Organic Chemistry · Ethers and Epoxides; Thiols and Sulfides

Thiols and Sulfides

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Why this matters
The college version
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Worked example
Key takeaway
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In 30 seconds

Thiols and sulfides are the sulfur analogs of alcohols and ethers. In a thiol, sulfur replaces the oxygen of an alcohol, giving R-SH (e.g., CH3CH2SH, ethanethiol). In a sulfide (thioether), sulfur bridges two carbon groups, R-S-R' (e.g., CH3SCH3, dimethyl sulfide). Because sulfur sits below oxygen in the periodic table, these compounds differ from their oxygen cousins in three decisive ways: thiols are much stronger acids, hydrogen-bond far more weakly, and oxidize easily to disulfides. This topic explains those differences and follows sulfur's oxidation chemistry from disulfides through sulfones.

Why this matters

Sulfur chemistry is everywhere in biology and industry. The amino acids cysteine (HSCH2CH(NH2)COOH) and methionine (CH3SCH2CH2CH(NH2)COOH) carry thiol and sulfide groups, and bonds from oxidized cysteine side chains lock proteins into their three-dimensional shapes. Coenzyme A, which ferries acetyl groups through metabolism, acts through a terminal thiol. Industrially, volatile thiols are added to natural gas as odorants, and dimethyl sulfoxide (DMSO) — an oxidized sulfide — is a common solvent and drug-delivery vehicle. On exams, thiol acidity and the thiol → disulfide oxidation are the highest-yield ideas; both reappear in later biochemistry chapters.

The college version

Core Concepts

Naming thiols and sulfides

Thiols are named with the parent alkane and the suffix -thiol: CH3SH is methanethiol, CH3CH2CH2SH is propane-1-thiol. The sulfur-bearing carbon gets the lowest possible number. When the –SH group is a substituent rather than the principal function, it is called (e.g., 2-mercaptoethanol, HOCH2CH2SH). Sulfides are named like ethers — the two alkyl groups followed by "sulfide": CH3SCH2CH3 is ethyl methyl sulfide. The IUPAC alternative treats one group as an alkylthio substituent, giving (methylsulfanyl)ethane.

Acidity: the biggest thiol–alcohol difference

The O–H bond of an alcohol is a poor acid, but the S–H bond of a thiol is a good one. Typical values are:

$p K a (RSH) \approx 10 - 11 p K a (ROH) \approx 16 - 18$

Sulfur is larger and more polarizable than oxygen, so the anion RS^- is better stabilized than an alkoxide RO^-. A practical consequence: hydroxide, which cannot deprotonate most alcohols, deprotonates thiols completely:

$RSH + OH - ⇌ RS - + H 2 O (K \approx 105)$

The resulting thiolates are excellent nucleophiles, which is why thiols are alkylated so easily (see below).

Oxidation: thiols → disulfides; sulfides → sulfoxides → sulfones

Mild oxidants — even oxygen in air — couple two thiols into a disulfide:

$2 RSH + [O] ⟶ RSSR + H 2 O$

The reaction oxidizes each sulfur from −1 to 0 as two S–H bonds are replaced by one S–S bond (two electrons total for the pair). Stronger oxidants push all the way to sulfonic acids RSO₃H. The process is reversible: reducing agents such as zinc in acid or dithiothreitol (DTT) convert disulfides back to thiols. Sulfides oxidize analogously, first to sulfoxides R₂S=O (hydrogen peroxide is enough), then to sulfones R₂SO₂. DMSO is dimethyl sulfoxide; sulfolane is a cyclic sulfone industrial solvent.

Making thiols and sulfides by S_N2

Thiolates are soft, powerful nucleophiles, so the classic synthesis of a sulfide is an S_N2 displacement:

$CH 3 S - + CH 3 CH 2 Br ⟶ CH 3 SCH 2 CH 3 + Br -$

Thiols themselves are made by S_N2 of an alkyl halide with hydrosulfide ion (HS−), or more cleanly via thiourea, which avoids over-alkylation by the nucleophilic product thiol. Once made, sulfides can be alkylated a second time to sulfonium salts R₃S⁺, which are good alkylating agents; S-adenosylmethionine (SAM), the biological methyl donor, is a sulfonium salt.

Biological roles

Cysteine thiols and methionine sulfides are the two sulfur amino acids. Oxidation of two cysteine –SH groups forms a cystine cross-link that stabilizes folded proteins (insulin is the classic example). Enzyme-controlled thiol–disulfide exchange lets cells sense oxidative stress. Coenzyme A's terminal –SH attacks acetyl groups to form acetyl-CoA, the citric acid cycle's entry point. Volatile thiols give skunk spray and garlic their odor, and a mercaptan is added to natural gas at parts-per-million levels as a leak warning.

Common Confusions

Do not confuse	With	Difference
Thiol, R-SH	Alcohol, R-OH	Thiols are ~10⁶× more acidic and hydrogen-bond far less (lower boiling points)
Sulfide, R-S-R'	Disulfide, R-S-S-R'	Sulfide has one S atom; disulfide has an S–S bond formed by oxidizing two thiols
Sulfoxide, R₂S=O	Sulfone, R₂SO₂	Sulfoxide is the first oxidation product (one O); sulfone the second (two O); different functional groups, not synonyms
"Mercaptan"	"Thiol" as a different species	Same thing — mercaptan is the traditional common name for a thiol
Thiol acidity at physiological pH	Thiol acidity in the lab	pKa ≈ 10.5 means thiols are mostly protonated at pH 7.4 — "acidic" ≠ fully ionized in the body

Eli explains

The same idea, in plain words

Explain it like I’m 10

Thiols and sulfides are like alcohols and ethers, but with sulfur instead of oxygen. A thiol is an "S–H" molecule with a sour side — it easily gives away its hydrogen, which is why thiols are good acids. Two thiols can grab each other through their sulfur atoms — a disulfide "handshake" that holds proteins in shape, which is why hair straighteners and protein chemistry both care about S–S bonds.

Worked example

Example 1: How much thiol is deprotonated at physiological pH?

Problem. A thiol with pK_a = 10.5 is dissolved at pH 7.4 (blood pH) and at pH 12. What fraction is deprotonated in each case?

Setup. Henderson–Hasselbalch:

$pH = p K a + log 10 [RS -] [RSH]$

At pH 7.4. Substitute pH = 7.4 and pK_a = 10.5:

$7.4 = 10.5 + log 10 [RS -] [RSH] ⟹ log 10 [RS -] [RSH] = -3.1 ⟹ [RS -] [RSH] \approx 8 \times 10 -4$

At pH 12:

$12 = 10.5 + log 10 [RS -] [RSH] ⟹ [RS -] [RSH] = 10 1.5 \approx 32$

Interpretation. At pH 7.4 the thiol is almost entirely protonated (~0.1% ionized), so enzymes must shift this equilibrium (higher local pH or hydrogen bonding) to make cysteine a nucleophile. At pH 12, over 97% is thiolate, ready for S_N2 alkylation.

Example 2: Stoichiometry of thiol oxidation to a disulfide

Problem. How many grams of dimethyl disulfide, CH3SSCH3, form from 10.0 g of methanethiol, CH3SH, assuming complete reaction? Molar masses: CH₃SH = 48.11 g mol^-1, CH₃SSCH₃ = 94.20 g mol^-1.

Balanced equation:

$2 CH 3 SH + [O] ⟶ CH 3 SSCH 3 + H 2 O$

Moles of thiol:

$n(CH 3 SH) = 10.0 g 48.11 g mol -1 = 0.2079 mol$

Mole ratio and dimensional analysis:

$m(CH 3 SSCH 3) = 0.2079 mol CH 3 SH \times 1 mol CH 3 SSCH 3 2 mol CH 3 SH \times 94.20 g 1 mol = 9.79 g$

Answer. 9.79 g of dimethyl disulfide — the 2:1 thiol-to-disulfide ratio is the most commonly tested stoichiometric trap in sulfur chemistry.

Key takeaways

Thiol = R-SH; sulfide (thioether) = R-S-R'; disulfide = R-S-S-R'.
Thiols are roughly 10⁵–10⁶ times more acidic than alcohols (pK_a ≈ 10–11 vs 16–18); hydroxide deprotonates thiols but not alcohols.
Thiols hydrogen-bond weakly: boiling points are lower than the analogous alcohols (ethanethiol ≈ 35 °C vs ethanol ≈ 78 °C).
Mild oxidation couples thiols to disulfides (2 RSH → RSSR); reduction (DTT, Zn/H⁺) reverses it.
Sulfides oxidize to sulfoxides (e.g., DMSO) and then sulfones; thiols oxidize further to sulfonic acids.
Thiolates are soft, excellent S_N2 nucleophiles; sulfides alkylate to sulfonium salts.
Biology: cysteine/disulfide cross-links, methionine, coenzyme A's –SH, SAM as a methyl donor.
Safety principle: many thiols are volatile, intensely odorous, and toxic — handle in a fume hood and avoid skin contact; never intentionally smell concentrated thiols.

Check yourself

5 review questions from the chapter. Try each one, then open the answer.

Write the general structures of a thiol, a sulfide, and a disulfide, and give one biological molecule for each.
Show answer
Thiol: R-SH (cysteine); sulfide: R-S-R' (methionine); disulfide: R-S-S-R' (cystine in proteins).
Why is ethanethiol (bp ≈ 35 °C) a liquid while a molecule of similar mass, but with an O–H group, boils much higher?
Show answer
Alcohols form strong O–H···O hydrogen bonds; thiols form very weak S–H···S bonds because S–H is less polar, so less energy is needed to separate thiol molecules into vapor.
Which reagent can deprotonate a thiol but not an alcohol: water, hydroxide, or methoxide? Explain with pKa values.
Show answer
Hydroxide: pK_a(RSH) ≈ 10.5 < pK_a(H₂O) = 15.7 < pK_a(ROH) ≈ 16–18. The equilibrium RSH + OH^- → RS^- + H₂O is strongly favorable, while alcohol deprotonation by OH⁻ is unfavorable.
A disulfide bridge in a protein is broken during lab work. What kind of reagent (oxidizing or reducing) would restore the two thiols?
Show answer
A reducing agent (e.g., dithiothreitol, DTT, or Zn/H⁺) — reduction of the S–S bond regenerates two –SH groups.
Rank these sulfur species by oxidation level of sulfur: sulfide, sulfone, sulfoxide, disulfide.
Show answer
Lowest to highest: sulfide (−2) → disulfide (−1 per S) → sulfoxide (S=O) → sulfone (+4). Adding oxygen raises the oxidation level.

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Study tools & related lessonsKey vocabulary · Related

Key vocabulary

Thiol (mercaptan): A compound with an S–H group on a carbon chain, R-SH
Sulfide (thioether): A compound with sulfur bonded to two carbons, R-S-R'
Disulfide: Two sulfur atoms linked, R-S-S-R'
Thiolate: The deprotonated thiol, RS^-
Sulfoxide / sulfone: Stepwise oxidation products of a sulfide, R₂S=O then R₂SO₂
Mercapto-: Prefix for an –SH substituent

Sources & references

openstax.org — Organic Chemistry

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