Chapter 14: Ethers and Epoxides; Thiols and Sulfides

14.1 Introduction to Ethers – An ether group is an oxygen atom

that is bonded to two carbons. The ether carbons can be part of
alkyl, aryl, or vinyl groups.
14.2 Nomenclature of Ethers
1. Name each –R group of the ether
2. Arrange them alphabetically
3. add “ether” to the name – three separate words
-or-
1. Make the larger of the –R groups the parent chain
2. Name the smaller of the –R groups as an alkoxy substituent

CH3CH2CH2CH2OCH2CH3 O

butyl ethyl ether 1-methylethyl 2-methylpropyl ether

(1-ethoxybutane (isobutyl isopropyl ether)
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(1-isopropoxy-2-methylpropane)

14.3 Structure and Properties of Ethers

The O-atom of ethers is sp3 hydrbidized

water methanol dimethyl ether

Ether can only act as a hydrogen bond acceptor

H-bond H-bond
acceptor acceptor R
R R R
δ– δ–
O H-bond O δ– O δ– O
H R
H donor R M+
δ+ H δ
– δ+ δ+ H
δ– O
R
δ+ O δ+ O
δ–
R R R

CH3CH2CH2CH2CH3 CH3CH2CH2CH2OH CH3CH2OCH2CH3

MW = 72 MW = 74 MW = 74
bp = 36° C bp = 116° C bp = 35° C

In general, the C-O bonds of ethers have low reactivity – this

makes then good solvents for other reactions.
O
O
O
O
diethylether tetrahydrofuran 1,4-dioxane 280

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14.4 Crown Ethers (please read)

Polyethers
Polyethylene glycol (PEG)
O O H
H O O
n

Monensin – ionophore antibiotic

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16.5: Preparation of Ethers

a. Addition of alcohols to alkenes (recall hydration of alkenes in
and oxymercuration from Chapter 9)

b. Condensation of alcohols (not very useful)

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c. The Williamson Ether Synthesis (the workhorse of ether
syntheses) - Reaction of an alkoxide with an alkyl halide or
tosylate to give an ether. Alkoxides are prepared by the reaction
of an alcohol with a strong base such as sodium hydride (NaH).

The Williamson ether synthesis is an SN2 reaction.

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The Williamson Ether Synthesis:

• Few restrictions regarding the nature of the the alkoxide
• Works best for methyl- and 1°-halides or tosylates.
• E2 elimination is a competing reaction with 2°-halides or
tosylates
• 3°-halides undergo E2 elimination
• Vinyl and aryl halides do not react

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14.6 Reactions of Ethers – typical ethers are not very reactive
Acid Cleavage of Ethers
recall the reaction of an alcohol with HX to give a halide
RCH2-OH + H-X RCH2-X + H2O

The mechanism for the acid cleavage of ethers is similar

RCH2-O-CH2R’ + H-X RCH2-X + R’CH2-OH (X)

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Autoxidation (please read)

14.7 Nomenclature of Epoxides – a reactive cyclic ether
O
O O
O
oxirane oxetane oxolane oxane
(epoxide) (furan) (pyran)

a.  The ether oxygen is treated as a substituent, and two

numbers are given as designate its location; or
b.  Oxirane is used as the parent name

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14.8 Preparation of Epoxides
a.  Reaction of alkenes with a peroxyacid (Chapter 9.9)

b. Base promoted ring closure of a vicinal halohydrin –this is an

intramolecular Williamson ether synthesis.

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14.9 Enantioselective Epoxidation (please read) – the previous

are stereospecific but not enantiospecific, and give racemic
products. Epoxidations useing a chiral catalysts can give epoxides
in high enantiomeric excess.
14.10 Ring-opening of Epoxides – epoxides are more reactive
than a typical ether do to the strain of the three-membered ring.
Epoxides undergo ring-opening reaction with nucleophiles.

O OH
+ Nu: – Nu
then H 2O

Nu:– = HO– (hydroxide)

RO– (alkoxides)
RS– (thiolates)
–CN (cyanide)

R–MgBr (Grignard reagents)

H– (LAH)

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Regio- and stereochemistry of epoxide opening
Epoxides react with anionic nucleophiles (under basic conditions)
through an SN2. The nucleophile adds to the less hindered
(substituted) carbon of unsymmetrical epoxides and there is
inversion of stereochemistry at the carbon undergoing
substitution.

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The regiochemistry of epoxide opening under acidic conditions is

dependent on the substitution of the epoxide.
Nucleophiles will preferentially add to a tertiary carbon over
primary of secondary under acidic conditions (SN1 like
regiochemistry). The ring opening proceeds with inversion of
stereochemistry. Nucleophiles will preferentially add to a primary
carbon over a secondary (SN2 like regiochemistry).

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14.11 Thiols and Sulfides
Thiols (mercaptans) are sulfur analogues of alcohols.
Thiols have a pKa ~ 10 and are stronger acids than alcohols.

RS-H + HO– RS– + H-OH

(pKa ~10) (pKa ~15.7)

RS– and HS – are weakly basic and strong nucleophiles.

Thiolates react with 1° and 2° alkyl halides to yield sulfides (SN2).

NaH, THF _ Br
CH3CH2-SH CH3CH2-S Na+ CH3CH2-S-CH2CH2CH2CH3
SN2

_
+ THF
HS Na+ Br-CH2CH2CH2CH3 HS-CH2CH2CH2CH3
SN2

OTs SR
THF
+
RS – Na +
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Oxidation States of organosulfur compounds

Thiols can be oxidized to disulfides
[O]
2 R-SH R-S-S-R
[H]
thiols disulfide
O2C O
H
N
O2C O -2e-, -2H+ H3N N CO2
H H
2 H3N
N
N CO2
O
S
H
O +2e-, +2H+
SH S
O
glutathione O2C
H
N NH3
N
H
O CO2

Oxidation of thiols to sulfonic acids

[O] [O] O [O] O
R SH 2
R S OH R S OH R S OH
O
Thiol sulfenic acid sulfinic acid sulfonic acid

Oxidation of thioethers
O– O–
[O] [O] +2
R S R' R S R' R S R'
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O– 292
Thioether Sulfoxide Sulfone

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Bioactivation and detoxication of benzo[a]pyrene diol epoxide:

P450 H2O
O2
HO
O
OH
benzo[a]pyrene
NH2 OH
N HO
N
O
P450 N N
DNA HO
NH
HO DNA
OH N N
N N
glutathione G-S
transferase DNA

SG
HO
O2C O
HO H
N
H3N N CO2
OH H
O
SH

Glutathione (G-SH)

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Sulfides (thioethers) – sulfur analogs of ethers.

Reaction of a thiolate anions with 1° and 2° alkyl halides and
tosylates (analogous to the Williamson ether synthesis)
alcohol or
R’-CH2X
R-SH + NaOH water solvent R-S- Na+ R-S-CH2R’
pKa ~ 11 pKa ~ 16-18

Thiolates are more reactive nucleophiles and less basic

than alkoxides
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Alkylation of Sulfides to Sulfonium Salts – The sulfur atom of
sulfides is much more nucleophilic than the oxygen atom of
ethers, and will react with alkyl halides to give stable sulfonium
salts.
N NH 2
H 3C
CH3 S O N N
S H3C I S I
H3C CH3 H3C CH3 –O N
2C
dimethyl sulfide trimethyl sulfonium NH 3+ HO OH
iodide
S-adenosylmethionine (SAM)

14.12 Synthesis Strategies Involving Epoxides

Epoxide ring opening by a nucleophile installs two functional
groups on adjacent positions
OH
O NaCN

then H 2O NC

or extend a carbon chain by 2 (or more)

O
Mg(0), THF
Br MgBr OH
then H 2O 295

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