Alkyl halide reaction with sulfides

The reaction often works poorly unless an excess of the nucleophile is used because the product thiol can undergo a second S 2 reaction with alkyl halide to give a sulfide as a by-product. To circumvent this problem, thiourea, (NH2J2C=S, is often used as the nucleophile in the preparation of a thiol from an alkyl halide. The reaction occurs by displacement of the halide ion to yield an intermediate alkyl isothiourea salt, which is hydrolyzed by subsequent reaction with aqueous base. 

Treatment of a thiol with a base, such as NaH, gives the corresponding thiolate ion (RS-), which undergoes reaction with a primary or secondary alkyl halide to give a sulfide. The reaction occurs by an Sn2 mechanism, analogous to the Williamson synthesis of ethers (Section 18.2). Thiolate anions are among... 

Thiols, the sulfur analogs of alcohols, are usually prepared by Sjv 2 reaction of an alkyl halide with thiourea. Mild oxidation of a thiol yields a disulfide, and mild reduction of a disulfide gives back the thiol. Sulfides, the sulfur analogs of ethers, are prepared by an Sk2 reaction between a thiolate anion and a primary or secondary alkyl halide. Sulfides are much more nucleophilic than ethers and can be oxidized to sulfoxides and to sulfones. Sulfides can also be alkylated by reaction with a primary alkyl halide to yield sulfonium ions. 

Alkylthio derivatives are normally prepared by alkylation of thiones, but they can also be prepared by alkanethiolysis reactions, and selective reaction can be achieved. Aromatic sulfides are commonly prepared by arenethiolysis reactions with halopyrimidines <1994HC(52)1>. In addition to halide displacement at the electrophilic 2-, 4-, and 6-positions, displacement can also occur at the unactivated 5-position when microwave irradiation is used. Thus, 5-bromopyrimidine 197 gave 5-phenylthiopyrimidine 198 in 96% yield after 40 h of microwave irradiation, whereas the thermal reaction only gave a 7% yield in the same time period <2002T887>. 

Trimethylphosphine is a colorless, pyrophoric2 liquid with a very unpleasant odor. It forms air-stable phosphonium salts with a variety of alkyl halides, and the corresponding oxide and sulfide upon reaction with 02 and sulfur. 

So the reaction of an alkyl halide with NaSH or Na2S cannot usually be made to stop after one alkylation as the anion of the first product is at least as nucleophilic as HS or S2. This is obvious in reactions with Na2S. Less obviously with NaSH the first reaction 18 gives the thiol 19 but this is in equilibrium with RS- and a second displacement 20 gives the sulfide 21. We shall see shortly how to get round this problem. A more important example—the failure of the alkylation of ammonia to give a useful amine synthesis—has chapter 8 to itself. 

The synthesis of the cation is typically performed by alkylation of an amine, phosphine or sulfide, most commonly using an alkyl halide [ ]. In most cases the reaction is carried out with chloro-, bromo- and iodoalkanes as readily available alkylating reagents, with the reaction conditions becoming more gentle changing from chloride to bromide to iodide, as can be expected for nucleophilic substitution... 

Reaction with an alkyl halide to yield a sulfide (Sec. 18.8)... 

The neutral complex [Fe2(CO)6S2] (65) is known to undergo reduction to form the disulfide-bridged dimeric compound [Fe4S4(CO)i2]2- (66),60 which on further reduction yields [Fe2(CO)6S2]2 (67).61-62 The nucleophilic character of the bridging sulfides in the fully reduced dianion 67 is demonstrated by its reaction with a variety of metal halides to yield metal clusters in which the butterfly unit of 67 acts as a bidentate ligand coordinated via the bridging sulfides.63-66 With alkyl halides, 67 reacts to form S-alkylated products.60-63... 

Silver salts are also utilized to perform nucleophilic additions to disulfide bonds to yield sulfenamides (146). If alkyl halides are treated with stoichiometric AgBF4 in dimethyl sulfoxide solvent (DMSO, solvent), the corresponding aldehydes/ ketones will form in good yields. This reaction is an alternative to the well-known Swern oxidation (147). In addition, silver can drive the formation of dialkylper-oxonium ions from alkyl halides, which then oxidizes sulfoxides or sulfides (148,149). In the presence of AgN03, sulfides can be oxidized into a-chloro sulfoxides by SO2CI2 (Fig. 36) (150). 

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