Preparation of Sulfur Functional Groups

Thiols (RSH) are prepared by a simple substitution reaction with the addition of NaSH to RX. Substitution (or substitution reaction) is a chemical reaction where one functional group replaces another functional group. The reaction proceeds via an SN2 mechanism with inversion of stereochemistry. For example, a bromine is replaced with a thiol when sodium hydrosulfide is added to bromopropane (C₃H₇Br). When adding hydrosulfide (SH^–) to an alkyl halide (RX), the thiol product (RSH) can act as a nucleophile and attach another alkyl halide to make a thioether (RSR). To prevent this second S_N2 reaction of the thiol product with unreacted alkyl halide from happening, an alternate method is used. In this method, thiourea (${\rm {(NH_2)_2C{=}S}}$) is used as the nucleophile (molecule that donates a pair of electrons) instead of hydrosulfide. In the first step, an alkyl isothiourea salt intermediate is produced. In the second step, the salt is hydrolyzed in a reaction with an aqueous base. Sulfides (RSR) are prepared in a similar reaction to the Williamson ether synthesis. A thiol is treated with sodium hydroxide (NaOH) followed by an alkyl halide (RX). In this reaction, the hydrogen of the thiol is removed by the NaOH to produce an alkanethiolate, which acts as a nucleophile to attach an alkyl halide and produce the sulfide or thioether (RSR). Thiols are more acidic than alcohols, so NaOH is used instead of NaH, which is used in in the first step of the reaction. Thiols are readily oxidized to disulfides, and the thiols are converted to disulfides by oxygen in the air. Disulfide bonds are commonly formed in biological systems from the oxidation of sulfhydryl (${-}{\rm {SH}}$) groups. Many proteins partially owe their three-dimensional structure to disulfide bonds between cysteine residues on the same protein or on neighboring protein molecules. The conversion of a thiol to a disulfide is a redox reaction in which the thiol is in the reduced state and disulfide is in the oxidized state. The interconversion of thiols to disulfides and disulfides to thiols is most commonly mediated in the body by a coenzyme, glutathione, which absorbs oxidants to form a disulfide bond. Glutathione prevents damage to parts of cells by binding free radicals, peroxides, lipid peroxides, and heavy metals. Following oxidation, NADPH, a reducing agent present in plant and animal cells, acts as an electron donor to reduce glutathione. The reduction of glutathione by NADPH is catalyzed by the enzyme glutathione reductase. The ratio of reduced to oxidized glutathione in a cell may reveal what level of oxidative stress the cell is under. The reduced glutathione can be oxidized again and recycled by the body. Oxidation is a reaction that involves the removal of an electron from an atom. It often involves the addition of oxygen to a molecule. Oxidation of a sulfide can make a sulfoxide (RSOR) by oxidizing a sulfur atom to a sulfur-oxygen double bond. If the oxidizing agent is strong enough and present in excess, oxidation can proceed to produce a sulfone (RSO₂R) by adding a second sulfur-oxygen double bond to the sulfoxide. Controlling the oxidation of sulfides is important; therefore, sodium metaperiodate (NaIO₄) is used as an oxidizing reagent. With sodium metaperiodate, the reaction can be regulated to produce either a sulfoxide or a sulfone by controlling the amount of peroxide present. One equivalent of hydrogen peroxide converts sulfides to sulfoxides, and the addition of two equivalents of peroxide results in the sulfide being converted to a sulfone.