Synthesis of Thiols

Thiols can be made fi-om haloalkanes by nucleophilic substitution of the halide ion by the sulfhydryl ion (HS ), which is an excellent nucleophile. Because thiolate ions are also excellent nucleophiles, thioethers can react again to give a thioether. To limit this competing second reaction, a large excess of HS must be used. 

The sulfur atom of thiourea is a better source of a sulfur nucleophile in a reaction that will convert a alkyl halide to a thiol. Thiourea reacts with alkyl halides to give an isothiouronium salt. Subsequent hydrolysis of this salt in the same reaction vessel yields a thiol. 

The overall driving force for this reaction is the formation of urea, whose carbonyl bond is much stronger than the C=S bond of thiourea. 

1 Write the structural formula of each of the following esters. 

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Brust M ef a/1994 Synthesis of thiol-derivatised gold nanopartioles in a two-phase liquid-liquid system J. Chem. Soc. Chem. Comm. 801... 

The principal impetus behind the synthesis of thiols came from the need to produce synthetic mbber in the early 1940s. These mbbers, styrene—butadiene mbbers (SBRs), were produced by many companies at that time. Originally, 1-dodecanethiol was utilized, but the most important thiol became / fZ-dodecanethiol, which was made from propylene tetramer, using an acid-catalyzed process (54,55). 

Synthesis of thiols, selenols, sulfides, selenides, sulfoxides, sulfones, and se-lenones of heterocyclic series 98JCS(P1)1973, 99JCS(P1)641. 

Scheme 5. Synthesis of thiol and thioether fimctionalized primary phosphines 11 and 12... 

The subjects of this chapter are the exploration of the scope and hmitations of the new Pd-Sn catalyzed hydrogenolysis route for the synthesis of thiols via 2-(perfluoroalkyl)ethane thiocyanate, the characterization of the surprisingly active and robust Pd-Sn catalysts, and the attempted correlation of the characterization of the catalysts with observed onset of hydrogenolysis reactivity and snrprisingly long lifetime in the presence of known catalyst poisons. ... 

Brust, M., Walker, M., Bethell, D., Schiffrin, D.J. and Whyman, R. (1994) Synthesis of thiol-derivatized gold nanopartides in a 2-phase liquid—liquid system. Journal of the Chemical Society, Chemical Communications (7), 801—802. 

SYNTHESIS OF THIOLS, THIOETHERS, THIOACETALS AND S-ALKYL THIOCARBOXYLIC ESTERS... 

As indicated above, the traditional base-catalysed hydrolysis of 0,5-dialkyl thio-carbonates for the synthesis of thiols is generally unsatisfactory, as oxidation leads to the formation of disulphides. Under phase-transfer conditions, the procedure produces thioethers to the virtual exclusion of the thiols, as a result of the slow release of the thiolate anions in the presence of the electrophilic ester. However, a simple modification of the reaction conditions provides an efficient one-pot reaction [50] from haloalkanes (Table 4.15) via the intermediate formation of the thermally labile (9-/ert-butyl-5-alkyl dithiocarbonates (Scheme 4.8). 

One-pot synthesis of thiols from potassium O-t-butyl dithiocarbonate... 

M. Brust, M. Walker, D. Bethell, D. J. Schiffrin, and R. Whyman, Synthesis of thiol-derivatised gold nanoparticles in a 2-phase liquid-liquid system, J. Chem. Soc.—Chem. Commun. 801-802 (1994). 

Boeckler C, Frisch B, Schuber F. Design and synthesis of thiol-reactive lipopep-tides. Bioorg Med Chem Lett 1998 8 2055. 

Roth A, et al. Synthesis of thiol-reactive lipopeptide adjuvants. Incorporation into liposomes and study of their mitogenic effect on mouse splenocytes. Bioconjugate Chem 2004 15 541. 

Scheme 15.1 One-phase synthesis of thiol-functionalized iridium nanoparticles as proposed by Ulman and coworkers.

Scheme 19 Synthesis of thiol containing 2,5-DKP s for use in MMP inhibition. Solid support was done using TentaGel S OH or ArgoGel-OH. (Trt = triphenyhnethyl, TES = triethylsilane). Two representative 3D conformations of 119A (blue) and 119B (cyan). Yield shown represents yield over all steps...

Premachandran RS, Baneijee S, John VT, McPherson GL, Akkara JA, Kaplan DL (1997) The enzymatic synthesis of thiol-containing polymers to prepare polymer-CdS nanocomposites. Chem Mater 9(6) 1342-1347... 

Other authors have described the lipase-catalyzed chemoselective acylation of alcohols in the presence of phenolic moities [14], the protease-catalyzed acylation of the 17-amino moiety of an estradiol derivative [15], the chemoselectivity in the aminolysis reaction of methyl acrylate (amide formation vs the favored Michael addition) catalyzed by Candida antarctica lipase (Novozym 435) [16], and the lipase preference for the O-esterification in the presence of thiol moieties, as, for instance, in 2-mercaptoethanol and dithiotreitol [17]. This last finding was recently exploited for the synthesis of thiol end-functionalized polyesters by enzymatic polymerization of e-caprolactone initiated by 2-mercaptoethanol (Figure 6.2)... 

The formation of a P=0 bond is the driving force in the reaction of thioalkoxy-phosphonium salts, having non-nucleophilic counter anions, with carboxylates or alcoholates, thereby cirumventing the inconvenience of using thiols or thiolates in the synthesis of thiol esters or sulphides the yields are fair to excellent433,781 (reaction 235). 

The synthesis of thiols by the photochemical reaction of an olefinic compound with hydrogen sulphide is possible in the presence of an initiator which contains the phos-phorane group76. 

The reaction of elemental sulfur with organometallic compounds is one of the standard methods of synthesis of thiols [3, 4], In this way, the ortho lithiation of lithium benzenethiolate led to the preparation of 1,2-benzenedithiol (1), and a convenient one-pot procedure which can be used on a large scale was worked out [5]. 

Scheme 1 The one- and two-phase Brust-Schiffrin method for the synthesis of thiol-capped gold nanoparticles, and the first step of the reaction prior to the reduction step with NaBIL [63]...

The synthesis of thiols 19 is well managed if thiourea 28 is used instead of NaSH or Na2S as the nucleophile. Thiourea is itself highly delocalised but it is still a good nucleophile for saturated carbon through the sulfur atom 29. The product is a thiouronium salt 30 and is not nucleophilic at all, being a cation. Hydrolysis with aqueous base liberates urea 31 and the thiol 19. 

Fig. 56 Synthesis of thiol-functionalised dextran by conversion of dextran with acetylthiosuccinic anhydride...

The MNK rearrangement is the most widely used method for the production of aromatic thiols. The reaction often represents the method of choice for the synthesis of thiols due to its high yields and good tolerance towards the aromatic ring substituents such as aldehydes [37,38], esters [39], halogens [40] and pyrones [41,42]. 

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