18.7 Thiols and Sulfides

Thiols and Sulfides

Structure and properties of thiols

Thiols (R-SH) are the sulfur analogs of alcohols (R-OH). Instead of an oxygen atom, a sulfur atom is bonded to an R group and a hydrogen atom. The -SH group is called the sulfhydryl group, and the hydrogen attached to sulfur is the thiol proton.

Naming: Replace the "-ol" suffix of the corresponding alcohol with "-thiol." For example, $CH_3CH_2SH$ is ethanethiol.

Thiols are significantly more acidic than alcohols, and there are three reasons for this:

• The S-H bond is weaker than the O-H bond, so it breaks more easily
• Sulfur's larger atomic radius spreads out the negative charge on the resulting thiolate anion ($R-S^-$), stabilizing it better than an alkoxide ($R-O^-$)
• Sulfur is more polarizable, which further stabilizes the conjugate base

This difference shows up clearly in $pK_a$ values: thiols fall around 10–11, while alcohols are around 16–18. That's roughly a millionfold difference in acidity.

Synthesis of thiols and sulfides

Thiol synthesis typically relies on $S_N2$ reactions. Hydrosulfide ion ($HS^-$) is a strong nucleophile that displaces a halide from an alkyl halide:

$CH_3CH_2Br + HS^- \rightarrow CH_3CH_2SH + Br^-$

Thiols can also be prepared by reducing sulfonic acids ($R-SO_3H$) or sulfonyl chlorides ($R-SO_2Cl$) with $LiAlH_4$.

Sulfide synthesis ($R-S-R'$) uses a two-step process:

1. Deprotonate the thiol with base (e.g., NaOH) to form the thiolate anion: $CH_3CH_2SH + NaOH \rightarrow CH_3CH_2S^- + H_2O$

2. The thiolate acts as a nucleophile and attacks an alkyl halide via $S_N2$: $CH_3CH_2S^- + R'X \rightarrow CH_3CH_2SR' + X^-$

Thiolates are excellent nucleophiles because sulfur is large and polarizable, so this reaction works well with primary and secondary alkyl halides.

Practical note: Thiols have strong, unpleasant odors (think skunk spray or natural gas odorant). Work with them in well-ventilated areas, and store both thiols and sulfides under inert atmosphere to prevent unwanted oxidation.

Sulfides vs ethers in reactions

Sulfides ($R-S-R'$) are the sulfur analogs of ethers ($R-O-R'$), but the two behave quite differently in reactions. The key differences come down to sulfur being larger, more polarizable, and less electronegative than oxygen.

Nucleophilicity: Sulfides are much stronger nucleophiles than ethers. Sulfur's larger, more diffuse electron cloud makes it more polarizable, so sulfides react readily with alkyl halides via $S_N2$. Ethers, by contrast, are poor nucleophiles under most conditions.

Oxidation: This is where sulfides and ethers diverge most dramatically.

• Sulfides can be oxidized to sulfoxides ($R-\overset{O}{S}-R'$) with one equivalent of oxidant ($H_2O_2$ or a peroxyacid like mCPBA)
• With excess oxidant, sulfoxides are further oxidized to sulfones ($R-SO_2-R'$)
• Ethers are generally resistant to oxidation under these same conditions

Sulfoxide formation is also stereoselective. Because the sulfur in a sulfoxide bears three different groups plus a lone pair, it becomes a stereocenter. The R or S configuration of the product depends on the specific oxidant and reaction conditions used.

Organosulfur compounds and their properties

Organosulfur compounds are organic molecules that contain one or more sulfur atoms. A defining feature of sulfur chemistry is the wide range of oxidation states sulfur can adopt, from -2 (as in thiols and sulfides) all the way up to +6 (as in sulfates).

Common classes of organosulfur compounds include:

• Thiols ($R-SH$): acidic, nucleophilic, and prone to oxidation to disulfides
• Sulfides ($R-S-R'$): strong nucleophiles, oxidizable to sulfoxides and sulfones
• Disulfides ($R-S-S-R'$): formed by mild oxidation of thiols, and critically important in protein structure (cysteine disulfide bridges hold proteins in their 3D shape)
• Sulfoxides ($R-SO-R'$): chiral at sulfur, useful in asymmetric synthesis

Across all these classes, sulfur-containing compounds tend to be better nucleophiles than their oxygen analogs. This higher nucleophilicity traces back to the same principle: sulfur's larger size and greater polarizability make its electrons more available for bonding with electrophiles.