Copyright © 1998 by Saunders College Publishing
Requests for permission to make copies of any part of the work should be mailed to:Permissions Department,
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Copyright © 1998 by Saunders College Publishing
11-1

Copyright © 1998 by Saunders College Publishing
11-2

u
The functional group of an ether is an oxygen atom bonded to two carbon atoms u
Oxygen is sp 3 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
Copyright © 1998 by Saunders College Publishing

u u
IUPAC: the longest carbon chain is the parent. Name the OR group as an alkoxy substituent
Common names: name the groups attached to oxygen followed by the word ether
CH
3
CH
3
CH
2
OCH
2
CH
3
Ethoxyethane
(Diethyl ether)
CH
3
OCCH
3
CH
3
2-Methoxy-2-methylpropane
(tert-Butyl methyl ether)
OH
OCH
2
CH
3 trans-2-Ethoxycyclohexanol
11-4
Copyright © 1998 by Saunders College Publishing

u
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.
O
O
Oxirane
(Ethylene oxide)
O
Oxolane
(Tetrahydrofuran, THF)
O
Oxane
(Tetrahydropyran, THP)
O
1,4-Dioxane
11-5
Copyright © 1998 by Saunders College Publishing

u
Sulfide: the sulfur analog of an ether u
Name the alkyl or aryl groups attached to sulfur followed by the word sulfide
CH
3
SCH
3
Dimethyl sulfide
CH
3
CH
3
CH
2
SCHCH
3
Ethyl isopropyl sulfide
11-6
Copyright © 1998 by Saunders College Publishing

u u
The functional group of a disulfide is an
S-S- group
-
Name the alkyl or aryl groups bonded to sulfur followed by the word disulfide
CH
3
-S-S-CH
Dimethyl disulfide
3
11-7
Copyright © 1998 by Saunders College Publishing

u
Ethers are polar molecules; oxygen bears a partial negative charge and each carbon a partial positive charge
11-8
Copyright © 1998 by Saunders College Publishing

u
Ethers are polar molecules, but because of steric hindrance, only weak dipole-dipole attractive forces exist between their molecules in the pure liquid state u
Boiling points of ethers are
• lower than alcohols of comparable MW and
• close to those of hydrocarbons of comparable MW u
Ethers hydrogen bond with H
2
O and are more soluble in H
2
O than are hydrocarbons
11-9
Copyright © 1998 by Saunders College Publishing

u
Williamson ether synthesis: S
N
2 displacement of halide, tosylate, or mesylate by alkoxide ion
CH
3
CH
3
CHO
-
Na
+
Sodium isopropoxide
+ CH
3
I
Iodomethane
(Methyl iodide)
S
N
2
CH
3
CH
3
CHOCH
3
+
2-Methoxypropane
(Isopropyl methyl ether)
Na
+
I
-
11-10
Copyright © 1998 by Saunders College Publishing

u
Williamson ether synthesis: yields are
• highest with methyl and 1° halides,
• lower with 2° halides (competing

• fails with 3° halides (

CH
3
E2
CH
3
CBr + CH
3
CH
2
O
-
Na
+
Sodium ethoxide
CH
3 tert-Butyl bromide
CH
3
CH
3
C=CH
2
2-Methylpropene
+ CH
3
CH
2
OH + Na
+
Br
-
11-11
Copyright © 1998 by Saunders College Publishing

u
Acid-catalyzed dehydration of alcohols
• diethyl ether and several other ethers are made on an industrial scale this way
• a specific example of an S
N
2 reaction in which a poor leaving group is converted to a better one
2 CH
3
CH
2
Ethanol
OH
H
2
SO
4
140 o
C
CH
3
CH
2
OCH
2
Diethyl ether
CH
3
+ H
2
O
11-12
Copyright © 1998 by Saunders College Publishing

u
A three-step mechanism for acid-catalyzed dehydration of alcohols to ethers
Step 1: proton transfer to form an oxonium ion
O proton transfer
CH
3
CH
2
-O-H + H-O-S-O-H
O
CH
3
CH
2
+
-O-H
H
An oxonium ion
+
O
-
O-S-O-H
O
11-13
Copyright © 1998 by Saunders College Publishing

CH
3
Step 2: nucleophilic displacement of OH
2 by the OH group of the alcohol to give a new oxonium ion
CH
2
-O-H +
+
CH
3
CH
2
-O-H
S
N
2
H
+
CH
3
CH
2
-O-CH
2
CH
3
H
A new oxonium ion
+ O-H
H
11-14
Copyright © 1998 by Saunders College Publishing

Step 3: proton transfer to solvent to complete the reaction
CH
3
CH
2
+
-O-CH
2
CH
3
+ O-CH
2
CH
3 proton transfer
H H
CH
3
CH
2
-O-CH
2
CH
3
+
+
H O-CH
2
CH
3
H
11-15
Copyright © 1998 by Saunders College Publishing

u
Acid-catalyzed addition of alcohols to alkenes.
Yields are highest using
• an alkene that can form a stable carbocation
• methanol or a 1° alcohol
CH
3
CH
3
C=CH
2
+ CH
3
OH acid catalyst
CH
3
CH
3
COCH
3
CH
3
2-Methoxy-2-methylpropane
(tert-Butyl methyl ether)
11-16
Copyright © 1998 by Saunders College Publishing

u
A three-step mechanism for the addition of an alcohol to an alkene
Step 1: protonation of the alkene to form a carbocation
CH
3
CH
3
C=CH
2
+ H O
+
CH
3
H
CH
3
CH
3
CCH
+
3
+ O CH
3
H
11-17
Copyright © 1998 by Saunders College Publishing

Step 2: reaction of the alcohol (a Lewis base) with the carbocation (a Lewis acid)
CH
3
CH
3
CCH
+
3
+ HOCH
3
CH
3
CH
3
H
CCH
3
O
+
CH
3
11-18
Copyright © 1998 by Saunders College Publishing

CH
Step 3: proton transfer to solvent to complete the reaction
3
O H +
CH
3
CH
3
H
CCH
O
+
3
CH
3
CH
3
O
+
H
H
+
CH
3
CH
3
CCH
3
O
CH
3
11-19
Copyright © 1998 by Saunders College Publishing

u
Symmetrical sulfides, R
2
S, are prepared by treatment of 1 mol of Na
2
S with 2 mol of an alkyl halide. This method can also be used to prepare five- and six-membered cyclic sulfides
2 RX + Na
2
S RSR
A sulfide
+ 2 NaX
ClCH
2
CH
2
CH
2
CH
2
Cl
1,4-Dichlorobutane
Na
2
S
S
N
2
S
Thiolane
(Tetrahydrothiophene)
11-20
Copyright © 1998 by Saunders College Publishing

u
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)
CH
3
(CH
2
)
8
CH
2
S
-
Na
Sodium 1-decanethiolate
+
+ CH
3
I
S
N
2
+ Na
+
I
-
CH
3
(CH
2
)
8
CH
2
SCH
3
1-(Methylthio)decane
(Decyl methyl sulfide)
11-21
Copyright © 1998 by Saunders College Publishing

u
Ethers are cleaved by HX to an alcohol and an alkyl halide
R-O-R + H-X R-O-H + R-X
• cleavage requires both a strong acid and a good nucleophile, hence 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 -
11-22
Copyright © 1998 by Saunders College Publishing

u
A dialkyl ether is cleaved to two moles of alkyl halide
(CH
3
CH
2
CH
2
CH
2
)
2
O
Dibutyl ether
+ 2 HBr heat
2 CH
3
CH
2
CH
2
CH
2
Br + H
2
O
1-Bromobutane
11-23
Copyright © 1998 by Saunders College Publishing

u
The mechanism for HBr and HI cleavage of 1° and 2° dialkyl ethers is divided into two steps
Step 1: proton transfer to the oxygen atom of the ether to form an oxonium ion
CH
3
CH
2
-O-CH
2
CH
3
+ H O
+
H proton transfer
H
CH
3
CH
2
+
-O-CH
2
CH
3
H
An oxonium ion
+ O H
H
11-24
Copyright © 1998 by Saunders College Publishing

Br
-
Step 2: Nucleophilic displacement on the primary carbon
+
+
CH
3
CH
2
-O-CH
2
CH
3
S
N
2
H
CH
3
CH
2
Br + O-CH
2
CH
3
H
•
The alcohol is then converted to the alkyl bromide or iodide by another S
N
2 reaction (Section 8.3)
11-25
Copyright © 1998 by Saunders College Publishing

u
3° and benzylic ethers are particularly sensitive to cleavage by HX
• tert-butyl ethers are cleaved by HCl at room temp
CH
3
O-CCH
3
CH
3
+ HCl
S
N
1
CH
3
OH + Cl-C-CH
3
CH
3
• in this case, protonation of the ether oxygen is followed by C-O cleavage to give the tert-butyl cation
11-26
Copyright © 1998 by Saunders College Publishing

u
Ethers react with O
2 at a C-H bond adjacent to the ether oxygen to form explosive hydroperoxides
OOH
CH
3
CH
2
OCH
2
Diethyl ether
CH
3
+ O
2
CH
3
CH
2
OCHCH
3
A hydroperoxide u
Hydroperoxide : a compound containing the
OOH group
11-27
Copyright © 1998 by Saunders College Publishing

u
Sulfides can be oxidized to sulfoxides and sulfones, by the proper choice of experimental conditions
S-CH
3
H
2
O
2
25 o
C
Methyl phenyl sulfide
O O
S-CH
3
Methyl phenyl sulfoxide
HIO
4
25 o
C
S-CH
3
O
Methyl phenyl sulfone
11-28
Copyright © 1998 by Saunders College Publishing

Ethers Protecting Grps u
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 u
Suppose you wish to carry out this transformation
?
HC CCH
2
CH
2
CH
2
OH
4-Pentyn-1-ol
CH
3
CH
2
C CCH
2
CH
2
CH
2
OH
4-Heptyn-1-ol
11-29
Copyright © 1998 by Saunders College Publishing

Ethers Protecting Grps
•
The new C-C bond can be formed by alkylation of the acetylide anion (Section 10.5)
•
The OH group, however, is more acidic (pK a than the terminal alkyne (pK a
25)
16-18)
• treating the compound with 1 mol of NaNH
2 will form the alkoxide anion rather than the acetylide
HC CCH
2
CH
2
CH
2
OH
4-Pentyn-1-ol
+ Na
+
NH
2
-
HC CCH
2
CH
2
CH
2
O
-
Na
+
+ NH
3
11-30
Copyright © 1998 by Saunders College Publishing

Ethers Protecting Grps u
A protecting group must be
• easy to add
• easy to remove
• resistant to the reagents used to transform the unprotected group u
In this chapter, we discuss three -OH protecting groups
• tert-butyl ether group
• trimethylsilyl (TMS) group
• tetrahydropyranyl (THP) group
Copyright © 1998 by Saunders College Publishing
11-31

Ethers Protecting Grps u
The tert-butyl protecting group
• formed by treatment of an alcohol with 2methylpropene in the presence of an acid catalyst
HC CCH
2
CH
2
CH
2
OH
4-Pentyn-1-ol
CH
2
=C(CH
3
)
2
H
2
SO
4
CH
3
HC CCH
2
CH
2
CH
2
OCCH
3
CH
3
11-32
Copyright © 1998 by Saunders College Publishing

Ethers Protecting Grps
• the protected compound is then alkylated
HC CCH
2
CH
2
CH
2
CH
3
OCCH
3
1. Na
+
NH
2
-
2 . CH
3
CH
2
Br
CH
3
CH
3
CH
3
CH
2
C CCH
2
CH
2
CH
2
OCCH
3
CH
3
11-33
Copyright © 1998 by Saunders College Publishing

Ethers Protecting Grps
• the tert-butyl group is removed by treatment with aqueous acid
CH
3
H
3
O
+
/H
2
O
CH
3
CH
2
C CCH
2
CH
2
CH
2
OCCH
3
CH
3
CH
3
CH
2
C CCH
2
CH
2
CH
2
OH
4-Heptyn-1-ol
CH
3
+ H
2
C C
CH
3
11-34
Copyright © 1998 by Saunders College Publishing

Ethers Protecting Grps u
Trimethylsilyl (TMS) group
• treat the alcohol with chlorotrimethylsilane in the presence of a 3° amine, such as triethylamine
• the function of the 3° amine is to neutralize the HCl
CH
3
CH
3
(Et)
3
N
RCH
2
OH + Cl-Si-CH
3
RCH
2
O-Si-CH
3
CH
3
Chlorotrimethylsilane
CH
3
A trimethylsilyl ether
11-35
Copyright © 1998 by Saunders College Publishing

Ethers Protecting Grps u
The TMS group is removed by treatment with aqueous acid or with F in the form of tetrabutylammonium fluoride
CH
3
RCH
2
O-Si-CH
3
+
CH
3
A trimethylsilyl ether
H
2
O
H
+
CH
3
RCH
2
OH + HO-Si-CH
CH
3
3
11-36
Copyright © 1998 by Saunders College Publishing

Ethers Protecting Grps u
The tetrahydropyranyl (THP) group is used to protect OH groups of 1° and 2° alcohols. We discuss the chemistry of this group in Chapter
15.
H
+
RCH
2
OH +
O
Dihydropyran the THP group
RCH
2
O O
A tetrahydropyranyl ether
11-37
Copyright © 1998 by Saunders College Publishing

u u
Epoxide: a cyclic ether in which oxygen is one atom of a three-membered ring
Simple epoxides are named as derivatives of oxirane.
2
CH
2
3
CH
2
1
O
Oxirane
(Ethylene oxide)
H
3
C
H
C C
H
CH
3
O cis-2,3-Dimethyloxirane
(cis-2-Butene oxide)
11-38
Copyright © 1998 by Saunders College Publishing

u u
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
H
1
O
2
H
1,2-Epoxycyclohexane
(Cyclohexene oxide)
11-39
Copyright © 1998 by Saunders College Publishing

Synthesis of Epoxides 1 u
Ethylene oxide, one of the few epoxides manufactured on an industrial scale, is prepared by air oxidation of ethylene
Ag
2 CH
2
=CH
2
+ O
2
2 CH
2
CH
2
O
Oxirane
(Ethylene oxide)
11-40
Copyright © 1998 by Saunders College Publishing

Synthesis of Epoxides 2 u
The most common laboratory method for synthesis of epoxides is oxidation of an alkene using a peroxycarboxylic acid (a peracid)
O
COOH
Mg
2+
CO
-
O 2
Magnesium monoperoxyphthalate
(MMPP)
O
CH
3
COOH
Peroxyacetic acid
(Peracetic acid)
11-41
Copyright © 1998 by Saunders College Publishing

Synthesis of Epoxides 2 u
Epoxidation of cyclohexene
O
Cyclohexene
+ RCOOH
A peroxycarboxylic acid
CH
2
Cl
2
H
O +
O
RCOH
H
1,2-Epoxycyclohexane
(Cyclohexene oxide)
A carboxylic acid
11-42
Copyright © 1998 by Saunders College Publishing

Synthesis of Epoxides 2 u
Epoxidation is stereoselective:
• epoxidation of cis-2-butene gives only cis-2,3dimethyloxirane and
• epoxidation of trans-2-butene gives only trans-2,3dimethyloxirane
H
C C
CH
3
H
3
C
H trans-2-Butene
RCO
3
H H
3
C
H
C
CH
H
3
C
O trans-2,3-Dimethyloxirane
11-43
Copyright © 1998 by Saunders College Publishing

Synthesis of Epoxides 2 u
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 stereoselective 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
11-44
Copyright © 1998 by Saunders College Publishing

Synthesis of Epoxides 2 u
A mechanism for alkene epoxidation
R R
O
3
C
2
O
H
O
4
1
C C
H
O C
O
C C
O
11-45
Copyright © 1998 by Saunders College Publishing

Synthesis of Epoxides 3 u
A second general method involves
1. treatment of an alkene with Cl
2 form a halohydrin or Br
2 in H
2
O to
2. treatment of the halohydrin with base, causing an
CH
3 internal S
N
2
Cl
2
CH CH
2
, H
2
O
Propene
Cl
CH
3
CH-CH
2
NaOH, H
2
O
CH
3
CH CH
2
HO
1-Chloro-2-propanol
(a chlorohydrin)
O
Methyloxirane
(Propylene oxide)
11-46
Copyright © 1998 by Saunders College Publishing

Synthesis of Epoxides 3 u u
Each step is stereoselective
• anti stereoselective for halohydrin formation
• inversion of configuration for the S
N
2 reaction
Given this stereoselectivity, show that cis-2butene gives cis-2,3-dimethyloxirane
H H
H
3
C
C C
CH
3
1 . Cl
2
, H
2
O
2. NaOH, H
2
O cis-2-Butene
H
3
C
H
C C
H
CH
3
O cis-2,3-Dimethyloxirane 11-47
Copyright © 1998 by Saunders College Publishing

u
Because of the strain associated with the three-membered ring, epoxides readily undergo a variety of ring-opening reactions
C
O
C + HNu
HO
C C
Nu
11-48
Copyright © 1998 by Saunders College Publishing

u
Acid-catalyzed ring opening
• in the presence of an acid catalyst, epoxides are hydrolyzed to glycols
+ H
2
O
H
+
HOCH
2
CH
2
OH CH
2
CH
2
O
Oxirane
(Ethylene oxide)
1,2-Ethanediol
(Ethylene glycol)
11-49
Copyright © 1998 by Saunders College Publishing

Step 1: proton transfer to the epoxide to form a bridged oxonium ion intermediate
H
2
C CH
2
O
H O
H
+
H
H
2
C CH
2
O
+
H
11-50
Copyright © 1998 by Saunders College Publishing

Step 2: attack of H
2
O from the side opposite the oxonium ion bridge
H
O
H
H
2
C CH
O
H
+
2
H
+
O
H
2
C CH
2
O
H
H
11-51
Copyright © 1998 by Saunders College Publishing

Step 3: proton transfer to solvent to complete the hydrolysis
H
O
H
H
+
O
H
2
C CH
2
O
H
H
H
O
H
2
C CH
2
O
H
+ H O
+
H
H
11-52
Copyright © 1998 by Saunders College Publishing

11
Reactions of Epoxides
H
O
H
(2)
H
2
C CH
2
O
(1)
H O
+
H
(1)
H
H
2
C CH
2
O
H
+
(2)
H
+
O
H
2
C CH
2
O
H
O
(3)
H
(3)
H
H
Copyright © 1998 by Saunders College Publishing
H
O
H
2
C CH
2
O
H
+ H O
+
H
H
11-53

u
Attack of the nucleophile on the protonated epoxide shows anti stereoselectivity
• hydrolysis of an epoxycycloalkane gives a trans-
1,2-diol
H
O + H
2
O
H
+
H
1,2-Epoxycyclopentane
(Cyclopentene oxide)
OH
OH trans-1,2-Cyclopentanediol
11-54
Copyright © 1998 by Saunders College Publishing

u
Compare the stereochemistry of the glycols formed by these two methods
H
RCO
3
H
O
H
+
H
2
O
H
OH
OH trans-1,2-Cyclopentanediol
OH
OsO
4
, t-BuOOH
OH cis-1,2-Cyclopentanediol
11-55
Copyright © 1998 by Saunders College Publishing

u
Ethers are not normally susceptible to attack by nucleophiles u
Because of the strain associated with the three-membered epoxide ring, epoxides undergo nucleophilic ring opening readily
11-56
Copyright © 1998 by Saunders College Publishing

u
Their nucleophilic ring openings show a stereoselectivity typical of S
N
2 reactions, namely inversion of configuration at the carbon from which oxygen is displaced
CH
3
OH
CH
3
O
-
Na
+
CH
3
CH CH
2
O
Methyloxirane
(Propylene oxide)
+
CH
3
CHCH
2
OCH
3
OH
1-Methoxy-2-propanol
11-57
Copyright © 1998 by Saunders College Publishing

u
Reaction of epoxides with Gilman reagents is an important method for forming new C-C bonds
• ring opening shows typical S
N
2 regioselectivity
O
CH-CH
2
Styrene oxide
1. (CH
2
=CH)
2
CuLi
2. H
2
O, HCl
OH
CH-CH
2
-CH=CH
2
1-Phenyl-3-buten-1-ol
11-58
Copyright © 1998 by Saunders College Publishing

CH
3
HSCH
2
CHOH
A

-mercaptoalcohol
Na
+
SH
-
/H
2
O
HOCH
2
CH
3
CHOH
A glycol
H
2
O/H
3
O
+
CH
3
HC CCH
2
CHOH
A

-alkynylalcohol
CH
3
CH
2
CH
O
Methylo xirane
1 . HC C
-
2 . H
2
O
Na
+
11-59
Copyright © 1998 by Saunders College Publishing

Na
+
C N
-
/H
2
O
CH
3
N CCH
2
CHOH
A

-hydroxynitrile
CH
3
CH
2
CH
O
Methylo xirane
NH
3
1 . (R
2 . H
2
2
Cu)Li
O
CH
3
H
2
A

NCH
2
CH
3
CHOH
RCH
2
CHOH
An alcohol
11-60
Copyright © 1998 by Saunders College Publishing

u
Treatment of an epoxide with lithium aluminum hydride, LiAlH
4
, reduces the epoxide to an alcohol
• the nucleophile attacking the epoxide ring is hydride ion, H: -
CH
O
Phenyloxirane
(Styrene oxide)
CH
2
1 . LiAlH
4
2 . H
2
O
CHCH
2
-H
OH
1-Phenylethanol
11-61
Copyright © 1998 by Saunders College Publishing

u
Crown ether: a cyclic polyether derived from ethylene glycol or a substituted ethylene glycol O
O O u
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. For example, 18crown-6
O
O
O
18-Crown-6
11-62
Copyright © 1998 by Saunders College Publishing

u
18-crown-6 viewed through the plane of the molecule and from above.
Pink spheres are unshared pairs of electrons on oxygen
Copyright © 1998 by Saunders College Publishing
11-63

u
The diameter of the cavity created by the repeating oxygen atoms is comparable to the diameter of alkali metal cations
• when potassium ion is inserted into the cavity of
18-crown-6, the unshared pairs of electrons on the six oxygens provide very effective solvation for K +
•
18-crown-6 does not coordinate well with Na + (it is slightly smaller) or with Li + (it is considerably smaller)
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Copyright © 1998 by Saunders College Publishing

Copyright © 1998 by Saunders College Publishing
K +
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