Ethers, Sulfides (omit),
and Epoxides
Chapter 11
1
Structure
• The functional group of an ether is an
oxygen atom bonded to two carbon atoms.
– In dialkyl ethers, oxygen is sp3 hybridized
with bond angles of approximately 109.5°.
– In dimethyl ether, the C-O-C bond angle is
110.3°.
H
H
••
H
C
H
O
••
C
H
H
2
Structure
– In other ethers, the ether oxygen is bonded to
an sp2 hybridized carbon.
– In ethyl vinyl ether, for example, the ether
oxygen is bonded to one sp3 hybridized
carbon and one sp2 hybridized carbon.
Ethoxyethene
(Ethyl vinyl ether)
CH3 CH2 -O- CH= CH2
3
Nomenclature
• IUPAC: the longest carbon chain is the parent.
Name the OR group as an alkoxy substituent.
• Common names: name the groups bonded to
oxygen in alphabetical order followed by the word
ether.
OH
CH3 OCCH3
CH3 CH2 OCH 2 CH3
OCH2 CH3
Ethoxyethane
(Diethyl ether)
CH3
trans- 2-Ethoxycyclohexanol
CH3
2-Methoxy-2methylpropane
(tert- Butyl methyl ether)
4
Nomenclature
• Although cyclic ethers have IUPAC
names, their common names are more
widely used.
– IUPAC: prefix ox- shows oxygen in the ring.
– The suffixes -irane,
irane -etane,
etane -olane,
olane and -ane
show three, four, five, and six atoms in a
saturated ring.
2
O
3
1O
O
O
O
O
Oxirane
Oxolane
Oxan e
Oxetan e
1,4-D ioxane
(Ethylene oxid e)
(Tetrahydrofuran) (Tetrahydropyran)
5
Physical Properties
• Although ethers are polar compounds, only
weak dipole-dipole attractive forces exist
between their molecules in the pure liquid state.
Note bene: there is NO
intramolecular H-bonding
6
Physical Properties
• Boiling points of ethers are
– lower than alcohols of comparable MW.
– close to those of hydrocarbons of comparable MW.
• Ethers are hydrogen bond acceptors.
– They are NOT soluble in H2O, but
– They are more soluble in H2O than are hydrocarbons..
Note bene: there IS
intermolecular H-bonding
7
Preparation of Ethers
• Williamson ether synthesis: Ether
synthesis by the SN2 displacement of
halide, tosylate, or mesylate by alkoxide
ion.
CH3
-
CH3 CHO N a
+
Sodium
isopropoxide
+
CH3 I
CH 3
SN 2
Iodomethane
(Methyl iodide)
CH3 CHOCH3
OR'
1) Nao
R (H)
R (H)
ROH
+ -
Na I
2-Methoxypropane
(Isopropyl methyl ether)
OH
R
+
2) R'X
1o or 2o
R
R (H)
R (H)
Ether
8
Preparation of Ethers
–Yields are highest with methyl and
1° halides,
–lower with 2° halides (competing βelimination)
CH3
CH3
SN2
- +
+ +
CH3 CO K
CH3 Br
CH3 COCH3 + K Br
CH3
CH3
Potass ium
Bromometh ane
2-Meth oxy-2-meth ylp ropan e
t ert-bu toxid e (Meth yl b romid e)
(t ert -Bu tyl methyl ether)
9
Preparation of Ethers
reaction fails with 3° halides
(β-elimination only).
CH3
CH3 CBr
+
CH3
2-Bromo-2methylprop ane
-
CH3 O Na
+
Sodium
methoxide
E2
CH3
+
CH3 C=CH2 + CH3 OH + Na Br
-
2-Methylprop ene
10
Preparation of Ethers
• Acid-catalyzed dehydration of alcohols
– Diethyl ether and several other ethers are
made this way on an industrial scale.
– A specific example of an SN2 reaction in
which a poor leaving group (OH-) is converted
to a better one (H2O).
2 CH3 CH2 OH
Ethanol
H2 SO4
140°C
CH3 CH2 OCH2 CH3 + H2 O
D iethyl eth er
11
Preparation of Ethers
– Step 1: Proton transfer gives an oxonium ion.
fas t and
reversib le
O
CH3 CH2 -O-H + H-O-S-O-H
O
O
+
CH3 CH2 -O-H + O-S-O-H
O
H
An oxon ium ion
– Step 2: Nucleophilic displacement of H2O by
the OH group of the alcohol gives a new
oxonium ion.
+ SN2
CH3 CH2 -O-H + CH3 CH2 -O-H
H
+
CH3 CH2 -O-CH2 CH3 +
H
A new oxonium ion
O-H
H
12
Preparation of Ethers
Step 3: Proton transfer to solvent completes the
reaction.
+
CH3 CH2 -O-CH2 CH3 + O-H
H
H
proton
tran sfer
+
CH3 CH2 -O-CH2 CH3 + H O-H
H
13
Preparation of Ethers
• Acid-catalyzed addition of alcohols to
alkenes
– Yields are highest using an alkene that can
form a stable carbocation and
– using methanol or a 1° alcohol that is not
prone to undergo acid-catalyzed dehydration.
2
4
2
2
14
Preparation of Ethers
1. Use an alkene that can form a stable
carbocation (2o or 3o)
2. Use a 1° alcohol (that is not prone to
undergo acid-catalyzed dehydration).
CH3
CH3 C= CH2 + CH3 OH
acid
catalyst
CH3
CH3 COCH3
CH3
2-Methoxy-2-methyl
propane
15
Preparation of Ethers
– Step 1: Protonation of the alkene gives a
carbocation.
CH3
CH3 C=CH2 + H
+
O CH3
CH3
CH3 CCH3 +
+
H
O CH3
H
– Step 2: Reaction of the carbocation (an
electrophile) with the alcohol (a nucleophile)
gives an oxonium ion.
CH 3
CH3 CCH3 + HOCH3
+
CH3
CH3 CCH3
+
O
CH3
H
16
Preparation of Ethers
Step 3: Proton transfer to solvent completes the
reaction.
CH3
CH3
O H + CH3 CCH3
+
O
H
CH3
CH3
+
CH3 O H + CH3 CCH3
H
O CH3
17
Epoxides
• Epoxide: A cyclic ether in which oxygen is
one atom of a three-membered ring.
– Simple epoxides are named as derivatives of
oxirane.
– Where the epoxide is part of another ring
system, it is shown by the prefix epoxy-.
2
H2 C
3
1
O
CH2
1O
Oxirane
(Ethylene oxide)
H
2
H
1,2-Epoxycyclohexane
(Cyclohexene oxide)
18
Epoxides
• Epoxide: A cyclic ether in which oxygen is
one atom of a three-membered ring.
– Common names are derived from the name
of the alkene from which the epoxide is
formally derived.
2
H2 C
3
CH2
1O
Oxirane
(Ethylene oxide)
H3 C
H
H
C
C
O
cis- 2,3-Dimethyloxirane
(cis- 2-Butene oxide)
H
1
CH3
O
2
H
1,2-Epoxycyclohexane
(Cyclohexene oxide)
19
Synthesis of Epoxides
• Ethylene oxide, one of the few epoxides
manufactured on an industrial scale, is
prepared by air oxidation of ethylene.
2 CH2 = CH2 + O 2
Ag
2 H2 C
CH2
O
Oxirane
(Ethylene oxide)
procaine
20
Synthesis of Epoxides
• The most common laboratory method is
oxidation of an alkene using a
peroxycarboxylic acid (a peracid).
O
COOH
O
CH3 COOH
Peroxyacetic acid
(Peracetic acid)
Cl
meta- Chloroperoxybenzoic acid
(MCPBA)
21
Synthesis of Epoxides
• Epoxidation of cyclohexene
+
Cycloh exene
O
RCOOH
H
CH2 Cl2
A p eroxycarboxylic acid
O
+
O
RCOH
H
1,2-Ep oxycyclohexan e A carboxylic
(Cycloh exene oxide)
acid
22
Synthesis of Epoxides
• Epoxidation is stereospecific:
– Epoxidation of cis-2-butene gives only cis-2,3dimethyloxirane.
– Epoxidation of trans-2-butene gives only
trans-2,3-dimethyloxirane.
H
CH3
C
RCO3 H
C
H3 C
H
H
H3 C
C
C
CH3
H
O
+
H
H3 C
C
C
O
t rans-2,3-D imethyloxirane
(a racemic mixture)
trans-2-Buten e
H
CH3
23
Synthesis of Epoxides
• A mechanism for alkene epoxidation.
R
O
C
O
3
2
H
R
O
O
H
O
4
O
1
C
C
C
C
C
24
Synthesis of Epoxides
• Epoxides are also synthesized via halohydrins.
OH
O
Cl 2 , H2 O
Na OH, H2 O
CH 3 CH= CH2
CH3 CH- CH 2
CH3 CH CH2
SN 2
Cl
Propene
A chlorohydrin
Methyloxirane
(racemic)
(racemic)
2
2
25
Synthesis of Epoxides
The second step is an internal SN2 reaction.
O
O
internal S N 2
C
C
C
+
Cl
C
Cl
An epoxide
26
Synthesis of Epoxides
– Halohydrin formation is both regioselective
and stereoselective; for alkenes that show
cis,trans isomerism, it is also stereospecific.
– Conversion of a halohydrin to an epoxide is
stereoselective:
H
H3 C
C
C
H
1 . Cl 2 , H2 O
CH3
2 . Na OH, H2 O
cis- 2-Butene
H3 C
H
C
C
H
CH3
O
cis- 2,3-Dimethyloxirane
27
Synthesis of Epoxides
• Problem: Account for the fact that conversion of
cis-2-butene to an epoxide by the halohydrin
method gives only cis-2,3-dimethyloxirane.
H
H3 C
H
C
C
cis- 2-Butene
1 . Cl 2 , H2 O
CH3 2 . Na OH, H O
2
H3 C
H
C
C
H
CH3
O
cis- 2,3-Dimethyloxirane
28
Reactions of Epoxides
• Ethers are not normally susceptible to
attack by nucleophiles.
• Because of the strain associated with the
three-membered ring, epoxides readily
undergo a variety of ring-opening
reactions.
Nu
C
C
+ HN u :
O
C
C
HO
29
Reactions of Epoxides
• Acid-catalyzed ring opening
– In the presence of an acid catalyst, such as
sulfuric acid, epoxides are hydrolyzed to
glycols.
OH
H+
O + H2 O
Oxirane
(Ethylene oxide)
HO
1,2-Ethanediol
(Ethylene glycol)
30
Reactions of Epoxides
Step 1: Proton transfer to oxygen gives a bridged
oxonium ion intermediate.
Step 2: Backside attack by water (a nucleophile) on
the oxonium ion (an electrophile) opens the ring.
Step 3: Proton transfer to solvent completes the
reaction.
H
H
2
H2 C
CH2
O
1
H2 C
(1)
CH2
O+
H
+
H O H
O
2
H
H
H
+O 3
CH2 CH2
O
H
3
CH 2
OH
OH
CH 2 + H3 O +
OH
H
31
Reactions of Epoxides
Attack of the nucleophile on the protonated
epoxide shows anti stereoselectivity.
– Hydrolysis of an epoxycycloalkane gives a trans1,2-diol.
O +
H2 O
1,2-Epoxycyclopentane
(Cyclopentene oxide)
(achiral)
H+
OH
OH
+
OH
OH
trans- 1,2-Cyclopentanediol
(a racemic mixture)
32
O
C
CH2
OH
H 3O+
C
R
CH2
R
R
OH
R
33
Reactions of Epoxides
The value of epoxides is the variety of nucleophiles that
will open the ring and the combinations of functional
groups that can be prepared from them.
CH3
HSCH2 CHOH
A β-mercaptoalcohol
CH3
HOCH2 CHOH
A glycol
CH3
HC CCH2 CHOH
A β-alk yn ylalcoh ol
+
H2 O/ H3 O
Na+ SH-/ H2 O
CH3
H2 C
Na+C N- / H2 O
CH3
N CCH2 CHOH
A β-hydroxynitrile
CH
O
Methyloxiran e
+
1 . HC C Na
2 . H2 O
NH3
CH3
H2 NCH2 CHOH
A β-aminoalcohol
34
Medicinal Chemistry
Cocaine
Topical anesthetic (local)
CNS stimulant
NOT exam material
35
Medicinal Chemistry
2
3
3
2
3
2
Alkanolamines
(Ethanolamines)
Procaine
36
Medicinal Chemistry
Synthesis of Procaine
37
Medicinal Chemistry
Synthesis of Procaine
O
HN(CH2CH3)2
38
Medicinal Chemistry
Synthesis of Procaine
2
2
H 2 Ni
2
2
Procaine
(novocaine)
39
Medicinal Chemistry
40