Organic
Chemistry
William H. Brown
Christopher S. Foote
Brent L. Iverson
11-1
Ethers &
Epoxides
Chapter 11
11-2
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
11-3
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
CH3 CH2 -O-CH=CH2
(Ethyl vinyl ether)
11-4
Nomenclature: ethers
 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)
11-5
Nomenclature: ethers
 Although
cyclic ethers have IUPAC names, their
common names are more widely used
• IUPAC: prefix ox- shows oxygen in the ring
• the suffixes -irane, -etane, -olane, and -ane show three,
four, five, and six atoms in a saturated ring
2
O
3
1O
O
O
O
O
Oxirane
Oxetane
Oxolane
Oxane
1,4-Dioxane
(Ethylene oxide)
(Tetrahydrofuran) (Tetrahydropyran)
11-6
Physical Properties
 Although
ethers are polar compounds, only weak
dipole-dipole attractive forces exist between their
molecules in the pure liquid state
11-7
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 more soluble in H2O than are hydrocarbons
11-8
Preparation of Ethers
 Williamson
ether synthesis: SN2 displacement of
halide, tosylate, or mesylate by alkoxide ion
CH3
-
CH3 CHO N a
Sodium
isopropoxide
+
+
CH3 I
SN 2
Iodomethane
(Methyl iodide)
CH3
CH3 CHOCH3
+
+ -
Na I
2-Methoxypropane
(Isopropyl methyl ether)
11-9
Preparation of Ethers
• yields are highest with methyl and 1° halides,
• lower with 2° halides (competing -elimination)
• reaction fails with 3° halides (-elimination only)
CH3
CH3
SN2
- +
+ CH3 CO K
+
CH3 Br
CH3 COCH3 + K Br
CH3
CH3
Potassium
Bromomethane
2-Methoxy-2-methylpropane
tert-butoxide (Methyl bromide)
(tert-Butyl methyl ether)
CH3
CH3 CBr
+
CH3
2-Bromo-2methylpropane
-
CH3 O Na
+
Sodium
methoxide
E2
CH3
+
CH3 C=CH2 + CH3 OH + Na Br
-
2-Methylpropene
11-10
Preparation of Ethers
 Acid-catalyzed
dehydration of alcohols
• diethyl ether and several other ethers are made on an
industrial scale this way
• a specific example of an SN2 reaction in which a poor
leaving group (OH-) is converted to a better one (H2O)
2CH3 CH2 OH
Ethanol
H2 SO4
140°C
CH3 CH2 OCH2 CH3 + H2 O
Diethyl ether
11-11
Preparation of Ethers
• Step 1: proton transfer gives an oxonium ion
fast and
reversible
O
CH3 CH2 -O-H + H-O-S-O-H
O
O
+
CH3 CH2 -O-H + - O-S-O-H
O
H
An oxonium 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 + O-H
H
H
A new oxonium ion
11-12
Preparation of Ethers
Step 3: proton transfer to solvent completes the reaction
+
CH3 CH2 -O-CH2 CH3 + O-H
H
H
proton
transfer
+
CH3 CH2 -O-CH2 CH3 + H O-H
H
11-13
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
CH3
CH3 C= CH2 + CH3 OH
acid
catalyst
CH3
CH3 COCH3
CH3
2-Methoxy-2-methyl
propane
11-14
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
CH3
CH3 CCH3 + HOCH3
+
CH3
CH3 CCH3
+
O
CH3
H
11-15
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
11-16
Cleavage of Ethers
 Ethers
are cleaved by HX to an alcohol and a
haloalkane
R-O-R + H-X
R-O-H + R-X
• cleavage requires both a strong acid and a good
nucleophile; therefore, the use of concentrated HI
(57%) and HBr (48%)
• cleavage by concentrated HCl (38%) is less effective,
primarily because Cl- is a weaker nucleophile in water
than either I- or Br-
11-17
Cleavage of Ethers
A
dialkyl ether is cleaved to two moles of
haloalkane
O
Dibutyl ether
+ 2HBr
heat
2
Br + H2 O
1-Bromobutane
11-18
Cleavage of Ethers
• Step 1: proton transfer to the oxygen atom of the ether
gives an oxonium ion
CH3 CH2 -O-CH2 CH3 + H
+
O H
fast and
reversible
H
+
CH3 CH2 -O-CH2 CH3 + O H
H
H
An oxonium ion
• Step 2: nucleophilic displacement on the 1° carbon
gives a haloalkane and an alcohol
+
Br: + CH3 CH2 -O-CH2 CH3
H
-
SN2
CH3 CH2 -Br +
O-CH2 CH3
H
• the alcohol is then converted to an haloalkane by
another SN2 reaction
11-19
Cleavage of Ethers
 3°,
allylic, and benzylic ethers are particularly
sensitive to cleavage by HX
• tert-butyl ethers are cleaved by HCl at room temp
• in this case, protonation of the ether oxygen is
followed by C-O cleavage to give the tert-butyl cation
O
A tert-butyl
ether
+ HCl
OH
+
+ ClSN1
Cl
A 3° carbocation
intermediate
11-20
Oxidation of Ethers
 Ethers
react with O2 at a C-H bond adjacent to
the ether oxygen to give hydroperoxides
• reaction occurs by a radical chain mechanism
O-O-H
+ O2
O
Diethyl ether
+ O2
O
Diisopropyl ether
 Hydroperoxide:
O
A hydroperoxide
O-O-H
O
A hydroperoxide
a compound containing the OOH
group
11-21
Silyl Ethers as Protecting Groups
 When
dealing with compounds containing two or
more functional groups, it is often necessary to
protect one of them (to prevent its reaction) while
reacting at the other
• suppose you wish to carry out this transformation
OH
?
OH
H
4-Pentyn-1-ol
4-Heptyn-1-ol
11-22
Silyl Ethers as Protecting Groups
• the new C-C bond can be formed by alkylation of an
alkyne anion
• the OH group, however, is more acidic (pKa 16-18) than
the terminal alkyne (pKa 25)
• treating the compound with one mole of NaNH2 will
give the alkoxide anion rather than the alkyne anion
pKa 25
H
pKa 16-18
O-Na+
OH
+ Na+ NH2 -
H
+ NH3
11-23
Silyl Ethers as Protecting Groups
A
protecting group must
• add easily to the sensitive group
• be resistant to the reagents used to transform the
unprotected functional group(s)
• be removed easily to regenerate the original functional
group
 In
this chapter, we discuss trimethylsilyl (TMS)
and other trialkylsilyl ethers as OH protecting
groups
11-24
Silyl Ethers as Protecting Groups
 Silicon
is in Group 4A of the Periodic Table,
immediately below carbon
• like carbon, it also forms tetravalent compounds such
as the following
O=Si=O
Silicon dioxide
H
H-Si-H
H
Silane
CH3
CH3 -Si-CH3
CH3
Tetramethylsilane
CH3
CH3 -Si-Cl
CH3
Chlorotrimethylsilane
11-25
Silyl Ethers as Protecting Groups
 An
-OH group can be converted to a silyl ether by
treating it with a trialkylsilyl chloride in the
presence of a 3° amine
CH3
RCH2 OH + Cl-Si-CH3 + Et 3 N
CH3
Chlorotri- Triethylmethylsilane amine
CH3
RCH2 O-Si-CH3 + Et 3 NH+ ClCH3
A trimethylsilyl
Triethylether
ammonium
chloride
11-26
Silyl Ethers as Protecting Groups
• replacement of one of the methyl groups of the TMS
group by tert-butyl gives a tert-butyldimethylsilyl
(TBDMS) group, which is considerably more stable
than the TMS group
• other common silyl protecting groups include the TES
and TIPS groups
Me
Me Si Cl
Me
Trimethylsilyl
chloride
(TMSCl)
Et
Et Si Cl
Et
Me
Si Cl
Me
Triethylsilyl t-Butyldimethylsilyl
chloride
chloride
(TESCl)
(TBDMSCl)
Si Cl
Triisopropylsilyl
chloride
(TIPSCl)
11-27
Silyl Ethers as Protecting Groups
• silyl ethers are unaffected by most oxidizing and
reducing agents, and are stable to most nonaqueous
acids and bases
• the TBDMS group is stable in aqueous solution within
the pH range 2 to 12, which makes it one of the most
widely used -OH protecting groups
• silyl blocking groups are most commonly removed by
treatment with fluoride ion, generally in the form of
tetrabutylammonium fluoride
RCH2 O Si
+
-
F
+ -
Bu4 N F
THF
RCH2 OH + F Si
A TBDMS-protected
alcohol
11-28
Silyl Ethers as Protecting Groups
• we can use the TMS group as a protecting group in the
conversion of 4-pentyn-1-ol to 4-heptyn-1-ol
OH
1 . ( CH3 ) 3 SiCl
H
H
4-Pentyn-1-ol
CH3
O Si CH3
CH3
4 . Bu4 N+ F-
CH3
O Si CH3
CH3
+
2 . Na NH2
Br
3.
OH
4-Heptyn-1-ol
-
CH3
+ F Si CH3
CH3
11-29
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• common names are derived from the name of the
alkene from which the epoxide is formally derived
2
H2 C
3
CH 2
1O
Oxirane
(Ethylene oxide)
H3 C
H
H
C
C
CH 3
O
cis-2,3-Dimethyloxirane
(cis-2-Butene oxide)
1
H
O
2
H
1,2-Epoxycyclohexane
(Cyclohexene oxide)
11-30
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 + O2
Ag
2 H2 C
CH2
O
Oxirane
(Ethylene oxide)
11-31
Synthesis of Epoxides
 The
most common laboratory method is
oxidation of an alkene using a peroxycarboxylic
acid (a peracid)
O
COOH
Cl
meta-chloroperoxybenzoic acid
(MCPBA)
O
COOH
CO
O
Mg
2
2+
O
CH 3 COOH
Peroxyacetic acid
(Peracetic acid)
Magnesium
monoperoxyphthalate
(MMPP)
11-32
Synthesis of Epoxides
 Epoxidation
+
Cyclohexene
of cyclohexene
O
RCOOH
H
CH2 Cl2
A peroxycarboxylic acid
O
+
O
RCOH
H
1,2-Epoxycyclohexane A carboxylic
(Cyclohexene oxide)
acid
11-33
Synthesis of Epoxides
 Epoxidation
is stereospecific:
• epoxidation of cis-2-butene gives only cis-2,3dimethyloxirane
• epoxidation of trans-2-butene gives only trans-2,3dimethyloxirane
H
CH3
C
H3 C
C
H
trans-2-Butene
RCO3 H
H
H3 C
C
CH3
H +
C
O
H
H3 C
C
C
O
trans-2,3-Dimethyloxirane
(a racemic mixture)
H
CH3
11-34
Synthesis of Epoxides
A
mechanism for alkene epoxidation must take
into account that the reaction
• takes place in nonpolar solvents, which means that no
ions are involved
• is stereospecific with retention of the alkene
configuration, which means that even though the pi
bond is broken, at no time is there free rotation about
the remaining sigma bond
11-35
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
11-36
Synthesis of Epoxides
 Epoxides
are can also be synthesized via
halohydrins
CH3 CH=CH2
Cl2 , H2 O
Propene
OH
O
NaOH, H2 O
CH3 CH-CH2
CH3 CH CH2
SN 2
Cl
A chlorohydrin
Methyloxirane
(racemic)
(racemic)
• the second step is an internal SN2 reaction
O
C
C
Cl
internal S N2
O
C
C
+ Cl
An epoxide
11-37
Synthesis of Epoxides
• halohydrin formation is both regioselective and stereoselective;
for alkenes that show cis,trans isomerism, it is also stereospecific
(Section 6.3F)
• conversion of a halohydrin to an epoxide is stereoselective

Problem: account for the fact that conversion of cis-2butene to an epoxide by the halohydrin method gives
only cis-2,3-dimethyloxirane
H
H3 C
H
1 . Cl 2 , H 2 O
C C
CH 3 2 . NaOH, H O
2
cis-2-Butene
H3 C
H
C
C
H
CH 3
O
cis-2,3-Dimethyloxirane
11-38
Synthesis of Epoxides
 Sharpless
epoxidation
• stereospecific and enantioselective
T i( O-iPr) 4
R2
(-)-Diethyl
tartrate
R1
+
R3
T i( O-iPr) 4
tert-Butyl
hydroperoxide
O
R3
+
OH
+
OH
OH
A
R2
(+)-Diethyl R
3
tartrate
OH
Et OOC
R1
OOH
OH
An allylic
alcohol
R2
R1
O
OH
B
OH
COOEt
OH
(2S,3S)-(-)-Diethyl tartrate
Et OOC
COOEt
OH
(2R,3R)-(+)-Diethyl tartrate
11-39
Reactions of Epoxides
 Ethers
are not normally susceptible to attack by
nucleophiles
 Because of the strain associated with the threemembered ring, epoxides readily undergo a
variety of ring-opening reactions
Nu
C
C
O
+ HN u :
C
C
HO
11-40
Reactions of Epoxides
 Acid-catalyzed
ring opening
• in the presence of an acid catalyst, such as sulfuric
acid, epoxides are hydrolyzed to glycols
O + H2 O
Oxirane
(Ethylene oxide)
H+
HO
OH
1,2-Ethanediol
(Ethylene glycol)
11-41
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
H2 C
O
1
+
H O H
(1)
CH2
O+
H
2
O
H
H
H
+O 3
CH2 CH2
OH
O
H
3
OH
CH2 CH2 + H3 O+
OH
H
11-42
Reactions of Epoxides
 Attack
of the nucleophile on the protonated
epoxide shows anti stereoselectivity
• hydrolysis of an epoxycycloalkane gives a trans-1,2diol
+
O +
H2 O
1,2-Epoxycyclopentane
(Cyclopentene oxide)
(achiral)
H
OH
OH
+
OH
OH
trans-1,2-Cyclopentanediol
(a racemic mixture)
11-43
Reactions of Epoxides
 Compare
the stereochemistry of the glycols
formed by these two methods
H
RCO3 H
O
OH
+
H
H2 O
+
OH
OH
trans-1,2-Cyclopentanediol
(formed as a racemic mixture)
H
OsO4 , t-BuOOH
OH
OH
OH
cis-1,2-Cyclopentanediol
(achiral)
11-44
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-mercaptoalcohol
CH3
HOCH2 CHOH
A glycol
CH3
HC CCH2 CHOH
A-alkynylalcohol
+
H2 O/ H3 O
+
-
CH3
Na SH / H2 O
H2 C
Na+C N- / H2 O
CH3
N CCH2 CHOH
A-hydroxynitrile
CH
O
Methyloxirane
-
1 . HC C Na
2 . H2 O
+
NH3
CH3
H2 NCH2 CHOH
A-aminoalcohol
11-45
Reactions of Epoxides
 Treatment
of an epoxide with lithium aluminum
hydride, LiAlH4, reduces the epoxide to an
alcohol
• the nucleophile attacking the epoxide ring is hydride
ion, H:CH
CH 2
O
Phenyloxirane
(Styrene oxide)
1 . LiAlH4
2 . H2 O
CH- CH 3
OH
1-Phenylethanol
11-46
Ethylene Oxide
• ethylene oxide is a valuable building block for organic
synthesis because each of its carbons has a functional
group
OH
N C
(1)
O
+
-
Na CN
CH3 NH2
(3)
H2 / M
(2)
OH
CH3 N
H
-
(8) CH3 C C Na
OH
H2 N
O
(4)
Cl
OH
SOCl2
CH3 N
(6)
CH3 N
Cl
OH
+
(5) H2 SO4
(7) NH3
OH
CH3 N
O
CH3 N
N-H
11-47
Ethylene Oxide
• part of the local anesthetic procaine is derived from
ethylene oxide
• the hydrochloride salt of procaine is marketed under
the trade name Novocaine
O
O
O
H2 N
N
N
OH + HO
H2 N
Procaine
O
Ethylene
oxide
+
N
H
Diethylamine
11-48
Epichlorohydrin
 The
epoxide epichlorohydrin is also a valuable
building block because each of its three carbons
contains a reactive functional group
• epichlorohydrin is synthesized from propene
Cl
+ HCl
+ Cl2 500°C
Propene
3-Chloropropene
(Allyl chloride)
OH
Step 2: Cl
Cl
Cl + HCl
+ Cl2 / H2 O
Step 1:
OH
Step 3: Cl
Cl + Ca(OH) 2
Cl
O
+ CaCl2
Epichlorohydrin
(racemic)
11-49
Epichlorohydrin
• the characteristic structural feature of a product
derived from epichlorohydrin is a three-carbon unit
with -OH on the middle carbon, and a carbon, nitrogen,
oxygen, or sulfur nucleophile on the two end carbons
Cl
O
Nu
Nu
O
OH
Nu
Nu
Nu
Epichlorohydrin
11-50
Epichlorohydrin
• an example of a compound containing the threecarbon skeleton of epichlorohydrin is nadolol, a adrenergic blocker with vasodilating activity
Cl
O
HO
N
OH H
HO
Nadolol
(racemic)
O
OHO
HO
a nucleophile derived
by removal of the acidic
H from an -OH group
H2 N
the nitrogen
nucleophile
of a 1° amine
11-51
Crown Ethers
 Crown
ether: a cyclic polyether
derived from ethylene glycol or a
substituted ethylene glycol
• the parent name is crown, preceded by
a number describing the size of the
ring and followed by the number of
oxygen atoms in the ring
O
O
O
O
O
O
18-Crown-6
11-52
Crown Ethers
 The
diameter of the cavity
created by the repeating
oxygen atoms is comparable
to the diameter of alkali
metal cations
• 18-crown-6 provides very
effective solvation for K+
11-53
Thioethers
 The
sulfur analog of an ether
• IUPAC name: select the longest carbon chain as the
parent and name the sulfur-containing substituent as
an alkylsulfanyl group
• common name: list the groups bonded to sulfur
followed by the word sulfide
S
Ethylsulfanylethane
(Diethyl sulfide)
S
2-Ethylsulfanylpropane
(Ethyl isopropyl sulfide)
11-54
Nomenclature
 Disulfide:
contains an -S-S- group
• IUPAC name: select the longest carbon chain as the
parent and name the disulfide-containing substituent
as an alkyldisulfanyl group
• Common name: list the groups bonded to sulfur and
add the word disulfide
S
S
Ethyldisulfanylethane
(Diethyl disulfide)
11-55
Preparation of Sulfides
 Symmetrical
sulfides: treat one mole of Na2S with
two moles of a haloalkane
2 RX
RSR + 2 N aX
A sulfide
+ N a2 S
+ Na2 S
Cl
Cl
1,4-Dichlorobutane
SN2
+ 2 Na+ Cl-
S
Thiolane
(Tetrahydrothiophene)
11-56
Preparation of Sulfides
 Unsymmetrical
sulfides: convert a thiol to its
sodium salt and then treat this salt with an alkyl
halide (a variation on the Williamson ether
synthesis)
-
+
+ CH3I
CH3(CH2)8CH2S Na
Sodium 1-decanethiolate
SN2
CH3(CH2)8CH2SCH3 + Na+ I1-Methylsulfanyldecane
(Decyl methyl sulfide)
11-57
Oxidation Sulfides
 Sulfides
can be oxidized to sulfoxides and
sulfones by the proper choice of experimental
conditions
S- CH3
Methyl phenyl
sulfide
O
N aIO 4
S- CH3
o
H2 O2
25oC
25 C
Methyl phenyl
sulfoxide
2CH3 -S-CH3 + O2
Dimethyl sulfide
oxides of
nitrogen
O
S- CH3
O
Methyl phenyl
sulfone
O
2CH3 -S-CH3
Dimethyl sulfoxide
11-58
Ethers
&
Epoxides
End of Chapter 11
11-59