and phenyliodoso dichloride have been recommended for the chlorination of organometallic. What has to be kept in mind, however, is the proneness of such reagents to lose their halogen by nucleophilic substitution rather than to transfer it to a metal-bearing carbon, a susceptibility they share with p-toluenesulfonyl chloride. 

The conversion of indoles to oxindoles can be achieved in several ways. Reaction of indoles with a halogenaling agent such as NCS, NBS or pyridin-ium bromide perbromide in hydroxylic solvents leads to oxindoles[l]. The reaction proceeds by nucleophilic addition to a 3-haloindolenium intermediate. 

Both halogens of the dihalogenothiazoles can be replaced by nucleophiles. At any rate, the halogen in position 2 is always more reactive than those in positions 4 or 5, as previously discussed. Analogously,the halogen can be selectively removed only from position 2 by reduction with metals (Table V-5). 

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... 

Halogen Substituents. Halogen functional groups are readily replaced by nucleophiles, eg, hydroxide ion, especially when they ate attached at the a- or y-position of the pyridine ting. This reaction has been exploited in the synthesis of the insecticide chlorpyrifos [2921-88-2J (43) (42), and the insecticide tiiclopyi [55335-06-3] (44) (14,43). 2,3,5,6-Tetiachloiopyiidine [2402-79-1] reacts with caustic to form the hydioxylated material [6515-38-4], which then can be used to form (44) and (43). 

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. 

Nitro groups on azole rings are often smoothly displaced by nucleophiles even more readily than are halogen atoms in the corresponding position. Thus 2,4,5-trinitroimidazole (450) is converted by HCl successively into (451) and (452) (80AHC(27)24l). 

Halogen atoms at the 5-position of tetrazoles are reactive and easily replaced by nucleophiles. 5-Bromo-l-methyltetrazole is significantly more reactive than the 2-methyl isomer (77AHC(21)323). 

The acid-catalyzed additions of bromide and chloride ion to thiiranes occurs readily, with halide preferentially but not exclusively attacking the most substituted carbon atom of the thiirane. The reaction of 1-substituted thiiranes with acetyl chloride shows a slight preference for halide attack at the less substituted carbon atom (80MI50601). For further discussion of electrophilic catalysis of halide ion attack see Section 5.06.3.3.2. The reaction of halogens with thiiranes involves electrophilic attack on sulfur (Section 5.06.3.3.6) followed by nucleophilic attack of halide ion on carbon. 

The nucleophilic displacement of halogens by pentafluorophenoxide ion resulted in the formation of the corresponding esters [31] (equation 29) (Table 12). Reactions of trifluoromethanesulfinyl fluoride with fluoro alcohols in the presence of sodium fluoride or cesium fluoride are used to prepare sulfmates [32] (equation 30) (Table 12). 

Acid halides are among the most reactive of carboxylic acid derivatives and can be converted into many other kinds of compounds by nucleophilic acyl substitution mechanisms. The halogen can be replaced by -OH to yield an acid, by —OCOR to yield an anhydride, by -OR to yield an ester, or by -NH2 to yield an amide. In addition, the reduction of an acid halide yields a primary alcohol, and reaction with a Grignard reagent yields a tertiary alcohol. Although the reactions we ll be discussing in this section are illustrated only for acid chlorides, similar processes take place with other acid halides. 

Interestingly, the photolysis of methyl 3-azido-2.6-difluorobenzoate (61) in diethylamine yields, in addition to the two expected 3//-azepines 62 and 63, a third azepine 64 formed by nucleophilic displacement of allylic fluorine from the 3-position by diethylamine.188 Displacement of allylic halogen from haloazepines has been noted previously.177... 

The two isomeric possibilities are 1,2- and 2,1-benzisoxazole. Both are preferentially halogenated by electrophilic halogen in the homocyclic ring, initially in the 5-position, although substituents can modify this behavior [67AHC(8)277]. Nucleophiles attack the heteroring (84MI26). 

Both electrophilic and nucleophilic reactions can generate halogenopur-ines with differences in regioselectivity dependent on substituents and on the nature of the substrate (anion, neutral molecule, or cation). In the neutral molecule nucleophilic displacements occur in the order 2 > 4 > 6 in the anion the imidazole ring may be sufficiently 7r-excessive for attack to occur at C-2, and the nucleophilic substitution order becomes 4 > 6 > 2. Strong electron donors are usually necessary to promote 2-halogenation by electrophilic halogen sources. 

Nucleophilic substitutions of halogen by the addition-elimination pathway in electron-deficient six-membered hetarenes by sulfinate anions under formation of sulfones have been described earlier120. The corresponding electron-poor arenes behave similarly121 (equation 30). A special type of this reaction represents the inverse Smiles rearrangement in equation 31122. 

Besides radical additions to unsaturated C—C bonds (Section III.B.l) and sulfene reactions (see above), sulfonyl halides are able to furnish sulfones by nucleophilic substitution of halide by appropriate C-nucleophiles. Undesired radical reactions are suppressed by avoiding heat, irradiation, radical initiators, transition-element ion catalysis, and unsuitable halogens. However, a second type of undesired reaction can occur by transfer of halogen instead of sulfonyl groups283-286 (which becomes the main reaction, e.g. with sulfuryl chloride). Normally, both types of undesired side-reaction can be avoided by utilizing sulfonyl fluorides. 

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