Halogens halide nucleophilicity

When halogenation of alkenes is carried out in aqueous solvent, a vicinal halohydrm is obtained. The reaction is regioselective, and follows the Markovnikov rule. The halide adds to the less substituted carbon atom via a bridged halonium ion intermediate, and the hydroxyl adds to the more substituted carbon atom. The reaction mechanism is similar to the halogenation of alkenes, except that instead of the halide nucleophile, the water attacks as a nucleophile. 

Although aryl halides are generally inert to nucleophilic substitution, aryl halides that also contain a nitro group ortho or para to the halogen undergo nucleophilic aromatic substitution, as shown in the following example. 

In contrast, nucleophiles react with the cations quite easily. The isomeric halides [HalCgHsFeCsHsJ+BF,- (Ilal is F, or Cl) and [C HeFeC5H4Cl]+ BF4 readily exchanged their halogens for nucleophiles such as AlkO, ArO , AlkS, ArS , NHj", NHR , CN, and phthalimide anion 346-349). 

The typical reaction of alkyl halides, we have seen (Sec. 14.5), is nucleophilic substitution. Halogen is displaced as halide ion by such bases as OH, OR, NH3, CN ", etc., to yield alcohols, ethers, amines, nitriles, etc. Even Friedel-Crafts alkylation is, from the standpoint of the alkyl halide, nucleophilic substitu tion by the basic aromatic ring. 

The formation of halides by the nucleophilic substitution of leaving groups is commonly used in the synthesis of more elaborate structures. The synthesis of inexpensive bulk chemicals like solvents, however, is mostly done by oxidation or addition reactions. Halides are either used as intermediates or are valuable end products. Authors of publications, especially patent literature, often claim one reaction for three or even four halogens. In practice, this rarely holds true and each of the halogens quite often requires different conditions. The usual order of halide nucleophilicity is I" > Br > Cl > F". In dimethyl-formamide the reverse order Cl > Br > I is observed. This order goes along with the order of the basic... 

The displacement of amino groups with nucleophiles is not normally very favourable and was not directly addressed in CHEC-I. However, substituted amino groups can compete with halogen in nucleophilic displacement reactions depending upon conditions. Thus, in the preparation of 5-(substituted amino)-4-alkoxy-3(2//)-pyridazinones from 5-(substituted amino)-4-chloro or bromo-3(2//)-pyridazinones (Scheme 59), reaction with alcohols under phase transfer conditions resulted in displacement of the amino substituent, while alkoxides in dipolar aprotic solvent gave the required displacement of halide <86AP(319)60>. 

The methods described above for alkyl halides (on sp hybridized carbons) cannot be applied to the synthesis of aryl halides (on sp hybridized carbons). The introduction of a halogen to benzene (or a benzene derivative) can be accomplished either by an electrophilic aromatic substitution reaction (Cy FeCls or Br2/FeBr3) or by treatment of a diazonium salt (ArNaO with a halide nucleophile (Cul, CuBr, HBF4, or KI). 

The situation is once more reversed on passing from an alkyl halide to an acyl halide. Nucleophilic displacements of halogen in the latter take... 

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

Enzymatic reactions " and electrolysis have also been applied in the stereoselective halogenation but are limited to specific substrates. Generally, these approaches are based on the use of an electrophilic halogen source or an anionic halide nucleophile. For the approaches that use electrophilic halogen sources, the formation of a halonium intermediate is the key to stereochemical control. A subsequent nucleophilic attack of the halonium intermediate typically yields a product with an anti-relationship (Scheme 42.1). 

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. 

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... 

Alkoxide ion (RO ) The oxygen atom of a metal alkoxide acts as a nucleophile to replace the halogen of an alkyl halide The product is an ether... 

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... 

A key step in the reaction mechanism appears to be nucleophilic attack on the alkyl halide by the negatively charged copper atom but the details of the mechanism are not well understood Indeed there is probably more than one mechanism by which cuprates react with organic halogen compounds Vinyl halides and aryl halides are known to be very unreactive toward nucleophilic attack yet react with lithium dialkylcuprates... 

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... 

---