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Chapter 16
Ethers, Epoxides, and Sulfides
Dr. Wolf's CHM 201 & 202
16-1
Nomenclature of Ethers, Epoxides, and Sulfides
Dr. Wolf's CHM 201 & 202
16-2
Substitutive IUPAC Names of Ethers
name as alkoxy derivatives of alkanes
CH3OCH2 CH3
methoxyethane
CH3CH2OCH2CH2CH2Cl
1-chloro-3-ethoxypropane
CH3CH2OCH2 CH3
ethoxyethane
Dr. Wolf's CHM 201 & 202
16-3
Functional Class IUPAC Names of Ethers
name the groups attached to oxygen in
alphabetical order as separate words; "ether" is
last word
CH3OCH2 CH3
ethyl methyl ether
CH3CH2OCH2CH2CH2Cl
3-chloropropyl ethyl ether
CH3CH2OCH2 CH3
diethyl ether
Dr. Wolf's CHM 201 & 202
16-4
Substitutive IUPAC Names of Sulfides
name as alkylthio derivatives of alkanes
CH3SCH2 CH3
methylthioethane
SCH3
(methylthio)cyclopentane
CH3CH2SCH2 CH3
ethylthioethane
Dr. Wolf's CHM 201 & 202
16-5
Functional Class IUPAC Names of Sulfides
analogous to ethers, but replace “ether” as last
word in the name by “sulfide.”
CH3SCH2 CH3
ethyl methyl sulfide
CH3CH2SCH2 CH3
SCH3
cyclopentyl methyl sulfide
diethyl sulfide
Dr. Wolf's CHM 201 & 202
16-6
Names of Cyclic Ethers
O
Oxirane
(Ethylene oxide)
O
Oxetane
O
Oxolane
(tetrahydrofuran)
O
O
Oxane
(tetrahydropyran)
Dr. Wolf's CHM 201 & 202
O
1,4-Dioxane
16-7
Names of Cyclic Sulfides
S
S
Thiirane
Thietane
S
Thiolane
S
Thiane
Dr. Wolf's CHM 201 & 202
16-8
Structure and Bonding
in
Ethers and Epoxides
bent geometry at oxygen analogous
to water and alcohols,
i.e. sp3 hybidization
Dr. Wolf's CHM 201 & 202
16-9
Bond angles at oxygen are sensitive
to steric effects
O
O
H
H
105°
108.5°
O
O
CH3
CH3
112°
Dr. Wolf's CHM 201 & 202
H
CH3
C(CH3)3
(CH3)3C
132°
16-10
An oxygen atom affects geometry in much the
same way as a CH2 group
most stable conformation of diethyl ether
resembles pentane
Dr. Wolf's CHM 201 & 202
16-11
An oxygen atom affects geometry in much the
same way as a CH2 group
most stable conformation of tetrahydropyran
resembles cyclohexane
Dr. Wolf's CHM 201 & 202
16-12
Physical Properties of Ethers
Dr. Wolf's CHM 201 & 202
16-13
Ethers resemble alkanes more than alcohols
with respect to boiling point
boiling point
36°C
35°C
O
OH
Dr. Wolf's CHM 201 & 202
Intermolecular hydrogen
bonding possible in
alcohols; not possible
in alkanes or ethers.
117°C
16-14
Ethers resemble alcohols more than alkanes
with respect to solubility in water
solubility in water (g/100 mL)
very small
7.5
O
OH
Dr. Wolf's CHM 201 & 202
9
Hydrogen bonding to
water possible for ethers
and alcohols; not
possible for alkanes.
16-15
Crown Ethers
Dr. Wolf's CHM 201 & 202
16-16
Crown Ethers
structure
cyclic polyethers derived from repeating
—OCH2CH2— units
properties
form stable complexes with metal ions
applications
synthetic reactions involving anions
Dr. Wolf's CHM 201 & 202
16-17
18-Crown-6
O
O
O
O
O
O
negative charge concentrated in cavity inside
the molecule
Dr. Wolf's CHM 201 & 202
16-18
18-Crown-6
O
O
O
O
O
O
negative charge concentrated in cavity inside
the molecule
Dr. Wolf's CHM 201 & 202
16-19
18-Crown-6
O
O
O
K+
O
O
O
forms stable Lewis acid/Lewis base complex
with K+
Dr. Wolf's CHM 201 & 202
16-20
18-Crown-6
O
O
O
K+
O
O
O
forms stable Lewis acid/Lewis base complex
with K+
Dr. Wolf's CHM 201 & 202
16-21
Ion-Complexing and Solubility
K+F–
not soluble in benzene
Dr. Wolf's CHM 201 & 202
16-22
Ion-Complexing and Solubility
O
O
O
K+F–
O
O
benzene
O
add 18-crown-6
Dr. Wolf's CHM 201 & 202
16-23
Ion-Complexing and Solubility
O
O
O
O
O
O
F–
O
benzene
O
O
K+
O
O
O
18-crown-6 complex of K+ dissolves
in benzene
Dr. Wolf's CHM 201 & 202
16-24
Ion-Complexing and Solubility
O
O
O
O
O
O
K+
O
O
benzene
O
F– carried into benzene
to preserve electroneutrality
Dr. Wolf's CHM 201 & 202
O
O
O
+ F–
16-25
Application to organic synthesis
Complexaton of K+ by 18-crown-6 "solubilizes"
salt in benzene
Anion of salt is in a relatively unsolvated state
in benzene (sometimes referred to as a
"naked anion")
Unsolvated anion is very reactive
Only catalytic quantities of 18-crown-6 are
needed
Dr. Wolf's CHM 201 & 202
16-26
Example
KF
CH3(CH2)6CH2Br
18-crown-6
benzene
Dr. Wolf's CHM 201 & 202
CH3(CH2)6CH2F
(92%)
16-27
Preparation of Ethers
Dr. Wolf's CHM 201 & 202
16-28
Acid-Catalyzed Condensation of Alcohols*
2CH3CH2CH2CH2OH
H2SO4, 130°C
CH3CH2CH2CH2OCH2CH2CH2CH3
(60%)
*Discussed earlier in Section 15.7
Dr. Wolf's CHM 201 & 202
16-29
Addition of Alcohols to Alkenes
(CH3)2C=CH2 + CH3OH
H+
(CH3)3COCH3
tert-Butyl methyl ether
Dr. Wolf's CHM 201 & 202
16-30
The Williamson Ether Synthesis
Think SN2!
primary alkyl halide + alkoxide nucleophile
Dr. Wolf's CHM 201 & 202
16-31
Example
CH3CH2CH2CH2ONa + CH3CH2I
CH3CH2CH2CH2OCH2CH3 + NaI
(71%)
Dr. Wolf's CHM 201 & 202
16-32
Another Example
CH2Cl
+
CH3CHCH3
ONa
CH2OCHCH3
Dr. Wolf's CHM 201 & 202
CH3
(84%)
16-33
Another Example
Alkoxide ion can be derived
from primary, secondary, or
Alkyl halide must
be primary
CH2Cl
tertiary alcohol
+
CH3CHCH3
ONa
CH2OCHCH3
Dr. Wolf's CHM 201 & 202
CH3
(84%)
16-34
Origin of Reactants
CH3CHCH3
CH2OH
OH
HCl
CH2Cl
Na
+
CH3CHCH3
ONa
CH2OCHCH3
(84%)
CH3
Dr. Wolf's CHM 201 & 202
16-35
What happens if the alkyl halide is not primary?
CH2ONa + CH3CHCH3
Br
Dr. Wolf's CHM 201 & 202
16-36
What happens if the alkyl halide is not primary?
CH2ONa + CH3CHCH3
Br
CH2OH
+
H2C
CHCH3
Elimination by the E2 mechanism becomes
the major reaction pathway.
Dr. Wolf's CHM 201 & 202
16-37
Reactions of Ethers:
A Review and a Preview
Dr. Wolf's CHM 201 & 202
16-38
Summary of reactions of ethers
No reactions of ethers encountered to this
point.
Ethers are relatively unreactive.
Their low level of reactivity is one reason why
ethers are often used as solvents in chemical
reactions.
Ethers oxidize in air to form explosive
hydroperoxides and peroxides.
Dr. Wolf's CHM 201 & 202
16-39
Acid-Catalyzed Cleavage of Ethers
Dr. Wolf's CHM 201 & 202
16-40
Example
CH3CHCH2CH3 HBr
OCH3
heat
CH3CHCH2CH3
+ CH3Br
Br
(81%)
Dr. Wolf's CHM 201 & 202
16-41
Mechanism
CH3CHCH2CH3
O ••
CH3 ••
H
••
Br ••
••
CH3CHCH2CH3
+
O
CH3 •• H
Dr. Wolf's CHM 201 & 202
16-42
Mechanism
CH3CHCH2CH3
O ••
CH3 ••
H
••
Br ••
••
CH3CHCH2CH3
••
–
•• Br ••
••
CH3CHCH2CH3
+
O
CH3 •• H
Dr. Wolf's CHM 201 & 202
•• O
••
••
•• Br
••
H
CH3
16-43
Mechanism
CH3CHCH2CH3
O ••
CH3CHCH2CH3
Br
CH3 ••
H
••
Br ••
••
HBr
CH3CHCH2CH3
••
–
•• Br ••
••
CH3CHCH2CH3
+
O
CH3 •• H
Dr. Wolf's CHM 201 & 202
•• O
••
••
•• Br
••
H
CH3
16-44
Cleavage of Cyclic Ethers
O
Dr. Wolf's CHM 201 & 202
HI
150°C
ICH2CH2CH2CH2I
(65%)
16-45
Mechanism
••
ICH2CH2CH2CH2I
O
••
HI
••
O+
H
Dr. Wolf's CHM 201 & 202
16-46
Mechanism
••
ICH2CH2CH2CH2I
O
••
HI
•• –
•• I •
•
••
••
O+
H
Dr. Wolf's CHM 201 & 202
••
•• I
••
••
•• O
H
16-47
Mechanism
••
ICH2CH2CH2CH2I
O
••
HI
•• –
•• I •
•
••
HI
••
O+
H
Dr. Wolf's CHM 201 & 202
••
•• I
••
••
•• O
H
16-48
Preparation of Epoxides:
A Review and a Preview
Dr. Wolf's CHM 201 & 202
16-49
Preparation of Epoxides
Epoxides are prepared by two major methods.
Both begin with alkenes.
reaction of alkenes with peroxy acids
(Section 6.19)
conversion of alkenes to vicinal
halohydrins, followed by treatment
with base (Section 16.10)
Dr. Wolf's CHM 201 & 202
16-50
Conversion of Vicinal Halohydrins
to Epoxides
Dr. Wolf's CHM 201 & 202
16-51
Example
H
H
OH
H
Br
NaOH
O
H2O
H
(81%)
Dr. Wolf's CHM 201 & 202
16-52
Example
H
H
OH
NaOH
O
H2O
H
H
Br
•• –
•• O ••
via:
(81%)
H
H
•• Br ••
••
Dr. Wolf's CHM 201 & 202
16-53
Epoxidation via Vicinal Halohydrins
Br
Br2
H2O
OH
anti
addition
Dr. Wolf's CHM 201 & 202
16-54
Epoxidation via Vicinal Halohydrins
Br
Br2
NaOH
H2O
O
OH
anti
addition
inversion
corresponds to overall syn addition of
oxygen to the double bond
Dr. Wolf's CHM 201 & 202
16-55
Epoxidation via Vicinal Halohydrins
H3C
H
Br
Br2
H
H2O
CH3
H3C
H
H
CH3
NaOH
O
OH
anti
addition
inversion
corresponds to overall syn addition of
oxygen to the double bond
Dr. Wolf's CHM 201 & 202
16-56
Epoxidation via Vicinal Halohydrins
H3C
H
Br
Br2
H
H2O
CH3
H3C
H
H
CH3
NaOH
H3C
H
H
CH3
O
OH
anti
addition
inversion
corresponds to overall syn addition of
oxygen to the double bond
Dr. Wolf's CHM 201 & 202
16-57
Reactions of Epoxides:
A Review and a Preview
Dr. Wolf's CHM 201 & 202
16-58
Reactions of Epoxides
All reactions involve nucleophilic attack
at carbon and lead to opening of the ring.
An example is the reaction of ethylene oxide
with a Grignard reagent (discussed in Section 15.4
as a method for the synthesis of alcohols).
Dr. Wolf's CHM 201 & 202
16-59
Reaction of Grignard Reagents
with Epoxides
R
MgX
CH2
H2C
O
R
CH2
CH2
OMgX
H3O+
RCH2CH2OH
Dr. Wolf's CHM 201 & 202
16-60
Example
CH2MgCl
CH2
+ H2C
O
1. diethyl ether
2. H3O+
CH2CH2CH2OH
(71%)
Dr. Wolf's CHM 201 & 202
16-61
In general...
Reactions of epoxides involve attack by a
nucleophile and proceed with ring-opening.
For ethylene oxide:
Nu—H
CH2
+ H2C
O
Nu—CH2CH2O—H
Dr. Wolf's CHM 201 & 202
16-62
In general...
For epoxides where the two carbons of the
ring are differently substituted:
Nucleophiles attack here
when the reaction is
catalyzed by acids:
Anionic nucleophiles
attack here:
R
CH2
C
H
Dr. Wolf's CHM 201 & 202
O
16-63
Nucleophilic Ring-Opening
Reactions of Epoxides
Dr. Wolf's CHM 201 & 202
16-64
Example
CH2
H2C
O
NaOCH2CH3
CH3CH2OH
CH3CH2O
CH2CH2OH
(50%)
Dr. Wolf's CHM 201 & 202
16-65
CH3CH2
Mechanism
•• –
O ••
••
CH2
H2C
O ••
••
Dr. Wolf's CHM 201 & 202
16-66
CH3CH2
Mechanism
•• –
O ••
••
CH2
H2C
O ••
••
CH3CH2
Dr. Wolf's CHM 201 & 202
••
O
••
CH2CH2
•• –
O ••
••
16-67
CH3CH2
Mechanism
•• –
O ••
••
CH2
H2C
O ••
••
CH3CH2
Dr. Wolf's CHM 201 & 202
••
O
••
CH2CH2
••
•• –
O ••
••
•• O
CH2CH3
H
16-68
CH3CH2
Mechanism
•• –
O ••
••
CH2
H2C
O ••
••
CH3CH2
Dr. Wolf's CHM 201 & 202
O
••
••
O
••
•• O
•• –
CH2CH2
CH2CH2
CH2CH3
O
H
••
– ••
•• O
••
CH3CH2
••
••
••
O
••
H
••
CH2CH3
16-69
Example
CH2
H2C
O
KSCH2CH2CH2CH3
ethanol-water, 0°C
CH3CH2CH2CH2S
CH2CH2OH
(99%)
Dr. Wolf's CHM 201 & 202
16-70
Stereochemistry
H
H
O
NaOCH2CH3
CH3CH2OH
OCH2CH3
H
H
OH
(67%)
Inversion of configuration at carbon being
attacked by nucleophile
Suggests SN2-like transition state
Dr. Wolf's CHM 201 & 202
16-71
Stereochemistry
H3C
H
R
H3C H
CH3
R
O
R
NH3
H2O
H2 N
H
H
S
OH
CH3
(70%)
Inversion of configuration at carbon being
attacked by nucleophile
Suggests SN2-like transition state
Dr. Wolf's CHM 201 & 202
16-72
Stereochemistry
H3C
H
R
CH3
R
R
NH3
H2O
O
H3C H
H
S
OH
CH3
d+
H3N
(70%)
H3C
H
O
H3C
Dr. Wolf's CHM 201 & 202
H2 N
H
d-
H
16-73
Anionic nucleophile attacks less-crowded carbon
H3C
CH3
C
H
C
O
NaOCH3
CH3OH
CH3O
CH3
CH3CH
CCH3
OH
CH3
(53%)
consistent with SN2-like transition state
Dr. Wolf's CHM 201 & 202
16-74
Anionic nucleophile attacks less-crowded carbon
MgBr
+
CHCH3
H2C
O
1. diethyl ether
2. H3O+
CH2CHCH3
OH
(60%)
Dr. Wolf's CHM 201 & 202
16-75
Lithium aluminum hydride reduces epoxides
CH(CH2)7CH3
H2C
O
Hydride attacks
less-crowded
carbon
H3C
1. LiAlH4, diethyl ether
2. H2O
CH(CH2)7CH3
OH
Dr. Wolf's CHM 201 & 202
(90%)
16-76
Acid-Catalyzed Ring-Opening
Reactions of Epoxides
Dr. Wolf's CHM 201 & 202
16-77
Example
CH2
H2C
O
CH3CH2OH
CH3CH2OCH2CH2OH
H2SO4, 25°C
(87-92%)
CH3CH2OCH2CH2OCH2CH3 formed only on heating
and/or longer reaction times
Dr. Wolf's CHM 201 & 202
16-78
Example
CH2
H2C
O
HBr
10°C
BrCH2CH2OH
(87-92%)
BrCH2CH2Br formed only on heating and/or
longer reaction times
Dr. Wolf's CHM 201 & 202
16-79
Mechanism
CH2
H2C
O ••
••
••
•• Br
••
H
Dr. Wolf's CHM 201 & 202
H2C
•• –
• Br •
• •
••
CH2
+
O ••
H
16-80
Mechanism
CH2
H2C
H2C
O ••
••
••
•• Br
••
•• –
•• Br •
•
••
H
CH2
+
O ••
H
••
• Br •
•
•
CH2CH2
Dr. Wolf's CHM 201 & 202
••
O
••
H
16-81
Figure 16.6
Acid-Catalyzed Hydrolysis of Ethylene Oxide
Step 1
CH2
H2C
O ••
H
••
•• O
+
H
H
Dr. Wolf's CHM 201 & 202
H2C
H
•• O ••
CH2
+
O ••
H
H
16-82
Figure 16.6
Acid-Catalyzed Hydrolysis of Ethylene Oxide
H
Step 2
O ••
H
••
H2C
H
CH2
+
O ••
H
+ •
H O•
CH2CH2
Dr. Wolf's CHM 201 & 202
••
O
••
H
16-83
Figure 16.6
Acid-Catalyzed Hydrolysis of Ethylene Oxide
H
+
H O ••
Step 3
H
H
H
H
•O•
• •
O ••
••
H
CH2CH2
+ •
H O•
CH2CH2
Dr. Wolf's CHM 201 & 202
••
O
••
••
O
••
H
H
16-84
Acid-Catalyzed Ring Opening of Epoxides
Characteristics:
nucleophile attacks more substituted carbon
of protonated epoxide
inversion of configuration at site of nucleophilic
attack
Dr. Wolf's CHM 201 & 202
16-85
Nucleophile attacks more-substituted carbon
H3C
CH3
C
C
H
O
CH3OH
H2SO4
CH3
OCH3
CH3CH
OH
CCH3
CH3
(76%)
consistent with carbocation character at
transition state
Dr. Wolf's CHM 201 & 202
16-86
Nucleophile attacks more-substituted carbon
H3C
d+ CH3
C
d+
C
H
OH
d+
CH3
CH3OH
H2SO4
OCH3
CH3CH
OH
CCH3
CH3
(76%)
consistent with carbocation character at
transition state
Dr. Wolf's CHM 201 & 202
16-86b
Stereochemistry
H
H
OH
O
HBr
H
H
Br
(73%)
Inversion of configuration at carbon being
attacked by nucleophile
Dr. Wolf's CHM 201 & 202
16-87
Stereochemistry
H3C
H
R
H3C H
CH3
R
O
CH3OH
H2SO4
R
CH3O
H
H
S
OH
CH3
(57%)
Inversion of configuration at carbon being
attacked by nucleophile
Dr. Wolf's CHM 201 & 202
16-88
Stereochemistry
H3C
H
R
CH3
R
CH3OH
O
CH3O
H2SO4
H3C H
H
H
S
OH
CH3
d+
CH3O
H
Dr. Wolf's CHM 201 & 202
R
H3C
H
d+
H3C
d+
O H
H
16-89
anti-Hydroxylation of Alkenes
H
H
O
CH3COOH
O
H
H2O
HClO4
H
H
OH
H
(80%)
Dr. Wolf's CHM 201 & 202
OH
16-90
Epoxides in Biological Processes
Dr. Wolf's CHM 201 & 202
16-91
Naturally Occurring Epoxides
are common
are involved in numerous biological processes
Dr. Wolf's CHM 201 & 202
16-92
Biosynthesis of Epoxides
C
C
+ O2 + H+
+ NADH
enzyme
C
C
+ H2O + NAD+
O
enzyme-catalyzed oxygen transfer from O2 to alkene
enzymes are referred to as monooxygenases
Dr. Wolf's CHM 201 & 202
16-93
Example: biological epoxidation of squalene
O2, NADH
monoxygenase
O
this reaction is an important step in the biosynthesis
of cholesterol
Dr. Wolf's CHM 201 & 202
16-94
Preparation of Sulfides
Dr. Wolf's CHM 201 & 202
16-95
Preparation of RSR'
prepared by nucleophilic substitution (SN2)
–
S ••
••
R
••
CH3CHCH
+
CH2
R'
X
NaSCH3
R
••
S
••
R'
CH3CHCH
CH2
methanol
Cl
Dr. Wolf's CHM 201 & 202
SCH3
16-96
Oxidation of Sulfides:
Sulfoxides and Sulfones
Dr. Wolf's CHM 201 & 202
16-97
Oxidation of RSR'
•• –
•• O ••
•• –
•• O ••
R
••
S
••
R'
R
+
S R'
••
R
++
S R'
• O ••
•
•• –
sulfide
sulfoxide
sulfone
either the sulfoxide or the sulfone can be isolated
depending on the oxidizing agent and reaction
conditions
Dr. Wolf's CHM 201 & 202
16-98
Example
••
NaIO4
••
water
SCH3
•• –
•• O ••
+
SCH3
••
(91%)
Sodium metaperiodate oxidizes sulfides to sulfoxides and no
further.
Dr. Wolf's CHM 201 & 202
16-99
Example
1 equiv of H2O2 or a peroxy acid
gives a sulfoxide, 2 equiv give a
sulfone
••
SCH
••
CH2
H2O2
(2 equiv)
•• •–
•• O •
++
SCH
CH2
• O ••
•
•• –
Dr. Wolf's CHM 201 & 202
(74-78%)
16-100
Alkylation of Sulfides:
Sulfonium Salts
Dr. Wolf's CHM 201 & 202
16-101
Sulfides can act as nucleophiles
R
••
S ••
+
R"
X
R
R'
+
••
S
R"
X–
R'
product is a sulfonium salt
Dr. Wolf's CHM 201 & 202
16-102
Example
CH3(CH2)10CH2SCH3
CH3I
+
CH3(CH2)10CH2SCH3 I–
CH3
Dr. Wolf's CHM 201 & 202
16-103
Spectroscopic Analysis of Ethers
Dr. Wolf's CHM 201 & 202
16-104
Infrared Spectroscopy
C—O stretching: 1070 and 1150 cm-1 (strong)
Dr. Wolf's CHM 201 & 202
16-105
Figure 16.8 Infrared Spectrum of Dipropyl Ether
CH3CH2CH2OCH2CH2CH3
C—O—C
3500
3000
2500
2000
1500
1000
500
Wave number, cm-1
Dr. Wolf's CHM 201 & 202
16-106
1H
NMR
H—C—O proton is deshielded by O; range is
ca. d 3.3-4.0 ppm.
d 0.8 ppm
d 1.4 ppm
d 0.8 ppm
CH3 CH2 CH2 OCH2 CH2 CH3
d 3.2 ppm
Dr. Wolf's CHM 201 & 202
16-107
CH3 CH2 CH2 OCH2 CH2 CH3
10.0
9.0
8.0
7.0
6.0
5.0
4.0
3.0
2.0
1.0
0
Chemical shift (d, ppm)
Dr. Wolf's CHM 201 & 202
16-108
13C
NMR
Carbons of C—O—C appear
in the range d 57-87 ppm.
26.0 ppm
O
Dr. Wolf's CHM 201 & 202
68.0 ppm
16-109
UV-VIS
Simple ethers have their absorption
maximum at about 185 nm and are
transparent to ultraviolet radiation above
about 220 nm.
Dr. Wolf's CHM 201 & 202
16-110
Mass Spectrometry
Molecular ion fragments to give oxygen-stabilized
carbocation.
•+
CH3CH2O CHCH2CH3
m/z 102
••
CH3
+
CH3CH2O
CH
m/z 73
CH3
••
Dr. Wolf's CHM 201 & 202
+
CH3CH2O
••
CHCH2CH3
m/z 87
16-111
End of Chapter 16