Special Topic

F
Thiols, Sulfur Ylides,
and Disulfides

Cystine

Sulfur is directly below oxygen in group VIA of the periodic table, and, as we might
expect, there are sulfur counterparts of the oxygen compounds that we studied in earlier
chapters.
Important examples of organosulfur compounds are the following:
R′
+
R—SH R—S—R′ ArSH R—S—S—R′ R—S—R″
Thiols Thioethers Thiophenols Disulfides Trialkylsulfonium
ions
O O S O O
R—S—R′ R—S—R′ R—C—R′ R—S—OH R—S—OH
O O
Sulfoxides Sulfones Thioketones Sulfinic acids Sulfonic acids

The sulfur counterpart of an alcohol is called a thiol or a mercaptan. The name mercaptan
comes from the Latin phrase mercurium captans, meaning “capturing mercury.” Mercaptans
react with mercuric ions and the ions of other heavy metals to form precipitates.
Several simple thiols are shown below:

SH SH SH SH
Ethanethiol 1-Propanethiol 3-Methyl-1-butanethiol 2-Propene-1-thiol
(added to (found in onions) (produced by skunks) (allyl mercaptan,
natural gas) found in garlic)

F-1

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 F-2  Special Topic F  THIOLS, SULFUR YLIDES, AND DISULFIDES

Compounds of sulfur, in general, and the low-molecular-weight thiols, in particular,

are noted for their disagreeable odors. 3-Methyl-1-butanethiol is one unpleasant con-
stituent of the liquid that skunks use as a defensive weapon. 1-Propanethiol evolves from
freshly chopped onions, and allyl mercaptan is one of the compounds responsible for the
odor and flavor of garlic.
Aside from their odors, analogous sulfur and oxygen compounds show other chemical
differences. These arise largely from the following features of sulfur compounds:
1.  The sulfur atom is larger and more polarizable than the oxygen atom. As a result,
­sulfur compounds are more powerful nucleophiles, and compounds containing
−SH groups are stronger acids than their oxygen analogues. The ethanethiolate
ion ( CH3CH2⋅⋅ S⋅− ), for example, is a much stronger nucleophile when it reacts at
⋅⋅⋅ ⋅⋅ ⋅− ). On the other hand, since
carbon atoms than is the ethoxide ion ( CH3CH2O
⋅⋅ ⋅
ethanol is a weaker acid than ethanethiol, the ethoxide ion is the stronger of the
two conjugate bases.
2.  The bond dissociation energy of the S−H bond of thiols (∼365 kJ mol−1) is
much less than that of the O−H bond of alcohols (∼430 kJ mol−1). The weakness
of the S−H bond allows thiols to undergo an oxidative coupling reaction when they
react with mild oxidizing agents; the product is a disulfide:

2 RS−H  +  H2O2  ⟶  RS−SR  +  2 H2O

A thiol A disulfide

Alcohols do not undergo an analogous reaction. When alcohols are treated with oxidiz-
ing agents, oxidation takes place at the weaker C−H (∼380 kJ mol−1) bond rather
than at the stronger O−H bond.
3.  Because sulfur atoms are easily polarized, they can stabilize a negative charge on an
adjacent atom. This means that hydrogen atoms on carbon atoms that are ­adjacent
to an alkylthio group are more acidic than those adjacent to an alkoxyl group.
Thioanisole, for example, reacts with butyllithium in the following way:

SCH3 + BuLi SCH2 −

Li+ + Butane

Thioanisole

Anisole (CH3OC6H5) does not undergo an analogous reaction. The S O group

of sulfoxides and the positive sulfur of sulfonium ions are even more effective in
­delocalizing negative charge on an adjacent atom:

−
O O O
NaH
S S − S + H2
CH3 CH3 CH3 CH2 CH3 CH2
Dimethyl sulfoxide

CH3 CH3
+ base +
S S −
CH3 CH3 ( −HBr) CH3 CH2
Trimethylsulfonium A sulfur ylide
bromide

The anions formed in the reactions just given are of synthetic use. They can be used
to synthesize epoxides, for example (see Section F.3).

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 F.2 Physical Properties of Thiols F-3

F.1 Preparation of Thiols
Alkyl bromides and iodides react with potassium hydrogen sulfide to form thiols.
(Potassium hydrogen sulfide can be generated by passing gaseous H2S into an alcoholic
solution of potassium hydroxide.)
EtOH
R−Br  +  KOH  +  H2S  →   R−SH  +  KBr  +  H2O
heat
(excess)

The thiol that forms is sufficiently acidic to form a thiolate ion in the presence of potas-
sium hydroxide. Thus, if excess H2S is not employed in the reaction, the major product
of the reaction will be a thioether. The thioether results from the following reactions:

−
R SH + KOH R S K+ + H2O

R S − K+ + R Br R S R + KBr
Thioether

Alkyl halides also react with thiourea to form (stable) S-alkylisothiouronium salts.
These can be used to prepare thiols.

+ CH2CH3 Br−
S S
C + CH3CH2 Br EtOH
C
H 2N NH 2 H 2N NH 2

Thiourea S -Ethylisothiouronium
bromide
(95%)

aq. HO−, then H 3O+

O
C + CH3CH2SH
H 2N NH 2

Urea Ethanethiol
(90%)

F.2 Physical Properties of Thiols

Thiols form very weak hydrogen bonds; their hydrogen bonds are not nearly as strong
as those of alcohols. Because of this, low-molecular-weight thiols have lower boiling
points than the corresponding alcohols. Methanethiol has a boiling point of 6 °C,
whereas methanol boils at 65 °C. Ethanethiol boils more than 40 °C lower than ethanol
(37 °C versus 78 °C). The relative weakness of hydrogen bonds between molecules of
thiols is also evident when we compare the boiling points of ethanethiol and its isomer
dimethyl sulfide:

SH Me2S
bp 37 °C bp 38 °C

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 F-4  Special Topic F  THIOLS, SULFUR YLIDES, AND DISULFIDES

F.3 The Addition of Sulfur Ylides to Aldehydes

and Ketones

[ Helpful Hint ] Sulfur ylides also react as nucleophiles at the carbonyl carbon of aldehydes and
In Section 11.13 we discussed ketones. The intermediate that forms usually decomposes to an epoxide rather than
methods for synthesizing to an alkene:
epoxides from alkenes. + −
+ + −
Na CH2SOCH3
(CH3)2S + CH3I (CH3)2S —CH3 (CH3)2S —CH2 (CH3)2S CH2
CH3SOCH3,
I
− 0 °C
Trimethylsulfonium Resonance-stabilized sulfur ylide
iodide

O O −

C C +
H − + CH2 S(CH 3) 2
CH2S(CH3)2 H

Benzaldehyde

O
HC
CH2 + S(CH3)2

(75%)

Practice Problem F.1 Show how you might use a sulfur ylide to prepare
(a) (b)  O

F.4 Thiols and Disulfides in Biochemistry

Thiols and disulfides are important compounds in living cells, and in many biochemical
oxidation–reduction reactions they are interconverted:
[O]
2 RSH  ⥫⥬  R−S−S−R
[H]
Lipoic acid, for example, an important cofactor in biological oxidations, undergoes this
oxidation–reduction reaction:

O O
[H]

OH [O] OH
S S SH SH
Lipoic acid Dihydrolipoic acid

The amino acids cysteine and cystine are interconverted in a similar way:

O O O
[O]
HO SH HO S S OH
[H]
NH2 NH2 NH2
Cysteine Cystine

As we shall see in Chapter 24, the disulfide linkages of cystine units are important in
determining the overall shapes of protein molecules.

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 F.4  Thiols and Disulfides in Biochemistry F-5

Give structures for the products of the following reactions: Practice Problem F.2
(a)  S
Br
+
H2N NH2
(b)  Product of (a) + HO /H2O, then H3O+ ⟶
−

(c)  Product of (b) + H2O2 ⟶

(d)  Product of (b) + NaOH ⟶
(e)  Product of (d) + benzyl bromide ⟶

Allyl disulfide, CH2=CHCH2S−SCH2CH=CH2, is another important component of Practice Problem F.3

oil of garlic. Suggest a synthesis of allyl disulfide starting with allyl bromide.
S
S
Allyl disulfide

Starting with allyl alcohol, outline a synthesis of British Anti-Lewisite (BAL, an antidote Practice Problem F.4
for mercury poisoning and against arsenic compounds once used as war gases).

HS OH
SH
British Anti-Lewisite (BAL)

A synthesis of lipoic acid (see structure just given) is outlined here. Supply the missing Practice Problem F.5
reagents and intermediates.

O
CH2 CH2 NaBH4
(a) C10H17ClO3
Cl CO2Et AlCl3

Cl OH
(b) (c)

Cl CO2Et Cl CO2Et (d)

S CO2H (1) Na, liq. NH3

(2) H3O+

O2
(e) C8H16S2O2 lipoic acid

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